Laval médical, 1 février 1970, Février

[" , stair HR a Ait Ri sn sac R EMRE A HE RT 8 - \u2014\u2014 Laval médical | | Revue canadienne de lactualité médicale et biologique 1 Co Sommaire en page 8 Dans ce numéro : Deuxième symposium mondial sur la transplantation cardiaque Second world symposium on heart transplantation & C 2 & $ y 24 pp EE BR EEE FNS I TR SEAT IE LEA Lo Dans l'étreinte de la dyspnée .1.DD.M.- EXPECTORANT Solution Par comprimé (c.à thé) rainuré Gaïacolate de Glycéryle 50 mg.100 ma.lodure de Potassium .Dihydroxypropylthéoph Maléate de Mépyramine Dose moyenne : À NE 5 omprimé, 4 fois par jour.Enfants (6 ans et plus) : V2 AN) CN selon l'âge et le poids) 3 fois par jour.Enfants (6 uns et moins) : V2 c.AYhe/19Bj., 2 à 3 fois par jour, à 8 heures d'intervalle.Dose d'attaque (crise d'asthme) INDquié/ les doses mentionnées plus haut.N.B.- Pour les enfants, selon le poids et en respectant des intervalles de 8 heures.PRECAUTIONS : Ne pas administrer dans les 12 heures qui suivent l'emploi d\u2019une théophylline.Des doses fortes ou prolongées données aux enfants, aux femmes enceintes et à certains sujets peuvent déterminer des symptômes d\u2018hypothyroidie ou d\u2018iodisme.CONTRE-INDICATIONS : intolérance aux composants, Ulcère gastro-duodénal.Hyperthyroïdie.Tuberculose et syphilis latentes ou actives.EFFETS SECONDAIRES : Ceux des iodures (rhinite, érythème, fièvre, angine); des antihistaminiques (sécheresse des muqueuses, somnolence, état dépressif), Embarras gastrique.ÉGALEMENT b 1 e D.M e (sans Gaïacolate de Glycéryle) DOCUMENTATION DÉTAILLÉE SUR DEMANDE Le plus important laboratoire K ROUGIER INC.pharmaceutique authentiquement ul Laval Médical Vol.41- Fév.1970 OLLIE CL Yo wo = TNR Soi OST payes ESS tete Tomb © LA FACON CLASSIQUE! Aujourd\u2019hui, il en existe une autre , , + rf AAI ol fH | \u2026 qui offre une meilleure garantie: le Normosol-R.| Une solution de remplacement qui constitue un succédané i du plasma vous permet de mieux sustenter vos patients.Employez Normosol-R dans presque tous les cas ou vous utiliseriez les solutions salines normales.Il convient beaucoup mieux que celles-ci pour restaurer le volume des liquides extra-cellulaires perdus lors d\u2019un traumatisme, d'une intervention chirurgicale, dans les cas de brûlures et dans l\u2019état de choc.En fait, les solutions salines dites \u201cnormales\u201d ne sont ni normales ni physiologiques.Elles contiennent trop de sodium et beaucoup trop de chlorure.Elles ne fournissent ni potassium ni magnésium ni aucune source de bicarbonate; Leur administration prolongée peut entraîner un excès de chlorure ou de sodium et des carences en potassium ou en magnésium.Normosol-R renferme la plupart des principaux ions du plasma normal; en outre, il procure deux sources de bicarbonate: (1) l\u2019acétate, supérieur au lactate parce qu'il est métabolisé plus rapidement; (2) le gluconate, pour assurer une réserve de bicarbonate, souhaitable chez un * patient en chirurgie ou après l'intervention chirurgicale.Normosol-R ne renferme pas de calcium.!| convient donc bien pour commencer la transfusion sanguine.|| est présenté sous la forme simple ou avec dextrose 5%.|| existe aussi en formule de maintien quotidien: Normo- sol-M D5-W Ces trois variétés peuvent fournir au chirurgien au moins les trois quarts de ses besoins essentiels de solution.Nous vous invitons à consulter bientôt votre représentant Abbott au sujet des solutions Normosol.Indications: les solutions Normosol-R sont indiquées pour remplacer les pertes importantes; Normosol-M D5-W existe également pour le maintien quotidien de I'équilibre hydro-électrolytique.Précautions: n'est pas destiné à corriger les importantes déficiences préexistantes d'électrolytes spécifiques, ni à remplacer les succédanés volhémiques indiqués du plasma ou du sang.Normosol-R D5-W ne doit pas être administré par voie sous- cutanée.Agir avec précaution afin d'éviter une surcharge de l'appareil circulatoire.ABBOTT 491YF-68 Normosol:R /Normosol-R D-5W Composition de chaque 100 ml: chlorure de sodium.526 mg: acétale de sodium.222 mg; gluconate de sodium, 502 mg: chlorure de potassium.37 mg: chlorure de magnésium, 14 mg: on fixe le pH au moyen d'acide chlorhydrique.Le Normosol-R D5-W renferme aussi, par 100 ml, 5 g de dextrose U.S.P.ainsi que 30 mg de bisulfite de sodium.Chaque litre fournit les milliéquivalents suivants: Na 140: K 5: Mg 3; CI 98; HCO3 provenant de l\u2019acétate 27; HCO4 provenant du gluconate 23.Documentation complète envoyée sur demande.(A) *Nom déposé Président : Président : Directeur : Rédacteur en chef : Secrétaire à la rédaction : Adjoint au directeur : Secrétaire administrative : Agent de publicité ! Secrétariat : Laval médical Revue canadienne de l\u2019actualité médicale et biologique Bureau de direction Docteur Renaud Lemieux Administration et rédaction Docteur Renaud Lemieux Docteur R.Gingras Docteur G.-A.Bergeron Docteur Pierre Potvin M.Jean Arcand Mlle J.Bergeron Beaudin Publicité Inc.Comité d\u2019orientation et de planification Docteur Jean-Marie Lemieux, président Monsieur Jean Arcand Docteur Georges-A.Bergeron Docteur Jean-Paul Dechêne Docteur Jean Delâge Docteur Jacqueline Demers-Larue Docteur Raynald Déry Docteur Paul Fugère Docteur Jean-Baptiste Jobin Docteur Pierre Jobin Docteur Fernand Labrie Docteur Yves Marquis Docteur Corneille Radouco-Thomas Docteur Alain Rousseau Docteur Pierre Potvin, secrétaire Faculté de médecine Université Laval Québec 418 / 656-2944 Enregistrement no 2158 Courrier de la deuxième classe Ary Hohe HH ati titania i ga où titres Laval Médical Vol.41-Fév.1970 & rer Sr hy amen PTE vr ¢ PS ; ww \u20ac & .a vas @ > NZ ig \u201cSN Fo » ; \u2014 ry = | J y ! fw A A œ i\" / ey # iJ A Bd CF L\\ À = | + 3 .« = / 4 £ | 4 al + 2 3 ; | ; i ok + gs Sap ) La la NAAN «= È AN a ERI =x IN pie WN TURON-ARMELLE \u2014 \u201cMELANCOLIE\u201d \u2014 Médaille d'Argent 1965 \u2014 Arts, Sciences, Lettres antidépresseur \"SURMONTIL Renseignements trimipramine complets sur demande $ Poulenc \u2026 SL ow 3 4 Laval Médical Vol.41-Fév.1970 COMITÉ M.le professeur Rosaire GINGRAS, SCIENTIFIQUE doyen de la Faculté de médecine ; M.le professeur Pierre JOBIN, directeur du Département d'anatomie ; professeur André JACQUES, directeur du Département d\u2019anesthésie et de réanimation ; professeur Louis-Marie BABINEAU, directeur du Département de biochimie ; professeur Wilfrid CARON, directeur du Département de chirurgie ; professeur Jean-Luc BEAUDOIN, directeur du Département de médecine ; professeur Léo GAUVREAU, directeur du Département de microbiologie ; professeur Charles-A.MARTIN, ; directeur du Département de psychiatrie ; professeur René SIMARD, directeur du Département d'obstétrique et gynécologie ; professeur Carlton AUGER, directeur du Département de pathologie ; Donat LAPOINTE, directeur du Département de pédiatrie ; professeur Corneille RADOUCO-THOMAS, directeur du Département de pharmacologie ; professeur Claude FORTIER, directeur du Département de physiologie ; professeur M.le professeur Paul FUGÈRE, directeur du Département d'oto-rhino-laryngologie et d'ophtalmologie ; professeur adjoint Luc AUDET, directeur du Département de radiologie ; M.le professeur agrégé Alain ROUSSEAU, directeur de la section d\u2019ophtalmologie.le professeur Raoul KOURILSKY, de Paris.le professeur Albert JENTZER, de Genève.le professeur Henry L.BOCKUS, de Philadelphie.CORRESPONDANTS M M M M.le professeur Alexandre BRUNSCHWIG, de New-York.M M M ÉTRANGERS .le professeur Charles H.BEST, de Toronto.le professeur Jean MARCHE, de Paris.professeur P.M.F.BISHOP, de Londres. pes lorsque vous ne pouvez tical 1570 attendgejles résultatside \u20ac = [| IEE > sensibilité, ENT # g \\e NT ON - = \\1 VL Ciné + WLS Gd PAR LA NOVOBIOCINE at .mie et fa tes confi KS) ro tection & Ko A S n due.co = 3 lon fet G ram- atif Gran\u201d pOSi neg Ry 3 $ Eu Dans 5 oH] @ A OVO AR Rk dut ome: pay WJ de,novol do dektétra CY- ii majori CE ef ; que o [2 ime tou Ne 7% I 5 in sjinfec orres! 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nuit\u201d LA COMPAGNIE ELI LILLY (CANADA) LIMITÉE + TORONTO, ONTARIO \u201cLa > Renseignements détaillés sur demande.| ns SERENA Laval Médical 21 Vol.41-Fév.1970 Rendez votre foie comme un sou neuf Cholérétique Antispasmodique Lipotropique SON ACTION EST TRIPLE Chaque dragée contient : Acide déhydrocholique .300 mg Méthylbromure d'homatropine .1.5 mg Bitartrate de choline .150 mg dl-Méthionine .100 mg Posologie : une ou deux dragées 2 ou 3 fois par jour aprés les repas.\u2014\u2014 @ STIMULANTE de la BILIGÉNÈSE par l'acide déhydrocholique CALMANTE des SPASMES par le méthylbromure d\u2019homatropine MOBILISATRICE des GRAISSES par association potentialisee de deux facteurs lipotropes dl-méthionine et bitartrate de choline J.M.NARSAN & CIE LTÉE MONTRÉAL CANADA Membre de l'Association des Fabricants du Québec de produits pharmaceutiques.CH) Anping Hifi Composition\u2014Chaque capsule \u2018Spansule\u2019 à désagrégation prolongée renferme 15 mg de Dexedrine* (sulfate d'amphétamine dextrogyre, SK&F) et 7,5 mg de prochlorpérazinet, sous forme de maléate.En flacons de 100 et de 500.Posologie\u2014Une capsule par jour, prise dans la matinée.Précautions\u2014Chez les femmes enceintes, tous les médicaments doivent être prescrits avec circonspection, surtout durant le premier trimestre.Les phénothiazines peuvent potentialiser les dépresseurs du SNC.Employer avec précaution en présence d'hypertension et de maladie coronarienne.L'emploi excessif des amphétamines par des sujets instables peut entraîner une dépendance psychologique.Effets secondaires\u2014Les réactions indésirables (prin- Laval Médical Vol.41- Fév.1970 oH >.cipalement la nervosité et l'insomnie) sont rares et, le cas échéant, légères et transitoires.Contre-indications\u2014Hyperexcitabilité, agitation anormale, anxiété, hyperthyroïdisme, allaitement.Ne pas administrer aux patients recevant des IMAO.Renseignements complets sur demande.Autre présentation\u2014Comprimés \u2018Eskatrol\u2019, autre forme pharmaceutique, particulièrement indiquée chez les patients dont l'hyperorexie est limitée à une certaine heure de la journée.*Marque déposée au Canada | me +La prochlorpérazine seule est présentée au Canada par Poulenc Limitée sous la marque déposée Stémétil.Sis &F smith Kline & French 1.A.C., Montréal 379, Québec EL:M10F édical v, 190 i PE TEE Et A Cp A Et Laval médical VOLUME 41 NUMÉRO 2 FÉVRIER 1970 Editorial É LA GREFFE CARDIAQUE : TROIS ANS APRÈS OU LE CESSEZ-LE-FEU Le Laval Médical offre, dans les pages qui suivent, le compte rendu du deuxième Symposium mondial sur la transplantation cardiaque.Tenu à Montréal en juin dernier et fort habilement dirigé par notre ami Pierre Grondin, il fait, en réunissant toutes les compétences dans ce domaine, le point sur un épisode unique dans l\u2019histoire de la médecine, celui des greffes cardiaques.|| est aujourd\u2019hui curieux de constater qu\u2019en si peu de temps, plus de quarante équipes chirurgicales à travers le monde se soient adonnées en même temps à une entreprise aussi complexe, aussi ardue et, il faut le dire, aussi hasardeuse, pour ensuite, en même temps, et de façon définitive, semble-t-il, cesser toute agression clinique dans ce domaine.ll est trop tôt pour établir le bilan définitif de ces trois années mais il est indiscutable que plusieurs effets bénéfiques en ont résulté.Les greffes de cœur ont d'abord démontré de façon indiscutable l\u2019assurance technique, les moyens matériels et dans plusieurs cas, la virtuosité des chirurgiens contemporains.Alors que la médecine se veut de plus en plus quantitative et automatisée, la chirurgie cardiaque est un des derniers châteaux forts de l\u2019action individuelle qui ne peut être exactement reproduite.S\u2019il en était besoin, ces transplantations ont encore une fois démontré que la médecine moderne est une médecine d'équipe réunissant des compétences diverses.Sur le plan scientifique, ces greffes ont permis pour la première fois chez l\u2019homme, l\u2019observation de cœurs anatomiquement dénervés.Le syndrome clinique du rejet, avec ses trois phases successives, semble, sur les plans clinique, électrique et biologique, assez bien caractérisé.(1) 108 Yves MORIN Laval Médical Vol.41- Fév.1970 Personnellement, ce qui nous a le plus fasciné à cet égard est l\u2019apparition inopinée, dans les cœurs greffés, d\u2019une maladie coronarienne qui, chez les survivants du rejet précoce, a souvent (comme chez le docteur Blai- berg et le Père Boulogne) été la cause du décès de ces malades.|| faut au départ déterminer, sinon la similitude, du moins l\u2019apparentage, entre ces coronaropathies et l\u2019artériosclérose banale.Mais la réalité de ces insuffisances coronariennes se constituant en quelques mois pourrait possiblement aider à confirmer une hypothèse, chère à l\u2019auteur de ces lignes et qui veut que la maladie coronarienne évolue par poussées relativement brèves.La plupart des greffes ont donné sur l\u2019écueil du rejet : ce revers de l\u2019immunologie chez des malades par ailleurs fort bien contrôlés stimulera sûrement des recherches qui pourront en venir éventuellement à un « antibiotique » du rejet.Malgré tout, surtout si l\u2019on tient compte du nombre assez considérable (plus de 130) de cas étudiés, il est possible de penser que la masse des données objectives et des conclusions probables qui ont résulté de tout ceci est assez faible.Par nécessité, on n\u2019a que rarement établi de protocole prospectif, ou procédé en cours de route à des réévaluations critiques et, à cet égard, il faut noter que les séries les plus considérables ne sont pas nécessairement celles qui présentent les survies les plus longues.Il ne nous appartient pas de dire si chacune des 130 greffes était justifiée : on ne peut soustraire au médecin traitant, s\u2019il tient compte à la fois du tableau clinique présenté par son malade et de l\u2019état actuel des connaissances médicales, le droit de prendre de telles décisions et rien ne nous laisse croire, dans les cas qui nous intéressent, qu\u2019elles étaient prises en dehors de ces normes.Il faut, enfin, je pense, déplorer certains excès auxquels s\u2019est livrée la presse populaire dans cette affaire.Dans plusieurs cas et malgré le désir de la famille, un exposé détaillé de l\u2019état du donneur a été divulgué et comme le fait remarquer un des participants de ce Symposium, cette publicité de mauvais goût est responsable de la rareté actuelle des donneurs pour les greffes de reins.Quoi qu\u2019il en soit, le compte rendu de ce Symposium mérite d\u2019être lu avec attention : son intérêt certain rend le Laval Médical doublement heureux de publier ce qui est, pour une bonne part, l\u2019œuvre de collègues du Québec.Yves MORIN, M.D., Directeur de l\u2019Institut de cardiologie de l'Hôpital Laval, Québec dise lang 47 Il ll fesp Jef fom dis oy lan posi Mug qi ly Pour San fig ding! JE Introduction SCRIPTA MANENT En raison de l\u2019excellence des travaux et des discussions du Deuxième Symposium sur la transplantation cardiaque, tenu à Montréal les 6, 7 et 8 juin 1969, le Comité d\u2019Organisation a réalisé l\u2019importance de les colliger dans une publication.Cette réunion scientifique, nous Pespérons, a permis de faire le point sur les greffes cardiaques, et nous croyons que les informations échangées doivent être mises à la disposition de tous les Centres qui, de par le monde, s\u2019intéressent à ces problèmes.De plus, l\u2019annonce faite à Montréal qu\u2019un Troisième Symposium serait tenu à Paris, en 1970, nous a stimulés à faire paraître ces travaux assez tôt pour qu\u2019ils servent de référence à cette réunion et aux réunions futures.L'organisation du Deuxième Symposium fut pour nous une expérience tout à fait enrichissante.L'idée première de tenir une telle réunion à Montréal revient à son Honneur le Maire Pierre GRONDIN, S.M., M.D.So outstanding were the papers and the discussions of the Second World Symposium on Heart Transplantation held in Montreal, June 6, 7 and 8, 1969, that the Organization Committee felt compelled to collect them in a monograph.This scientific gathering, we hope, has marked an important step in the history of cardiac allografis, and we believe that the informations released and the point of views expressed should be made available to all Centers in the World interested in this field.Moreover, the announcement made in Montreal that a Third Symposium would be held in Paris, in 1970, has stimulated us to publish these manuscripts early enough so that they can serve as references to this coming meeting.The Organisation of the Second World Symposium was for us a most valuable experience.The first one to suggest that such a meeting be Comité d'organisation.De gauche à droite : M.Jacques Lefebre, I.C.M., Mile Alice Sanche, Montréal, Dr Charles Dubost, Paris, qui a accepté d'organiser un troisième Symposium, Dr Christiaan Barnard, Cape Town (Premier Symposium), Dr Pierre Grondin, Président, Mme Ghis P.Chouinard, I.C.M., Hon.Jean-Paul Cloutier, Ministre de la Santé au Québec, et Dr Napoléon Tremblay, Coordonnateur. 110 Pierre GRONDIN Jean Drapeau.Plusieurs participants ont, comme nous, regretté son absence physique aux réunions du Symposium.Monsieur le Maire était à cette époque en tournée européenne pour mousser la cause de la Cité de Montréal aux Jeux Olympiques.Monsieur Drapeau fut vraiment l\u2019âme-clef dans la préparation de ce grand évènement.Son enthousiasme et son dévouement nous ont permis de former un Comité d\u2019organisation que j'aimerais vous présenter : En premier lieu, le Gouvernement du Québec sous l\u2019instigation du Premier Ministre, le très honorable Jean-Jacques Bertrand, et du Ministre de la santé, l'honorable Jean-Paul Cloutier, a accepté d\u2019être l'hôte de cette extraordinaire réunion.Ils ont délégué à notre Comité le docteur Napoléon Tremblay, coordinateur au Ministère de la santé.C'est grâce à l'expérience, au dévouement et à la sagesse de ce médecin, que le Symposium a pu être réalisé, et ce dans un décor vraiment merveilleux.Quant à la Ville de Montréal, elle était représentée au sein du Comité par Monsieur Jean Dupire, hôte officiel de la Cité, assisté de Mademoiselle Alice Sanche, son adjointe.Si, comme le veut l\u2019axiome « Le Québec sait faire », il est maintenant classique de dire « Montréal sait recevoir ».L'expérience acquise par ces deux personnalités lors de l'Expo 1967 s'est manifestée dans l\u2019atmosphère d'hospitalité et de dignité qui a régné au cours de cette consultation internationale.L'Institut de Cardiologie était représenté par monsieur Jacques Lefebvre, directeur des relations publiques, par madame Ghislaine P.Chouinard, secrétaire du Département de chirurgie, et par moi-même.A l'exemple des transplantations d\u2019organes, l\u2019organisation d\u2019un Symposium est vraiment un travail d\u2019équipe.Le succès remporté est dû en grande partie au travail constant de chacun.Je profite de l\u2019occasion pour rendre un hommage tout à fait mérité à chacun de mes collaborateurs.Les participants à cette réunion scientifique étant des universitaires de haute renommée, nul Lavul Médical Vol.41- Fév.1970 held in Montreal was His Worship Mayor Jean Drapeau.Like many others, we have deplored his physical absence from the social activities of the Symposium.At that time, Mayor Drapeau was in Europe, promoting the cause of the City for the coming Olympic Games.Mayor Jean Drapeau was truly the life and soul in the preparation of this great event.His enthusiasm and his devotion have permitted to constitute an Organization Committee that | would like to introduce : First, the Quebec Government, through his Prime Minister, the Honourable Jean-Jacques Bertrand, and his Minister of Health, the Honourable Jean-Paul Cloutier, has accepted to sponsor this extraordinary international scientific reunion.At the Organization Committee, the Quebec Government was represented by Doctor Napoleon Tremblay, Co-ordinator at the Ministry of Health.Because of his experience and his wisdom, the Symposium was held in a magnificent setting.The City of Montreal has delegated to our Committee Mr.Jean Dupire, Official Greeter and Cultural Affairs Officer, and Miss Alice Sanche, his Assistant.Throughout the world, the hospitality of the City of Montreal is well known.The experience accumulated during Expo 67 by these two City officials was invaluable.It has widely contributed to the atmosphere of dignity that has prevailed throughout this international gathering.The Montreal Heart Institute had three representatives on this Committee : Mr.Jacques Le- febvre, Director of Public Relations, Mrs.Ghislaine P.Chouinard, Executive Secretary in the Department of Surgery, and myself.The organization of the World Symposium requires a carefully planned team work much like an organ transplantation program.To achieve success, the constant offort of each member of the team is needed.| take this opportunity to pay a well deserved tribute to each of my collaborators in this venture.Lui Vol.4 ne Auto 12K den fend fesse Mer W war ls ç fami lion ini Diy lh gy ii, m Tig | img Gel Bing ny te, og fg Ding \"oo Teh Par Leu Qs \u201cElle ® % de I hi \u201cin \u201ca ly ify diey! 16 Jean lord villes peau uv Jean pre 1 and ta el his ques ont spot nile ii] Jctor ini > and a me g our yo HE: fo fs #0 J 188 ii ali gp | ps hi Laval Médical Vol.41\u2014 Fév.1970 ne pouvait mieux les recevoir que l\u2019ont fait les Autorités de l\u2019Université de Montréal.Tous se rappellent les commentaires élogieux à l'égard de notre Université canadienne française, entendus après la conférence de monsieur le professeur Roger Gaudry, Recteur, lors du déjeuner offert aux participants le samedi 7 juin.Voulant assurer au Symposium un caractère vraiment international, nous avions invité tous les chefs d\u2019équipes chirurgicales qui, au ler janvier 1969, avaient effectué une transplantation cardiaque chez l\u2019homme.Tous les Centres invités étaient représentés au Symposium, sans Discussion animée.Dr Jacques Gélinas, sous-ministre à la Santé, Dr Christiaan Barnard, Le Cap, Hon.Roch Boivin, ministre d\u2019État, et Hon.Jean-Jacques Bertrand, Premier Ministre du Québec.Animated discussion.From left to right: Dr.Jacques Gelinas, Deputy Minister Dept.of Health, Dr.Christiaan Barnard, Cape Town, Hon.Roch Boivin, State Minister and Hon.Jean-Jacques Bertrand, Prime Minister of Quebec.exception.A ces chefs de file, nous ajoutions leurs collaborateurs immédiats dans les disciplines connexes comme la cardiologie, l'immunologie, la pathologie, la bactériologie, la neurochirurgie, etc.En tout, 107 invités officiels participèrent à cette consultation internationale.Leurs connaissances et leur prestige ont, plus que tout autre facteur, contribué au succès de cette réunion.En plus des invités d'honneur, 325 médecins se sont inscrits comme participants.Ils venaient de tous les coins du monde partager avec nos invités leur expérience tant au laboratoire qu\u2019en clinique, sur les problèmes de la transplantation cardiaque.Ces derniers ont joué un rôle précieux dans les discussion et les conclusions de cette consultation scientifique.INTRODUCTION 111 The vast majority of our guest of honour at the Symposium were world renown University teachers.The Authorities of our University of Montreal have greeted them with a dignity second to none.We shall long remember the eloquent comments that have followed the conference of the Chancellor, Professor Roger Gau- dry at the luncheon on Saturday.To assure the world-wide character of the Symposium, we had invited each Director of the surgical teams who, as of January 1st, 1969, had performed one human heart transplant.Every Center invited was represented at the meeting.With these surgeons, we had invited their immediate collaborators in related fields such as Cardiology, Immunology, Pathology, Bacteriology, Neurosurgery, etc.A total of 107 official guests have actively participated to this international consultation.Their prestige and knowledge have, more than any other factor, contributed to the success of this meeting.Besides these guest of honour, 325 medical specialists have registered as participants.They came from every corner of the world to share with our guest their experience both in the laboratory and in clinical situations.These have played an important role in the discussions and 112 Pierre GRONDIN Laval Médicat C\u2019est avec une légitime fierté que tout Québec se remémore ces trois jours de juin 1969, où il ui a été donné d'être l'hôte d\u2019un nombre imposant d'illustres chercheurs.À tous, un grand merci.Vol.41- Fév.1970 in the conclusions of this scientific consultation.It is with rightfull pride that the Province of Quebec remembers these three days of June 1969, when it was privileged to serve as host to such an illustrious group of researchers.THE Brie finn A im.THE FIRST HEART TRANSPLANT IN MAN \u201c Brief Review With Notes On A More Recent Case * io James D.HARDY, M.D., F.A.C.S., Department of Surgery and University Hospital, University of Mississippi Medical Center, Jackson, Mississippi.Après une expérience de plus de 100 cas de transplantation cardiaque chez le chien, ainsi que des expériences additionnelles chez des veaux, des singes et des cadavres humains, la première transplantation cardiaque humaine fut effectuée le 22 janvier 1964.Le receveur fut un patient de 68 ans, hypertendu, atteint d\u2019un infarctus du myocarde et en état de choc profond.À cette époque, le concept de mort cérébrale n\u2019était pas accepté et il fallait attendre l\u2019arrêt cardiaque complet avant d'arrêter la ventilation pour enlever un rein en vue d\u2019une transplantation.Ainsi, on se rendit compte que le donneur humain sur lequel on comptait n'allait pas nécessairement mourir au moment même où le receveur entrait en phase terminale.La possibilité de greffer un cœur de primate fut retenue après la publication des premiers succès de Reemtsma et Creech dans la transplantation de reins de chimpanzé à l\u2019homme.Dans ce premier cas de transplantation cardiaque humaine, le cœur d\u2019un grand chimpanzé We are met here to assess current horizons and progress in clinical heart transplantation.Virtually every group working in the field is represented, and this Congress will surely achieve significant progress.It was suggested that my opening remarks include a review of our 1964 case, as well as our more recent clinical experience.In the Spring of 1963 our group concluded that animal studies, begun in 1956 and pursued continuously thereafter, justified a gradual approach to heart transplantation in man (3, 5, 6, 7, 10 and 11).Many potential recipients were screened throughout the ensuing months, but no appropriate and clearly terminal potential recipient presented until January 22, 1964.By this time our laboratory ex- * Presented at the Second world symposium on heart transplantation, Montreal, Canada, June 6-8, 1969.Dr Carlos M.Chavez participated in both cases.Dr Hilary H.Timmins, Akio Suzuki, Martin H.McMullan and Patricia C.Moynihan of the Department of Surgery and Drs Patrick H.Lehan and Harper K.Hellems of the Department of Medicine collaborated in the second case.(suite du résumé en page suivante) perience encompassed well over a hundred heart transplants in dogs, and additional experiments had been carried out in calves, monkeys and the human cadaver.The 68-year-old chronically hypertensive patient had sustained myocardial infarction (and at eventual autopsy the pathologists estimated that approximately 90 per cent of his coronary arterial supply was occluded).When he lapsed into profound shock which could not be reversed, he was moved quickly to an operating room, anesthetized with minimal anesthesia through the tracheostomy tube, and placed on cardiopulmonary bypass through a median sternotomy incision.He had remained mentally obtunded since admission to the hospital, and permission for possible heart transplantation was obtained from the family (2).This document clearly stated that, while many heart transplants had been performed in animals by us and by others, any heart transplant would represent the first heart transplant in man.The proposed transplantation Laval Médical Vol.41- Fév.1970 James D.HARDY mâle fut utilisé.Le débit cardiaque du cœur de primate était de 4,25 litres/minute et le débit du receveur avant l\u2019état de choc, de 3,6 litres/minute.Durant l'intervention, le cœur du donneur fut perfusé par voie rétrograde dans le sinus coronarien et la défibrillation fut facile.La fréquence cardiaque fut maintenue à 100 par minute au moyen d\u2019un pacemaker à fréquence fixe et après 30 minutes de circulation extracorporelle partielle le cœur put reprendre sa fonction seul.Une tension artérielle de 80 à 90 mm Hg fut obtenue durant une heure.À ce moment, on se rendit compte que l\u2019état avancé de détérioration métabolique préopératoire du receveur ainsi que la taille modeste de l\u2019organe transplanté rendaient aléatoire un succès à long terme.L'autopsie n\u2019a révélé aucune preuve de rejet aigu.Cette première transplantation cardiaque chez l\u2019homme établit d\u2019abord la possibilité scientifique de transplanter un cœur et ensuite stimula de façon concrète la continuation d\u2019études expérimentales en laboratoire.La deuxième transplantation eut lieu le 6 janvier 1969 sur un receveur de 48 ans atteint d\u2019une maladie coronarienne occlusive triple et ayant fait was cleared with the administrative officials of the University of Mississippi Medical Center.Although a patient with severe brain damage and \u2018\u2018\u201cbrain death\u2019\u2019 had represented a potential human donor, he remained alive supported by a ventilator.At that time the concept of brain death as we know it today was not accepted, and it was our policy to await complete cardiac arrest before stopping the ventilator and removing a kidney for transplantation.Accordingly, since we had realized that the potential human donor might not die at precisely the same time that the potential recipient went into terminal collapse.the availability and possible need of a lower primate heart for transplantation had been raised in discussions with the patient\u2019s family.Reemtsma and Creech had already reported early success with chimpanzee kidney transplants in man (9).The heart of a large male chimpanzee was readily inserted as shown in Figure 1 (4).The cardiac output of the primate had been 4.25 L/min, and the pre-shock cardiac output of the human recipient had been 3.6 L/min.During transplantation the donor heart was well preserved by retrograde coronary sinus perfusion and it was easily defibril- lated.The electrodes of a Chardack-Greatbatch fixed-rate pacemaker were applied to the left ventricle, and the heart rate was increased to 100 beats per minute.After 30 minutes of partial bypass support of the beating heart, as had been practiced in the laboratory, the bypass catheters were removed.The transplanted heart thereafter supported the blood pressure in the range of 60 to 100 mm Hg, usually 80 to 90.for approximately one hour (1).SUTURE OF ATRIAL SEPTUM ~ Figure 1 \u2014 Operative technique used for insertion of first heart transplant in man.(With permission from J.A.M.A.).Li il wl Ti File ory Riding inl Laval Médical THE FIRST TRANSPLANT IN MAN 115 me Vol.41- Fév.1970 425 | plusieurs infarctus.Le donneur mourut d\u2019hémorragie intracrânienne à im J l\u2019âge de 44 ans.Il était compatible au point de vue du groupe sanguin et 8 présentait une histo-compatibilité du groupe C selon Terasaki.Après once arrêt cardiaque, le cœur du donneur fut refroidi à 4° C, transporté chez er à le receveur et implanté.Après suture de l'oreillette gauche, l\u2019aorte fut elle anastomosée et les autres anastomoses furent effectuées sous perfusion 20 coronarienne.Le cœur reprit sa fonction facilement mais le patient mourut note d\u2019hémorragie intracranienne le septième jour après l\u2019opération.Une in- veur filtration myocardique importante à cellules rondes fut notée malgré un sun traitement considéré optimal a I'\u2019Azathioprine, la Prednisone et la globuline ag antilymphocytaire.bord En conclusion, si la transplantation cardiaque est réservée aux quel- 2 de ques patients manifestement en phase terminale et si d'autre part des ; À critères stricts sont observés quant à la sélection du donneur et le choix | du receveur il est possible de ne pas ébranler l'opinion publique de façon ial néfaste.| | | | At this point it was concluded that the advanced 1.The first clinical heart transplant had been state of preoperative metabolic deterioration of the recipient, plus the modest size of the transplanted organ, rendered long-term success unattainable in this instance.Microscopic studies of the transplant at autopsy revealed neither damage from the retrograde coronary sinus perfusion nor evidence of readily carried out with the methods which we had previously employed in a large number of laboratory experiments.2.The suture techniques in use in many laboratories had been found satisfactory.3.The heart had been well preserved by retro- 1 acute rejection (Figure 2).grade perfusion of the coronary sinus with oxygen- On the basis of this initial clinical experience, ated blood (5).the following conclusions were published at that 4.The heart had fibrillated throughout the an- ] time (4) : astomotic maneuvers, and it had been converted to a regular rhythm by a single weak shock of the pulse defibrillator.5.The transplanted heart had reacted immediately to intravenously injected digoxin, as reflected in the development of partial heart block with pulsus bigeminus.6.The cardiac pacemaker had readily broken through this arrhythmia when the amplitude of the current was increased.7.The function of the transplant fully supported the scientific feasibility of heart transplantation in man, and the results rendered continuing labora- or Soma om lf vnc try studies more mesninel jection.In addition, the absence of red blood cell extra- It was further stated that \u2018\u2018with further refine- ee me ee fe ment in physiology and dm hea ei operation not result in excessively high intravascular pressures, Nay some day add years of life to many patients\u201d.A 116 Perhaps most important of all, this first heart transplant in man assaulted the frontiers of human imagination and acceptance as no previous operation had done.It thus initiated vigorous and profound dialogue and debate which facilitated a more general acceptance of clinical heart transplantation later on.Actually, it was apparent that the technical aspects of heart transplantation were more easily carried out in the human being than in the dog, due to the larger size and toughness in man of the structures to be anastomosed.À SECOND HEART TRANSPLANT Our second clinical heart transplant was performed on January 6, 1969.The recipient was a 48-year-old white man who had severe, triple vessel coronary atherosclerotic occlusive disease, as He had experienced multiple myocardial infarctions, had demonstrated by coronary arteriograms.sustained one cardiac arrest, had a ventricular aneurysm of moderate size and had anginal pain at bed rest despite usual medication.The consulting members of the Department of Medicine, Cardiology Division, as well as members of the Committee on Human Investigation, concurred in the opinion that the patient represented an appropriate recipient for heart transplantation: he was immobilized by his disease, his life prognosis for more than a few months was poor, and heart transplantation could conceivably offer a rewarding prolongation of Life.The donor was a 44-year-old man who died from spontaneous intracranial hemorrhage.The donor and recipient were both ABO group O, and the histocompatibility matching was Terasaki Class C (with Class A the best mateh and Class D the worst).Following brain death, as certified by the neurological consultants, the donor was heparinized and cooled through the femoral vessels, using partial cardiopulmonary bypass with a disposable bag oxygenator.Appropriate written permission had of course been obtained from his family.The blood pressure had become unobtainable when the femoral James D.Laval Médical Vol.41- Fév.1970 HARDY vessels were exposed, but the heart was not removed until it had arrested in ventricular fibrillation.The organ was then cooled further in Ringer\u2019s lactate at 4°C, and was transported to an adjacent operating room, where it was inserted into the recipient using Barnard\u2019s modification of the basic Lower- Shumway technique.Although the chest of the recipient had been opened through a median stern- otomy incision at the time the heart of the donor was exposed, the recipient was not placed on cardiopulmonary bypass and the heart excised until we were satisfied that a suitable donor heart was available.Thereafter the organ was readily sutured into place using double rows of 000 and 0000 mercilene After the left atrium and the aorta had been sutured, the left ventricle was vented and all sutures.air removed, and the aortic clamp was opened to perfuse the heart.The right atrial wall was then sutured, and last the pulmonary artery.The heart had exhibited total fibrillation soon after the aortic clamp had been released, followed by atrial beats with continued ventricular fibrillation.However, it resumed a normal rhythm spontaneously as the pulmonary artery anastomosis was being completed.Postoperative course.The patient developed a marked systolic arterial hypertension in the postoperative period, at times in the range of 290/ 120 mm Hg.This was to be compared with his preoperative systolic pressure of 80-90 mm Hg.Unfortunately, perhaps the result of the severe hypertension, he suffered an intracranial hemorrhage and died on the seventh postoperative day.The autopsy confirmed the intracranial hemorrhage, and it also revealed a surprisingly extensive round cell infiltration of the myocardium (Figure 3), this despite what had been considered optimal treatment with azathioprine, prednisone and antilymphocyte globulin (ALG).In retrospect, it might have been wise to have reduced the blood pressure with drugs.However, it was continuously expected that the cireulation would adjust itself to the large new heart, and we were reluctant to complicate the postoperative course with a hypotensive drug.ley any tal Tg diy be § li} Yr à bj Luval Médical Vol, 41- Fév.1970 Our present position regarding heart transplantation in man Our attitude toward clinical heart transplantation remains unchanged.This is an experimental procedure, but we believe it is justified in the individual who has clearly pre-terminal heart disease and who has only a few weeks to live.My associates and I agree that the patient must understand the high risks involved, and that heart transplantation nust not be employed where other and less drastic treatments are available to provide even a modest extension of reasonably comfortable life.The medical and the lay public may be expected to subject heart transplantation to an increasingly critical analysis.If we restrict heart transplantation to the few patients who are clearly terminal and who may benefit therefrom, we can preserve what we have gained, while extending knowledge and the potential for treatment with this method.If we do not rigidly enforce strict criteria for recipient and donor selection, much can be lost and progress ean be seriously retarded.SUMMARY 1.The first heart transplant performed in man has been reviewed.The organ was readily inserted, Figure 3 \u2014 Microphotograph of left ventricle in human- to-human heart transplant, January 1969.Patient died on seventh postoperative day from effects of an intracranial hemorrhage.Note the remarkable round cell infiltration and evidence of myocardial necrosis, depiste treatment with azathioprine, prednisone, and antilymphocyte globulin (ALG).In contrast, the residual atrial segment of the recipient showed none of these changes.THE FIRST TRANSPLANT IN MAN 117 and it supported the recipient for one hour after cardiopulmonary bypass support had been discontinued.The organ failed because of the preoperative metabolic deterioration of the recipient and the relatively small size of the transplant.Microscopic sections demonstrated complete absence of myo- cardial injury from either the retrograde coronary sinus perfusion during transplantation or acute allograft rejection reaction.2.This initial heart transplant demonstrated that the blood pressure could be thus supported in a human being, if for a limited period of time in this instance.The operation so assaulted the frontiers of human imagination and acceptance that This did much to prepare human minds for the cautious world-wide dialogue was precipitated.acceptance of heart transplantation which exists at the present time.3.Our second clinical heart transplant is mentioned briefly, The insertion of a large and hypertrophied donor organ from a large subject into a slight recipient was followed by severe systemic hypertension in the recipient.Intracranial hemorrhage occurred, which proved fatal on the seventh postoperative day.Despite treatment with azathio- prine, prednisone and ALG, an advanced stage of rejection was found at autopsy.4.We believe that continued clinical heart transplantation is justified if rigid criteria for recipient selection are met.The patient must be clearly terminal, and all other modes of therapy must have been exhausted.In such instances, heart trans plantation may prolong life and at the same time afford knowledge which alone will gradually improve results in the field.REFERENCES 1.Harpy, J.D., et Cuaviz, C.M., The first heart transplant in man ; developmental animal investigations with analysis of the 1964 case in the light of current clinical experience, Am.J.Cardiol., 22: 772, 1968.2.Harpy, J.D., et Cuavez, C.M., The first heart transplant in man ; historical reexamination of the 1964 case in the light of current clinical experience, Transplantation Proceedings, Heart Transplantation Suppl.In press. 118 ?Le } 4 3 6 .Harpy, J.D., CHavrz, C.M, ERASLAN, S., ADKINS, J.R., et WiLLIAMS, R.D., Heart transplantation in dogs © Procedures, physiologic problems and results in 142 experiments, Surgery, 60 : 361, 1966.Harpy, J.D, CHavrz, C.M., Kurrus, F.D., NEELY, W.A., ERASLAN, S., TURNFR, M.D., FABIAN, L.W., et LABECKI, T.D., Heart transplantation in man : developmental studies and report of a case, J.AM.A.\u2026 188 : 1132, 1964.5.Harpy, J.D, KUrrvs, F.D, Cuavez, C.M., et WEBB, W.R., Heart transplantation in infant calves ; evaluation of coronary sinus perfusion to preserve organ during transfer, Ann.New York Acad.Sc.120 : 766, 1964.Kurrus, F., Harpy, J.D., CHaAvrz, C.M., et ELLIOTT, R.L., Heart transplantation, Fed.Proc, 23 : 201, 1964.James D.HARDY 10.11.Laval Médical Vol, 41- Fév.1970 .Lek, S.S., et Wess, W.R., Cardiac metabolism as influenced by ischemia, refrigeration and enzyme precursors, Am.Surg\u2026 25 : 776, 1959.Lowrr, R.R., Storer, R.C.,, et SHuvmway, N.E, Homovital transplantation of the heart, J.Thoracic and Cardiovas.Surg., 41 : 196, 1961.REEMTSMA, K., MuCRACKEN, B.H., SCHLEGEL, J.U., PEARL, M.A., PEARCH, C.W., DeWrrT, C.W.SMITH, P.E., Hrwrrr, R.L., et Crercn, O., Jr, Renal heterotransplantation in man, Ann.Surg., 160 : 384, 1964.WEBB, W.R., et Howarp, H.S., Restoration of fune- tion of the refrigerated heart, S.Forum, 8: 302, 1957.WEBB, W.R., et Howarp, H.S., Cardiopulmonary transplantation, S.Forum.8 : 313, 1957.Non \"ih ly Ting il, li ity | j ps EXPERIENCE AT CAPE TOWN WITH HUMAN ye i TO HUMAN HEART TRANSPLANTATION È racit Christiaan N.BARNARD, M.D., | i Cape town, South Africa.E X ï dr.3 \" L'auteur relate l\u2019expérience de Cape Town avec cing transplantations È en cardiaques.: 5 Parmi ces cing patients, deux souffraient de maladie cardiaque isché- i mique, un de myopathie cardiaque, et deux de fiévre rhumatismale.aug Au cours de la transplantation, la technique était telle qu\u2019elle évitait pe tout dommage au nœud sino-auriculaire, en ouvrant l'oreillette droite, par une incision partant de la veine cave inférieure vers l\u2019appendice auriculaire droit.Le diagnostic de rejet se basait d\u2019abord sur l'évidence clinique d\u2019une défaillance cardiaque et sur les changements électrocardiographiques.Parmi ceux-ci, c\u2019est l\u2019abaissement du voltage qui est le signe initial du rejet.L'étude des changements enzymatiques ne fut d'aucune aide dans le diagnostic.(suite du résumé en page suivante) I have been requested to participate in this ses- in whom we anticipated death would occur within sion by discussing our experience at Cape Town a very short time if they were not given this final, with human to human heart transplantation.The ultimate aid.exploration of any new field in medicine brings Four of the five patients are still alive.The first forth many new problems and thoughts, but time died 18 days after surgery.The remaining four will only allow my discussion to cover four aspects, patients are now alive eighteen months, nine namely : months, two months and one month and a half @) The material selected ; respectively.' o .Pafare \u20ac PAPY 5 tian ta 6 f 1 «+ 1 b) Some aspects of the surgical technique; Before surgery all patients were fully investi- | ¢) The most important changes indicative of gated by means of right and left heart catheteriza- 1 acute rejection : and tion and angiography.The pertinent findings are | d) Our current views on the imniunosuppressive Æiven in Tables 1, II, III, IV and V.regime.To date we have performed five heart transplants.Tape 1 The first two patients suffered from ischemic heart Catheter findings in the first patient (W.) six month disease, the third from cardiac myopathy, and the before cardiac transplantation after extensive bed rest .oe and medical (treatment last two from rheumatic carditis.We selected pa- tients who had reached the end stage of their con- LL .Right atrium (mean) 10 mm Hg dition \u2014 p: ç ë , ë \u201c ç .; Hor patients who had run a progressively Right ventricle .85/15-9 mm Hg downhill course and in whom other medical and Right brachial .130/75 mm Hg P.A.wedge pressure (mean) .35 mm Hg surgical forms of management had failed; patients gree ag ad farled; pa 125/25-30 mm Hg 2,43 1/min/m2 11 units Left ventricle * Paper presented at the Second world symposium Pulm.vase.resistance on heart transplantation, Montreal, June 6-8, 1969. Christiaan N.BARNARD Laval Médical Vol.41- Fév.1970 Le traitement immunosuppresseur après l\u2019intervention, consiste en hautes doses de Prednisolone, 500 mg au cours des premiers jours, réduits à 100 mg au cours des jours suivants, I'lmuran, dont l'administration se fera ultérieurement en fonction de la formule leucocytaire, et les globulines antilymphocytaires données pendant trois mois à raison de 5 à 10 ml par voie intraveineuse deux fois par jour, au cours du premier mois.On donnera une seule dose par jour au cours du deuxième mois, et au cours du troisième mois on administrera la dose trois fois par semaine.Pour éviter le rejet, on administrera une fois par semaine une dose élevée de stéroïdes.Ainsi, dans les cas de rejet, on note, après l\u2019administration de Prednisone, une amélioration dans le voltage.As already mentioned the first two patients suffered from coronary heart disease.This was verified by means of selective coronary angiography which showed that in both patients the three major coronary vessels were grossly diseased.Severe myo- cardial death was illustrated by the poor countrac- tions of the left ventricles on the left ventrieulo- grams.Total heart failure was shown in both patients with a rise in right atrial pressures, left atrial pressures, a rise in the end diastolic pressures TasLE 11 (\u2018atheter findings in the second patient (B.) prior to heart transplantation of the left ventricles and low cardiac indices.The highest pulmonary vascular resistance in this series was found in the first patient who had pulmonary vascular resistance one third of systemic.Figures 1 and 2 show photographs of the hearts of the first two patients immediately after removal and the extensive myocardial death especially of the left ventricular muscle ean be clearly seen.The third patient suffered from cardiac myo- pathy.Haemodynamic studies again show both Tape IV Catheter findings in the fourth patient (K.) after his condition fuiled to improve after aortic valve replacement Right atrium (mean) _.7 mm Hg Right ventricle .50/3-7 mm Hg Right brachial .150/90 mm Hg P.A.wedge pressure (mean) .26 mm Hg Left ventricle .125/25-30 mm Hg Cardiac index ne 1,94 1/min/m2 Pulm.vasc.resistance .\u2026.\u2026\u2026 2,5 units Right atrium (mean) Les 21 mm Hg Right ventricle 75/12-32 mm Hg Right brachial 110/60 mm Hg P.A.wedge pressure (mean) 28 mm Hg Left ventricle |.120/20-12 mm Hg 1,2 1/min/m2 9,5 units Tape III Catheter findings in the third patient (S.) three months Lefure cardiac transplantation, after extensive TABLE V Catheter findings in the fifth patient (F.) after her condition failed to improve after mitral valve medical treatment replacement Right atrium (mean) .15 mm Hg Right atrium (mean) .\u2026 a 10,5 mm Hg Right ventricle 22000000 53/13-16 mm Hg Right ventricle 32/9 mm Hg Right brachial .Lens 148/04 mm Hg Right brachial 100/72 mm Hg P.A.wedge pressure (mean) .34 mm Hg P.A.wedge pressure (mean) .165 mm Hg 117/15-27 mm Hg 1,66 1/min/m2 4,2 units Left ventricle 12220000 116/9-11 mm Hg 1,2 1/min/m?5,5 units Left ventricle Lai Ya, © | ui Flu inal (if his 58 Wi im JUS Tose po! ire wf Laval Médical Vol.41- Fév.1970 right and left heart failure, with a low cardiac index.His condition failed to improve on prolonged bed rest and medical treatment, The heart on removal (Figure 3) showed no coronary or valvular disease, but only the abnormally thickened pale muscle of the ventricular chambers.The fourth patient presented with severe aortic incompetence and therefore was first submitted to an aortic valve replacement.Despite the haemo- dynamic correction he remained in total heart failure, as can be seen from the catheter findings three months before cardiac transplantation.It was thus concluded that the heart failure was now caused by disease of the heart muscle and this was Figure 1 \u2014 The heart of the first patient after excision.Note extensive scarring in the left ventricle.Figure 2 \u2014 The heart of the second patient.Note the dilatation of the left ventricle with extensive scarring and a localized aneurysm in the apex.EXPERIENCE AT CAPE TOWN verified on noting the extensive scarring of the muscle after the heart was removed (Figure 4).The fifth patient also suffering from rheumatic heart disease presented with severe mitral incompetence.This was corrected with a xenograft replacement of the mitral valve (Figure 5) but, in spite of this, the patient remained in total heart failure with eritical attacks of pulmonary edema.Catheter findings a few weeks before surgery showed no valvular defect but total heart failure as a result of myocardial involvement.Technique : As changes in the electrocardiogram are early signs of the onset of acute rejection, a technique was evolved to ensure normal electrocardiogram after transplantation.The technique of Lower and Shumway (1) was modified in that the entire donor heart was removed after ligating the superior vena cava.The right atrium was opened for anastomosis by making an ineision from the inferior vena eaval orifice to the right atrial appendage (Figure 6), thus avoiding damage to the sino-auricular node.Figure 3 \u2014 Heart of the third patient after excision showing the pale, thickened left ventricular muscle. 122 Christiaan N.BARNARD Laval Médical Vol.41- Fév.1970 The left atrium was opened by excising a square atria of the patient.There is thus no danger to the of myocardium between the entrances of fhe four sino-aurieular or atrio-ventricular nodes and the pulmonary veins.The openings thus created are transplanted heart will resume its beating in sinus anastomosed to the remnants of the right and left rhythm with normal conduction.Diagnosis of rejection: In our experience the earliest changes indicative of rejection are: Firstly, clinical evidence of cardiac failure.This can be noticed at the bedside by the onset of a rise in jugular venous pressure, ankle edema and hepa- tomegaly.The patient may complain of shortness of breath.A gallop rhythm and a functional mitral systolic murmur indicative of cardiac dilatation can be heard on auscultation.Secondly, changes in the electrocardiogram.(Careful recording of electrocardiograph voltage is Figure 4 \u2014 Heart of the fourth patient after excision showing extensive muscular damage.Figure 5 \u2014 Heart of the fifth patient after excision showing xenograft replacement of the mitral valve.The xenograft Figure 6 \u2014 Diagram illustrating opening of atrial cham- was in good condition.bers to avoid damage to conducting system.Lot Mi Ter Thy Jal Prob Jian bi thy Tal Ti ih = = =\" % eal 16 ie he Jy Laval Médical Vol.41- Fév.1970 of the greatest value in the early diagnosis of rejection.A progressive drop in the electrocardiograph voltage often occurs before any other symptoms or signs.An initial progressive drop in the electrocardiograph voltage following cardiac transplantation is probably due to œdema, surgical trauma and pericardial effusion, but the voltage rapidly recovers (Figure 7).Our studies on the changes in the serum enzymes were of no value in the diagnosis of rejection.Treatment of rejection: As has been pointed out by other workers, the patient who receives a cardiac transplantation has probably a more active immunological system compared to that of a kidney transplant patient who has been chronically immunosuppressed by the chronic uraemic state.It therefore appears essential in the patient receiving a heart to initially use high doses of immunosuppression.We commence with 500 mg of Prednisolone on the day of opera- ECG EXPERIENCE AT CAPE TOWN 123 tion, reducing it by 100 mg every day until the fifth day.For the following two weeks a dose of 100 mg per day is maintained and then it is slowly lowered to 50 mg per day.This dosage is continued for the first month, after which it is again gradually reduced to 30 mg daily and this dose is maintained for one year.Imuran is prescribed at the highest tolerated dose, observing carefully the white cell count and the liver funetion tests.Antilymphocyte globulin is given for three months in doses of 5 ml to 10 ml intravenously every 12 hours for the first month.This dosage is given once a day for the second month and for the third month is administered three months times a week.Once rejection is well-established in the transplanted heart it may be difficult to reverse and as to date, an artificial heart has not been developed to take over cardiac function during this period, there is thus a great danger to the patient\u2019s life.Even if rejection is reversed it has been our experience that the patient never improves to the wl v 5.7\" INFECTION ™ NAST | .30, REJECTION , \\ ve / B Ni 5 i / A rm r\u2014\u2014\u2014\u2014\u2014 \u2018 20 \\/ Ns >a PrN N__ | ~~ - Nm\u201d mv ° À.\u2014 10.751 .meme eee \u2014 tem em um me S TS ~~ \u2014 meet ~~./ son = ANS | my 25 IMPROVEMENT CIRCULATION ; \u2019 oo?JT me K I / Nos sl - Ne\u201d NA NZ .4 , 251 \\, .et ~.mv NS Nem (TS sms TS 15 Fl tn, a se sam EE ot my HEART FAILURE T WAVE CHANGES Lo , Te LAN LADA 0 2 4 6 8 0724 6 18 20 22 DAYS 24 26 28 30 32 34 36 38 40 42 44 46 Figure 7 \u2014 Graph showing the initial drop in the electrocardiograph voltage, especially well show in patients one, three and five.In patients two and four prolonged diminution in voltage was associated with rejection.2) peace 124 Christiaan N.BARNARD Laval Médical Vol.41- Fév.1970 i armel CSSS \u201cI en TNS NA ECE cron mln Nf nv 5 ALE I mes ' paneling wo mys Bi \u2014 U ] preop 50 PREDNISOLONE 200 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 S80 DAYS SMITH Figure 8 \u2014 A graph of the voltage and immunosuppressive regime in the third patient with the introduction if intermittent high doses of steroids.Note the improvement in the electrocardiograph voltage after the introduction of the intermittent steroids.state he was in before the rejection episode.It therefore appears to be of utmost importance to prevent rejection, and we feel that this can be done by treating the patients weekly with a single high dose of steroids.In the third patient this regime was started on the fortieth day, once maintenance immunosuppression had been reached.The patient received 200 mg Prednisolone per week as a booster.It will be noticed from Figure 8 that when this was started there was an improvement in the eleetro- cardiograph voltage andt he voltage never dropped below baseline again.So far there has been no eli- nical evidence of rejection.He has virtually normal activity and is able to play tennis.In conclusion, we began with dying patients and in a year and a half have one man surviving eighteen months post-operatively.Another man is able to play tennis nine months after a heart transplantation.These achievements, in our opinion, make heart transplantation a worthwhile procedure, and although we realize that this is not eu- rative surgery, there are many other forms of palliative surgery which are accepted, and this form We have many critics who say this is not worthwhile, but the of palliation should be continued too.persons really qualified to judge this are our patients.We are not treating our crities, we are treating our patients.When I asked Blaiberg: \u2018\u2018Tell He replied: \u2018\u2018Thirty minutes after it was performed, me, when was this operation worthwhile 2°\u2019.because then I could breathe again without having to struggle for my breath.\u201d REFERENCE !.Lower, R.R., Storer, R.C., and Suumway, N.E, Homovital transplantation of the heart, J.Thoracic Cardiovas.Surg., 41 : 196, 1961.ae EX {ical i EXPERIENCE WITH CARDIAC TRANSPLANTATION IN FOURTEEN PATIENTS * | 7 Edward B.STINSON, M.D., John S.SCHROEDER, M.D., Donald C.HARRISON, M.D., Eugene DONG, Jr., M.D., Richard L.POPP, M.D.and Norman E.SHUMWAY, M.D.Avant la transplantation, onze patients étaient atteints d\u2019Une maladie | coronarienne obstructive et trois d\u2019une cardiomyopathie.Tous les patients Il : subirent une exploration complète avant l\u2019intervention sauf quatre dont l\u2019état était trop précaire.En moyenne, l\u2019index cardiaque était de 1,8 l/min/m:, Une dysfonction hépatique fut notée chez dix patients et une dysfonction rénale chez sept.Tous étaient de classe IV au point de vue de l\u2019incapacité fonctionnelle.Sur le plan immunologique, tous étaient - compatibles au point de vue du système ABO et tous avaient un cross- $ match lymphocytaire négatif.Le cœur fut préservé par hypothermie exter- j ne.La modification de la technique chirurgicale concernant l\u2019auriculoto- Ek mie droite telle que décrite par Barnard fut adoptée.: Aprés l'opération, le myocarde fut supporté par pacing épicardique ventriculaire droit, Digoxin et Isoprotérénol.Quant au traitement immuno- suppressif, huit patients reçurent de l'Imuran à la dose de 0,5 mg/kg/jour avant l\u2019intervention pendant une à quatre semaines.Les corticostéroïdes po furent prescrits au moment de l'intervention et la globuline antilymphocy- pit taire immédiatement avant.En cas de rejet, un traitement à l\u2019Actinomycine un D et des doses massives de Méthylprednisone furent administrés.Chez | (suite du résumé en page suivante) INTRODUCTION with a range of 33 to 58 years.Twelve were male | | | and two female.I jents the pr i | Since January, 1968, 14 patients have undergone and two female.In 11 patients the preoperative - , ; ; di .1 ar 3 « J .al cardiac transplantation at Stanford University lagnosis was coronary artery disease and in three ; Medical Center.In this report we wish to present cardiomyopathy.Preoperative evaluation included, N cl .in addition to routine studies of pulmonary, he- patie, and renal function, complete hemodynamic our general experience with patient selection, sur- | gical technique, methods of postoperative study and | | management, and survival.assessment with left ventriculography in all but four patients whose preoperative conditions were PATIENTS AND METHODS too precarious to allow formal investigation.In , .those patients undergoing cardiac catheterization The average age of these patients was 49 years, 08 the average cardiac index at rest was 1.8 L/min/M* * Paper presented at the Second world symposium on (range 1.2 to 3.2 L/min/M?).Pulmonary hyper- Cou heart transplantation, Montreal, Canada, June 6-8, 1969.; fr From the Department of Surgery, Division of Cardiovascular Surgery (Stinson, Dong and Shumway), and Department of Medicine, Division of Cardiology (Schroeder, Popp and Harrison), Stanford University School of Medicine, Stanford, California.Supported in part by U.S.Public Health Service Grant HE-08696 and U.S.P.H.S.Research Grant FR 70, General Clinical Research Centers Branch.Reprint requests Division of Cardiovascular Surgery, Stanford University School of Medicine, Stanford, Calif.94305 (Dr Stinson).tension at rest was present in nine of ten patients, ranging from 33/13 to 78/33 mm Hg (mean 19 to 53 mm Hg), and elevation of the pulmonary vascular resistance to an average of 4.6 units (range 1.2 to 8.5 units).Preoperative evidence of hepatic dysfunction was present in ten patients and renal dysfunction in seven.All patients suffered Class IV disability. 126 STINSON, SCHROEDER, HARRISON, DONG, Jr., POPP and SHUMWAY Laval Médical Vol.41-Fév.1970 la plupart des patients, l\u2019héparinisation intraveineuse fut également employée au cours des épisodes de rejet.Le diagnostic de rejet est basé sur l\u2019altération électrocardiographique.Des mesures de l'épaisseur de la paroi et du diamètre du cœur furent effectuées au moyen d\u2019ultrasons.Dans les cas de rejet, Une corrélation importante fut trouvée entre l\u2019augmentation du diamètre du ventricule droit et l\u2019augmentation totale de l\u2019aire cardiaque.En plus, ces mesures permettent de déceler une diminution de l\u2019amplitude du mouvement de la paroi postérieure au cours de la systole.RÉSULTATS : 1.En fonction de la greffe cardiaque.|| n\u2019y eut qu'un seul échec postopératoire immédiat.Ce cœur avait fait un arrêt anoxique avant l\u2019opération et avait reçu Une injection intracardiaque d\u2019épinéphrine.Une nouvelle transplantation fut effectuée six heures après la première intervention.Preoperative lymphoeyte typing and crossmateh were performed in all cases and served as the basis for recipient selection in most.However, for the ten antigens typed (1) a compatible match was obtained in only three instances.In all cases the lymphocyte crossmatch was negative and ABO compatibility was present.Surgical technique: Surgical techniques have included routine cardiopulmonary bypass methods utilizing whole blood prime.A modified central cannulation technique was adopted after the first 5 cases because of a high incidence of postoperative complications related to the femoral cutdown site.At the present time arterial cannulation is performed via a stab wound in the ascending aorta; the inferior vena cava is cannulated through the superior caval \u2014 right atrial junction, and the superior vena cava via the right internal jugular vein approached through a separate incision.Since the institution of this technique for cannulation no further complications related to wound healing have occurred.Methods of excision and implantation of the donor heart have been previously described (4).In all cases hypothermia of the graft induced by surface cooling with saline at 2 to 6°C has been employed.Modification of the right atrial incision to avoid placing the sino-atrial node contiguous to the right atrial suture line has eliminated the intermittent nodal rhythm noted in two of the first five cases in whieh the donor right atrium was opened out by interconnection of the vena caval orifices posteriorly.Postoperative management : Three forms of myocardial support immediately following surgery have been used.These include cardiac pacemaking via a right ventricular epi- cardial wire to maintain the cardiac rate above 80 beats/minute, intravenous digoxin in standard doses, and isoproterenol.Each of these methods of postoperative support to the grafted heart has been shown in the laboratory to result in significant improvement in cardiac performance.Respiratory assistance has been provided all patients for periods up to 24 hours postoperatively.Currently, nasotracheal intubation is avoided because of the danger of delayed pressure necrosis which occurred in two of the seven patients in which this route of intubation was employed.Immunosuppressive therapy : In all but the first two patients basie immuno- suppressive agents have included azathioprine, cor- ticosteroids, and antilymphocyte globulin (ALG).In eight patients pretreatment with azathioprine in a dose of 0.5 mg/kg/day has been given for periods of one to four weeks before surgery.A loading Loi Ya. i Laval Médical CARDIAC TRANSPLANTATION IN FOURTEEN PATIENTS 127 vo Vol.41-Fév.1970 i Un infarctus hémorragique large fut observé dans la portion supérieure ba | du septum musculaire et une injection intramurale d\u2019épinéphrine fut mise ré | en cause.2.Rejet.Chez 11 des 14 patients un ou plusieurs épisodes de rejet li furent diagnostiqués.Deux patients moururent de rejet aigu.Deux autres ir patients succombèrent au cours de la période postopératoire immédiate i de complications chirurgicales.Aucun rejet ne fut trouvé à l\u2019autopsie.3.Résultat global.Actuellement, six des quatorze patients sont en vie, respectivement neuf mois et demi, huit mois, sept mois, trois mois et che à demi, deux mois et deux semaines après l\u2019intervention.Onze autres patients [op complètement explorés et acceptés pour une transplantation moururent ole avant qu\u2019un donneur compatible ne puisse être trouvé.Dans ce groupe, alin.| la survie maximale fut de 12 semaines et la survie moyenne de un mois.ms ok ah sit pr pd ow ne 1 r oi dose of azathioprine, 4 to 5 mg/kg, is given immediately preoperatively.On the first postoperative day maintenance azathioprine in a dose of 2 to 3 mg/kg/day is begun.Corticosteroids are begun at the time of surgery with the intravenous administration of methylprednisolone, 3 to + mg/kg, during surgery.Maintenance therapy with pred- nisone, 60 mg/day, is begun on the first postoperative day, and gradually tapered after the first two postoperative weeks to 0.5 mg/kg/day by the end of the first postoperative month.ALG, initiated immediately preoperatively, has been administered postoperatively according to a regimen based on that originally described by Starzl (3).Therapy for diagnosed rejection has consisted of a \u201cpulse-type\u2019\u201d regimen, employing actinomyein D and massive doses of methylprednisolone (500 to 1.000 mg) administered rapidly intravenously on a daily basis until initial reversal of the signs of rejection.In most patients intravenous heparinization has also been used during initial rejection episodes.Diagnosis of rejection: In our experience techniques directed at the documentation of the manifestations of local organ dysfunction have been the most effective in the early diagnosis of rejection.These include 12-lead electrocardiograms obtained twice daily during the first two postoperative weeks and daily thereafter until discharge, using marked skin sites for the precordial leads to insure uniform placement; ultrasound- cardiographic measurements (2) of posterior (left) wall thickness, right ventricular diameter, total heart size, and slope and amplitude of the posterior wall systolic movement; and auscultation and phonocardiographie documentation of abnormal sounds.Numerous other clinical and laboratory findings have been correlated with cardiac rejection, but none has proven.in our experience, to be as reliable in the early identification of advancing cardiac rejection.To date, however, no reliable as well as entirely specific index of cardiac rejection is available.Electrocardiographie changes taken as indicative of rejection include progressive diminution in voltage, rightward deviation of the mean frontal plane axis, atrial arrhythmias, and ischemic ST depression.Significant correlation with rejection of various ultrasound-cardiographic measurements has included inerease in posterior wall thickness, increase in right ventricular diameter, increase in total heart size.and decrease in the amplitude and rate of posterior wall movement during systole.The ausculta- tory finding most consistently associated with rejection and confirmed by phonocardiography has been an early diastolic gallop rhythm.Atrial gallop rhythms and perieardial friction rubs, though occasionally present, have been inconstant and have appeared transiently in some cases, unassociated with other indication of rejection.In no patient in this series has rejection been diagnosed and treated without significant changes in these parameters.RESULTS Graft function: In all cases but one immediate function of the graft has been satisfactory.In two patients with severe preoperative elevation of the pulmonary vascular resistance isoproterenol was employed in the immediate postoperative period because of moderate right ventricular failure.Intravenous digoxin was used in standard doses in eight other patients because of mild to moderate elevation of central venous pressure (to 14 to 20 cm water), and pacing was employed in five additional patients for periods of 24 to 60 hours postoperatively to maintain the heart rate above 80 beats/minute.By the third postoperative day clinically observed hemodynamic parameters have generally been normal, and digitalis has not been continued.In one case immediate postoperative failure of the graft occurred, with hypotension and recurrent ventricular arrhythmias.In this instance anoxic cardiac arrest had developed in the donor pre- operatively, requiring vigorous resuscitative measures including intracardiac administration of epinephrine.Retransplantation was performed six hours following the initial procedure.Examination of the excised first graft showed a large hemorrhagic in- faretion in the superior portion of the muscular ventricular septum, thought to be due to intramural injection of epinephrine.Following retransplanta- tion myocardial function was satisfactory.In long-term surviving patients normal activity has been well tolerated.Each patient has partiei- pated actively in a continuing physical therapy program.Measured work levels tolerated for ten minutes without undue symptoms by the four patients presently surviving beyond three postoperative months vary between 300 and 500 kilogram- meters, corresponding to 4 to 6-fold inereases in oxygen consumption.Serial ballistocardiograms and STINSON, SCHROEDER, HARRISON, DONG, Jr., POPP and SHUMWAY Laval Médical Vol.41- Fév.1970 exercise electrocardiograms in these patients have given normal results.Rejection: In 11 of the 14 patients acute rejection diagnosed by the parameters listed above were treated one or more times.Two patients died of uncontrolled rejection.In each of these the electrocardio- graphie, ultrasound-cardiographie, and auseultatory phenomena associated with rejection were progressive until death.In two additional patients succumbing to postsurgical complications in the early postoperative period rejection was not clinically identified.In only one long-term survivor have rejection phenomena been entirely absent.In the nine remaining patients 19 episodes of rejection were treated with reversal of the changes which prompted therapy.In none of the surviving patients has clinical evidence of residual myocardial damage been present.One episode of possible acute rejection, diagnosed by electrocardiographic and ultrasound-cardiogra- phic criteria, was treated and reversed at five months postoperatively.Although histopathological findings in other cases suggest a high incidence of obliterative arterial lesions, clinical evidence of chronic rejection sought by serial exercise electrocardiography and ballistocardiography has not been apparent.Survival: At the present time 6 of the 14 patients in this series are alive, at 915, 8, 7, 314, 2 months and 2 weeks postoperatively.All of these patients were treated at least once postoperatively for rejection.Additional causes of death include combined drug toxicity and rejection in two patients, a cerebro- vascular accident at three weeks postoperatively in one patient, and fatal hepatitis at 414 months post- operatively in one additional patient.These survival data contrast with those characterizing non-transplanted cardiac recipients.Eleven patients in the latter group were fully evaluated and accepted for transplantation, but died before a i in] [85 | lg mid wl tli Jratrs IES colt il rte hie pie oid ing We anil ul pie 3 fi ji ae?i je i Jt it fil) Laval Médical Vol.41- Fév.1970 suitable donor could be obtained.In this group maximum survival was twelve weeks and the mean survival one month.Three additional patients await transplantation at the present time, all less than four weeks following acceptance into the program.DISCUSSION This experience demonstrates that successful cardiac transplantation can result in significant prolongation of useful life, The rapid rate of attrition in non-transplanted recipients, we believe, contributes to the justification of continued clinical investigation of this procedure.Several factors combine to suggest an irreducible minimum mortality rate following cardiac transplantation, exceeding that achieved in the related field of cadaver remal transplantation.These include the generally greater age of cardiac recipients, the advanced effects of chronic congestive heart failure on secondary organs, the mechanical limitations imposed by persistent elevation of pulmonary vascular resistance in the recipient, the unavailability of effective temporizing support for CARDIAC TRANSPLANTATION IN FOURTEEN PATIENTS 129 graft failure, and difficulty in the diagnosis of chronic rejection.Improvements in understanding and management of these factors, as well as advances in donor-recipient matching and immuno- suppressive therapy, imply improved results with extension of clinical experience.REFERENCES I.Boomer, W., Tripp, M., et BopMER, J., Application of a fluorochromatic cytotoxicity assay to human leukocyte typing, in Histocompatibility testing, ed.Curroni, E.S., Marriuz, P.L., et Tosi, R.M, Copenhagen, Ejnar Munksgaurds Forlag, 1967, pp.341-350.2.SCHROEDER, J.S., Popp, R.L., Stinson, E.B., Donc, E., J., Swumway, N.E., et Harrison, D.C., Acute rejection following cardiac transplantation : pho- nocardiographic and ultrasound observations, Circulation, In press.J.STARZL, T.E., PorrER, K.A., IWASAKI, Y., MARCHIORO, T.L., et KAasuIiwacI, N., The use of heterologous antilymphocyte globulin in human renal homo- transplantation, in Study group on antilympho- cytic serum, edited by G.E.W.Wolstenholme and O\u2019Connor, London, 1967, Churchill, p.4.4.Srixson, E.B,, Doxa, E., Jr., IBEN, A.B., et SHUMWAY, N.E., Cardiac transplantation in man.III.Surgical aspects, Am.J.Surg., In press. RESULTS OF CARDIAC TRANSPLANTATION * Denton A.COOLEY, M.D., and Grady L.HALLMAN, M.D.Ce travail rapporte vingt transplantations cardiaques chez dix-neuf patients.Dans cette série, on note une seconde transplantation six mois après le rejet du premier cœur, et une transplantation cœur-poumon chez un enfant.En plus, on rapporte un remplacement cardiaque total par une prothèse mécanique.Cette prothèse fut remplacée par une allogreffe 64 heures plus tard.La plupart des patients souffraient de maladie coronarienne occlusive.Un patient présentait en plus une maladie multivalvu- laire.Deux cas de myocardiopathie furent également soumis à la transplantation cardiaque.La transplantation cardio-pulmonaire combinée fut effectuée pour un canal atrio-ventriculaire complet compliqué d\u2019hyperten- sion pulmonaire, de pneumonie et d\u2019infarctus pulmonaire.Au point de vue de l\u2019histo-compatibilité tous les patients furent placés dans les groupes D et C de Terasaki.Over the past year and a half the elinical feasibility of cardiac transplantation has been validated (1,2, 4, 6 and 14).Salvage of patients dying of advanced incurable heart disease is now possible, but application of the procedure is limited and long-term results are hindered by a variety of unsolved problems which arise in selection of suitable recipients, timely acquisition of histocompatible donors, and management of effective immuno- suppression without complications.At the Texas Heart Institute we have performed a total of 20 cardiac transplants in 19 patients.Included in this series are: a man who received a second allograft when his first was rejected after 624 months, an infant who received a combined heart-lung transplant, and a man whose circulation was successfully supported by a total mechanical cardiac replacement until a suitable allograft was obtained 64 hours later.* Paper presented at the Second world symposium on heart transplantation, Montreal, Canada, June 6-8, 1969.From the Cora and Webb Mading Department of Surgery, Baylor College of Medicine, and the Texas Heart Institute of St.Luke's and Texas Children\u2019s Hospitals, Houston, Texas.Supporter in part by U.S.Public Health Grants (HE- 03137) (HE-05387) (HE-05435).Indications: All transplant recipients had irreversible end- stage heart disease refractory to other medical therapy.Coronary artery occlusive disease was the indication for operation in most patients.One patient had severe rheumatic multivalvular disease.A child with endocardial fibroelastosis and myocardiopathy and a man with myocardiopathy also received allo- grafts.Subsequent experience suggests that myo- cardiopathy may be a contraindication, since the autoimmune factors which destroyed the original heart could react similarly to an allograft (11).The infant who received a combined cardiopulmonary transplant had complete atrioventricularis communis, pulmonary hypertension, pneumonia.atelectasis, and pulmonary infarctions (5).Irreversible cerebral damage (usually due to intra- cranial hemorrhage, trauma, or tumor) was confirmed in each donor by atonia, fixed and dilated pupils, arreflexia, apnea, and an isoelectric en- cephalogram (3).Histocompatibility : Through a collaborative study with Terasaki (15) & Laval Médical RESULTS OF CARDIAC TRANSPLANTATION 131 Vol.41 - Fév.1970 | RÉSULTATS : Cinq décès furent causés par infection.Cinq autres patients sont morts de rejet chronique entre le quatrième et le septième mois après l\u2019opération.Le patient le plus âgé est mort d\u2019une affection rénale et hépatique pré-existante.Le patient le plus jeune, celui qui reçut Une trans- LHD.eff plantation cardio-pulmonaire mourut d'insuffisance pulmonaire après 14 mis | heures.Le décés le plus tardif, du groupe C au point de vue de l\u2019histo- er compatibilité, est attribuable à une attaque de la maladie de Adams-Stokes en au neuvième mois.Trois patients sont actuellement en vie respectivement get à trois jours, trois mois et plus de six mois après la transplantation.(ore: al trans- go fl en: En conclusion, on note une plus longue survie lorsque l'histo-compa- tibilité est meilleure.La rareté en donneurs ainsi que le degré d'urgence dictés par une dégradation rapide du receveur furent à la base d'une médiocre compatibilité.Une façon d'éviter cet écueil pourrait être l\u2019emploi d\u2019une prothèse cardiaque totale maintenant la vie d\u2019un patient moribond fits en attendant qu\u2019une allogreffe histo-compatible soit obtenue.donors and recipients were tissue typed and matched according to ABO red cell compatibility, lym- phoceyte eross mateh for preformed antibodies, and lymphocyte antigen match (Terasaki\u2019s grading scale: A-F').Our tissue match grades ranged from D to C plus, with a mean grade of C minus.No patients had A or B matches.sepsis 54 hours after operation.Sepsis and throm- boeytopenia with gastrointestinal hemorrhage resulted in the early death of a woman who had blood cultures of Serratia marcescens, and one man died after nine weeks from a massive herpetic infection with secondary Pseudomonas pneumonia.Two other deaths were due to pneumonia.One of these oceur- Hil red 32 hours after allografting in a man whose cir- qui Immunosuppressive therapy: culation had been maintained for 64 hours by an pur orthotopic cardiac prosthesis (7 and 8).The me- 1 Our immunosuppressive program is modeled after chanical device was inserted when cardiae function | that employed by Starzl et al.(12) for renal allo- failed during myocardial exeision with ventriculo- Ce grafts.Used in conjunction with azathioprine and plasty.The prosthesis performed efficiently as a 5 corticosteroids, antilymphoeytic globulin (ALG) pr has provided better control of rejection while allow- TABLE I po ing smaller dosages of other drugs.pu Causes of death in cardiac transplant recipients Results: Following implantation each cardiac allograft functioned satisfactorily resulting in improved cardiae output.Most patients were ambulatory in the first postoperative week.Three were able to leave the hospital, and two returned to work.Infection caused five deaths (Table I).One patient died of gram negative bacterial pneumonia and CAUSE OF DEATH NUMBER OF PATIENTS Infection.Chronic rejection .Acute rejection .Preexisting diseases Pulmonary insufficiency .Probable arrhythmias .Sl mmm worm 132 Denton A.COOLEY and Grady L.HALLMAN total cardiac replacement until a suitable donor heart was obtained.Chronic rejection accounted for five deaths (Table I) oceurring from four months to nearly seven months after operation.One of these patients underwent re-transplantation when irreversible rejection of his first allograft set in after 624 months.He died nearly three days later.Three patients died of acute rejection (Table I).Two of these had myocardiopathy, and all had grade D tissue matches.The oldest patient (62 years) died of preexisting renal and hepatic failure.The youngest, a 2-month-old infant who received the heart- lung transplant, died of pulmonary insufficiency after 14 hours (7).The longest survivor, a grade C plus tissue match who had had no significant episodes of rejection, died of a probable Stokes-Adams attack after almost nine months.Three patients are alive today at three days, nearly three months, and more than six months after operation.Hyperglycemia, cushinoid habitus, osteoporosis, leukopenia, thrombocytopenia, and reduced resistance to infection were among the complications of immunosuppressive therapy.Discussion : Reports of renal allografts have shown a strong relationship between histocompatibility and results (13).We have made a similar observation in this series of cardiac allografts, which have consistently displayed longer average survival with less incidence of rejection in higher grade tissue matches (10).Evidently, optimal histocompati- bility is a basic requirement for improved results in cardiac transplants; but the emergency condition of potential recipients coupled with the scarcity of donors makes this a difficult requirement to meet.A hopeful solution to the dilemma is offered by the recent clinical suceess of an orthotopic cardiac prosthesis which sustained the life of a dying recipient until a suitable allograft was obtained (7 and 8).The knowledge gained from the cardiac transplant program \u2014 that a cardiac allograft can sup- Laval Médical Vol.41- Fév.1970 port human eirculation, and that the denervated allograft responds sluggishly to influences which increase or decrease cardiac output (9) \u2014 contributed heavily to the development of the orthotopic cardiac prosthesis as well as stimulating several other areas of research in immunology.These encouraging signs of progress give promise of enhancing the therapeutic value of cardiac transplantation by eventually solving its current problems.REFERENCES 1.BARNARD, C.N., À human cardiac transplant: An interim report of a successful operation performed at Groote Schuur Hospital, Capetown, South African Med.J., 41 : 1271, 1967.DuBost, C., et CACHERA, J.-P., Un cas de greffe allogé- nique du cœur chez l\u2019homme compatible dans le système HL-A et traitée par un globuline anti- lymphocytaire hérérologue, Presse méd., 76 : 1651 et 1713, 1968.BKECHER, H.K., et al, A definition of irreversible coma, J.A.M.A., 205 : 337, 1968.CooLry, D.A., BLoonwWELL, R.D., HALLMAN, G.L,, and Nora, J.J., Transplantation of the human wo = heart : Report of four cases, J.A.M.A., 205 : 479, 1968.ÿ.Coorry, D.A., Broonwrrr, R.D., Nora, J.J, McNamara, D.G., LEAHCMAN, R.D., and HALL- MANN, G.L., Organ transplantation for advanced cardiopulmonary disease, Ann.Thorac.Surg., 8: 30, 1969.6.Cooury, D.A., HALLMAN, G.L., BLoobpwiLL, R.D,, Nora, J.J., and LEACHMAN, R.D., Human heart transplantation : Experience with twelve cases, Am.J.C'ardiol., 22 : 804, 1968.CooLEY, D.A., LiorTA, D., HALLMAN, G.L., BLOODWELL, R.D., LEACHMAN, R.D., and MILAM, J.D., First human implantation of cardiac prosthesis for staged total replacement of the heart, Trans.Amer.Soc.Artif.Int.Organs, 15 : 252, 1969.8.Coorry, D.A., LIOTTA, D., HALLMAN, G.L., BLOODWELL, R.D., LEACHMAN, R.D.and MrIzAM, J.D, Or- thotopic cardiac prosthesis for two-staged cardiac replacement, Am.J.Cardiol., In press.~2 9.HALLMAN, G.L., LEATHERMAN, L.L., LEACHMAN, R.D.and Coorey, D.A., Performance of the transplanted human heart, J.Cardiov.Surg.In press.10.Nora, J.J., CooLEY, D.A., HALLMAN, G.L., BLoOD- weLL, R.D., LEacEMAN, R.D., RocHELLE, D.G., F'ERNBACH, D.J., MILAM, J.D., MONTGOMERY, J.R., and TRENTIN, J.J., Rejection of the transplanted human heart : Indices of recognition and problems in prevention, New Engl.J.Med., 280 : 1079, 1969.Lu Yo in 8 Laval Médical RESULTS OF CARDIAC TRANSPLANTATION 133 me Vol.41 - Fév.1970 aval | {1.SANDLERS, V., Idiopathic disease of the myocardium, L., The clinical use of antilymphocyte globulin in di | A prospective study, Arch.Int.Med.112: 661, renal homotransplantation, Transplantation, 5: | 1963.1100, 1967.I | 12.STARZL, T.E., GroTH, C.G., TERASAKI, P.I., PUTMAN, 14.Stinson, E.B., Dove, E., Jr., SCHROEDER, J.S., Nor- ie i et ente soba Distacompe, r1soxN, D.C., and SHuMwAY, N.E., Initial clinical val > experience with heart transplantation, Am.J.tibility matching and human renal homotrans- .Curdiol., 22 : 791, 1968.plantation, Surg.\u2026 Gynec and Obst, 126 : 1023, ; À 1968.15.TERASAKI, P.I., VREDEVOE, D.L., and Mickey, M.R., je [3.STARZL, T.E., MArcHIoRro, T.L., HurcHIsoN, D.E., Serotyping for homotransplantation, Transplanta- pl Porter, K.A.CeriLLI, G.J., and BREI'TSCHNEIDER, tion, 5 : 1059, 1967.Jeux.À rary sah call il ul i i CLINICAL EXPERIENCE IN CARDIAC TRANSPLANTATION * Richard R.LOWER, M.D., V.Eric KEMP, M.D., and Walter H.GRAHAM, M.D.Les auteurs discutent les points saillants de leur expérience avec quatre cas de transplantation cardiaque.Deux patients avaient une maladie coronarienne obstructive importante, les deux autres avaient des cardio- myopathies.Un de ces derniers patients présentait en outre une fibroélas- tose endocardique touchant principalement le cœur de gauche.Les quatre patients subirent une exploration complète avant l\u2019opération.L'intervention démontra que les niveaux d\u2019hypertension pulmonaire pré-existants étaient compatibles avec de bons résultats.Il est évident qu'il est difficile d'évaluer le degré de résistance vasculaire pulmonaire fixée en présence d\u2019un débit cardiaque aussi faible que celui qu\u2019on observe chez ces patients.Le diagnostic de mort cérébrale fut établi suivant les critères discutés par le docteur Alksne au cours de ce symposium.Le pronostic après la transplantation cardiaque ne semble pas, dans cette série, en relation étroite avec les résultats de l\u2019histo-compatibilité.Le premier patient, du groupe B, est mort de rejet aigu confirmé histologiquement.Le second patient également du groupe B a fait trois épisodes de rejet.Chez le troisième patient, des anticorps préformés furent décelés et un rejet aigu l\u2019emporta au quatrième jour.Ces faits démontrèrent qu\u2019il On the occasion of this Symposium, a review is presented of our experience with four patients undergoing cardiac homotransplantation between May and October of 1968.The details of the preoperative and postoperative findings in these four patients have been previously presented and published (1, 3) and this review will summarize those points which we consider of special importance.The etiology of the heart disease in the first two patients was extensive three-vessel coronary atherosclerosis resulting in multiple episodes of infarction and fibrosis.The etiology in the latter two cases was unknown and classified as cardiomyopathy; the last patient had, in addition, gross endocardial * Presented at the Second world symposium on heart transplantation, Montréal, Canada, June 6, 1969.From the Departments of surgery and medicine, Medical College of Virginia, Richmond, Virginia.Supported in part by grants-in-aid from the American Heart Association and the National Heart Institute.fibroelastosis involving primarily the left atrium and ventricle.With respect to the significance of etiology in the selection of patients for transplantation and in the prognosis after transplantation, we must undoubtedly conclude that patients listed as \u2018\u2018cardiomyopathy\u2019\u2019 represent a variety of entities which may well have widely varying prognoses after transplantation.Whether such conditions as autoimmune disease, myocarditis, antiheart antibodies resulting from myocardial in- faretion, rheumatic disease, hyperlipemia or other conditions predisposing to coronary atherosclerosis constitute special risks to the homografted heart remains to be determined as our experience increases.The preoperative cvaluation in all patients included complete cardiac catheterization (Table I), coronary arteriography and left ventriculography.The clinical and laboratory data revealed that each patient had refractory biventricular failure ya 4 ~ 1.0, fe Laval Médical Vol.41- Fév.1970 CLINICAL EXPERIENCE IN CARDIAC TRANSPLANTATION 185 with pulmonary hypertension and a low cardiac index.The last patient with a cardiac index of 99 L/min/M?was moribund when he underwent operation.Despite the severity of the eardiac peut exister des antigénes d\u2019histo-compatibilité importants ailleurs que sur le lymphocyte et qu\u2019il faudrait employer d'autres cellules pour les dépister.Le dernier patient, du groupe C, mourut au 18° jour après l\u2019opération.COMMENT DIAGNOSTIQUER LE REJET AIGU ?La baisse de voltage du QRS est le signe diagnostique le plus important.L'accumulation du liquide médiastinal dans la phase post-opératoire immédiate peut cependant être responsable d'une baisse de voltage.Pour obvier à ce problème, l\u2019implantation d\u2019électrodes épicardiques est proposée.Comme autres changements électrocardiographiques significatifs, on note une déviation de l'axe électrique à droite, avec des troubles de conduction atrio-ventriculaire ou intraventriculaire.Ces signes disparaissent après l\u2019immunothérapie.Le syndrome clinique de rejet cardiaque est d\u2019abord caractérisé par une décompensation cardiaque droite.Un frottement péricardique peut être noté avec ultérieurement un souffle de régurgitation tricuspidienne ou mitrale.Le diamètre transverse du cœur augmente légèrement et les champs pulmonaires sont oligémiques.La congestion pulmonaire représente donc plutôt une infection ou une embolie.Afin de diagnostiquer rapidement un début de rejet, il est suggéré de supprimer la digitale et les diurétiques le plus rapidement possible après l'opération afin de ne pas masquer les premiers signes d\u2019une insuffisance cardiaque droite.Quant aux enzymes, les faits suivants furent notés : LDH-1 présente une élévation assez constante en cas de rejet.L\u2019élévation de LDH-5 peut être interprétée comme un premier signe de toxicité à l\u2019Imuran.compatible with a potentially successful result.The operability or inoperability of patients with pulmonary hypertension should be related to the degree of fixed pulmonary vascular resistance \u2014 a measurement which is difficult to establish in failure, each patient made an initial good recovery from operation and showed marked improvement in cerebral, hepatic and renal function as well as cardiac performance in the early postoperative period.Thus it was clear that the levels of pulmonary hypertension existing in these cases were the face of such low cardiac outputs.The question of how mueh increase in pulmonary resistance can be tolerated by the normal right ventricle of the transplant is reminiscent of the older discussions of the role of pulmonary hypertension in mortality TaBLE I Cardiac transplantation preoperative cardiac catheterization PATIENT RA (M) RV PA WEDGE LV CARDIAC INDEX J.P.1 45/0 50/15 15 120/0-23 1.18 LR.18 80/0-20 80/50 27 110/0-40 1.67 P.J.20 75/0-20 80/44 29 99/0-27 1.62 D.S.16 60/0-20 60/26 27 103/0-32 .995 136 Richard R.LOWER, V.Eric KEMP and Walter H, GRAHAM Laval Médical Vol.41- Fév.1970 following surgery from mitral stenosis.Only autopsy finding of massive infiltration of mono- considerable experience can provide a valid answer.In the case of each donor, the diagnosis of brain death was established by an independent team of neurologists and neurosurgeons according to criteria which are further discussed by D\".Alksne in this Although prolonged intravenous administration of catechola- Symposium.brain trauma and the mines have each been recognized as producing myocardial lesions in some patients, we doubt that these constitute a significant threat to the postoperative function of the usual donor heart.All efforts are pointed toward maintaining cardiovascular homeostasis in the donor prior to operation, and the prolonged administration of catechola- mines or the occurrence of transient cardiac arrest are common occurrences and do not contraindicate use of the donor heart.Histocompatibility typing (Table 11) was performed prospectively in each case by the method of Terasaki.Our results and that of others suggest that \u2018\u2018matching\u2019\u2019 as currently practiced probably does not bear a very close relationship to prognosis after cardiac transplantation.The first patient was a \u201c\u2018B + match\u2019 and was the first in the world experience to die of fulminating rejection.The nuclear cells, interstitial edema, hemorrhage and vascular necrosis dispelled any illusions we may have harbored that the human heart would be especially resistant to rejection.The second patient, also a \u2018\u2018B + match\u2019 with no detectable mismatch of major antigen groups, has weathered three rejection episodes.Nevertheless he has been completely rehabilitated and is at this moment the world\u2019s third longest surviving patient.The third patient has provided some special insights into the problem of histocompatibility mateh- ing.While the preoperative lymphoeyte-serum crossmatch revealed no evidence of preformed antibodies, subsequent analysis (3) of the preoperative serum by immune adherence revealed strong evidence that antibodies against cultured kidney cells of the heart donor existed in significant titer in the preoperative serum.The antibodies disappeared from the postoperative serum and were eluted in significant titer from the heart postmortem.The patient\u2019s clinical course strongly confirmed an element of previous sensitization, as fulminating rejection was manifested by the fourth day and inexorably progressed despite massive Tape II Histocompatibility typing (lymphocytotozicity) MCV heart transplants 8A 4A 4B 4C 7C 7D LA1 LA3 MATCH 1.Recipient \u2014 + + + \u2014 \u2014 \u2014 _ Donor \u2014 + + \u2014 \u2014 \u2014 \u2014 \u2014 B+ 8% of sera mismatched 2.Recipient + \u2014 \u2014 ; \u2014 \u2014 \u2014 \u2014 + | Donor LL \u2014 | + | \u2014 | \u2014 \u2014 Lo | \u2014 | \u2014 | B+ 6% of sera mitmatched 3.Recipient + \u2014 + + \u2014 \u2014 _ _ Donor + | 4+ | + | + | \u2014 | \u2014_ | \u2014 | \u2014 9% of sera mismatched 4.Recipient + + + + + + + \u2014 Donor | + \u2014 | +\u2014 | \u2014 + | \u2014 | \u2014_ + C 99%, of sera mismatched (Negative lymphocyte serum cross match in each case) Lai 1g ie Bio filer ; dir disp ele ; pi gl ju À B- Laval Médical Vol.41- Fév.1970 immunosuppressive therapy.Such findings indicate that some important histocompatibility antigens may not be expressed on the lymphocyte and require the use of other target cells for their detee- tion if we are to achieve more precise matching and avoid some cases of prior sensitization.The fourth patient, a \u201c\u201cC mateh\u2019\u2019, made an initial good recovery from operation, had a rejection episode at the end of one week which was clinically reversed, but again showed evidence of severe rejection at the end of two weeks which became refractory to massive immunosuppressive therapy.The histology in this patient who died after eighteen days, was of particular interest in that there was extensive interstitial hemorrhage, edema and vascular damage typical of acute reject- lon, but almost complete absence of mononuclear cell infiltration in the myocardium.The leukocytes scattered through the myocardium were predominantly polys.Again antibody was eluted in significant titer from the myocardium postmortem.The diagnosis of acute rejection: Coincident with this unexpectedly high incidence of acute rejection we have formulated certain impressions with regard to the diagnosis of acute cardiac rejection.Many of these mirror the conclusions reached in the laboratory during the past ten years in the observation of more than 200 dogs which received orthotopic cardiac homografts (1 4 and 5).There seems little doubt that the electrocardio- 2 gram remains the most sensitive and specific examination for the detection of early threatened rejection, not only in the early postoperative weeks, but even months after transplantation.We conelu- de from our own observations and from those of others, as well as from the extensive animal work that a decrease in QRS voltage is an invariable accompaniment of acute myocardial rejection and is the most important single diagnostic criterion.Because of the possibility in the early postoperative weeks of non-specific fluid accumulations which might also depress voltage, diagnostic aceuracy may be insured by the use of an implanted wire CLINICAL EXPERIENCE IN CARDIAC TRANSPLANTATION 137 electrode to obtain tracings directly from the myo- cardium (6) or alternately, placing radio opaque markers on the epicardium to help in excluding pericardial effusion.Other ECG changes which are of significant value in the diagnosis of rejection include an abrupt rightward shift in the mean frontal plane axis of the QRS, abnormal atrioventricular or intra- ventricular conduction and atrial arrhythmias.The decline in voltage and right axis shift occurred in each of seven rejection episodes observed in our patients.In the surviving patient, right bundle branch block was an additional finding in three rejection episodes at one week, three months and seven months.On each occasion the changes reverted to normal with immunosuppressive therapy.The vectocardiogram has also proven to be a sensitive and graphic means of demonstrating the changes in voltage during acute rejection.The clinical syndrome of cardiac rejection is characterized initially by a predominance of right heart failure.The patient notes fatigue rather than dyspnea.There is incipient weight gain which may progress to clinically detectable edema.Venous pulsations become visible and ultimately the venous pressure elevated.Auscultation reveals, in addition to the frequent but somewhat nonspecific pericardial rub, the more important finding of a right ventricular diastolic gallop sound.Later in rejection the regurgitant murmur of slight tricuspid or mitral insufficiency can also be heard.Corresponding to predominant signs of right ventricular failure is the X-ray finding of a minimal increase in transverse cardiac diameter and lung fields which appear almost oligemic rather than congested.Thus when pulmonary infiltrates appear in the postoperative period there is a much greater likelihood that they represent infection or embolism rather than rejection.Fluoroscopy during acute rejection will generally show diminished amplitude and asynchrony of ventricular pulsations.Because of the diagnostic importance of incipient right heart failure in the early detection of threatened rejection, it is strongly suggested that digitalis and diuretics be withdrawn from patients as 138 Richard R.LOWER, V.Eric KEMP and Walter H.GRAHAM soon as practical after operation to minimize masking of this important early sign.When detected at a sufficiently early stage, threatened rejection should generally be reversible by appropriate increases in immunosuppressive therapy as demonstrated some years ago by prolonged survival in dogs with transplanted hearts (4) and confirmed more recently by repeated myocardial biopsies in dogs (7) and by the clinical observations of the many members of this Symposium.Much attention has been given to evaluation of the serum enzymes in the diagnosis of early rejection \u2014 particularly the isozymes of LDH.I will only summarize our conclusions in this regard drawn from the clinical cases and from the animal studies.With a severe rejection crisis there is often a rise in LDH-I.However, typical ECG changes of rejection in such instances precede the enzymes changes.Moreover, one may see the typical ECG and clinical manifestations of acute rejection without any elevation in the serum enzymes.Elevations of the CPK or SGOT generally imply significant myocardial damage and may be considered an ominous sign in a severe rejection crisis.Serial determinations of the LDH isozymes may prove to be of further value in the detection of early imuran toxicity by a rise in Band 5.The role of humoral antibodies in the acute rejection crisis is not yet clearly established.The hope that detection of serum antibodies might provide a useful means of monitoring the immunologic status of the graft has not yet materialized, undoubtedly because the graft too rapidly sponges up the antibodies.In the three patients dying of acute rejection in this series, antibody was eluted in significant titer from the heart muscle in each case postmortem, although antibody was not detectable in the postmortem serum or other tissues.Immunofluorescence of the myoear- dium revealed only a diffuse staining and failed to show localization of the antibody (3).The most ominous threat to the prolonged survival and good function of the cardiac homograft is the development of the coronary arterial lesions of chronic rejection.These were reported (8) in Laval Médical Vol.41- Fév.1970 long-surviving dogs with heart homografts before any clinical trials were undertaken and have been subsequently reported with alarming frequency in autopsies performed after human cardiac transplantation, The lesions appear to represent a manifestation of chronic endothelial injury resulting in platelet agglutination with subsequent formation and organization of thrombus.Such lesions result in mild to marked focal areas of narrowing of the vascular lumens ultimately resulting in significant areas of myocardial ischemia.It is hoped that this Symposium will address itself to the task of determining those factors which are associated with the high risk of chronic rejection and those associated with relative freedom from this condition.Insofar as acute rejection is concerned, the important aim is early detection and prompt treatment, whereas with chronic rejection it must be prevention.BIBLIOGRAPHIE !.Kosek, J.C., HurLEY, E.J., SEWELL, D.H., et LOWER, R.R., Histopathology of orthotopic canine cardiac homografts and its clinical correlation, Transplantation Proc., 1: 311, 1969.2.Lower, R.R., et CLEVELAND, R.J., The current status of heart transplantation, Proceedings of the First Intl.Congress of the Transplantation Society, Advance in Transplantation, pp.657-659, Munks- gaurd, Copenhagen, 1968.J.Lower, R.R., Donc, E., Jr., et GLAZENER, F.S., Electrocardiograms of dogs with heart homografts, Circulation, 33 : 455, 1966.4.Lower, R.R., Donc, E., Jr., et SHuMwaY, N.E., Long- term survival of cardiac homografts, Surgery, 58 : 100, 1965.Lower, R.R., Kontos, H.A., KosEK, J.C., SEWELL, D.H., et GrRaHaM, W.H., Experiences in heart transplantation, technique, physiology and rejection, Am.J.Cardio., 22 : 766, 1968.6.Lower, R.R., Kosek, J.D., Kemp, V.E., GRAHAM, W.H., SEwELL, D.H,, et Lim, F., Rejection of the cardiac transplant, Am.J.Cardio., In press.Te ~2 .Sewrur, D.H., Kemr, V.E, et Lower, R.R., The epicardial ECG in monitoring cardiac homograft rejection, Circulation, 39 (suppl.1) : 21, 1969.8 WiLLiaMs, G.M., DEPLANQUE, B., GRAHAM, W.H., et Lower, R.R., The participation of antibodies in acute cardiac allograft rejection in man, New Engl.J.Med., In press.ln She Meg] Tig Ty | be I iy \u201cth, gy ify \u201cVe \u201con lien! tl fone A bem | pri | 1s ent à rst | il Isis ii pe al Joi Jv tit Tra js Ie fin! gage puits pei jf tai ÿ L.JE fill # go PL al ® wi gf {e i me THREE CASES OF ALLOGENIC HEART GRAFTS IN HUMANS * Ch.DUBOST and J.-P.CACHERA, Paris.TROIS CAS DE GREFFE CARDIAQUE Les trois patients présentaient une insuffisance coronarienne sévère et avaient souffert de plusieurs épisodes d\u2019'infarctus myocardique.De multiples lésions athéromateuses furent mises en évidence par coronaro- graphie sélective chez deux des trois patients.En plus, un cinéangio- gramme gauche a démontré une stagnation du colorant dans le ventricule gauche, ainsi qu\u2019une éjection systolique diminuée.Histocompatibilité : Quatorze antigènes leucocytaires furent testés chez les receveurs et les donneurs, suivant les techniques et la nomenclature décrites initialement par J.Dausset.Dans le premier cas, huit antigènes furent trouvés identiques, trois compatibles et deux incompatibles.Dans le second cas, on trouva également huit antigènes identiques, un compatible et deux incompatibles.Dans le troisième cas, neuf antigènes furent trouvés identiques, deux compatibles et deux incompatibles.Cardiac transplantation has entered its clinical phase since more than two years; the value of this procedure, as a palliation in curable heart diseases, was ascertained by several cases of long term survival (1, 2, 6, 7 and 8).However, this method, for the present, may not be considered, as discharged from the period of experimental and clinical research.Numerous problems remain to be solved concerning the physiology and the pathology of the grafted heart, as well as the early diagnosis of the rejection episodes, and more efficient and selective immunodepression.CLINICAL DATA The three patients who received a cardiac allo- graft were males aged 57, 48 and 56.All of them were suffering from a severe coronary insufficiency ; * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.3) (suite du résumé en page suivante) all had several attacks of myocardial infarction and several episodes of left ventricular failure with pulmonary edema; two of them had rest and exertion angina, with a very high daily consumption of trinitrin, two of them had several episodes of congestive heart failure.In three cases, ECG demonstrated definite se- quelae of extended myocardial infarction, associated with ischemic chronic changes.X-rays of the chest showed in case 1 an almost normal heart size; on the other hand, a marked cardiomegaly was observed in cases 2 and 3; moreover, in the three cases fluoroscopic examination of the heart demonstrated a significant lowering of the ventricular kinetics.Two of the patients were undergoing a selective coronarography ; in both cases, coronarography was showing diffuse and severe atherosclerotic changes in the three main coronary arteries, but predominant in the left coronary tree.Left cineangio- gram was also performed, and demonstrated a very 140 Ch.DUBOST and J.-P.CACHERA Laval Médical Vol.41- Fév.1970 Technique chirurgicale : Au moyen d'un oxygénateur à bulles jetable, amorcé d\u2019une solution de lactate Ringer, la température œsophagienne du cadavre est descendue à 20° C.Les veines caves sont alors clampées ainsi que l\u2019aorte et la perfusion isolée du cœur amène ce dernier à 10° C.Le cœur est excisé suivant la technique de Barnard.Dans le premier cas, le cœur fut perfusé de sang froid durant toute la durée de la réimplantation.Dans les deux autres cas, aucune perfusion cardiaque ne fut pratiquée.Dans les trois cas, le cœur greffé reprit un rythme sinusal immédiatement après la ressuscitation.Évolution postopératoire : Les soins postopératoires furent prodigués dans un environnement rigoureusement aseptique, à cause du risque accru d'infections en présence de doses élevées d\u2019immunosuppresseurs.De plus, on a rapporté certaines interférences entre les antigènes bactériens et les antigènes de transplantation.Toute inoculation septique pourrait donc stimuler les mécanismes de rejet.Par ailleurs, Un environnement stérile du patient permet la suppression d\u2019une antibiothérapie non spécifique et prophylactique.De par cette suppression précoce d'antibiotiques, on évite la sélection d\u2019une population poor ejection stroke volume in the left ventricle Several weeks before the procedure, the three and marked stagnation of the dye.Significant de- patients were clearly informed of the risks incured crease of the cardiac output of the left systolic by a still hazardous method; they came themselves volume, systolic index, and left ventricle ejection to the operative decision.time was appreciated in each case by the mean of cardio-green dilution curves.HISTOCOMPATIBILITY In case 2, a scanning of the lungs was done, for dismissing the diagnosis of chronic pulmonary Fourteen leukocyte antigens have been tested in embolism.recipients and prospective donors according to the In Table I are summarized the main clinical data technics and nomenclature deseribed initially by concerning the recipients and the donors.J.Dausset.Tape 1 Histocompatibility matching in 3 cases of cardiac allogenic graft.Leukocyte antigents are determined in the Dausset\u2019s nomenclature.(?: identification of the antigents was questionnable).Dal Da2 Da3 Da4 Da5 Da6 Da7 Da8 Dal0 Dall Dal2 Dal4 Da16 Da17 Recipient Bo.\u2014 + + \u2014 \u2014 + \u2014 \u2014 \u2014 + + + ?Donor Ga.\u2014 \u2014 + + + \u2014 \u2014 \u2014 \u2014 + + \u2014 ?\u2014 ?\u2014 \u2014 ++ + Recipient Fo.+ \u2014 Donor Fr.\u2014 Recipient Ma.\u2014 \u2014 _ \u2014 \u2014 _ Donor Du.! | [+ ++ + | [+ ++ + | tition! | in 10 QE olufion § cendue la per- exclsé perusé 3 CEUX 55 Hoi ors emer ope pot ènes d\u20ac pir 18 pores pun Je te ; jel pui x Laval Médical Vol.41- Fév.1970 THREE CASES OF ALLOGENIC HEART GRAFTS IN HUMANS 141 de germes endogènes résistants, ainsi que la prolifération d'agents myco- tiques ou viraux.Le régime immunosuppressif est ensuite décrit en détail.Résultats : Le troisième patient décéda environ 20 heures après l\u2019intervention.Le décès semble être attribuable à une embolie gazeuse.À l\u2019autopsie, aucun signe de rejet aigu ne fut noté.Les deux autres patients sont en vie, respectivement 17 et 10 mois après l\u2019opération.Dans le cas du deuxième patient, par opposition au premier, aucun épisode de rejet aigu ne fut observé.Cependant, plusieurs données indiquent l\u2019existence d\u2019un processus de rejection chronique : il existe des troubles de la repolarisation, avec déplacement vers le bas du segment ST dans les dérivations précordiales, suggérant une ischémie myocardique chronique.L\u2019étude des enzymes sériques a démontré à plusieurs reprises des élévations des enzymes d'origine myocardique, à savoir la phosphocréa- tokinase.Malgré un état clinique satisfaisant, la thérapie immunosuppressive fut augmentée à plusieurs reprises, afin de contrôler l\u2019évolution chronique du phénomène de rejet.The present properties of current immunodepres- sor means did not influence us in favour of slighting histocompatibility between recipient and donors.Therefore, no cardiac transplantation was deliberately planned outside a satisfactory leukocyte matching.Because of this delicate choice, some of the potential recipients on the waiting list for a curdiac allograft died.due to a lack of a suitable donor.Table 11 summarize the leukocyte antigens tested in the three recipients and the three donors used; the nomenclature used is the Dausset (Da) system.In case 1, identities were found in eight antigens (Dal, Da3, Da 4, Da 8, Da 10, Da 11, Da 12, Da 14) ; compatibilities in three antigens (Da 2, Da 7, Da 16); incompatibilities in two antigens (Da 5, Da 6).In case 2, identities were present in elght antigens (Da 2, Da 3, Da 4, Da 6, Da 7, Da 10, Da 11, Da 16) ; compatibilities in one (Dal); incompatibilities in two (Da 8, Da 12).In case 3, identities were present in nine antigens (Da 1, Da 2, Da 3, Da 5, Da 6, Da 8, Da 10, Da 16, Da 17) ; com- patibilities in two (Da 7, Da 11) ; incompatibilities in two (Da 4, Da 12).SURGICAL TECHNICS The procedure of excising the cardiac transplant was the same in the three cases.Immediately after stopping the mechanical artificial breathing, the donor\u2019s body was perfused by the mean of a cardio-pulmonary bypass established between the right atrium and the ascending aorta.(Disposable plastic-bag Rygg oxygenator primed with Ringer- lactate solution).The esophagal temperature of the cadaver was lowered at 20° C; then the venæ cavæ and the aorta were clamped, and perfusion of the isolated heart was continued by the mean of the aortie cannula, until the myocardial temperature dropped around 10° C.Then the heart was exei- sed following the technic described by Barnard (1).In ease 1, the transplant was perfused with cool blood through the aortic cannula during the whole re-implantation procedure. 142 In cases 2 and 3, no organ perfusion was done; the sole hypothermia was able to preserve the myo- cardium during the ischemic period.The way of cutting the right atrium on the donor\u2019s heart was judged of great importance, in order to avoid the zone of the sinus node or the atrio-ventricular conduction pathways.In this regard, incision was made vertically, from the I.V.C.to the S.V.C., parallel and close to the inter-atrial grove.The incision described by Cooley (7), from the 1.V.C.to the apex of right appendage, was not used.In the three cases, the grafted heart beated in sinus rhythm immediately after ressuscitation; in two instances, no electrical shock was necessary, and the heart resumed spontaneously his normal activity as soon as the clamps were released, Ch.DUBOST and J.-P.CACHERA Laval Médical Vol.41- Fév.1970 POST-OPERATIVE COURSE Post-operative cares were managed in aseptic conditions, using a sterile unit especially built for this purpose and placed under continuous bacteriological supervision.Such sterile conditions are probably a great benefit after cardiac transplantation.The reasons are: 1.The septic risk commonly observed after cardiac open surgery is substantially increased by the use of maximal doses of immunodepressor agents ; 2.Interferences between bacterial antigens and transplantation antigens have been reported; any septic inoculation should stimulate the graft rejection mechanisms (9).3.Sterile environment of the grafted patient allows the early suspension of non-specific antibiotic Tape II Summarizing the main clinical data in recipients and donors in three cases of cardiac transplantation DAYS OF TRANSPLANTATION AcE CASES SEX WEIGHT ABO gr.CLINICS Recipient Bo.5.12.1968 57 M.Donor Ga.38 M.\u2014 Coronary insufficiency \u2014 Angina pectoris at rest \u2014 3 myocardial infarctions \u2014 Atherosclerotic, obstructions in the 3 main coronary arteries on coronarography 63 A+ 62 A+ \u2014 Massive spontaneous cerebral haemorrhage on the 5.7.1968 Recipient Fo.24.11.1968 48 M.Donor Fr.46 M.\u2014 Coronary insufficiency \u2014 Angina at rest \u2014 2 myocardial infarctions \u2014 Cardiac failure \u2014 Triple atherosclerotic coronary disease 55 A+ \u2014 Massive spontaneous cerebal haemorrhage 65 A+ Recipient Ma.26.11.1968 56 M.Donor Du.33 M.\u2014 Coronary insufficieney \u2014 2 myocardial infarctions \u2014 Angina at rest \u2014 Cardiac failure 96 B+ \u2014 Cranio-cerebral trauma \u2014 Fracture of parietal bone with meningo-cerebral injury 60 0+ AL Ihe Tit) Ly w) Pity dle | Pep Ty de \u201cvi \"6 fi) Uy Me [iii 1600 ie voll for this dei a lé hs dre, RS ble Bib: eus an À; 307 à ques pic Ï cho = Laval Médical Vol.41- Fév.1970 prophylaxy; and thus, avoiding the selection of endogenous resistant population of germs, and the facilation of fungie or viral infestations.Along the three first post-operative days, the patients received intravenously a solution of Isopropyl- norepinephrine (Isuprel 1,2 mg in 250 ml of iso- tonic glucose).The immunosuppressive therapy involved : 1.Azathioprine (Imuran) 250 mg on the morning before the transplantation and then 3 mg/kg daily ; 2.Prednisone : 200 to 300 mg intravenously on the first postoperative day, and them 1 mg/kg orally; 3.Antilymphocyte globulin (ALG).An antilymphoeyte IgG was prepared and purified by Choay Laboratories®.The treatment with ALG started on the day before the transplantation at the dose of 10 ml subcutaneously; the daily dose was then 20 ml during the first post-operative days.A horse ALG was used in the cases 1 and 3; in case 2; the patient became intolerant to the horse proteins, and developed fever and hypotension after injections of ALG; thus, a sheep ALG was prepared and used without any other intolerance symptoms.Details concerning management of long terms survivors after cardiac allograft, the schedule of the controls, and the inereasing detection of the early rejections signs are reported in another issue (3).RESULTS One patient (case 3) died on the first postoperative day, by a sudden cardiac arrest on the 20th hour after the procedure.The early postoperative cause had been uneventful: the patient was awake and soon conscious in the operating theater, E.C.G.was in sinus rhythm, arterial pressure and urinary flow were normal.However, routine recording of the E.E.G.had shown a transient 1.Laboratoires Choay, 48 ave.Th.-Gauthier, 75, Paris 16\u2018, France.THREE CASES OF ALLOGENIC HEART GRAFTS IN HUMANS 143 and unilateral drop of the cerebral activity, during the heart\u2019s ressuscitation.which was interpreted as a gas embolism of slight degree; as a matter of fact.several clonic attacks occured on the 10th postoperative hour, resulting in the left brachial mono- plegia.Despite the spontaneous maintenance of con- sciensness and satisfactory A.P.levels, the patient was maintained under mechanical ventilatory assistance with tracheal intubation; suddenly, the E.C.G.tracing became isoelectric.The attempts for ressuscitation of the heart remained uneffective.Microscopic examination of the grafted heart showed histological changes compatible with prolonged cardiac massage, but no patterns suggestive of an acute early rejection process.Two other grafted patients are still alive respectively 17 and 10 months postoperatively 2.In the two patients, cardiac sounds and peripheral arterial pressure are normal, pulsation rate is around 100 per mn, E.C.G.is almost normal, X-rays evaluation of the cardiac volume is normal.the apicogram and the systolic ejection time of the left ventricule measured from the indirect carotid pulse tracing are normal.E.C.G.data concerning the two patients are reported in another paper (4).Several episodes of rejection have been early detected in patient n° 1: data about the rejection signs observed and the emergency treatment applicated to them are described in another publication (3).In patient n° 2, no definite acute episode of rejection was so far encountered.However, several clues support the hypothesis of a latent chronic rejection process, ?.e.: \u2014 troubles in the electrical repolarization of the heart.with low shift of the ST segment in the precordial loads, suggestive of a chronic myo- cardial ischemia; \u2014 repeated peaks in seric enzymes levels of a myocardial origin, namely phosphoereatokinase (PCK) (5).2.Since this paper was submitted, one patient (case 1) died from a sudden cardiac arrest. 144 Despite a satisfactory clinical condition of the patient, in several instances the long term immuno- suppressive therapy was increased, in an attempt to check the chronie evolutility of the rejection phenomenon.SUMMARY AND CONCLUSIONS Three cases of allogenic cardiac graft in humans are reported.The grafted patients were in the three instances males in the fifth or sixth decade of life ; all of them were suffering from severe athero- sclerotic coronary insufficiency, resulting in several attacks of myocardial infarction and in several episodes of cardiac failure.Among the three patients operated upon, there was one operative death, from a sudden cardiac arrest, without any pattern suggestive of an acute rejection process.Two patients are alive and in good clinical condition respectively 17 and 10 months after receiving the cardiac graft.At least, two episodes of acute rejection have been observed in the first patient; early detection of the first signs of rejection and prompt and intensive immunosuppression have made the crisis reversible and healing without evidence of sequelae.In the second patient, no acute crisis of rejection was so far observed, but several symptoms consistant with a chronic evolutivity of rejection.The satisfactory results observed in the two long- term survivors may be imputable to : 1.careful study of leukocytes compatibilities between donors and recipients, involving 14 antigens in the Dausset system ; 2.adequate prophylaxy of the septie risk using a sterile post-operative unit under bacteriological control and thus avoiding the use of non specific antibiotics ; 3.flexible immunodepression using an active heterologous ALG.4.accurate and continuous detection of the early signs of rejection.Ch.DUBOST and J.-P.CACHERA Laval Médical Vol.41- Fév.1970 ACKNOWLEDGEMENTS We gratefully thank for their active contribution to this work : CL.d\u2019Allaines, Ph.Blondeau, À.Piwni- ca, A.Carpentier (surgical teams); J.Passelecq, J.C.Salamagne, R.Stepler (anesthesiology); C.Prigent, Ph.Besse (pumps oxygenators) ; J.P.Beuzelin, J.M.Briotet (post-operative cares); J.Dausset, J.Dormont, L.Sehwarzenberg (immunology) : J.Acar (bacteriology) ; M.de Mendoca, K.Schwartz (biochemistry); F.Coffre, M.La- pierre, I.Steimesse (nurses).REFERENCES 1.BARNARD, C.N., A human cardiac transplant, an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town, South African Med.J., 41 : 1271, 1967.2.BARNARD, C.N., Human cardiac transplantation : an evolution of the first two operations performed at the Groote Schuur Hospital, Cape Town, Am.J.Cardiol.\u2026 22 : 584, 1968.3.CACHERA, J.-P., and Duwrosr, Ch., Management of long term survivors after cardiac allograft in humans, paper presented to the Second world symposium on heart transplantation, Montreal, 6, 7, 8 June 1969, In press.4.CACHFRA, J.-P., and LACASSAGNE, J, P., Electrocardio- graphic signs of rejection after cardiac allogenic graft, Paper presented to the Second world symposium on heart transplantation, Montreal, 6, 7, 8 June 1969, In press.CLAUVEL, M., SCHWARTZ, K., CREPIN, Y., and CACHERA, J, P., Enzyme profiles after heart transplantation, Nature, 220 : 483, 1968.i.CooLEY, D.A., BLoopwELL, R.D., and HALLMAN, G.L, Cardiac transplantation for advanced acquired heart disease, J.Cardiovasc.Surg., 9 : 403, 1968.-7 .CooLEY, D.A., BLoopwELL, R.D., HALLMAN, G.L., and Nora, J.J., Transplantation of the human heart ; report of four cases, J.A.M.A., 205 : 479, 1968.8.DuBosT, Ch.,, and CACHERA, J.P., Un cas de greffe allogénique du cœur chez l\u2019homme compatible dans le système HL-A et traitée par une globuline anti- lymphocytaire hétérologue, Presse Méd., 76 : 1651, 1968.9.RAPAPORT, F.T., CHAsE, R.M., and SoLowEgy, A.C, Transplantation antigens activity of bacterial cells in different animal species and intra-cellular localization, Ann.N.Y.Acad.Sci., 192 : 102, 1966.EX Lai ined sth ii HEN yet # od pent i oi i worl pre i | | A uardi lk df oR per | | gas ati ok sea EXPERIENCE OF THE MONTREAL HEART INSTITUTE * Pierre GRONDIN et Gilles LEPAGE, M.D.Institut de cardiologie, Montréal, Canada Les auteurs présentent neuf cas de transplantation cardiaque effectués du 31 mai au 29 novembre 1968.La méthode de protection du cœur greffé qu\u2019ils décrivent est d\u2019abord une perfusion hypothermique totale du donneur, ajoutant un refroidissement sélectif du cœur par irrigation au soluté salin froid.Après une période d\u2019anoxie de l\u2019ordre de 50 minutes, la racine de l'aorte est perfusée pendant 12 à 36 minutes, au cours de l\u2019anastomose de l\u2019artère pulmonaire, et l\u2019anastomose de l\u2019aorte est faite au cours d\u2019une seconde période d\u2019anoxie de 8 à 20 minutes.La protection myocardique ainsi obtenue permet une excellente fonction du cœur greffé sans l\u2019aide d'aucun vasopresseur.Les auteurs croient que deux antigènes incompatibles sont le maximum qui devrait être accepté, que l\u2019électrocardiogramme quotidien est le meilleur indicateur du rejet, et que le traitement de la crise de rejet doit être précoce, vigoureux, mais préférablement de courte durée.From May 315t to November 29, 1968, nine patients underwent total cardiac transplantation at the Montreal Heart Institute.The first patient died 42 hours after operation from low output failure which necessitated repeated and prolonged periods of assisted circulation with the pump-oxygenator and this resulted in an hemorrhagic diathesis with bleeding in the lungs and kidneys.He was conscious until shortly before his demise.The transplanted heart was small and of poor quality, having suffered many anoxic episodes during the terminal illness of the donor, and it was unable to take over the full load of the circulation despite numerous cardiac drugs including ealeium chloride, digitalis, isoproterenol and epinephrine.This heart was removed at normal temperature, immersed in cold saline for a few minutes and sutured in place, the longest period of anoxia being 38 minutes.After suture of the atria, the aortic root was perfused for nineteen minutes at normal temperature while the pulmonary artery suture line * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.(suite du résumé en page suivante) was completed, and a second period of anoxia of 16 minutes occurred during the aortic anastomosis.Following this experience, our technique of protection of the donor heart was changed.All further patients received hearts that had been protected by hypothermic total body perfusion of the donor and cold saline irrigation of the heart until it felt cold to palpation, and had reached a temperature of approximately 18°C., a technique with which we were familiar, having used it in most of our open- heart cases for the previous three years.Again, after the atrial suture lines were completed, the heart was perfused through a canula inserted in the aortic stump (Figure 1) at a flow of 300 to 600 ml per minute at a temperature of 30° © for a period ranging from 12 to 36 minutes.The aortic suture was done during a further period of anoxia varying from 8 to 20 minutes.Upon release of the aortic clamp, vigorous ventricular fibrillation ensued in all patients, three of them reverting spontaneously to sinus rhythm, the others being easily defibrillated by electrical countershock.The bypass was discontinued while transfusing the patient from the pump to obtain a measured left atrial 146 Pierre GRONDIN et Gilles LEPAGE Laval Médical Vol.41- Fév.1970 Ils hésitent à utiliser de fortes doses de Prednisone en même temps que la globuline antilymphocytaire, croyant que peut-être une corticothé- rapie poussée nuise à l\u2019action de la G.A.L.lis croient que la radiothérapie cardiaque locale peut aider à prévenir le rejet précoce, qui survient de façon constante vers la fin de la première semaine.lls affirment enfin qu\u2019il faudra trouver une façon pratique de doser l\u2019activité immunosuppressive de la G.A.L., de façon à pouvoir diminuer rapidement l'administration des corticostéroïdes et ainsi diminuer leurs effets nocifs à long terme.pressure of between 15 and 20 mm Hg.All those hearts maintained an excellent aortic pressure throughout the operation, at a heart rate varying between 60 and 120/minute.A single patient had a heart rate initially as fast as 140/minute.No episodes of hypotension occurred in any of the patients during the remainder of the operation, and no vasopressor drugs were needed either (Table I).The last patient received an isoproterenol drip to inerease the heart rate which, by the end of the operation, had dropped to 55/minute.He was also intermittently stimulated by a pacemaker through » Figure 1 \u2014 Perfusion of aortic root during pulmonary artery anastomosis.View from head of table, showing the aortic root distended by blood perfusing the cononary arteries.The canula is connected to the arterial line through a standard coronary perfusion pump.Access to the pulmonary anastomosis, which here is almost completed, is not hindered by the perfusion.The clamp in foreground, is on the transsected aorta of the recipient.a Teflon covered wire attached to the right ventricle at the time of operation.This wire has also been used to obtain an epicardial electrocardiogram which can be very useful in the diagnosis of early rejection, at a time when limb leads tracings are affected by the early local postoperative changes.All of those patients recovered promptly and the early postoperative course was uneventful, with excellent cardiac performance.Indeed, one patient needed reoperation 36 hours after transplantation for a thrombosed aneurysm of the abdominal aorta TaBLE 1 Performance of transplanted heart.eurly postoperative.Blood pressure and heart rate at the end of surgery and during the first twenty-four hours.None of the last eight patients had to receive vasopressor drugs.The last patient received Isoproterenol for bradycardia.due to junctional rhythm.RECIPIENTS - EARLY P.0.PERIOD B.P.+ H.R.B.P.+ H.R.Veil oriented Extubation Ambulation end of surgery first 24 hrs (hrs P.0) (hrs P.0.) (hrs P.O.) | 90 100 intermitt.60 partial by-pass I 110 100 130 - 90 90 End of surgery 14 1/2 21 60 70 1 110 80 150 - 100 30 11 hrs 15 1/2 (aorto-iliac 80 80 - 90 graft) 1Y 130 90 130 - 90 85 71/2 hrs 12 32 80 60 - 80 Y 115 90 115 - 100 75 End of surgery 13/4 30 70 60 - 70 vi 110 120 130 - 100 100 End of surgery 11/2 11/2 70 50 - 70 vil 120 110 140 - 100 70 18 hrs 5 1/2 24 \u201c90 70 vin 110 95 130 - 90 90 End of surgery 6 3/4 6 3/4 \u201c60 60 - 80 x 110 55 - 70 End of surgery 10 1/4 10 1/4 55 70- 80 Lar Ya, wi lou tan nil the cove nt dent tent bn lg dl fo de fei H Ii a fl f Ay H lig | | ical a | lemps | cité | éveni mère doser | ER lous jt ver ns ale [ogni fay os AF nes ML | wil paie | nai rtd tl ry i Laval Médical Vol.41- Fév.1970 and both iliac arteries, which was treated by resection and bilateral bypass graft.During the five- hour operation (Figure 2), his new heart maintained a very stable blood pressure and the pulse rate did not vary more than 20 beats/minute from the usual steady rate of 80 to 90/minute.He recovered well from this second operation, but died on the eleventh day from a cerebrovascular acei- dent.Severe acute rejection of the heart was found at postmortem examination.All seven other patients recovered very well and had a remarkably benign postoperative course.Immunosuppressive therapy consisting of Aza- thioprine and Prednisone was used in all patients.All patients also received antilymphocyte globulin from the day of operation, except case 2, who was allergic to horse serum.Bovine A.L.G.was prepared for him and started during the seventh week.He received instead 500 roentgens of deep X-Ray therapy to the heart in five divided doses during the first six days.This patient was our longest survival.Azathioprine was given at approximately 6 mg per keg for the first 48 hours, and gradually 160 140 120 100 80 60 40 A Blood - 1000 cc, i + 20 Urine out put=325 cc 0 11 12 13 14 15 16 Figure 2 \u2014 Aneurysmectomy and aorto-femoral graft 33 hours post-transplantation.Pulse and blood pressure during resection of thrombosed aortic and iliac aneurysms, and bilateral aorto-femoral Dacron graft in patient No 3, 33 hours after heart transplantation.Blood pressure drop to 90 mm/Hg after tracheal intubation responded well to Vasoxyl, 2 mg i.v.(Arrow).EXPERIENCE OF THE MONTREAL HEART INSTITUTE 147 lowered to 2 to 3 mg per kg in order to maintain a platelet count above 150 000 and a white blood count in the vicinity of 5000 per cubic mm.Pred- nisone was given at a dose of 4 mg per kg initially and was gradually decreased so as to reach 2 mg per kg at two weeks and 0.5 mg per kg at one month in the early cases.In the last case, the plan was to reach 0.5 mg per kg at two months.However, these dosages had to be readjusted frequently according to the clinical status of the patient and the actual or suspected rejection episodes.Anti- lymphocyte globulin.prepared by the Tnstitute of Microbiology of the Université de Montréal, was given at 300 mg daily for two weeks, 250 mg daily for a further two weeks, and then, the frequency of the injections was gradually decreased so that, by the third month, the patients were receiving 250 mg every three days.In the last patient, the decrease was less rapid and he was receiving 250 mg every other day by the third month.In addition, human gamma globulin was given periodically to all patients to try and prevent viral infections.Despite the immunosuppressive therapy, six of the eight patients who survived operation experienced a mild rejection episode between the fifth and the seventh day, but it subsided without increasing the immunosuppressive therapy.Of the seven patients that survived more than one month, three died of acute rejection on the 38, 47 and 64th day, respectively.in spite of very intensive treatment including large doses of hydrocortisone, local X-Ray therapy, actinomyein and increased doses of A.L.G.and Prednisone.Three other patients died as a result of infection.One at 68 days from the consequences of a severe intercostal \u2018\u201cherpes zoster'\u2019 followed by herpes viremia, and two from pulmonary infeetion at 106 and 120 days.The longest survivor, the second patient, died from aspiration of vomitus 156 days postoperatively.Generalized osteoporosis and a compression fracture of the first lumbar vertebra resulting from cortico- steroid therapy undoubtedly contributed to this episode.He also presented mild evidence of rejection in the last few days before his death. 148 Pierre GRONDIN et Gilles LEPAGE Leucocyte typing had been done preoperatively on all patients by the \u2018\u2018leuco-agglutination\u2019\u201d method, and the length of survival was clearly related to the match (Figure 3).The four patients who had a B match, with only one or no incompatible antigens, had the longest survival, all over three months, the one exception being patient No.8, where an antinuclear factor was demonstrated in the serum before transplantation.The three patients with C match, with two or three incompatible antigens, survived an average of two months, whereas the single patient with a D match, with more than three incompatible antigens, survived only eleven days and had acute and severe rejection at postmortem examination (Table II).In conclusion, we believe that the method of protection of the donor heart that we have described, consisting of total body hypothermic perfusion of the donor, with added selective cooling of the heart with cold saline, and perfusion of the aortic root for a short period after approximately 50 minutes of anoxia, is a reasonable compromise and provides a good protection consistant with excellent cardiac performance in the critical period immediately post-transplantation.HISTOCOMPATIBILITY VS SURVIVAL TIME 200 2 150 0 = £ ® £100F © > > 5 S0F nm Inc, Ag: 0&1 283 iW in water, temporary cardiopulmonary bypass 1s instituted in the recipient (2 and 3), and the heart is removed by transecting the right atrium, ascending aorta, pulmonary arterv, and left atrium.The posterior walls of the atria with attached venae cava and pulmonary veins remain to permit attachment of the donor heart (4) (Figure 1).After the donor is given heparin the donor heart is excised and prepared by opening the posterior left atrium between the ostia of the pulmonary veins, ligating the superior vena cava.and incising * Paper presented at the Second world symposium on heart transplantation, Montreal, Canada, June 6-8, 1969.From the Cora and Webb Mading Department of Surgery, Baylor College of Medicine, and the Texas Heart Institute of St.Luke\u2019s and Texas Children\u2019s Hospitals, Houston, Texas.Supported in part by U.S.Public Health Grants (HE- 03137) (HE-05387) (HE-05435).it pd m0 / af ar \u2014 ea Figure 1 \u2014 Technique of cannulation for cardiac transplantation.Inferior caval catheter may be inserted through right atrium.(Inset) Portions of atria and great vessels remaining after excision of heart.Reprinted by permission from Cardiac transplantation for advanced acquired heart disease, Cooley, D.A., Bloodwell, R.D., and Hall- man, G.L., J.Cardiov.Surg.(Blalock Issue), 9 : 403-413, (Sept-Oct) 1968. Laval Médical bel Vol.41 -Fév.1970 idl Grady L.HALLMAN and Denton A.COOLEY Un des patients, un bébé de deux mois présentant un canal atrio- Is ventriculaire commun complet avec complication pulmonaire sévère, reçut ir une transplantation cardio-pulmonaire combinée à partir d\u2019un donneur por anencéphalique.Le cœur et les poumons du donneur furent excisés en bloc en divisant la tranchée, l\u2019aorte ascendante et les deux veines caves.Entre-temps le cœur et les poumons du receveur furent excisés en laissant ouvert la trachée et l\u2019aorte.Des rebords auriculaires furent préservés ily au niveau de chaque veine cave.Les nerfs phréniques furent également UT préservés sur des ponts de péricarde.Les poumons de l\u2019allogreffe furent introduits dans chaque cavité pleurale à travers les orifices du péricarde postérieur.Les anastomoses trachéales, aortiques et les veines caves furent effectuées au moyen de surjets.Ces deux techniques opératoires the right atrium from the inferior vena cava toward the right auricular appendage (Figure 2).This technique preserved the sino-auricular node and most of the internodal conduction pathways to the atrioventricular node (6, 7, 10 and 11).Neither perfusion nor hypothermia are used far the allo- graft (1 and 9).The donor heart is inserted by continuous suture anastomoses beginning at the lateral margins of the left atria (Figure 3) and progressing to the right atria.Adjacent septal margins of both atria are Figure 2 \u2014 Preparation of donor heart for transplantation.Incision in right atrium extends from inferior vena cava into appendage, avoiding S-A node.Left atrium opened posteriorly with incision connecting pulmonary veins.Reprinted by permission from Cardiac transplantation for advanced acquired heart disease, Cooley, D.A,, Bioodwell, R.D., and Haliman, G.L., J.Cardiov.Surg.(Blalock Issue), 9 : 403-413, (Sept-Oct) 1968, sont illustrées de huit schémas.attached to the recipient\u2019s atrial septum (Figure 4).The main pulmonary arteries and then the aortae are tailored and anastomosed, completing insertion (Figures 5 and 6).Following aspiration of intracardiac air with a needle and syringe, the aortic clamp is removed, and coronary flow restored.Cardiac action returns in either sinus rhythm or ventricular fibrillation (8).In case of the latter, conversion is accomplished with a direct current countershoek., At termination of cardiopulmonary Figure 3 \u2014 Donor heart reversed and placed in pericar- dial sac.Suture line begins at left border of left atria and is completed at atrial septum of recipient.Reprinted by permission from Cardiac transplantation for advanced acquied heart disease, Cooley, D.A., Bloodwell, R.D., and Hallman, G.L., J.Cardiov.Surg.(Blalock Issue), 9 : 403- 413, (Sept-Oct) 1968. Pump oxygenator Figure 7 \u2014 Diagram of operative technique for car- diopuimonary transplantation.Appearance after removal of recipient heart and lungs.Cut ends of trachea, aorta, and cuffs of atrium at each vena caval orifice.Venous return to pump-oxygenator through metal cannulae in cavae : arterial perfusion into ascending aorta.Phrenic nerves preserved on pedicles of pericardium.Reprinted by permission from Organ transplantation for advanced cardiopulmonary disease, Cooley, D.A., Bloodwell, R.D., Nora, J.J., McNamara, D.G.Leachman, R.D., and Hallman, G.L., Ann.Thorac.Surg., 8:30, 1969.REFERENCES I.Broobwern, R.D., Kip, J.N,, HALIMAN, G.L, BuUR- BETTER, W.J., McMURrrReEy, M., and CooLey, D.A.Cardiac valve replacement without coronary perfusion : clinical and laboratory observations, in Bruer, L.A., Ed., Prosthetic heart valves, Chapter 26, pp.397-418, Churles (.Thomas, Springfield, Ill, 1969.2.Coorry, D.A., BFALL, A.C., Jr., and Gro~pi~, P.Open heart operations with disposable oxygenators, 5 percent dextrose prime, and normothermia, Sur- gyery.52 : 713, 1962.3.Coorry, D.A, BEALL, À.C., Jr, and HALLMAN, G.L, Open heart surgery using disposable plastic oxy- genators, 5 percent dextrose for priming and maintenance of normothermia : experience with 1162 operations, Ann.Chir.Thorac.Cardiov., 4: 233, 1965.Laval Médical Vol.41- Fév.1970 Figure 8 \u2014 Diagram of operative technique for cardiopulmonary transplantation.After completion of tracheal and aortic anastomoses, venae cava approximated.Blood flow restored to donor heart when aortic clamp removed.Reprinted by permission from Organ transplantation for advanced cardiopulmonary disease, Cooley, D.A., Blood- well, R.D., Nora, J.J., McNamara, D.G., Leachman, R.D,, and Hallman, G.L., Ann.Thorac.Surg., 8:30, 1969.}.CooLky, D.A., BroonwELL, R.D, HALLMAN, G.L., and Nora, J.J., Transplantation of the human heart : report of four cases, J.A.M.A.205 : 479, 1968.7.CooLry, D.A., BuoonwrrL, R.D., Nora, J.J., McNa- MARA, D.G., LEACHMAN, R.D., and HALLMAN, G.L,, Organ transplantation for advanced cardiopulmonary disease, Ann.Thorac.Surg.\u2026 8: 30, 1969.d.Horsincer, J.W., Jr, WALLACE, A.G., and SEALY, W.C., The identification and surgical significance of the atrial internodal conduction tracts, Ann.Surg.167 : 447, 1968.James, T.N., The connecting pathways between the sinus node and A-V node and between right and left atrium in the human heart, Am.Heart.J., 66 : 498, 1963.S.Krars, A.S., Srrona, M.J, GirGIs, K.Z., and Gorp- STEIN, A, Jr, Observations during anesthesia for cardiac homotransplantation in ten patients, Anes thesiology.30 : 192, 1969.9.Lowrg, R.R., STorEr, R.C., HURLEY, E.S., Donc, E., Jr., Cox, R.B., and SHtrMwAY, N.E., Successful homotransplantation of the canine heart after anoxic preservation for 7 hours, Amer.J.Surg, 104 : 302, 1962.10.MFRIDETH, J., and Tires, J.L., The anatomic atrial connections between sinus and A-V node, Circule- tion.37 : 566, 1968.11.Tune, K.S.K., JAMEFs, T.N., ErFLER, D.B., and McCormack, L.J., Injury of the sinus node in open-heart poerations, J.Thorac.Cardiov.Surg.53 : 814, 1967.~2 W \u2018In UT \u201clt \u201c| MYOCARDIAL HYPOTHERMIA FOR CARDIAC TRANSPLANTATION * Edward B.STINSON, M.D., Eugene DONG, Jr., M.D.William W.ANGELL.M.D.and Norman E.SHUMWAY, M.D.7 CAE CAGE Z LE Quinze cents patients furent opérés par les auteurs pour remplacement valvulaire.Dans la moitié des cas, la seule méthode de préservation myocardique fut l\u2019hypothermie locale externe.L'hypothermie s'est avérée efficace et un retour de la fonction cardiaque fut observé dans tous les cas même après deux heures et demie d'arrêt anoxique.Expérimentalement, cette méthode fut vérifiée lors de transplantations cardiaques.Le cœur excisé est immergé dans un soluté salin à 4°C pendant 10 minutes.Après l\u2019anastomose des oreillettes, le cœur est de nouveau immergé au moyen d\u2019un cathéter intraventriculaire gauche passé par l\u2019auricule gauche.Grâce à cette méthode, la survie opératoire est de 90 pour cent.Le temps d\u2019anoxie myocardique était d\u2019environ 55 minutes.Des études élaborées, basées sur des mesures biochimiques et mécaniques démontrèrent qu\u2019un cœur normothermique reste viable en autant que la période d\u2019anoxie ne dépasse pas 30 a 40 minutes.A 24°C la période d\u2019anoxie peut atteindre 90 à 140 minutes et à 15°C le cœur peut reprendre sa fonction après un arrêt anoxique qui se prolonge pen- dant 180 à 280 minutes.INTRODUCTION It is apparent that various methods may be used satisfactorily for preservation of myocardial viability during clinical cardiac transplantation.These include coronary artery perfusion vie the aortic arch (2), localized myocardial hypothermia (7), and simple exposure of the graft to room temperature with rapid reestablishment of coronary eir- culation (4).For each method advantages and disadvantages have been proposed.In the absence of controlling data, we wish in this report simply to (suite du résumé en page suivante} present our technique and results of myocardial hypothermia in cardiac transplantation.That local myocardial hypothermia induced by surface cooling with isotonic saline is effective for short-term preservation of myocardial viability is attested by its successful clinical use in approximately 1,500 patients undergoing valve replacement or ventriculotomy at Stanford University Medical Center.In approximately half these cases hypothermia of the heart produced by surface cooling constituted the sole method of preservation; in the other half this was combined with selective low pressure perfusion of the left coronary artery.Periods of myocardial protection with hypothermia ab * Presented at the Second world symposium on car- - ; Pl diac transplantation, Montreal, Canada, June 6-8, 1969.alone have ranged up to 2.5 hours with full return ga = : : 0 v .» - * .y fi + From the Department of Surgery, Division of Car- of function.In no case in this clinical experience ait\u2019 | b diovascular Surgery, Stanford University Medicine, Stanford, California 94305.Supported in part by U.S.Public Health Service Grant HE-08696 and U.S.P.H.S.Research Grant FR 70, General Clinical Research Centers Branch.School of Reprint requests Division of Cardiovascular Surgery, Stanford University School of Medicine, Stanford California 94305 (Dr Stinson).has myocardial dysfunction related to inadequate protection during anoxia been identified.Laboratory experience: Myocardial protection obtained by hypothermia has contributed significantly to the success of 196 A Dn a) Laval Médical Vol.41- Fév.1970 STINSON, DONG, Jr., ANGELL and SHUMWAY L\u2019hypothermie locale externe fut employée comme méthode de préservation du myocarde au cours de 15 transplantations cardiaques chez 14 patients.Dix minutes de refroidissement par immersion furent pratiquées et après l\u2019'anastomose auriculaire gauche, le cœur fut de nouveau irrigué au moyen de soluté salin froid.L'ischémie myocardique dans les 15 cas fut en moyenne de 59 minutes.Dans tous les cas, un rythme sinusal fut obtenu lors de la réanimation.La fonction myocardique fut satisfaisante dans tous les cas sauf un.Dans ce cas particulier, on constate une hypotension et des arythmies ventriculaires récidivantes après l\u2019implantation d\u2019un cœur qui avait présenté un arrêt cardiaque pré-opératoire.Quoique cette technique soit suffisante pour le transfert d\u2019un cœur du donneur au receveur, des modifications additionnelles seront à l\u2019avenir nécessaires pour prolonger la conservation afin de pouvoir utiliser de façon efficace tous les organes possibles en vue d\u2019une transplantation.cardiac transplantation in the laboratory.Current techniques involve surface cooling of the hepari- nized donor heart immediately upon excision by immersion in saline at 4\u20146°C.After ten minutes an intramyocardial temperature of 6 \u201410° is attained.The heart is then removed from saline and implantation in the recipient accomplished by methods previously described (5).Following completion of the atrial anastomoses, the heart is again briefly cooled by irrigation of the left ventricle through an indwelling polyethylene tube placed through the left atrial appendage.Coronary circulation is reestablished following completion of the aortic and pulmonary artery anastomoses.In the past fifty consecutive cardiac homograft and autograft procedures performed in this laboratory, operative survival has been 90 per cent.The average myo- cardial anoxia time has been 55 minutes.Neither digitalis nor vasopressors have been employed: atrial pacing to maintain a heart rate greater than 120/beats/min.has been used, if necessary.In all subjects surviving operation cardiac output has been mildly to moderately depressed immediately following surgery, rising to normal levels within 48 to 72 hours postoperatively.In an attempt to define the relationships between preservation of organ viability, duration of anoxia, and mycoardial temperature during the anoxic interval, the following experiments were perform- ed (1).Ten donor hearts were stored in saline at each of three temperatures (37, 24 and 15°C) for variable periods of time.Following the anoxie interval, coronary cireulation was reestablished by perfusion of the aortic arch from the cannulated carotid artery of a second dog.Viability of the graft perfused in this manner by an intermediate host was assessed by observation of the cardiac rate, rhythm, and appearance, measurement of the strength of left ventricular contraction with the use of an intraventricular balloon, serial weights, measurement of serum lactic acid dehydrogenase, glutamic oxylacetie transaminase, and creatine phosphokinase levels in coronary sinus return, light microscopy, and electron microscopy.Orthotopic transplantation of five hearts from each of the subgroups served as the ultimate test of viability and provided confirmation of the validity of the other parameters listed as indices of viability.These experiments served to roughly define the allowable anoxic intervals for maintenance of organ viability at the given temperatures.Hearts stored at 37° remained viable for greater than 30 but less than 40 minutes, those at 24° remained viable for greater than 90 but less than 140 minutes, and those at 15° remained viable for greater than 180 but less than 280 minutes.The relationship of maximum duration of allowable cardiac anoxia to temperature is best expressed as a linear function of \u2014\u2014\u2014\u2014 Le mp \u2014 facil val tle lo pls J flan wie IA, le snif {lime dico il pré chez pa | Neal À aon Dans min | ant d santé cœur avenir er dé on, Laval Médical Vol.41 -Fév.1970 the logarithm of the temperature of storage.Two points derived from this relationship deserve emphasis.First, hearts remaining anoxic at greater than 37°C suffer rapid irreversible damage, and under the usual circumstances of organ procurement, cannot be transplanted successfully.Secondly, even moderate degrees of organ hypothermia significantly extend allowable anoxia time.Clinical experience: In the transplantation of 15 hearts in 14 patients local myocardial hypothermia has been employed as the sole method for organ protection.After full heparinization of the donor, the heart is excised and immediately immersed in saline at 4-6°C.Following a 10-minute period of initial cooling, during which time the atria and great vessels are prepared for anastomosis, the heart is removed from saline and the left atrial anastomosis begun.After completion of the left atrial anastomosis, the recipient pericardial well is irrigated continuously with saline at the same temperature to provide continued cooling of the dependent portions of the ventricles.Cooling is discontinued upon release of the aortic cross-clamp to reestablish coronary eir- culation.With this technique the myocardial is- chemia time in 15 cases has averaged 59 minutes (48 to 85 minutes).Tn all cases resuscitation of the graft and establishment of normal sinus rhythm was easily accomplished.In all but one instance immediate postoperative function was satisfactory.In patients with severe, long-standing pulmonary hypertension preoperatively, however, central venous pressure remained mildly to moderately elevated for 48 to 60 hours postoperatively, and myocardial support with digitalis and occasionally isoproterenol was employed.Signs of low cardiac output have been absent.In the one exception, immediate graft failure, including hypotension and recurrent ventricular ar- rhythmias, developed immediately following transplantation of the heart from a donor in whom ear- diac arrest had occurred preoperatively.Vigorous resuscitative measures, including intracardiac ad- MYOCARDIAL HYPOTHERMIA FOR CARDIAC TRANSPLANTATION 197 ministration of epinephrine, were required.In this case successful retransplantation was performed six hours following the initial procedure.Examination of the excised first graft showed a large hemorrhagic infarction in the upper portion of the muscular ventricular septum, thought to be caused by intramural injection of epinephrine.DISCUSSION The laboratory and elinical experience described here demonstrates that local myocardial hypothermia alone is satisfactory for short-term preservation of the heart.The limits of this technique are not well-defined, but have been extended to seven hours of hypothermic, anoxic cardiac arrest followed by successful orthotopic transplantation by Lower (6).The significant extension of allowable anoxia time by even moderate degrees of hypothermia is an important consideration in view of the usual circumstances surrounding transplantation.In our experience body temperature of organ donors has been maintained at 35-36°C to facilitate stable cardiovascular control.Myocardial temperature is further lowered by thoracotomy with exposure to room atmosphere and by ventilation with inspired gases at ambient temperatures.Simultaneous measurements of rectal and intramyocardial temperatures under open chest conditions in both dog and man have consistently demonstrated a temperature gradient producing myocardial temperatures 1-4°C less than general body temperature.Following excision of the donor heart, simple exposure to room atmosphere has resulted in an additional lowering of myocardial temperatures by approximately 3° over 30 minutes.These factors combine to produce a significant degree of moderate hypothermia in the heart which is not actively maintained at 87°C.The resulting extension of allowable anoxia time with maintenance of viability, as extrapolated from laboratory data, is approximately one hour (from 30\u201440 minutes to 80-100 minutes).Although this technique can easily accommodate the requirements for myocardial preservation in the eurrent clinical situation of transfer of graît from 198 a neurologically dead donor immediately to the recipient, additional modifications must be induced for prolonged storage because of persistent metabolic needs at organ temperatures above freezing (3).In the future such systems will become necessary for the efficient utilization of all available organ grafts.REFERENCES I.ANGELL, W.W., RIKKERSs, B.8., Doxg, E., Jr.and SHUMWAY, N.E., Organ viability with hypothermia, J.Thor.& Cardiovasc.Surg., in press.2.BARNARD, C.N.,, A human cardiac transplant: an interim report of a successful operation performed at Groote Schurr Hospital, Cape Town, South African M.J., 41 : 1271, 1967.STINSON, DONG, Jr., ANGELL and SHUMWAY 2 = va ~2 Laval Médical Vol.41 -Fév.1970 .BrocH, J.H., MANAX, W., G., Exar, Z.,, and LILLEHEI, R.C., Heart preservation in vitro with hyperbaric oxygenation and hypothermia, J.Thor.& Cardio- vasc.Surg., 48 : 969, 1964.Coorkry, D.A.HALLMAN, G.L., BroonwErL, R.D.Nora, J.J., and LEACHMAN, R.D., Human heart transplantation, Experience with twelve cases, Am.J.Cardiol., 22 : 804, 1968.LowER, R.R., and SHvmway, N.E., Studies on ortho- topic homotransplantation of the canine heart, Surgy.Forum, 11 : 18, 1960.Lower, R.R., Srorrr, R.C., HurLEY, E.J., Donc, E., Jr, Coux, R.B., and SHUMwAaYy, N.E., Successful homotransplantation of the canine heart after anoxic preservation for seven hours, Am.J.Surgery.104 : 302, 1962.SrINsox, E.B., Donc, E., Jr, IBEN, À.B., and Suuvm- way, N.E., Cardiac transplantation in man.III.Surgical aspects, Am.J.of Surgery.in press.M0 #1 STORAGE OF THE ISOLATED HEART * isi | | E.PROCTOR an bev | sl | En parvenant à entreposer un cœur isolé, on gagne du temps pour le nr; transport du cœur, pour pratiquer une opération élective, pour choisir le à ter receveur immunologiquement le plus compétent, pour obtenir l'anonymat | du cœur et ainsi éviter une publicité indésirable.De plus, il est possible a | que par cette méthode l\u2019on puisse ranimer un cœur endommagé par une esti fll anoxie ante mortem.nl Si le temps prévu pour le transport n\u2019excède pas une heure et demie, a le cœur peut être immergé, refroidi et transporté dans un sac de plastique contenant de la glace.pu Pour la préservation à long terme, jusqu'à 72 heures, une réanima- ' tion satisfaisante a été obtenue par une perfusion avec un soluté de Krebs 5 modifié.La faible pression oncotique fut corrigée par l\u2019addition de Dex- tran a 0,6 pour cent et par une basse pression de perfusion (20 cm d\u2019eau).Le système complet est placé dans un réfrigérateur à 5°C.Les cœurs ainsi traités furent vérifiés quant à leur performance mécanique, leur activité électrique et au point de vue microscopie électronique.Ces cœurs The essential gain from storing the isolated heart is time.1.Time to transport the heart from donor to recipient.2.Time to do an elective operation; this is even more important with the heart than the kidney due to the complexities of cardiopulmonary bypass and the larger number of staff involved.3.Time to tissue-type the heart and find the best recipient, instead of having a typed terminal recipient and hoping that the heart is suitable, 4 Time to gain anonymity of the heart and thus reduce much of the undesirable publicity that elings to this field.5.Time, one hopes, to resuscitate a heart too damaged by ante-mortem changes to transplant immediately .Realistic methods of preserving the heart (1) have included 1) metabolic inhibitors; 2) hypo- * Presented at the Second world symposium on heart transplantation, Montreal, Canada, June 6-8, 1969.1.Thoracic Research Unit, Guy\u2019s Hospital, London, S.E.1.England.(suite du résumé en page suivante) thermia ; 3) hyperbaria ; 4) \u2018supercooling\u2019; 5) perfusion \u2014 either normothermic or with elements of 1-4.The chosen method of storage depends upon the requirements \u2014 if all that is need is to transport a heart from one hospital to another within a city, with a travelling range of up to an hour and a half, then flush-cooling the heart with a water- based physiological solution at 5°C.followed by packing it in a plastic bag in ice for transport, should be adequate; we have satisfied ourselves of the reliability of this procedure by experimental orthotopic transplantation.On the other hand, if a period of storage of 24 hours or more is required, then, for all practical purposes hypothermic perfusion offers the most consistent results.\u2018Super- cooling\u2019 with glyeerol or dimethyl sulproxide \u2014 so successful with blood and semen \u2014 could be the method of the distant future, but currently the results with organs are disappointing.Our own method of storing hearts in a viable condition for up to 72 hours (2), uses a modified Krebs\u2019 solution (containing one quarter of calcium concentration ; insulin 15 units/litre ; hydrocortisone Laval Médical Vol, 41- Fév.1970 E.PROCTOR furent comparés à des cœurs de contrôle isolés et non préservés.La résistance vasculaire coronarienne semble être l\u2019indice le plus sûr quant à la possibilité de la performance future.Une augmentation de 60 pour cent de la résistance coronarienne après 10 minutes de perfusion par rapport à la résistance coronarienne initiale dénote une diminution de la viabilité.Cette méthode permet d'envisager l\u2019établissement d\u2019une banque cardiaque avec des réfrigérateurs de grande capacité dans lesquels seraient placés des modules isolés de perfusion.Un tel module est capable de préserver un cœur pendant dix heures sous sa forme portative, après quoi, en plaçant le module dans un grand réfrigérateur et en le branchant au réseau d'électricité, il devient ainsi une unité de la banque.La viabilité de ces cœurs reste connue à tout instant par la mesure de la résistance coronarienne.40 mg/litre; and procaine HCI 0.013 per cent) and hearts are to be stored at the same time, as in a \u2018heart-bank\u2019.on-line filtration with eight micron pore size cellulose filters.The lack of oncotie pressure is offset by the addition of 0.6 per cent dextran (70,000 m.w.), and a low (20 em H:0) perfusing pressure.Normal pH, pCO», and pO, are maintained with a 97/3 per cent oxygen/carbon dioxide gas mixture.The whole apparatus is placed within a refrigerator at 5°.Figure 1 shows three such systems photographed through the inner transparent door of a large refrigerator.The pots act as reservoirs, filters, and oxygenators, thus considerably simplifying the apparatus \u2014 an essential feature if a number of Figure 2 \u2014 Insulated portable container for transport of Figure 1 \u2014 Shows three small hearts being perfused with separate perfusion systems within a large refrigerator.The 8 micron cellulose filters are bolted to the bottom of the reservoir pots.Flowmeters measure gas and perfusate flow.hearts (10 hour travelling capacity).Contains 350 g.greyhound heart.Cooling blocks of 10% potassium chloride maintain temperature of 5°C, and battery drives perfusion pump.Gas cylinder at rear.Proposed basic module for « heart-bank»\u201d system (see text).Lary ; Ua Laval Médical Vol.41- Fév.1970 Due to using several hearts at a time, we have, for convenience, tested the majority of them on the arterio-venous circulation of larger dogs.They are STORAGE OF THE ISOLATED HEART 201 à patient was dead or not on the basis of the EEG, since few would dispute cerebral death after this period of unheparinised circulatory arrest.assessed for viability by mechanical performance; .\u201cy .>.electrical activity; electron microscopy; and by \u2018Heart bank\u201d: comparison with control isolated hearts that have .Based on the above long term storage system one not, been stored.; 21 ; LL 4 © 21, can envisage a \u2018heart-bank\u2019 as consisting of a large Viability during storage is difficult to assess, but, .CL , .ical end 11 refrigerator containing a number of self-contained empirica we find that the coronary vascular .; .P Ys .i i y perfusion modules of the type shown in Figure 2.resistance (CR) is the most reliable guide to future .; .\\ | ; : ; This battery powered system is capable, in the first performance.Values vary with different perfusates, but, with the above solution the final CR should not be more than 60 per cent greater than the initial CR instance, of supporting a heart for ten hours in the portable mode, after which, by insertion into ; A = ; a large refrigerator and switching to main electrie- after ten minutes of perfusion; higher values reflect \u2026 .sq A | Lu oo 1 ity it becomes a unit of the \u2018bank\u2019.Tissue-typing decreasing viability.Additionally, when conditions are standardised, we find that the initial CR becomes a measure of pre-existing damage.This may is done during this period, and when the correct recipient is located and prepared, the module becomes portable again and is transferred to the thea- become a useful parameter when techniques are .Ce .\u2018 ! 4 tre, its viability known at all times from the CR.developed for resuscitating hearts too damaged by ante-mortem changes to transplant immediately.If one could resuscitate a basically good heart that REFERENCES had been arrested for 30-40 minutes in an un- ; .J.HumpHRIES, À.L, Organ preservation :@ a review, heparinised body, not only would the number of Transplantation, 5: 1138, 1967.hearts available for transplantation be increased, Procror, E.Preservation of isolated hearts for 72 but it.would avoid the ethical problem of whether hours, Brit, Med.J.4: 296, 1968. biral fol AL EVALUATION OF THE CONDITION Thon OF THE ISOLATED HEART DURING PRESERVATION * ,Ç L It S.PITZELE, S.SZE, N.LAUZON, A.R.C.DOBELL and L.D.MACLEAN ; ANS el L'énergie myocardique est dérivée de la transformation d\u2019ATP en \u201d ADP.Grâce à des processus oxydatifs, cette réaction est suivie de la resynthèse d\u2019ATP.Une capacité contractile élevée sera en rapport avec feux un taux élevé d\u2019ATP, provenant d'une déplétion progressive du liquide Aig extracellulaire en phosphate inorganique.A l\u2019inverse, un faible niveau de | Tiny contractilité ira de pair avec une élévation des phosphates inorganiques.en Cette hypothèse de travail fut vérifiée chez le chien et une relation inverse | ,Ç | 2 z .: .dll fut démontrée entre la concentration en phosphates inorganiques dans le \u2026 liquide de perfusion et la capacité contractile du cœur.Expérimentale- ul ment, aprés 20 heures de perfusion au moyen de plasma, le phosphate ll inorganique total montre une élévation importante et irréversible et ce malgré l\u2019administration de calcium.L\u2019électrocardiogramme est normal, le ceeur n'est pas dilaté et cependant ce cceur est incapable d\u2019effectuer du travail mécanique.Ces dosages de phosphate sont faciles et rapides n a effectuer et peuvent présenter un intérét pour I'évaluation du ceeur lui- bn même et pour l\u2019évaluation des liquides de perfusion expérimentaux.Successful heart storage demands the delivery of + 5 PLASMA a heart that will immediately and totally support +10 Î e BLOOD the recipient\u2019s circulation.\u2018ol \\ ni The experience gained during prolonged storage ve \\ by © experiments using hypothermic perfusion techni- 7 \\ ques (1 and 2) have shown that the mechanical 1° pe .ro .+ 6 function of the ventricular myocardium can be \\ + 5 altered or even disappear completely even though _ ' a ° ; ë the general appearance of the heart, the regularity £ ** N of its rhythm and the ECG tracing remain satis- 4 *3 > i factory.+2 °e | | A These observations underline the need for a test +1 o No .> .N directly related to the mechanical function of the 04 ve q .I myocardium that can be monitored during the ol Be v : ++, | storage period._2 Se I 00e.; | - 3 v T T T T o 10 20 3 y > I > * Presented at the Second world symposium on heart 0% om 80 90 100 HO 20 transplantation, Montreal, Canada, June 6-8, 1969.LS 9 } From the Department of Experimental Surgery, McGill Figure 1 \u2014 Relationship between total inorganic phos- | University.phorus (Pi) and left ventricular pressure in 5 perfused 1 3 Supported by the Medical Research Council of Canada, hearts.Pi values on the ordinate are expressed in terms | 3 the Canadian Heart Foundation and the John A.Hart- of positive or negative differences in relation to the initial hs 3 ford Foundation.value at the start of perfusion.Ry (LEAS Po de I i: ide al & odes.| verse ans fale shee of oma.aol api qu ; LFA Laval Médical Vol.41 - Fév.1970 Theoretical basis: The mechanical energy of the heart muscle is derived from uncoupling of high energy phosphate bonds from adenosine triphosphate (ATP) yielding ADP and inorganie phosphate followed by re- synthesis of ATP as a result of oxidative processes.Every level of contractility corresponds to a given turnover rate of inorganic phosphorus in the eycle.A higher level of contractility will draw an additional amount of inorganic phosphorus (Pi) into the high energy pool and thus decrease the total amount of inorganic phosphorus in the extracellular fluid and perfusate.A lower level of contractility will have the opposite effect.CONDITION OF THE ISOLATED HEART DURING PRESERVATION 203 Experimental technique and results: 50 to 65 lbs.were removed extrapericardially and perfused at Five hearts from dogs weighing 26°- 28° ©.through the aortie areh, first with he- parinized blood, then with pooled filtered plasma.A left intraventricular balloon was inserted for measurement of left ventricular pressures (LVD).Variable levels of contractile activity were achieved either by stimulating the myocardium with caleium, or depressing it with pronestyl, potassium chloride or anoxia.Total circulating inorganic phosphorus was measured during steady state periods by the method of Taussky and Shore (3).The results illustrated graphically in Figure 1 to x ono\u201d UPTAKE 1-8 tmnt\u201d tec/mia.) 1-0 304 28 4 0er 100 Quai rora 2¢ INCARBONATE (meq /L) 24) mommy 0 mally ew est rare 221 _ a du.ei\" \u20144 a a Bard parka 100 ce fentro.Fa ! moe Steed pork «40 ocfun bd i I ! Ut i + 104 ; i Rist ll i Ll il) T=24°C To26C T 226°C + 84 + 61 aR (mq) / + 44 ssdaad [) + 24 \u201cNex Ov-One gumiye= © PLASMA © BLOOD 0« ET 6 3 4 e & © 12 14 06 18 20 22 24 +1 +2 +3 TIME (HOURS) Figure 2 \u2014 Variation of total Pi level, total bicarbonate concentration and O, uptake during preservation of a heart from a 57-ib dog.7 204 verify the existence of an inverse relationship between total inorganic phosphorus in the perfusate and the contractile ability of the heart.An inerease in total Pi is associated with a decrease and, in extreme cases, with an almost complete disappearance of the left ventricular ability to develop pressure.The results also show that the same hearts will develop a higher pressure and keep a better contractile function with blood perfusion rather than with plasma.Two of the five hearts tested behaved as well with plasma as with blood but it took comparatively larger doses of calcium to achieve this level of performance.Figure 2 shows the changes in circulating inorganic phosphorus during a long-term perfusion with blood and plasma.After the twentieth hour of plasma perfusion, total Pi showed a significant rise that became even more pronounced despite administration of caleium.Towards the end of the perfusion, the heart was not visibly enlarged and the electrocardiogram was regular, yet it was incapable of performing mechanical work.S.PITZELE, S.SZE, N.LAUZON, À.R.C.DOBELL and L.D.MACLEAN Laval Médical Vol.41- Fév, 1970 SUMMARY Evidence has been presented that the variations in inorganie phosphorus in the cireulating per- fusate are related to the mechanical capacity of a perfused heart.The measurement is rapid and straigthforward and may be of value in evaluating the heart itself and the adequacy of various experimental perfusates.REFERENCES {.PrrzELE, S., CHARRETTE, E.J.P., DoBELL, A.R.C., and MacLean, L.D., Method and apparatus for functional evaluation of isolated hearts, Surgery, 64 : 308-314, 1968.2.PrrzELE, S., and DoBELL, A.R.C., Functional evaluation of the isolated heart at normothermia and following 8-hour preservation at 30° C., in Organ perfusion and preservation, Appleton-Century-Crofts, New York, 1968, pp.513-525.el 3.Taussky, H.H., and SHorr, E., À micro-colorimetrie method for the determination of inorganic phosphorus, J.Biol.Chem., 202 : 675-685, 1953.PER (iio À 1 PERFUSION OF THE GRAFT DURING HEART TRANSPLANTATION * nitions | i | | vol 4 | C.CABROL, A.CABROL, G.GUIRAUDON, A.ZAFY, P.LE PICARD, S.MATTEI and J.LUCIANI t Ig pr if nif ; ; : CU La transplantation cardiaque ne semble plus poser de problèmes quant à la préservation de la viabilité du cœur du donneur.Cependant, dans l\u2019expérimentation animale, on a observé une mortalité assez élevée.En vue de réduire la mortalité et d'obtenir beaucoup plus d'animaux pour l\u2019étude du rejet et de son traitement, plusieurs techniques de préservation myocardique ont été utilisées.Trois méthodes furent employées : 1.Aucune protection myocardique ; 2.Après excision, immersion du cœur pendant 10 minutes dans du soluté salin à 4° C ; 3.Après excision, perfusion du cœur avec du sang oxygéné.Résultats Avec la première méthode, les résultats étaient très médiocres.La cause principale de la mort était la défaillance myocardique aiguë.Les contractions du cœur greffé restaient faibles, irrégulières, malgré l\u2019utilisation d\u2019une pompe de soutien, l\u2019utilisation de cardiotoniques et de natn: J hs qu for fun rh Bi: ratio ÿ dolor a pelt cpl, ariel pie J } vasopresseurs.Preservation of the donor heart viability during clinical transplantation seems to be no longer a problem.Successful cases have been reported in which various methods were used, including no myocardial protection at all.However, in animal experimentation this problem remains important and in our experience high immediate mortality following orthotopic heart homotransplantation in dogs was mainly due to acute myocardial failure in relation with poor preservation of the graft.In order to reduce the mortality and to obtain more animals for the study of early recognition and adequate treatment of rejection which is now the major concern in clinical heart transplantation, several technics of myocardial preservation were investigated.* Paper presented at the Second world symposium on heart transplantation, June 6-8, 1969.+ Division de chirurgie thoracique, Service N° 8, Hôpital de la Pitié, boulevard de l\u2019Hôpital, Paris XIIT°, France.(suite du résumé en page suivante) Material: Orthotopic heart homotransplantation was performed on 84 mongrel dogs weighing between 18 and 24 kilograms using an equal number of heart donors with the same characteristics.In the recipient animal the heart was exposed through a right lateral thoracotomy in the fourth intercostal space.Cardiopulmonary bypass was instituted between the two ven® cave (cannulated by way of the right femoral and external jugular veins) and the right femoral artery.General hypothermia (30°C) was induced.The ventricles were excised leaving the entire atrial cavities and the proximal aorta and pulmonary artery.In the donor, the heart was exposed through the same incision, fibrillated and exeised without any special preparation, by division of the vena cava and the pulmonary veins at their respective atrial junetions and by division of the pulmonary artery at the level of its bifurcation and the aorta after the innominate artery.A left ventricular vent was 206 C.CABROL et al, Laval Médical i bird Vol, 41-Fév.1970 Pd i Avec le refroidissement local, la fonction myocardique n\u2019apparait at guère meilleure, bien que les complications (hémorragie, perfusion mé- | fi diocre et insuffisance respiratoire) aient été moins fréquentes que lors- 0 qu\u2019aucune protection n\u2019était assurée.Dans les cas où l\u2019on utilisa une perfusion, l'activité cardiaque, après retrait de la pince aortique, était certainement meilleure.Le cœur restait rose, et non dilaté.La fibrillation ventriculaire active était transformée ; en rythme sinusal, à l\u2019aide d\u2019un seul choc électrique, et les contractions oe cardiaques étaient nettement vigoureuses et régulieres.Dans certains | i cas cependant, on observa une réponse myocardique médiocre, en rela- j tion avec une perfusion insuffisante de la greffe.Cette complication fut | éliminée en maintenant un bon remplissage de l\u2019aorte ascendante.En | fon \u2018 ler bs f im tea yas .; , ; 00] vue d'éviter une pression excessive dans le lit vasculaire coronarien, on tu utilisa une ligne de perfusion reliée à la pompe.La pression dans la ligne hr n\u2018excéde jamais les 100 cm d\u2019eau.Le cathéter de perfusion introduit isl dans l\u2019artère innominée doit être suffisamment gros pour assurer un flot LE me capable de fermer la valve aortique, qui peut être occasionnellement | lent ouverte durant les manipulations du cœur.: ; z , ., ; i | MN | En résumé, on peut dire que dans l'homo-transplantation cardiaque | a .2 ; eu orthotopique chez les chiens, les meilleurs résultats sont obtenus lorsqu'on l 5 perfuse le cœur.Le cœur du chien est très sensible a I'anoxie.Lt ) ing ; vent inserted through the left appendage.Anastomoses way of the innominate artery.Perfusion was stop- were carried out in the following sequence: left ped during the aortic anastomosis (Figures 1, 2 atrium, interatrial septum, right atrium, pulmonary and 3).| artery, aorta.After removing of the aortic clamp, | body temperature was raised to 35°C and ventri- Results: | cular fibrillation was reverted to normal rhythm .; ; | CC - \u2018 y When no protection of the graft was used the | with a direct current countershock.Two pace- | .; n ; results were very poor (Figure 1).Except various maker wires were sewn on the right ventricule and .; _ > other complications (hemorrhage, inadequate per- cardiopulmonary bypass discontinued as soon as 1e ue .he 1 ' | | 1 fusion, defective lung function) the main cause of H the heart appeared able to maintain arterial anc , - 1 6e | Art appes \u2018 | Le I Ti N \u2018 death (30 per cent) was acute myocardial failure.| venous pressures at normal levels.1e catheters .; .p \u2018 \u2019 0 Contractions of the grafted heart remained weak A were removed and the chest closed with bilateral ig | | ; .and irregular in spite of further pump assistance i underwater tube drainage.| Concerning the management of the graft during implantation three methods were employed.In 14 dogs no cardiac protection was used and 3 \u20ac the anastomoses were done on an anoxic heart.© VARIOUS COMPLICATIONS 36 % Z, EE E \u20ac Z Z In 20 dogs immediately after excision the heart ACUTE MYOCARDIAI was immersed in cold saline at 4° C for ten minutes ) su FAILURE ( 7 then sutured.In some cases after completion of the left atrial anastomosis the left ventricular vent was used for cold saline irrigation of the left heart.In 50 animals we started after its excision a perfusion of the graft with oxygenated blood by the SURVIVAL (2) 4% \" ANOXIC \" GRAFTS ( 14 dogs ) Figure 1 \u2014 Results with \u201canoxic\u201d grafts (14 dogs).og \u201cdin } If pari J Jos sp es img: | dos 9 fair | 18 on fi | TN ge ott mi 3 amet ik § que le | oh Laval Médical Vol.41- Fév.1970 and the use of cardiotonic and vasopressive drugs (Figure 4).With local cooling (Figure 2) myoéardial fune- tion of the transplant did not appear mueh better (Figure 5) although other complication were less frequent certainly due to increased technical experience.In cases where we employed perfusion of the graft (Figure 3), cardiac activity after removal of the aortic clamp was definitively better.The heart remained pink and not dilated.Active ventricular fibrillation readily reverted to sinus rhythm with a single counter shock and cardiac contraction were immediately vigorous and regular.Although the heart was still in bypass systolic peaks were often seen on the arterial pressure tracing.The by-pass could be easily discontinued with prompt restoration of a normal circulatory function without any drug support (Figure 6).In some cases (13 per cent) however we did observe the same poor myo- VARIOUS COMPLICATIONS # ACUTE MYOCARDIAL FAILURE / 10 } SURVIVAL (5) 25 % CUOLING OF THE GRAFT ( 20 dogs ) Figure 2 \u2014 Results with cooling of the heart (20 dogs).32 % PERFUSION OF THE GRAFT SURVIVAL (27) 54 7 ACUTE MYOCARDIAL FAILURE (7) 14 ( 50 dogs } Figure 3 \u2014 Results with perfusion of the heart (50 dogs).PERFUSION OF THE GRAFT DURING HEART TRANSPLANTATION 207 PRE OP.POST.OP.DOG 435, NO PRESERVATION OF THE GRAFT Figure 4 \u2014 L 1: Lead one of the electrocardiogram.\u2014 AP: Arterial pressure (femoral artery) before and after homotransplantation.No protection of the graft.AP AVF PRE OP.AFTER TRANSPLANTATION POST, OP.DOG v86 COOLING OF THE GRAFT Figure 5 \u2014 AP: Arterial pressure (femoral artery) and electrocardiogram (AVF) before, immediately after and six hours after homotransplantation.Protection of the graft by local hypothermia.AVF PRE OP.AFTER TRANSPLANTATION POST.OP.DOG 691, PERFUSION OF THF GRAFT Figure 6 \u2014 AP : Arterial pressure (femoral artery) and electrocardiogram (AVF) before, immediately after and six hours after homotransplantation.Protection of the graft by perfusion. 208 cardial response we have seen in the two previously described methods.This was almost invariably due to inadequate graft perfusion.To obviate this complication it is necessary to maintain a good filling of the ascending aorta.That can be easily appreciated by the palpating finger.But on the other hand we must avoid excessive pressure in the coronary vascular bed.For this purpose we used the same method we have always employed in our eli- nical coronary perfusion (Figure 7).The perfusion line is branched directly on the arterial line after the pump.The pressure which never exceed 100 em of water is easily monitored with the help of a serew clamp and a simple manometric tube.Moreover the perfusion catheter inserted in the in- nominate artery must be large enough to insure a Figure 7 \u2014 Extra-corporeal circuit and manometric tube used in heart homotransplantation.G : heart transplant O : oxygenator R : reservoir P : pump C.CABROL et al.Laval Médical Vol.41- Fév.1970 high flow capable to close promptly the aortic valve which can be occasionally opened during cardiac handling.Discussion: The present study convinced us that the perfusion of the heart is the best way to prevent myo- cardial damage during cardiac transplantation.This is specially important in dogs because of the peculiar sensibility of the canine heart to anoxia.This is also true in human transplantation although the human heart can tolerate longer ischemic periods.Judging also from our clinical experience with operations on the aortic valve, perfusion of the myocardium appears to be a more physiologic and safer approach to the problem of cardiac preservation.It gives the best chance to provide the recipient patient with a functionally sound organ and relieves the transplant team of the necessity for extreme speed in connecting the graft to the recipient\u2019s blood vessels.SUMMARY In order to obtain acceptable survival rate after orthotopic heart homotransplantation in dogs several methods of graft protection during implantation were investigated on 84 animals.Continuous perfusion of the transplant although it represents a more complicated method than simple anoxia or local hypothermia is certainly the safest technique at the present time.A Jie lay Try A PROPOS DE LA CONSERVATION DES ORGANES * Jean-Paul BINET t L\u2019auteur rapporte 25 expériences pour mettre au point une technique d\u2019autoperfusion de l\u2019ensemble cœur-poumons prélevé chez le chien.Le 9 cœur, les poumons et la trachée sont prélevés en bloc avant la mort de l\u2019animal, donc sans ischémie, et raccordés d\u2019une part à un réservoir contenant du sang et, d\u2019autre part, par la trachée, à un appareil « respirateur » a pression positive.La plus longue conservation de cette autoperfusion atteint 18 heures.L\u2019œdème pulmonaire qui survient en général entre la (uit septième et la dixième heure empêche la poursuite de l'expérience.De vu.nombreux paramètres hémodynamiques et humoraux ont été étudiés au cours de ces perfusions.Ce travail doit permettre d\u2019étudier les constantes de base de la conservation de l\u2019ensemble cœur-poumons, par une technique relativement simple.À propos de la discussion en cours, je viens rapporter l\u2019expérimentation faite à l\u2019hôpital Marie- Lannelongue (129, rue de Tolbiac, Paris XIII¢) par mes collaborateurs, M.Weiss, A.Brunet, A.M.De Groote, A.Pellet et C.Planche.Cette expérimentation a pu être faite avec le concours de l'INSERM et de la DGRST.Il s\u2019agit de la conservation «à court terme » du bloc cœur-poumons par autoperfusion.Vingt-cinq expériences ont été faites pour mettre dans les diverses cavités cardiaques et les gros vaisseaux, volume sanguin, débit : b) Les paramètres humorauæ: équilibre acido- basique, glycémie, lactate, potassium.Dernièrement, la possibilité de régler un débit d'apport à l\u2019oreillette droite a permis d'étudier les performances de la fonction cardiaque a différents débits.Toutes ces études ont été faites avant d\u2019essayer la transplantation.La plus longue conservation avec bonne fonetion au point une technique d\u2019autoperfusion de l\u2019ensem- à atteint dix-huit heures.Cependant.mises à part ble cœur-poumons prélevé chez le chien.Le bloc les premières expérimentations du débit, entachées Ih cœur-poumons-trachée est prélevé en bloc avant la d'erreurs techniques, elles ne semblent pas, en pi f mort de l\u2019animal (done, sans ischémie) et raccordé, MOYENNé, pouvoir dépasser douze heures.C\u2019est i | d\u2019une part, à un réservoir contenant 500 ml de sang l\u2019ædème pulmonaire qui survient en général entre homologue, d\u2019autre part.par la trachée à un appareil «respirateur » à pression positive.Les poumons sont régulièrement insuffiés, la température de l\u2019ensemble étant abaissée à 29°C.De nombreux paramètres ont été suivis de façon permanente pendant la durée de l\u2019expérimentation ; a) Les paramètres hémodynamiques: pression * Communication au Deuxième symposium mondial sur la transplantation cardiaque, Montréal, 6-8 juin, 1969.+ 3, rue Christophe-Colomb, Paris VIII, la septième et la douzième heures qui empêche la poursuite de l\u2019expérimentation.Ce travail doit permettre d\u2019étudier les constantes de base de la conservation de l\u2019ensemble cœur-poumons par une technique relativement simple.Les efforts devront être poursuivis concernant les variables, les températures de débit.la pression, la composition du sang.ainsi que les modifications de la pression de la pompe.Mais, en fait, seules la réimplantation orthotopique du poumon.hétéro ou orthotopique du cœur, permettront de tester la viabilité des organes conservés, ABOUT PERFUSIONAL METHOD OF ISOLATED HEART PRESERVATION ir War BEFORE ITS TRANSPLANTATION * aol Alexandr A.VISHNEVSKY and Vladimir F.PORTNOY, i Moscow, USSR.ih arte \\ Les auteurs décrivent une methode réduisant au minimum la période d\u2019ischémie myocardique du donneur avant que sa circulation ne soit rétablie.Après l'exposition du cœur, des canules sont introduites dans l\u2019aorte ascendante, l'oreillette droite et le ventricule gauche.Après quoi, on commence la perfusion des coronaires.À ce moment, le cœur est excisé.Le cœur est prélevé, toutes ses cavités étant fermées.La perfusion d\u2019un tel cœur humain pendant une période de sept heures, fut observée à l\u2019aide d\u2019une circulation extracorporelle, tout en maintenant en activité cardiaque électrique et une pression partielle d'oxygène avec un maximum de 200 mm Hg.Avec cette technique on peut préserver un coeur avant sa trans- plantation.In this report will be discussed one particular moment of the heart transplantation problem, which we think is of some interest.This is how to bring to a minimum the period of myocardial ischemia of a donor\u2019s heart before its circulation is finally restored in the recipient\u2019s organism, The perfusion techniques of the isolated heart during implantation, as is generally known, has its advocates: professor Hardy (1964), professor Bernard (1967) and some others of our colleagues.The first transplantation of the heart from one dog to another was performed in USSR in 1940 by V.Demichov, his experiments being well known in the world.We have devised in experiment and used in the clinical observation the technique of organ perfusion in order to preserve the heart during the period of its excision, transportation to recipient and some waiting before the recipient is prepared.After exposure of the donor\u2019s heart.catheters * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969, were introduced into ascending aorta, right atria and left ventricle.Then the coronary perfusion began.The heart is excised under the continuing perfusion (Figure 1).In the clinical observation we took the heart out with closed cavities; the vessels were ligated before excision, In experiment the same was done without ligation of vessels.Then, the isolated heart, placed into the cuvette, was well supplied with blood (Figure 2).We used a special reduced model of an apparatus Figure 1 \u2014 Excision of the heart under continuing perfusion ; Fay 1 tiny Balt td ne as oi ee et A CE te re a re HM IRL TLL RC IO RL UGH SR aa dhe Laval Médical PERFUSIONAL METHOD OF ISOLATED HEART PRESERVATION 211 Vol.41- Fév.1970 for artificial circulation (Figure 3).Our preliminary experiments have shown that it is possible to avoid myocardial damage for two to three hours, if we keep the blood pressure at a level of about w 60 mm He; the temperature at 36° C; the pOs of | arterial blood at no more than 200 mm He.Naturally, it is desirable that the period of isolated perfusion of the heart, out of the organism, @ must not be too prolonged.JE voi, 0 cisé, Le Figure 4 \u2014 Connection of the small apparatus for isolated d'un la organ perfusion (B) to the apparatus for extracorporal à li circulation (A).rogue de 2 a larÿ After the apparatus for extracorporal circulation of the recipient was on operation the small apparatus for isolated organ perfusion was connected with it (Figure 4).1e In these conditions professor Shumway\u2019s method gite of heart transplantation worked well.pins We have an interesting observation concerning a T-hours perfusion of animated human heart with- ant out its transplantation.In that experiment a steady 1b coronary circulation was maintained as well as a sith certain level of Ou consumption and electrical activ- itv of the heart.a With this technique we performed the trans- | plantation of the heart from one woman to another pur in November 1968.The patient lived during 33 hours and died from right ventricle insufficiency.© x We think that with good reason we can consider \u2018 perfusional technique for myocardial preservation Figure 3 \u2014 Reduced model of an apparatus for artificial circulation.À : pressure stabiliser ; B : heat exchanger ; | ; C : oxygenator ; D : circulation pump.method for practical purposes.before transplantation is a highly perspective RSH ph la pT | | GENETICS OF THE HL-A SYSTEM * | J.DAUSSET and J.COLOMBANI Durant les dernières années, on opéra un progrès rapide dans la connaissance et la compréhension de la génétique du système HL-A.Deux séries d'antigènes furent décrites et les antigènes de chaque série se comportent \u2014 au moins dans une population causasienne \u2014 comme allèles mutuellement exclusifs, situés sur deux sub-loci rapprochés.Dans | ce travail, de nouvelles données concernant les antigènes Da6 et Da9 (6b) sont présentées avec l\u2019hypothèse que ceux-ci appartiennent également au deuxième sub-locus.Cette étude fut menée chez 83 familles ayant 246 enfants.Les conclusions qui en découlent amènent l\u2019hypothèse que les deux antigènes Da6 et Da9 (6b) appartiennent ou sont extrêmement apparentés au deuxième sub-locus du système HL-A.L'étude des phénotypes de 312 individus de race caucasienne montre que lorsque l\u2019antigène HL-A5 est présent, l\u2019antigène Da6 est également i présent.De même lorsque l\u2019antigène HL-A7 est présent l\u2019antigène Da9 il: The HT-A system is in man analogous to the H2 In this paper new data concerning the antigens Le system in mouse and to all the other main histo- Da6 and Da9 (6P) are presented with the hypo- ! \u201d compatibility systems which have been described thesis that they also belong to the second sub-locus.| du in many species.Its importance in human histo- New family studies have been made which make it I compatibility is now well documented between rela- possible to increase the number of genotypes and ai tives.The relationship between HL-A groups and haplotypes genetically deducted.x graft survivals in non related pairs is now also u established, but for a long time it was not obvious MATERIAL AND METHODS TW because of the extreme complexity of the HL-A svstem and of the fact that many of the antigens Eighty-three families with 246 children have been | of this system were unknown.However during the studied.The antigenic determination was carried i A late years rapid progress was made in the knowledge out with the help of monospecific or practically and the understanding of the genetics of this sys- monospecific sera used in microlymphocytotoxicity Ti tem (2, 4, 8,10, 12 and 14).Two series of antigens and complement fixation on platelet techniques.; were described and the antigens of each series were The method for the deduction of genotypes and ; là shown to behave, at least in the Caucasian popula- haplotypes has been described elsewhere (7).The I tion, as mutually exclusive alleles at two very allelism of the antigens was studied by double back- iy closely linked sub-loci (6, 8 and 10).cross method.L a * This work was carried out in the \u201cInstitut de re- .ç leg cherches sur les maladies du sang, Hôpital Saint-Louis, RESULTS i ] Paris X° (France)\u201d.It was supported by Grant CA 5573 : of the National Cancer Institute, Bethesda, Md, U.S.A., The antigens of the first sub-locus: qu and contract PH 43 65 986 of the National Institute of hi .mh Allergy and Infectious Diseases, Bethesda, Md, U.S.A.Six well defined antigens behave as mutually ex- i and \u201cUnité de recherche n° 93\u201d of the \u201cInstitut na- | L tional de la santé et de la recherche médicale\u201d, Paris, France.clusive alleles at this first sub-locus.They are antigens HL-A1, HL-A2 (Mac), HL-A3, Dal5, Dal6 Laval Médical Vol, 41- Fév.1970 EAN § ns HLA sers ome Dans : Das ge a 2 QUE omer mor- amer > Def GENETICS OF THE HL-A SYSTEM 213 (6b) est toujours présent.Ceci est appelé phénomène d'inclusion.En plus si On assume que ces deux associations constituent deux entités, on n\u2019a trouvé aucun individu ne possédant plus que deux des antigènes ou entités Da4, HL-A8, Da6, Da9 (6b), « HL-A5-Da6 » « HL-A7-Da8 », il est fort probable que d\u2019autres sub-loci du système HL-A seront postulés.Par exemple, il y a lieu de supposer que les antigènes de Waldford Lc-17, Lc-20 sont des allèles au troisième sub-locus.De tout ceci il apparaît que le système HL-A est complexe et consiste en plusieurs sub-loci dont chacun d\u2019eux possède plusieurs allèles.|| est intéressant de noter que ces sub-loci sont dépendants l\u2019un de l\u2019autre.Ivanyi et Dausset ont postulé que chacun des antigènes connus \u2014 ainsi que ceux qui sont encore inconnus dans le système HL-A \u2014 est lui-même probablement formé par de nombreux facteurs antigéniques.Pareille hypothèse est basée sur l\u2019analogie de ce qui est connu pour l'antigène D du système Rhésus qui lui-même consiste en plusieurs facteurs RhA, RhB, RhC et RhD.Finalement, l\u2019indépendance du système HL-A, du système ABO, Rh, MNS, Kell, P.JR, et d\u2019autres a été établie.La plupart des antigènes connus du système HL-A ont trouvé place dans l\u2019un ou l\u2019autre des deux premiers sub-loci.|| semble probable que le comportement d\u2019un greffon cardiaque puisse être déterminé pour une grande part, par des incompatibilités de ces antigènes.(Le-11) and very probably Dal7 (10).The existence of at least one and very likely several other alleles must be postulated at this first sub-locus.The mutually exclusive relationship between these antigens has been proved by the double back-cross method usine informative families.It must be underlined that a cross-reaction has been observed between two antigens of this series, the antigens HL-A2 and Dal5 (5).This observation has been confirmed by Svejgaard and Kissmeyer- Nielsen (13).The antigens of the second sub-locus: Four antigens behave like alternative alleles at the second sub-locus.They are antigens HIL-AD, HL-A7, HL-AS8, and Da4 (8).As for the first sub- locus, the existence of at least one or probably several other alleles must be postulated at this sub- locus (6, 8 and 10).Informative families by the double back-eross method gave evidence, at least in the Caucasian population, of the allelism of these antigens.Looking at two other antigens not yet classified at any sub-locus, the following facts are observed: the haplotypes which govern antigen Da6 (4) never govern antigens Dad, HL-A8.HL-A7.On the other hand.there are haplotypes which govern both antigens Da6 and HL-A5; the haplotypes which govern antigen Da9 (8) [Van Rood\u2019s antigen 6 (15) ] never govern antigens Dat.HL-A35.or HL-A8.On the other hand.there are haplotypes which govern both antigens Da9 (6P) and HL-A7.The 189 haplo- types observed are given in Table I.The study of the phenotypes of 312 Caucasian individuals shows that when antigen HL-AS5 is present, antigen Da6 is also present (8).Likewise when antigen HI-A7 is present.antigen Da9 (6b) is also present (+ and 15), this phenomenon being the so-called \u2018\u2018inclusion\u2019\u2019 phenomenon.Furthermore.if we assume that the association HL-A5-\u2014 Da6, and HL-A7\u2014Da9 (6) constitutes two entities, no individual has been found possessing more than two of the antigens or entities Da4, HL-A8, Da6, Da9 (6b), \u201cHL-A5-Da6\u201d\u2019, fut attribuée à chaque transplantation cardiaque suivant le système de Montréal : Groupe B: 0 ou une incompatibilité ; Groupe C : 2 incompatibilités ; Groupe D : 3 incompatibilités ou plus.Ainsi groupées les différentes transplantations cardiaques furent comparées quant à la fréquence, l'importance et le délai postopératoire des crises de rejet.Aucune différence statistiquement significative ne put être établie entre ces trois groupes.Quarante et un cas seulement étaient suffisamment détaillés pour pouvoir être pris en considération dans une étude de survie à long terme.A survey! dealing with histocompatibility in heart transplantation has been conducted in an attempt to obtain, on as large a number of heart transplants as possible, pertinent informations as to the role of histocompatibility in transplant survival.The survey was aimed at establishing the policy of each center and at studying how the results of the histocompatibility tests, performed according to this policy, could be related to the outcome oË the transplant.A total of 19 centers answered the questionnaires and reported on seventy cases.In several instances, information obtained was not complete so that cor- * Presented at the Second world symposium on heart transplantation, Montreal, Canada, June 6-8, 1969.t Institut de microbiologie et d\u2019hygiène de l\u2019Université de Montréal, B.P.100, Ville de Laval, P.Q., Canada.1.This survey was made possible through the cooperation of the following transplantation centers: Ann Arbor, Bordeaux, Buenos Aires, Cape Town, Chicago, Dallas, Houston (De Bakey), Jackson, Milwaukee, Montreal, New York, Paris, Pittsburgh, Richmond, Sao Paulo, Sapporo, Toronto, Valparaiso.(suite du résumé en page suivante) relations could not be made.It appears that in 13 centers out of 16, the outeome of the compatibility is known before the transplant operation.Thirteen centers use the lymphocytoxieity technic, while five centers use leuko-agglutination, one center complement fixation on platelets and one center mixed leukocyte culture.Out of seventeen centers, fifteen take into account lenkoeyte ecross-match, seventeen consider ABO compatibility, eight consider Rh compatibility while four consider other red cell antigens such as Kell, Duffy and P.Only six centers out of sixteen test for preexisting anti-heart antibodies, while four eenters out of sixteen preclude intersexual donor-recipient combinations.All the leukocyte antigens are considered as equal in strength by six out of fifteen centers.The number of leukoeyte antigens (HLA and others) determined by the various centers vary greatly.However nine centers detect ten or more, three centers less than ten and two centers detect none (one of the latter uses mixed leukocyte culture).The main source of typing sera seems to be the NIH serum bank (used by nine centers) while eight centers use sera of local source and eight use sera from one of the well-established histocompatibility centers.A uniform compatibility grading was assigned to each transplant according to the Montreal system, 1.0.B: 0 or 1 incompatibility: C: 2 incompatibilities; D: 3 or more incompatibilities.These transplant patients, thus grouped, were compared with respect to the frequency, strength and time of rejection crises: no statistically significant difference could be established between these three groups.Only forty one cases had enough data to be used in a survival study.These were again grouped according to their mateh and each group compared as to the duration of survival and percentage of living patients (Figure 1).For the deceased patients, the average survival time was 14 weeks for both B and © matches, and à weeks for D matches.The percentage of survival is 56.5 per cent for the B group, 40 per cent HISTOCOMPATIBILITY IN 70 HEART TRANSPLANTS Laval Médical Vol.41- Fév, 1970 La survie moyenne des patients décédés était de 14 semaines pour les groupes B et C et de 5 semaines pour le groupe D.Le pourcentage de survie était de 56,5 pour cent dans le groupe B, de 40 pour cent pour le groupe C et de 14,3 pour cent pour le groupe D.Une des raisons pour laquelle aucune corrélation ne put être établie avec les crises de rejet est probablement la difficulté actuelle d\u2019avoir des critères du phénomène de rejet cardiaque qui soient universellement acceptés.En conclusion, un registre mondial de transplantations cardiaques serait des plus utiles pour obtenir des données standardisées portant sur un grand nombre de cas.72 56 24 B Cc D Figure 1 \u2014 Surviving (striped) and deceased (black) heart transplants grouped according to histocompatibility match (letters) and weeks of survival (numbers).for the © group and 14.3 per cent for the D group.In spite of the great heterogeneity of the crude data, there appears to be a good correlation between the histocompatibility mateh and the survival of the transplants.One of the reasons why no correlation was established with rejection crises could well be the present difficulty of having objective and universally accepted criteria for heart rejection.A world wide heart transplant registry would indeed be of great assistance in obtaining standardized data on a large number of cases.BED \u201cje 4.JE pui A RED CELL ANTIGEN COMPATIBILITY IN HEART TRANSPLANTATION * pe a or | Shin SEKIGUCHI, M.D.aus j ik | A na | Il existe peu d\u2019information concernant la comptabilité antigénique du E ul globule rouge dans la transplantation cardiaque.Il existe deux appro- i ns | ches à ce problème.1.Des expériences de greffes cutanées sont effectuées dans le système antigénique des globules rouges À et B, sur les groupes compatibles et incompatibles afin de déterminer la différence en survie des greffes dans les deux groupes.La plupart des expériences sont faites en prenant la peau d'individus A, B ou AB et en greffant cette peau sur un receveur O.Une présensibili- sation avec des globules rouges À ou B ou avec de la substance antigé- nique soluble A ou B est effectuée avant de pratiquer les greffes cutanées sur le receveur O.Une réjection accélérée survient chez le receveur lorsque le donneur de globules rouges et de peau était identique ou de même groupe ABO.L'induction d'un accroissement de possibilités immunologiques est démontrée lorsqu'une quantité donnée de substance antigénique (1 mg) est injectée chez des individus de groupe O avant que les greffes cutanées de A ou de B sont placées sur le receveur O.Comme résultat, on note une prolongation dans la survie des greffons cutanés plutôt qu'une et There is not enough information about red (suite du résumé en page suivante) from A, B, or AB individuals and grafting it on y cell antigen compatibility in heart transplanta- an O recipient (12, 13 and 14).Presensitization | tion (1 and 11) for an extensive discussion of the with A or B red cells (2 and 15) or soluble A or B subject therefore, it would be worthwhile to review antigen substance was done previous to the skin il briefly what we know about red cell antigens par- grafts on the O recipient.resulting in an accel- a @ ticularly of À and B, in relation to organ trans- erated rejection of the grafts in the recipient if 4 plantation in general.the donor of the red cells and the skin happened LAS) Basically, there have been two types of approach to be the same individual or had the same ABO to this problem: group (2 and 15).pli pre fr a li fit 1) The first being a series of skin graft experiments conducted in red cell antigen systems A and B (ABO system thereon), compatible and incompatible groups, in order to ascertain the difference in survival time of the grafts in the two groups.Most of the experiments were done by taking skin * Paper presented at the Second world symposium on heart transplantation, Montreal, Canada, June 6-8, 1969.1.Assistant haematologist.Director, tissue typing laboratory, The Toronto Western Hospital, Toronto, Ontario.(8) Induction of immunological enhancement has also been reported in the experiment where a given amount of antigenic substance (1 mg) was injected to the group O individuals before the incompatible skin grafts from A or B were placed on the O recipient (2) This resulted in the prolongation of skin grafts rather than the acceleration of the rejection of the grafts.Also, an in vitro coating of Al to O skin grafts by Anti-A antibodies has induced a significant increase in graft survivals (2). 290 Shin SEKIGUCHI Laval Médical bris Vol.41 -Fév.1970 {il 4 accélération du rejet des greffons.De même, le revêtement in vitro de greffes cutanées A par des anticorps anti-A induit une augmentation significative de survie du greffon.Des données cliniques détaillées de transplantations rénales démon- = trent des rejets immédiats en présence d'incompatibilité du système ABO.x 2.La seconde approche au problème est l'identification des antigènes des globules rouges dans les tissus humains.Grâce au développement Ha du test d\u2019agglutination mixte ceci est accompli par plusieurs investigateurs.nr Les antigènes A et B sont retrouvés dans les globules blancs, les plaquet- _ tes, les cellules épidermiques, le rein fœtal, le foie, la rate, les poumons, le cœur et la peau.La Les autres antigénes de globules rouges, mis à part A et B et H, n'ont .pas été identifiés positivement dans les cellules du tissu humain excepté dans les leucocytes où l\u2019on a trouvé les antigènes MN, et Tja (ou P).Hl L'antigéne Rh n\u2019a jamais été trouvé dans les cellules humaines autres mi que les globules rouges.D'où on a pu conclure que cet antigène n\u2019a pas 7 une importance significative dans la transplantation clinique.Il devient hay évident qu\u2019une investigation plus poussée est nécessaire dans le domaine des antigènes des globules rouges afin d\u2019exclure la possibilité de négliger | \u201c d\u2019autres antigènes de globules rouges qui pourraient être des antigènes dl importants dans la transplantation cardiaque.pi jt its Here, it is intriguing to note that the incom- in human renal transplantation (6).Skin grafts\u2019 « patibility within the subgroups of A, that is Al, experiments by others however, show the results \" A2 and others makes some difference in the host to be otherwise.It has also been shown that ABO ul when they are used to sensitize the O recipient and and HLA compatible control groups did not differ « also in the survival of the skin graft from the sub- from each other as far as survival is concerned, fs groups of À (2).For instance, skin from Al would suggesting that the other red cell antigens are not f react violently with O recipient whereas skin from strong transplant antigens (15).> A2 individual would not be rejected as the second No other important contribution regarding red i set reaction which is analogous to the situation in cell antigen system in relation to organ trans- ie hemolytic diseases of the newborn due to AB in- plantation has been available except one of Doctor w compatibility where only A1 or B children are af- Dossetor\u2019s cases in his series of renal transplanta- À fected while A2 children always escape the disease tion in which red cell antibodies might have been ct, (2 and 17).responsible for the failure of the kidney.Al There have been well-controlled clinical data of 2) The second approach to the problem is the ; renal transplantation in which immediate graft identification of the red cell antigens in human | 4 rejections were encountered in ABO incompatible tissue cells.With the development of Mixed Agglu- A pairs (6 and 17).tination Test, this has been accomplished by many 4 : Besides A and B antigens, I antigen has been investigators.A and B antigens have been found 1 attracting attention because of its possible role as to be present in blood leukocytes (7), platelets (4), A 3 à transplantation antigen.Shorter than normal epidermal cells (5), fetal kidney, liver, spleen, ; à survival time of the skin grafts has been reported lung, heart and skin (7).\u2026 â in P incompatible donor-recipient pairs (3) and Immunofluorescent technique has contributed A 2 supportive evidence to the effect has been presented some information regarding the distribution of the te 2 | Yédien! Fir, 10 il de 1500 démon 2 AB0) ligines pemerl paleufs aque mons H no cxceplt ou autres naps evi jomalfé negli genes Laval Médical Vol.41 \u2014 Fév.1970 TasLE 1 RED CELL ANTIGEN COMPATIBILITY 221 Red cell antibody screening (with pool of O cells) w C,D,E, e,d,e, C\u2014, v\u2014, M,S,N,s, PT, Lu (a\u2014), Le*, k, Kp®, F'ys, JK*P, Di (a\u2014), Vel, Wr (a\u2014), Mi (a\u2014), Lu?, Le\u201d, KK, Js (a\u2014), IR, Ge, VE, VS\u2014 (P2, Jk\u2019, Xg% A and B antigens on endothelium of vessels and REFERENCES sinusoids in spleen.These findings are in agree- ; !.BETHESDA CONFERENCE REPORT, Cardiac and other ment with experimental works on skin grafts and with clinical results of renal transplantation.The other red cell antigens, besides A, B, and H have not been positively identified in human tissue cells except in leukocytes where MN and Tja (or P) antigens have been identified (7).Among other things, this is due to such technical difficulties as host red cell contamination and loss of antigenic sites during the process of culturing (8, 10, 16 and 19).Rh antigen has never been found to be present in human cells other than in red cells (7 and 8) and this is a part of the theory that the said antigen is not considered to be significant in clinical transplantation.Thus it becomes obvious that more investigation is needed in the field of red cell antigens in order to exclude the possibility of missing out on some other red cell antigens besides A, B antigens which are significant transplantation antigens.We have been doing genotypes of Rh system and red cell antibody screening test in order to avoid any obvious incompatibility (Table I).So far none of the cases in our institution (University of Toronto Transplantation Team) has developed red cell antibodies.A complete profile of red cell antigens including the subgroups of A antigen (7) as well as HLA system are needed in all cases of organ transplantation in the future, placing more efforts on identification of red cell antigens on tissue cells, in order to accumulate data for better understanding of the relationship between red cell antigens and organ transplantation.wo Ty ~2 10.11.CEPPELLINI, .Hogmax, organ transplantation, Am.J.Cardiol, 22: 896- 912, 1968.R., BIGLIANT, S., CURTONI, E.S., and LerGHEs, G., Experimental allotransplantation in man.II.The role of Al, A2 and B antigens.III.Enhancement by circulating antibody, Transplantation Proceedlings, pp.390-394, 1969.CrPPELLINI, R., CurronI, E.S., MarTi0z, P.L, LEre- ure, G., Viserri, M, and COLUMBI, A, Survival of test skin grafts in man.Effect of genetic relationship and of blood groups incompatibility, Am.N.Y.Acad.Science, 129 : 421-445, 1966.Coomss, R.R.A., and Brprorp, D, The A and B antigens on human platelets demonstrated by means of mixed erythrocyte \u2014 platelet agglutination, Vox Sang.5 : 3, 1955.Coomss, R.R.A., Brprorp, D., and RourLaRD, L.M, A and B blood-group antigens on human epidermal cells, Lancet, 1 : 461-463, 1956.GLEASoN, R.E., and Murray, J.E., Report from kidney transplant registry.Analysis of variables in the function of human kidney transplants.I.Blood group compatibility and splenectomy, Transplantation, 5 : 343, 1967.GerNer, B.W., and Coomss, R.R.A, Examination of human leukocytes for the ABO, MN, Rh, Tj, Lutheran and Lewis systems of antigens by means of mixed erythrocyte-leukocyte agglutination, Voz Sang.3: 13-22, 1958.Hoemax, C., The principle of mixed agglutination applied to tissue culture systems, Voz Sang.4: 12-20, 1959.C.F., Blood group antigens A and B determined by means of fixed agglutination on cultured cells of human fetal kidney, liver, spleen, lung, heart and skin, Vox Sang.4: 319-332, 1959.HocMmAn, C.F., Blood group antigens on human cells in tissue culture.The effect of prolonged cultivation, Exp.Cell Research, 21 : 137, 1960.KANnTROWITZ, A.and Harrrr, J.D, Guest editors, Symposium on human heart transplantation, Am.J.Cardiol\u2026 22 : 761-843, 1968.Kvuuns, W.J., RAPAPORT, F.T., LAWRENCE, H.S., and Converse, J.M., Serum antibody response to tissue transplantation in man, Ann.N.Y.Acad.8ci., 120 : 36, 1964. 1D no ID 13.Kvxws, W.J., RAPAPORT, F.T., LAWRENCE, H.S., and CONVERSE, J.M, Relationship of human blood group antigens and antibodies to survival of skin homo- graîts, Transplantation, 4 : 250-259, 1966.14.RAPAPORT, F.T., and Rausser, J., Erythrocyte antigens as determinants of human histocompatibility, 58\"! Annual clinical congress, American College \u201cof Surgeons, Surgical Forum, 18 : 225-227, 1967.43.RAPAPORT, F.T., DAUssEr, J., LEGRAND, L., BARGE, A., LAWRENCE, H.S., and CONVERSE, J.M., Erythrocytes in human transplantation : Effects of pre-treat- ment with ABO group specific antigens, J.Clin.Investigation.47 : 2206-2216, 1968.16.SEkIevcHI, S., Unpublished observation.Shin SEKIGUCHI Laval Médical Vol.41 -Fév.1970 17.STARZL, T.E., Marniroso, T.L., HERMAN, G., et al., Renal hemografts in patients with major donor \u2014 recipient blood group incompatibilites (addendum), Surgery, 55 : 195, 1964.18.SZULMAN, À.E., The histological distribution of blood group substance A and B in man, J.Exper.Med., 115 : 977, 1960.19.Yuvis, E.J., Yunis, J.J., and BRAND, K.G., Demonstration of iso-antigenic receptors on human epidermal cells and established cell lines, Blood, 25 : 96-104, 1965.20.ZUELZER, W.W., and KAPLAN, E., ABO hetero-specific pregnancy and hemolytic disease.IV.Pathologic variants, Am.J.Dis.Child., 88 : 319, 1954.in ite AR ee ari PA RE 2eme iin) J ét.19 cu, Jogor \u2014 sndumi, PRE-EXISTING ANTIBODIES : RELEVANCE TO HEART TRANSPLANTATION * lion of Eng J.B.DOSSETOR Deas DD épi AB: + À quels antigènes correspondent les anticorps pré-existants ?|| faut ai considérer cinq groupes d\u2019antigènes : ih 1.Le globule rouge et les systémes ABO, Rhésus et autres ; 2.Le système HL-A ; 3.Les antigènes anti-cœur spécifiques ; 4.D'autres antigènes à l'exclusion des premiers, trouvés en dehors du coeur, a savoir la membrane cellulaire, la membrane nucléolai- ; re, le DNA, le RNA, les plaquettes et les granulocytes ; { 5.Les antigènes streptococciques et d\u2019autres micro-organismes.GROUPE |: Les antigénes du globule rouge.Les antigénes A et B doivent étre considérés comme des antigénes de transplantation.lls apparaissent dans le cœur, et sont importants dans les greffes cutanées de jumeaux identiques dans le sytème HL-A.Une présensibilisation cause un rejet accéléré.Quoique les antigènes Rhésus ne semblent pas importants dans la transplantation, il est prudent de ne pas pratiquer de greffe tissulaire chez un receveur Rh négatif sensibilisé si les autres antigènes du globule rouge sont négligés dans la transplantation parce que considérés comme immunologiquement faibles.Pre-existing antibodies to which antigens?That is the first question.There are five groups of antigens that have to be considered : 1) red cell: ABH, Rhesus and others; 2) HL-A; 3) organ specific heart antigens; 4) other antigens (not red cell, not HL-A) but found in tissues other than heart : cell membrane, nucleolar, DNA, RNA, platelet and granulocyte; and 5) streptococcal and other microorganisms.Although many of these are not of the histocompatibility type, it is the latter, or HL-A, that are the most important and erucial to success.The importance of the antigens of group 3 is unknown.For others, such as the less common red cell antigens, tissue distribution is not known for * Presented at the Second world symposium on heart transplantation, Montreal, Canada, June 6-8, 1969.Renal Urological Research, Royal Victoria Hospital.Supported by Grant MT-1903, Medical Research Council, Ottawa.New address : Edmonton.Dept.of Medicine, University of Alberta, Dans ces cas la présensibilisation (suite du résumé en page suivante) sure.Many of these are weakly immunogenic but may still be of significance when pre-immunisation happens to be present prior to transplantation.The rôle played by these non HL-A antigens may be determined by studies to detect their presence prior to transplantation, and to follow changes in antibody titers with transplantation and with subsequent rejection episodes.Group 1: Red cell antigens.Pre-existing antibodies exist \u2018naturally\u2019 to antigens A and B, and these two must be considered to be transplantation antigens.They occur in the heart (7, 15 and 16) they are important in skin grafts between HL-A identical siblings (1) and pre-sensitisation causes accelerated rejection (13).Early reports of success with renal allografts despite ABO incompatibility (3 and 14) were not borne out by later results (5 and 6).Although Rhesus antigens do not seem to be important in transplantation (5), it would Levi Laval Médical A il.Vol.41-Fév.1970 ID IN = J.B.DOSSETOR peut bien devenir un risque de transplantation.Par ailleurs, il est possible que le systéme antigénique P puisse étre important dans la transplantation.GROUPE [I : Antigénes HL-A.Des anticorps pré-existants contre les antigénes HL-A peuvent étre décelés par un cross-match entre le sérum du receveur et les lymphocytes du donneur.La positivité du test ira de pair avec un rejet immédiat de la greffe.Cependant, des tests faussement négatifs sont signalés par les auteurs.Ce principe peut être important dans la transplantation cardiaque chez une femme multipare qui peut avoir eu et perdu ultérieurement des anticorps lymphocytotoxiques contre les antigènes incompatibles de l\u2019époux.Si le donneur cardiaque a des antigènes en commun avec l'époux, des anticorps lymphocytotoxiques peuvent rapidement être reformés par un clone latent et ainsi causer une ; réjection cardiaque rapide.| GROUPE Ill : Anticorps contre des antigènes cardiaques (spécifiques d'organes).Kaplan donne une revue de l'apparition d'anticorps contre le | still be considered inadvisable to implant tissues into a sensitised Rh negative recipient as studies on tissue distribution of these antigens cannot be acecept- ed as having been exhaustive.Most believe that preexisting antibodies to rarer red cell antigens would not be important.We have evidence to the eon- trary, with pre-sensitisation to Duffy antigen (Fy2) where renal implantation was associated with disappearance of antibody, and excision of the failed transplant was associated with immediate reappearance this antibody (2).If other red cell antigens are being disregarded in transplantation not be- became sensitised by transfusions and hemodialysis to antigens (Te 4, 7, 9 and 11).After unsuccessful renal transplantation, during which time he was given two months of intensive immunosuppression, lymphoeytotoxic antibodies were found to have disappeared completely from his serum, including after excision of the graft.He was then dialysed with buffy coat free red cells for a five month period.Liymphocytotoxic antibodies were absent throughout this period.On exposure to his mother\u2019s blood antibodies returned against Te 4, the only incompatible antigen she carried.During subsequent Wie ity tig lig di Tieng They ly Toy \\ lig li cause of poor immunogens, then pre-sensitisation hemodialyses with whole blood, containing white \u201c may well be a transplantation hazard.There is cells, the other antibodies previously present, against hy evidence that P may be important in transplanta- Te 7, 9 and 11, reappeared.It was fortunate, in- ls tion (5) though this was not eonfirmed by others deed, that the mother\u2019s kidney was not transplanted 0 .(11 and 12).into this patient during the five month period when i the direct crossmatch was falsely negative.This Group 2: HL-A antigens.The evidence is now principle might be important in heart transplants fy so strong that pre-existing antibodies to HL-A anti- into multiparous women who might have had, but au gens, detected by a positive recipient serum/donor later lost lymphoeytotoxic antibodies against their le lymphocyte crossmatch, will cause immediate graft husbands, incompatible antigens.If the donor of + È failure (4 9 and 10).that it would be wrong to the heart had antigens in common with the hus- ti carry out any allograft without a negative eross- band, lymphoeytotoxic antibodies might rapidly be match of this type.Recent work in our laboratory has shown that there may be occasions when this crossmateh test is falsely negative (8).Thus, one of our patients with renal failure, whose lymphocytes carry Terasaki antigens (Te 2, 3, 5, 6 and 8) reformed by a latent clone and cause a rapid heart rejection because of latent sensitisation.Group 3: Antibodies to organ-specific heart antigens.Kaplan (8) has written a recent succinet i | i iit! su | oH iste Nation tre les sérum ia de ausse- impor i pet contre à des gues er Ung ques nie le pri red raie il ilk pi gu\u2019 pl ptt wl y hit ind ÿ qi.i Jae A Ri , mis ff i pl pe {her ot d his the ibe qi f it wo Laval Médical Vol.41- Fév.1970 PRE-EXISTING ANTIBODIES 225 sarcolème, le sarcoplasme, les éléments intermyofibrillaires.Par ailleurs, des anticorps contre les antigènes cardiaques peuvent apparaître dans différentes maladies incluant la période consécutive à la chirurgie cardiaque.L'importance de ces anticorps dans la transplantation cardiaque est actuellement inconnue mais il est certain qu\u2019ils peuvent être mesurés avant et après la transplantation cardiaque, et au cours des crises de rejet.GROUPE IV : Anticorps contre les antigènes cellulaires ne faisant pas partie des trois groupes précédents.Ces anticorps pourraient devenir d\u2019une grande importance si, à l\u2019avenir, on faisait des transplantations cardiaques pour des maladies du collagène avec phénomène vasculaire aigu ou, encore, en phase aiguë de fièvre rnumatismale ou d\u2019autres formes de myocardite.GROUPE V : Anticorps contre le streptococque et d\u2019autres organismes.Ces anticorps furent décrits par Rappaport et leur importance peut être plus grande qu\u2019on ne le croit actuellement.review of the incidence of antibodies fo sarco- lemmal, sarcoplasmic, intermyofibrillary structures, using fluorescence microscopy and to various heart antigen extracts, using in vitro techniques.Antibodies to heart antigens may occur in different disease states, including after cardiac surgery.Their pathogenic importance in heart transplantation is quite unknown and may not be great; but they should certainly be measured before and after heart transplantation and in rejection crises.Group 4: Antibodies to cellular, non EBC, non HL-A, non heart-specific antigens.These antibodies would be of great importance if the time ever eame when heart transplantation was done for acute collagen vascular diseases, acute rheumatic fever or other forms of acute myocarditis.At present this is not the case.Group 5: Streptococcal and other organisms.Preformed antibodies of this type.and their significance are reported elsewhere in these proceedings by Rapaport.Their importance may be greater than is presently realized.Analysis of rôle of preformed antibody in heart transplants, to date: Of 19 centres contributing data on 64 heart transplants, all were compatible with respect to ABO; 4 were incompatible for Rhesus and in 26 Rhesus compatibility does not seem to have been determined.The less common red cell antigens were not studied in 16 centres nor did any reporting centre record whether antibodies against Rhesus or other red cell antigens pre-existed in their patient\u2019s plasmas.Four centres did not do the recipient serum/donor-lymphoeyte crossmatch but the large majority who use this test included all the larger centres.One pre-transplant test in Montreal was positive by miero-leucoagglutination and it may be presumed this compares, prognostically, with the lymphocytotoxicity crossmatch.Acute rejection coincided with development of cytotoxic antibody against donor cells around the 7\" day in one New York patient; these antibodies had not been present prior to transplant raising the possibility of a false negative pre-transplant crossmatch.Sixteen of 19 centres do not seem to have looked for any organ specific heart antibodies \u2014 a fact which is both surprising and regrettable.We have no information of changes in organ specific antibodies after transplantation, or with rejection.REFERENCES {.CEPPETLINI, R., BIGLIANI, S., Curroxi, E.S., and LercHEB, G.Experimental allotransplantation in man : II.The role of A,, A.and B antigens ; IIL Enhancement by circulating antibody, Transplantation Proceedings, 1: N° I, Part 2, pp.390-394, 1969, 2.CEPPELLINI, R., CURTONI, E.S., Marrivz, P.L., LEIG- HEB, G., VisErTI, M, and CoLOMBI, À, Survival of test skin grafts in man : effect of genetic relationship and blood groups incompatibility, Ann.N.Y.Acad.Sci.129 : 421, 1966.DEMPSTER, W.J., Reassessment of the anurias after kidney transplantation, Brit.Med.J., 5347 : 1697- 1701, 1963.DoSSETOR, J.B., New Engl.J.Med., 278 : 1234, 1968.DossEror, J.B., Dalhousie Centennial, Sept.1968, Can.Med.Ass.J., 1969, In press.i.GLEASON, R.E., and Murray, J.E., Report from kidney transplant registry, Analysis oË variables in the function of human kidney transplants.I.Blood group compatibility and splenectomy, Truns- plantation, 5 : 843-359, 1967.HARTMANN, G., Group antigens in human organs, Munksgaard, Copenhagen, 1941.Su Tt om ~2 .KAPLAN, M.H., Auto-immunity to heart and its relation to heart disease : a review.Proc.VI Cong.of Allergology, Excerpta Medica International Congress, Series 162 : 312-324, 1968.KISSMEYER-NIELSEN, F., OLSENS, S., PETERSEN, V.P., and FJrLBorG, O., Hyperacute rejection of kidney allografts associated with pre-existing humoral J.B.DOSSETOR 10.11.12.16.Laval Médical Vol.41- Fév.1970 antibodies against donor cells, Lancet, 2 : 662-665, 1966.On, J.H., and Dossrror, J .B., To be published.Parr, R., and Terasaki, P.I., Significance of the positive crossmatch test in kidney transplantation, New Engl.J.Med., 280 : 735-739, 1969.PAYNE, R., In Histocompatibility testing, 1967, Series Hematologica 13, Munksgaurd, Copenhagen, 1967.Rararorr, F.T., LAWRENCE, H.S., THOMASs, L., CONVERSE, J., TILLET, M.S., and MULHOLLANF, J.M,, Erythrocytes in human transplantation : effects of pre-treatment with ABO group specific antigens, J, Clin.Invest.47 : 2206-2166, 1968.SrAarzyL, T.E., MaArcCHIORO, T.L., Houmes, J.H, et al.Renal homografts in patients with major donor-recipient blood group incompatibilities, Surgery.55 : 195-200, 1964 .SZULMAN, À.E., The histological distribution of blood group substances À and B in man, J.Exp.Med.111 : 785-800, 1960.SZULMAN, A.E., The histological distribution of blood group substances in man as disclosed by immunofluorescence.II.The H.antigen and its relation to A and B antigen, J.Exp.Med., 115: 977-996, 1962.(0 PR ly ie) x, 9 a 5.À, if he lation, Series n, 196i.L, Car AN fects iE LH p major pu ME of load Je.pion mel by FIRS i 1h COMPTE RENDU DE LA PREMIERE REUNION PLENIERE \u2014 PROCEEDINGS OF THE FIRST GENERAL SESSION : \u2014 Problems related to the choice of both donor and recipient ; \u2014 Surgical technique and organ preservation ; \u2014 Histocompatibility in heart transplantation.Chairman : Christiaan N.BARNARD, Cape Town.Reporters : Wilfred G.BIGELOW, Toronto, and Gilles LEPAGE, Montréal ; Denton A.COOLEY, Houston, and Yves CASTONGUAY, Montréal ; Jacques COLOMBANI, Paris, and E.F.POTWOROWSKI, Montréal.Transcript Editor : Gilles LEPAGE.Doctor Christiaan Barnard: Ladies and Gentlemen.This afternoon in this session, we are going to diseuss three aspects of heart transplantation.This first is the problems related to the choice of both donor and recipient.I have no doubt in my mind, in the light of the experience we have had in the last year and a half, we have to change certain of our criteria, which we accepted a year ago, in both the choice of the donor, and the choice of the recipient.Next is the surgical technique and organ preservation, which have been pretty uniform.But there are a few new points which, I think, should be mentioned.And lastly, the very important aspect of histo- compatibility in heart transplantation.We will now first hear from Doctor Bigelow and Doctor Lepage.Doctor W.G.Bigelow: We have had a stimulating and interesting session and I noticed that the audience were principally medical men so that we had to be rather careful to manage the discussion properly.The severest critic of surgery would have to admit that heart transplantation at least stimulates interest in a number of flelds that would perhaps never be explored.This was the case in point this The first speaker, Doctor Freidberg, gave some very interesting statistics.We are all afternoon.statistically oriented and we like to behave like exact scientists, and we feel better if our statisties are proving our point, although this is very difficult in the biological sciences.However he has taken 130 heart transplants that have been operated upon and he finds that there are 35 living.That, in itself, does not sound very happy.However, in analysing this, 35 per cent have lived over three months and 18 per cent over six months.Those are very interesting statistics.Then he does a very interesting bit of paper work: he excludes all those that died in the first week and finds that 41 of 74 lived over three months, or 54 per cent, and that 20 of 67 lived over six months, or 30 per cent.On the basis of these figures he feels, I think, we are evolving out of the era of experimental surgery as has been mentioned earlier this morning.The figures that Doctor Stinson has given from Doctor Shumway\u2019s group this morning suggest a half life of about seven or eight weeks for the usual recipient, without operation, and most of them are dead in three to four months so that these figures would confirm Doctor Freidbergs\u2019 contention.He suggested finally that there should be better matching, and that one should look for the significant antigens, and he feels these are the two large areas in selecting donors.His actual indications for surgery, T thought, were very liberal for a medical man.He was not challenged particularly on his paper, although it did contribute to the discussion.Doctor Kahn reviewed in somewhat more detail the very nice presentation he gave this morning with the beautiful and artistic slides and he had more of them this afternoon.He reviewed his first case with the pulmonary artery pressure of 70 mm Hg and that invoked discussion as to how high the pulmonary artery pressure or pulmonary vascular resistance could be before you consider doing a transplant, and 1 do not think we came to any conclusion.There were some very interesting comments made.Ie feels that there is no greater evidence of rejection in a cardiomyopathy and that transplantation is rather a good operation for this condition.Doctor Beanlands from Toronto challenged him and quoted a case of cardiomyopathy that had received a transplant.This patient died and at autopsy, the donor heart had all the histo- logical appearance of the original recipient\u2019s heart with the myocardiopathy picture.This brings to mind the importance of realizing of course that cardiomyopathy is a sort of biological scientific wastebasket and I am sure that it includes a number of entities.One wonders if it is not dangerous to use the word cardiomyopathy and infer that it is one disease.There is a suggestion, if this is hu man experimentation and if you are transplanting a cardiomyopathy, that the value of your eventual pathological interpretation in the donor heart may be reduced, because you might wonder whether the cells you see are the result of this original disease or due to rejection.Well if you heard a great calm descend on Salon \u201cA\u201d, it was when Doctor Heggtveit made a very challenging and disturbing presentation.Those of us who had not read his publications were interested to find that he has drawn some very worrysome lines across the whole picture of heart transplantation.He finds, along with his studies of brain damage, and also in subarachnoid hemorrhage, that there is subendocardial hemorrhage in the heart in 50 per cent of cases, focal necrosis in 25 per cent and a variety of other lesions including infarct.Now this is in the heart.And as he was making his presentation, we immediately thought that it might be in relation with vasopressor drugs and cardiac massage but in the cases he presented, he had apparently excluded cardiac massage, vaso- pressors and chest injury.Of course this lead on COMPTE RENDU DE LA PREMIÈRE RÉUNION PLÉNIÈRE Laval Médical Vol.41- Fév, 1970 to some questions as to how we can, in the individual with the brain damage, spot the myocardial damage.The electrocardiogram did not seem helpful and there did not seem to be any real correlation, from what I could gather from the discussion.Does this mean that the sooner we obtain the donor heart, the less likely one is to see the subendocardial hemorrhage and the focal necrosis?Is there a time limit?1 think Doctor Freidberg brought up the interesting point that, if this is so, if many of the hearts that we are transplanting do have some pathology due to the brain damage, then we may be misinterpreting the pathological picture we see in the transplanted patient when he dies and we examine his transplanted heart.1 guess we just have to take our chances and Doctor Lepage and I were discussing this in the 17 or 18 minutes we had to prepare this presentation.We felt that it might be wise to take a peak inside the ventricle if you have a moment to spare when you are doing a transplant.Doctor Lepage astutely said it would not change your mind as to whether you did the transplant or not, but if you saw a good deal of subendocardial hemorrhage in the donor heart that you are transplanting, it might help you interpret what happens to the patient afterwards.I am sure if there is discussion, Doctor Barnard, there may be members of the audience that would be interested in pursuing this question further.Doctor Alksne, a neurosurgeon, discussed the soundness of the Harvard guidelines for irreversible coma.He aceepted them.Ile said they were good.He did want to emphasize again points that had been mentioned in this report.What was the effect of sedatives, hypothermia, aleohol, anoxia and shock?He felt the Harvard report had placed insufficient emphasis on the danger of misinterpreting these things, and that there should be blood tests to correct or eliminate the possibility of the coma being affected by any of these factors.Doctor Alksne spoke about spinal and cerebral reflexes and he left me out in left field, I could not follow him.I do not think, Doctor Lepage, you quite followed him either did you?Or am I underestimating you?pare TE ss set Lot Ya, \"k fic IF fil lil UE meld sim À over 3 nil We a ik Jane ld ie al qd a pu Laval Médical Vol.41- Fév.1970 Doctor Lepage: I had the distinet impression, Doctor Bigelow, that Doctor Alksne\u2019s position was that, whereas cerebral reflexes, like movement of the eyes to turning of the head, movement to irrigation of the ear with cold or hot solutions, those reflexes were very important in determining brain death.However, spinal reflexes like deep tendon reflexes, their absence need not be among the criteria for brain death as far as he was concerned, because these can be present even with severely and completely destroyed brain.This is the impression I had, Doctor Bigelow.Doctor Bigelow: You did a lot better than I did, Doctor Lepage.Thank you very much.He suggested, along with the previous speaker, that there was some interesting research with which he was in contact where you stimulate the midbrain and you find myocardial How is this mediated?James Key of Toronto has stimulated the vagus damage.I know Doctor nerve many years ago and found that he induced intravascular aggregation of red blood cells or sludging.That in turn produces peripheral stasis in all the organs and one wonders if this is not one of the connecting links between organic and functional disease.It might be one of the explanations for why stimulation of the brain produces a myo- cardial lesion which could be vascular.Doctor Lepage: Doctor Alksne also pointed out that the time limit of 24 hours (two separate examination 24 hours apart as recommended by the Harvard committee) might be completely unnecessary in a good many cases and he pointed out that it was the individual physician\u2019s responsibility to determine the moment of brain death or whether brain death was present or not, and guidelines were just guidelines.Doctor Bigelow: The last speaker was Doctor Poirier.I had a feeling that he was teasing us, titillating us and PROCEEDINGS OF THE FIRST GENERAL SESSION 229 stimulating us to think, One moment he would say that the criterion of a flat E.E.G.is a good criterion of irreversible coma, and a moment later he would explain what a very rough test this is, that it does does not indicate the refinements of cerebral funec- tion.In fact, how could a heart continue beating with a flat E.E.G., unless there was some sort of activity coming down from the brain to maintain this rhythm?That is disturbing.However I caught him after the session and I sort of got him up against the wall and I said: Now do you or do you not believe in this flat E.E.G.?And he said : Oh yes, it is the best thing you have and it is a good criterion.And I said: How long do you think it should be flat?He said: Just a few minutes.So he is on our side.I thought for a moment he was going to sink the ship this afternoon.Now I would like to ask Doctor Lepage if that was his reaction to Doctor Poirier\u2019s talk, and also I am sure he has many other interesting comments to make on the discussion this afternoon.If I may turn this over to Doctor Lepage.Doctor Lepage: Yes that certainly was our impression of Doctor Poirier\u2019s comments on the value of a flat E.E.G,, and having lived with him for many months, I can assure you that what he says can be interpreted in a reasonable manner.Ie of course realizes the limitations of the instrument much better than we do, which makes him a little more eclectic than we might be.There are other comments that were made which I think bear some remarks.The size of the donor heart in relation to the recipient was discussed and it was everybody\u2019s feeling that, bar ring of course a tremendous difference in sizes, usually one adult heart could be implanted into another adult patient even though he is quite a bit bigger.So the size discrepancy does not make much difference as long as it is not too much exagerated.The question of the presence of pulmonary hypertension in the recipient was also discussed.It was the general feeling that mild to moderate pulmonary hypertension, particularly since so often the left atrial pressure is very elevated in those 230 COMPTE RENDU DE LA PREMIÈRE RÉUNION PLÉNIÈRE cases, is not of great importance.But most people present I think would be hesitant in suggesting for transplantation or accepting for transplantation a patient with a systemic pulmonary hypertension on the basis of arteriolar resistance.I think that was the essence of our session this afternoon.Thank you.Doctor C.Barnard: We now have a few minutes for questions and discussion.l\u2019d like to open this discussion by mentioning a few points that I think have not been mentioned here.When we met about a year ago discussing the same problem, we came to the conclusion, in the selection of the recipient, that we would take all comers, no matter what age they were, what they suffered from, or any other consideration.Now we have seen how poor our results are in heart transplantation, and I wonder if the time has not come, to improve our results, that we should make more of a selection of our recipients, and I think we should set an age limit.We know that in renal transplantation it has been decided that there should be an upper age limit.I think this is flexible because one man of 50 is younger than another man of 50, but I was interested to note that Doctor Kahn, who obtained those wonderful results, had none of his patients older than 30 years.We certainly have struggled more in the older age group patients.I have a patient now 63 that I have operated on and it certainly has been a real struggle to get this man through the postoperative period.especially as he had been ill for a long time.And he has now the extra disease of immunosuppression.So I'd like to hear the discussion on the age limit.I also wonder whether a single patient demand for organ transplantation is great enough and.since facilities are still small, whether we should not take into consideration, when we select our recipient, the chances of getting a compatible donor for the antigens of this patient.What are the chances of these individual single patients getting a compatible donor?I know Doctor Botha has done Laval Médical Vol.41 -Fév, 1970 some work on this and he may discuss this in a little more detail.Another thing we have found is that all our patients in the postoperative period have developed a Herpes virus infection.I would like to hear your views on whether it is not important to know that the patient has natural antibodies against the Herpes virus, in the selection of patients for transplantation.I was also very interested in the work of the group in Houston on the immunological potential of the patient, how this varies and whether one should take this into consideration in the selee- tion of the donor.Then there is the selection of the donor and should one accept patients of all age groups as long as they have a normal heart.We certainly have found the best immediate results in the patient who dies of subarchnoid hemorrhage, that has had some hypertension and has a hypertrophied left ventricle.He seems to have more reserve in the left ventricle than the ordinary patient.I will now leave the discussion open to you.Doctor Vineberg: Gentlemen.I do not see anywhere in this program any method whereby one can estimate the amount of muscle left in the heart of the recipient.Maybe some of this information may come out, it seems to me that this is a very important affair.As we have gone with our revascularization surgery, we have gone on from patients that were not in failure to patients that were truly in failure, patients that were supposed to have very bad contractile ventricles by L.V.studies and so on.Now these patients çome out of failure after internal mammary implantation.Doctor Johnson in Milwaukee and others are also watching large hearts come out of failure when they transplant a vein graft into a coronary artery.Now an aspect that seems very important to me.What are the true criteria for our removal of a man\u2019s heart?After all, the human heart muscle has at least 300 per cent reserve.| think it is time that we studied each heart to see what the reserve is, plus its possible potential with regard to revascularization, versus TL lk ligieas x pe ole Laval Médical Vol.41- Fév.1970 transplantation.We have been offering revasculari- zation surgery to patients with no more than 40 or 20 per cent of their myocardium left according to the scar seen at operation and pre-operative studies.\u2018What percentage of the transplanted patients had less than 40 per cent of their myocardium left, would you say?These are points that I think should be brought up and I think there should be some standardization as to what kind of a patient has his heart nipped out with another one put in.Doctor Barnard: Doctor Vineberg, the first point of course is that all the transplantations have not been done only on patients with coronary artery disease.Many had myocardial disease of other origins which could not be helped by implantation.The second thing is that, I can only speak for myself, the patients with coronary artery disease that we have operated on I do not think you would have found muscle to implant an internal mammary in.You could look at the pictures of these patients: the whole myo- cardium was really replaced with scar tissue.And I think the experience of most of the surgeons who have done transplantation was that at least 80 per cent of the left ventricular myocardium has been I think it is difficult to estimate beforehand how much myocardium is involved with fibrous tissue.left.But, on studying the left ventricular action, there has been hardly any contraction of the left ventricle before we transplanted.Are there any other discussions?We have another two or three minutes for this.Doctor P.Grondin: I would like to say a word about Herpes.It is true that Herpes has been a problem in our patients.I think it is possible to prepare highly selective gammaglobulin against Herpes from patients who have had this infection in the last three months.We then can have in store enough concentrated and highly selective gammaglobulin against this and other viral disease.We could cure those patients in spite of immunosuppression.PROCEEDINGS OF THE FIRST GENERAL SESSION 231 Doctor Barnard: Are there any more comments on this Herpes point?I think this is interesting.Doctor X : We have looked at a lot of patients who were either born with a defect in cellular immunity or develop one, because of immunosuppression, or what not, and those are the circumstances that give you the generalization of this otherwise latent virus.Unfortunately in all of the experience that I have had and that a lot of other people have had, we were not able to definitely turn off that with antibodies.It requires cells.And 1 am afraid that we are not going to be able to have an effective Herpes antiserum that is reallv going to alter the course.Perhaps, but I would be surprised.Doctor Grondin: We do not have much experience with this, but we had a patient with severe necrotic intercostal Herpes Zoster who went on to develop Herpes vire- mia.He was then very sick and almost dving.The only thing we had was non selective human gamma- globulin, We treated him with 100 ce 1.V., and in 24 hours, he recovered dramatically and was up and around.I have a feeling that this large amount of non selective gammaglobulin really prevented him from dying at that time.1 am told by our bacteriologists that the amount of specific globulin against Herpes in the general population is very small.But if one takes blood from people who have recently recovered from Herpes, one could have a much more potent globulin.Doctor Butler: I would like to make a comment at this point not in the heart transplant program.Doctor Arthur Beal] transplanted a human lung last August 31st in a patient who turned out to be particularly interesting.The recipient had a history of recurrent Herpes virus infection (fever blisters).The donor did not.To make a long story short, Doctor Gordon Ra ti CONNER Douglas did virologic studies to indicate post- operatively that the patient developed Herpes simplex infection of the transplanted lung but not of the remaining recipient lung.Now this raises some interesting theoretical implications one of which is that the patient, who had a history of recurrent Herpes infection, may have had the cellular immune mechanisms present that prevented infection in his residual lung whereas the donor lung may not have had the same mechanisms operative to prevent infection in that lung.Doctor Barnard: I am afraid we will have to stop this part of the discussion.We now go on to surgical technique and organ preservation chaired by Doctor Denton Cooley, Houston and Doctor Yves Castonguay, Montreal.Doctor Cooley: To discuss each of these papers separately we will start with the first paper by Doctor Paiement and his group from the Montreal Heart Institute on anesthesia.He pointed out that in his experience with nine patients, eight of whom did satisfactorily after transplantation, in each instance they used hypothermia in the donor down to 18° centigrade with total body perfusion.In his postoperative experience, they did not use vasopressors, Isoproterenol or cardiac stimulants, and he attributed this to the fact that these hearts were protected in this manner.I do not believe this is the uniform experience from other transplanters and I was somewhat surprised at this conclusion that he made.He emphasized the need for early ex- tubation of the patient after anesthesia and also brought up the matter of the importance of early ambulation, a point which Doctor Barnard himself questions, in that he sees no particular benefit in early ambulation, assuming that the allograft is in a somewhat precarious position at least for the first few days after transplantation.Doctor Barnard made a comparison with patients following myo- cardial infaretion, in which early ambulation has not been proved to be a desirable technique.These COMPTE RENDU DE LA PREMIÈRE RÉUNION PLÉNIÈRE Laval Médical Vol.41- Fév.1970 were the points that were brought out in this paper on anesthesia.Maybe Doctor Castonguay would add to this?Doctor Castonguay : I think that Doctor Paiement mentioned that six of the eight patients that did well after heart transplant did not receive any vasopressors.In the other two patients, a continuous drip of Epinephrine was used in one case for a period of two hours post- operatively, and in the other case Isuprel was used in the same manner for a period of about one hour post-operatively to control slow heart rate.We do not think that early extubation is an absolute necessity, but in our experience, these patients have done so well in the early postoperative period that we just felt they did not need to be intubated for a prolonged period of time.As for early ambulation, we think that getting out of bed soon after the operation is a good moral stimulant for these patients, and prevents known complications of long immobilization.I agree that the allo- graft might be in a somewhat precarious position, but I do not think it can be compared to an in- farcted myocardium where acute metabolic changes of the muscular fiber itself is responsible for the irritability and instability of the heart.Doctor Cooley: I think in this regard most of us believe that some form of cardiac stimulant postoperatively is essential.In most of our patients, not in all but in most of them, we have kept available an Isopro- terenol drip which ean be used in the first 24 to 48 hours and if the transplanted heart is deficient in anything, it seems to me that it is deficient in this particular drug.Vasopressors have not been utilized in our cases postoperatively and we have depended upon either Isoproterenol or injections of calcium chloride.In the majority of our patients we have also digitalized the recipient post- operatively, believing that the transplanted dener- vated myocardium is in need of some drug stimulant such as Isoproterenol or calcium or digitalis.In regard to the surgical technique, in my report, Laval fol J The et wih berg fy to the fro tal ing 1 li py hey of the Ay, yg Jul sta] eubla ily Jey Brg tigi ity The 0 Vu Th | yy | lay Mg, te fy Un ts tal, lay, ag Ty ny ig » ly Wédienl Fr 1910 Lis paper x vou pur Su art tras the other Irie was As poste sl pe hoe san al ils Pb pete pl le , dela a il fil Jul couplé he alle \u2018 pti pik jd fi for the Laval Médical Vol.41- Fév.1970 I pointed out that most surgeons have now adopted the standard technique of Shumway and Lower.Most surgeons it seems are using the modification which Doctor Barnard introduced in Philip Blai- berg where an effort was made to preserve the continuity of the sino-auricular internodal pathways to the atrio-ventricular node.This incision is made from the inferior vena cava toward the right auricular appendage.1 think we will recall this morning though, in Doctor Dubost\u2019s presentation, that his patient Father Boulogne had an incision between the venae cavae and from what I could see of the electrocardiogram, he does have sinus mechanism.So I do not think it is invariably true that an incision between the venae cavae is going to produce a nodal rhythm but I think the incidence should be far higher in those cases.It was reemphasized that complete excision of the right auricular appendage as well as the left auricular appendage of the recipient should be performed because these are relatively ischemic portions of the remaining atrium and may be a nidus for the formation of intra-atrial thrombosis and embolism.The question arose whether to use hypothermia or to maintain the recipient in a normothermic state.Those of you who know my attitude in this regard know that we adhere to the school which would maintain normothermia in the recipient.I think personally that the reason for the prompt recovery of the heart allograft in our cases is probably related directly to the use of normothermia.In addition to these reports we reported on a technique of total cardiopulmonary transplantation used in one moribond infant with a complete A.V.canal and extensive pulmonary damage.Doctor Barnard asked why we did a transplant there instead of a pulmonary banding, and I believe the reason we did this was the same reason he used cardiac transplantation in Doctor Blaiberg instead of an internal mammary implantation.We also reported on our two stage technique of cardiac replacement utilizing orthotopic cardiac prosthesis first and three days later replacing the prosthesis with a cardiac allo- graft.This technique will be shown in a movie this evening which Doctor Liotta will narrate for us.PROCEEDINGS OF THE FIRST GENERAL SESSION 233 The third paper was from the Palo Alto group and was presented by Doctor Stinson.In his paper on myocardial protection in heart transplantation, Doctor Stinson advocated the use of moderate topical cooling of the heart and did not believe that simultaneous perfusion of the allograft was necessary.They have tried both apparently and have settled on the topical cooling.He reported some interesting laboratory experiments in which they tried to determine the recuperability of the hearts which were preserved ischemic at varying temperatures: at 15° temperature he was able to ressus- citate an animal heart 230 minutes after it had been removed trom the pericardium, So that it does appear that induced hypothermia in animals does preserve the contractility of the heart for prolonged periods.Doctor Barnard and several others advocated the use of both hypothermia and perfusion of the heart.In our group and in many others, simple normothermic conditions and total ischemia are used for the relatively brief period of time taken to transfer the heart from donor to recipient.Now then, the last two papers were primarily directed toward the same subject: methods of storage and preservation of the heart.Of course this is something of vital importance to organ trans- planters and particularly to heart transplanters, sinee we have, to this time, not found reliable or dependable methods of preservation of the heart.Doctor Proctor\u2019s presentation was particularly interesting in this regard.He had a technique with the isolated heart in a chamber with no oxygenator at all, and perfusing Krebs solution, was able to maintain the viability of the animal heart for prolonged periods of time.Again, as I said, he used no oxygenator in his system.Doctor Pitzele showed a very interesting film strip on the technique that they had used in preservation of the heart.In contrast to Doctor Proctor\u2019s group, Doctor Pitzele had removed the heart intact in the pericardium as a protection and I suppose also as support.His venae cavae were ligated so that the allograft would recirculate all of the coronary sinus blood.The technique he used involved the use of plasma as a medium and he used a membrane oxygenator with 234 COMPTE RENDU DE LA PREMIÈRE RÉUNION PLÉNIÈRE rather low flows, about 150 ec per minute.He said that the plasma developed a partial pressure of oxygen of 500 mm He, a very interesting fact to me.He also related of course that the problem with these preserved hearts is to know if they have sufficient reserve to justify one using them in a human recipient.The factors which he thought were the best index of this myocardial viability or reserve were found in the level of inorganic phosphates in the perfusate and 1 thought that this was the principal contribution he made in this regard.Doctor Barnard: Well this part is open for discussion now.I might just mention a few other points.One might say the transplant team has two patients to look after, the donor and the recipient.When the donor is handed over by the other team, then I think the prime purpose of the transplant team is to keep the heart of that donor in as good a condition as possible until that heart has been transplanted in the patient and of course the best way to keep that heart in a good condition until it is taken out is to keep the best circulation possible in the donor.It is important here to correct such things as blood volume, metabolic acidosis, electrolyte imbalance and also to stimulate the heart if necessary.Doctor Cooley questioned the advisability of per- fusing the heart after it is removed.I mentioned that it is interesting to me that during the operation we preserve the brain, the liver and the kidneys and all the other organs of the patient by perfusion, vet we feel it is bad to preserve the heart by perfusion.Another point, which was mentioned by Doctor Stinson this morning and which I think is important is that 1 think inguinal canulation of any kind is dangerous.I think that actually some patients were lost from infection that started at the inguinal region and spread.It is a region that does not heal well afterwards and is very near areas of infection.One thing that T want to point out about Doctor Cooley\u2019s heart prosthesis is that I do not think Laval Médical Vol.41-Fév.1970 that when a patient wakes up properly and has good cerebral funetion, it necessarily means that the patient has a good perfusion.I think he pointed out, and that is important, that the patient had very poor urinary output after the prosthesis was inserted and to me, that indicates poor cireulation.This is now open for discussion.Doctor Proctor: 1 would just like to make one correction to Doctor Cooley's discussion.Our technique for storing the heart for long periods involved oxygenating the Krebs solution to a pO» of 400-500 mm He.Doctor Heggtveat: I would like to raise a point here that was toueh- ed on briefly at a meeting of a Study Group on myocardial infarction at the World Health Organization headquarters in Geneva in March: what is being done with these exeised living, beating, ische- mic human hearts?Are they being dissected conventionally and tossed in a bucket of formalin?It would seem that this is unique experimental material.Could not these hearts be kept beating in vitro for a period of time and their metabolism studied prior to their dissection\u2019 Doctor X: One word about non-perfusion of the heart during transplantation.We say the simpler the better.We do not perfuse our hearts because I think it has been demonstrated that the heart can be maintained during 40 minutes or more without harm and I think the perfusion methods now in use are not physiological so one does not know if one is harming the heart or helping it by perfusion.Doctor Dobell: We had an experience that may be unique.Most of these denervated hearts have sustained a reasonable heart rate after transplantation.For some reason our heart recipient, in sinus rhythm, had a bradycardia.The heart rate when the patient was awake would run around 60 and when the patient was asleep around 45.Under these conditions the patient would develop a gallop rhythm and it was Bari fol.41-] dhs np fet wi Josie beat 1 mad be en aly Jy Wonder Yost he DEA Duel Ig The Pty i Tyg Fi fly.1 she].al, date fi Te ay le gy lity li ns \u201cpy Me lig uy ili, oy LL Tag, try Hi Lédival -Pir, 140 | ad ls pans {lit de pui tent bad (sis Wak rtm.qd ht J i sung rng tle ik pas tl gop ot re ar iy, se du al If pal I pte i | able | Laval Médical Vol.41-\u2014 Fév.1970 obviously not a desirable rate.Fortunately we had implanted wires into the myocardium and the patient was driven with a pacemaker for one month, postoperatively, with repeated evaluation of his own heart rate which was always slow.Finally a demand pacemaker was implanted at à rate of 85 and he continues to be paced at 85, breaking through only in periods of rather extreme exertion.I am wondering if anybody else has had this experience ?Most hearts, I gather, beat at a rate of about 80 or 90, but this one chose not to.Doctor Webb: I would like to emphasize the problems oË storage.The problems of technique have been well handled, as illustrated by some 30 centers throughout the world that have handled the technique very successfully.The problems of storage still remain to be solved: three days is not enough even with Euro- pool.We need long term storage to allow proper matching of the recipient with the donor.Our perfusion system as described today is still incomplete.We can supply metabolites but do not get rid of the end products of metabolism because there is not a liver or a kidney in the system.Freezing remains the only way we can possibly achieve long term preservation of organs and unfortunately no one as yet has come up with any possible solution to the freezing problem.Until we do solve long term preservation, we are not going to be able to achieve the results that we would like to have.Also, of course, when our immunologists develop true tolerance, or even true enhancement, then cardiac transplantation will truly come into its own.But these two major problems still remain unsolved.Doctor Neville: Nothing has been said about donor and recipient committees in hospitals.In our institution, it was decreed that a separate donor and recipient committees be mandatory.It was stipulated that we could not remove the donor heart until it had ceased functioning and E.E.G.was flat.Under these conditions it is still possible to heparinize the patient (a) PROCEEDINGS OF THE FIRST GENERAL SESSION Do co pn and ecannulate the vessels in the groin before death.Then, when the heart stops beating the donor ean be placed on peripheral cardiopulmonary bypass with an oxygenator.In our only heart transplant, Doctor Pifarre, my associate, and another oxygen- ator team, waited until the donor heart ceased fune- tioning.Peripheral cardiopulmonary bypass was stituted immediately and they were able to remove a beating viable heart after we had placed the recipient on bypass and excised his heart.By utilizing this technique it is possible to obtain a well oxygenated donor heart and still comply with the demands of the various peer groups.Doctor Barnard: I might mention that, in our first three patients, we did not remove the donor heart until the heart had stopped beating.In the last two we removed the heart while it was still beating and to me it seemed to make very little difference in the immediate postoperative take-over of this heart, whether one left it until it stopped beating or whether you took it out while it was beating.The other point that I think was stressed at this session and I think should be mentioned again for people who study preservation of hearts is this: I do not think it is enough just to see how long they can keep that heart beating, I think that means very little.I think they will have to show us that that heart can take-over the circulation properly after it has been stored for any length of time.This is the acid test, not how long you can keep it beating.Are there any other questions?Doctor Cooley: I would like to discuss the point that you raised about whether this prosthesis was actually providing a satisfactory cardiac output.The electromagnetic flow studies which we did directly on the pumping device revealed a cardiac output of 5 to 5.5 liters per minute.Moreover during the postoperative period, the patient\u2019s blood pressure could be ajusted at most any level that we desired, and it was usually 110 to 120 over 80.It is my conten- 236 tion that if there was a reduced renal function, and of course there was, it was due primarily to humoral factors rather than to hemodynamic factors.This device will pump large quantities of blood, water, or whatever you use as a medium.This patient had high plasma hemoglobin immediately upon discontinuing cardiopulmonary bypass, and I believe this led to tubular necrosis.Doctor Liotta: I would like to make a few comments.With the heart prosthesis, the circulatory situation can be handled according to the physician.The patient that had a prosthesis may have had too low a cardiac output, but this could have been easily corrected or controlled.If it happened in this patient, it was not a failure of the procedure or of the system, but a technical failure on our part to interpret which cardiac output would be necessary for this particular situation.Doctor Barnard: What was the renal function in your animal work with this prosthesis?Doctor Liotta: Variable.In some animals it was excellent, in others, it was poor, and sometimes related to cardiac output.It is a very well known fact that the kidney is the more sensitive and best flowmeter we can use, much better than electro-magnetic flow- meters.But in animals, mainly the calf, it is a little more difficult to obtain an acceptable cardiac output from the prosthesis.Doctor Ersek: In Turkey, we did the transplantation in this way.After the heart stopped, we started perfusion and then we cooled the donor down to 18° and then we removed the heart and we transplanted without any perfusion at all.After releasing the cross- clamped aorta, the heart started to beat in half a minute spontaneously.We believe that this technique has the following advantages: 1) Confirmation of legal death as accepted in the Turkish penal code, because you have to have a stopped heart COMPTE RENDU DE LA PREMIÈRE RÉUNION PLÉNIÈRE Laval Médical Vol.41- Fév.1970 before using this heart in Turkey; 2) À better preservation of the donor heart by core cooling with perfusion; 3) The preparation of the recipient is not unduly hurried since the donor is supported by total body perfusion.The decision to transplantation can be made following the direet examination of the donor heart; 4) No crowding of the operating field by cannulae and tubes since the coronaries are not perfused during the anastomoses.No suction for coronary cireulation ; 5) Consequently, the operation can be performed in a very comfortable manner similar to work on cadavers.Doctor Barnard: We now come to the session on histocompatibility in heart transplantation.Who is going to discuss this, Doctor Colombani, or Doctor Potworowski?Doctor Colombani: We shall summarize this session on histocompati- bility in heart transplantation in two parts.The first part was devoted to the problem of ABO compatibility and the second to HLA compatibility.In heart transplantation as well as in kidney transplantation, ABO compatibility is now always respected.Doctor Sekiguchi spoke about the problem of red blood cell antigen compatibility in heart transplantation: ABO compatibility is always respected but problems of interpretation arise with Rh and other blood group antigens compatibility.There is no evidence that Rh compatibility plays a role in heart or kidney transplantation.Nevertheless, Rh compatibility is generally respected as in the case of transfusions.From the study of red blood cell antigen compatibility, it was suggested that it might be useful to determine as many antigens as possible from donors and recipients in order to allow an a posterior: analysis.The problem of pre-existing anti-red cell antibodies was presented by Doctors Sekiguchi and Dos- setor.Doctor Dossetor reported one case in which anti-red blood cells as well as anti-lymphocytes cytotoxic antibodies existed and this case was terminated promptly in rejection.The role of the anti-red cell antibody in this case is questionable besa anti cel an the thane For Doctor these 1% 37 Jo ili 1 he EX lig The ie ly leg Rls) mit; | te ha fil aft gy Sug ly dug) 0 gg Th a Médical Fig, 16 \u201cpr | ng ith Ape appurted rsp maf thè opet- li I.quel afi pus diet \u201cA I, pit Laval Médical Vol.41- Fév.1970 because there were at the same time anti-lymphocyte antibodies.It is clear that the presence of anti-red cell antibodies reflects a general immunization of the recipient, which means that he has a better chance of having anti-tissue antibody.For HLA, the problem was discussed mostly by Doctor Terasaki and ourselves.The deseription of these antigens is becoming more complete : there are now six officially recognized antigens: HLA 1, 2, 3, 5, 7, 8, and others which are under study in the different laboratories working in this field.It can be expected that in the next year, six or more new antigens will become official.These antigens are determined by genes which are located in a chromosomal region subdivided in at least two sub-loci.The importance of these antigens in transplantation was studied experimentally with skin-grafts.It was then studied in the case of kidney transplantation and is now studied in the case of heart transplantation.The experimental skin-grafts made from child to father led to the conclusions that to obtain a good tolerance of the graft it is necessary to realize an identity for two antigens at one sub-locus, and for at least one antigen at the other sub-locus.That means that if one only had the antigens well determined at the two described sub-loci, i.e.a minimum of four antigens, one can accept one incompatibility but no more.The same conclusion can be obtained when the correlation between kidney graft and HLA compatibility is studied.This fact was presented by Doctor Terasaki who showed that in kidney transplantation for what he called a D match (that is two incompatibilities or more), one can expect rejection after six months to one year.Finally, this problem of HLA compatibility is now being introduced in the field of heart transplantation and from a survey made by Doctor Potworowski who sent a questionnaire to the different teams working in this field, it was observed rather surprisingly that HLLA antigens were often determined before transplantation: from the 16 teams questioned, 13 said that they tried to determine tissue antigens before transplantation.That means that probably one day or another, they will take them into account.In Doctor Terasaki\u2019s PROCEEDINGS OF THE FIRST GENERAL SESSION 237 study of 49 cases of heart transplants, these were classified for HLA compatibility, and the letters B, C, D, refer to the match in terms of Doctor Tera- saki\u2019s nomenclature: B is a good match and D is a bad match and it seems that the B matches behaved better than the D matches.The same conclusion can be obtained from Doctor Potworowski\u2019s survey which he will comment himself.Doctor Potworowski: It is apparent from our survey of 51 heart reei- pients that over half of the B matches are still alive whereas only between 30 and 40 per cent of the C matches are alive and only 14 per cent of the D matches are alive.The average survival time for the deceased recipients is about fourteen weeks for the B and C matches with no significant difference between the B\u2019s and the C\u2019s and, for the D matches, average We could not find any correlation between the match and the rejection survival is about four weeks, crises, either their number nor their strength.Doctor Colombani: Finally the last part dealt with the possibility olf pre-existing anti-tissue antibodies before transplantation.It is clear now that a positive cross- match for tissue antigens, made for example by the lymphoeytotoxicity technique with the serum of the recipient against the lymphocytes of the donor, means a very bad prognosis and must be considered as a straight \u2018\u201cveto\u2019\u2019 for transplantation.The problem of organization of prospective typing in heart transplantation was also raised and it seems that the same principle should apply to heart transplantation as for kidney transplantation, that is making a pool of prospective recipients previously typed and waiting for a donor.Finally it was suggested that it would be very useful to collect the data from the teams working in heart transplantation in a heart transplant registry similar to the kidney transplant registry which gave very interesting results about the relationship between success and histocompatibility. 238 COMPTE RENDU DE LA PREMIÈRE RÉUNION PLÉNIÈRE Doctor Barnard: This session is now open for discussion.Being a surgeon 1 would not start the discussion, I will leave it to somebody else.Doctor Kahn: Are some transplantation antigens stronger, and therefore more important than others in heart transplantation ?Doctor Colombani: You want to know if there are strong antigens and weak antigens?I think that even for kidney transplantation, it is not possible at the present time to answer this question but it seems likely (that\u2019s just an opinion) that all the presently described antigens have the same strength.Doctor Barnard: Any other questions?Doctor X : I would like to know.Doctor C.Barnard: \u2018What is your name, please?Doctor Marius Barnard: Marius Barnard, Sir.I would like to know, as I am listening to people discussing matches, how one can refuse to transplant, unless he has a B or a C minus match, a desperately ill patient, when we have heard about some very good results with a C plus or a D match.Doctor C.Barnard: Doctor Cooley, would you like to answer that question?Did you get the question ?Doctor Cooley: My attitude and opinion about the selection of donors and recipients have not changed very much in the last twelve months since we had the conference in Cape Town.I believe that there are other extenuating circumstances which should determine the advisability of a transplantation and Laval Médical Vol.41 -Fév, 1970 these extenuating eircumstances are very well known to anyone who is actively engaged in any clinical program.I do not think that we can say that a man who is 50 years of age is any less likely to benefit from the operation than a man who is 45.The question we are here to answer is whether a man has a right to live longer.And it is a matter of interest about tissue matches.What does one do as we did three days ago, when he has an ideal donor in term of physical qualities, when he has a man who is at the point of death who could benefit from a cardiac transplant?Does one wait for the tissue typing?It takes two to five hours in our institution to get an answer on the tissue typing.This point came up again with us just this week, we transplanted this man, he subsequently was proved to have a D mateh and I think it is far better to have a D match and be alive than wait for a B match and be dead.So even though these are interesting points, they cannot be the determinants in a clinical situation.I do not think that we have yet reached that point, where we can be so rigid in our methods of selection.Doctor Barnard: Well, I will speak for myself.I think that I, in the future, will not select old patients anymore for cardiac transplantation.I do not think I will select these patients of 65 or old 60\u2019s for cardiac transplantation because I have a lot of other patients I can operate on and I am quite sure I can get better results in the younger patients.Secondly I will not select, if I have other patients, a patient in which my chances of getting a well matched donor are poor.I would rather select a patient in wiheh my chances of getting a good match is good.Now if, with that patient, I get a D match, I will transplant, but my chances of getting a B mateh or a C mateh is much greater.I think those are my personal views and I think that is the only way, with the present poor methods of immunosuppres- sion, we are going to obtain better results.As we all agree on that point, I think we will thank the people who have discussed these papers and I hope you have a lovely evening.THE | voi À i Jin | 7\" § THE USE OF ALG IN 56 CASES OF HEART TRANSPLANTATION * tan Tr Gilles LAMOUREUX t ske Head of the Immunodiagnostic Laboratory Wid of the Institute of Microbiology and Hygiene lr of the University of Montreal 1 mater SUE Un questionnaire sur la nature du sérum antilymphocytaire (SAL) utilisé dans les transplantations cardiaques ainsi qu\u2019un questionnaire concernant | son emploi dans chaque cas de transplantation ont été envoyés à tous les | centres où une greffe cardiaque avait été effectuée avant janvier 1969.arlk Les données recueillies a la suite de ce guestionnaire nous ont permis LS | d\u2019évaluer le rôle du SAL au cours de 56 transplantations de cœurs humains réalisées dans 22 hôpitaux un peu partout à travers le monde.Les sources de SAL utilisées pour les transplantations cardiaques jm étaient différentes quant à l\u2019antigène utilisé, les méthodes et la voie d'im- % munisation, l\u2019animal de production, le temps des saignées et les méthodes | an lei he has , Hsph is 1 15H de purification.Trois préparations de SAL sur 14 utilisées pour les greffes cardiaques itt fe se sont montrées immunosuppressives chez les singes inférieurs et les ist primates et cinq préparations ont inhibé chez l'homme l\u2019immunité cellulaire vis-à-vis certains antigènes.La dose de sérum utilisée a varié suivant les ill i polit (suite du résumé en page suivante) | This Second world symposium has two main ob- suppressive activity.The second questionnaire dealt | jectives: first to evaluate the present situation of with the use of ALG in each case of heart trans- gathered so far and, secondly, to foresee the pros- tration of ALG, the incidence of local and systemic pects for future heart transplantations.My contri- reactions, the induction of anti-horse antibodies, bution to this Symposium will be to summarize the the number of rejection episodes, the survival time data obtained with the use of antilymphoeytie of the patients, and the role of ALG in these trans- serum in 56 cases of heart transplantation.plantations.The results obtained from these ques- Two questionnaires related to the use of ALG tionnaires, with the kind collaboration of each cen- were sent to each center where heart transplantations had been performed before January 1969.LB heart transplantation on the basis of observations plantation; we have recorded data on the administer, will be summarized in this presentation.| | | | | itt\u201d The first questionnaire dealt with the production Answers to the questionnaires: sot {£ the anti-h n lymphoeytic sera used in the i» 1 ° r Uman [ymphoeysic = re 4 ! .The questionnaires were sent to 32 centers, where A417 treatment of these heart transplantations: the anti- ; .To .an over-all total of approximately 100 heart trans- th?gens used and the techniques of production, the .i ; / i tv of the i Tobuli à the i y plantations had been performed before January Gi arity g n vitro ; 3 ol oY y .\u2026 a a an a © ?\u2019 1969; 22 of these centers (68 per cent) completed i: and in vivo t t sess t - .a ; | nd an vio tests performed to assess thew Hmino the questionnaires.ALG was used in the treatment ar .pil?\u2014 of 56 of the 70 cases of heart transplantations per- | | * 1e si » .J Paper presented at the Second world symposium on formed in these 22 hospitals.In two centers out il ! heart transplantation, Montreal, June 6-8, 1969.9 ; + 531 des Prairies Blvd, Laval des Rapides, P.Q.uf Canada, was not used in the treatment schedule.of the 22 which answered the questionnaire ALG Gilles LAMOUREUX Laval Médical Vol.41- Fév.1970 hôpitaux, entre 0,1 mg à 10 mg d\u2019'IgG par kilogramme de poids, et la majorité des patients ont reçu le SAL à partir du jour de la transplantation pour une période variant de deux semaines à plus de huit mois.La douleur locale et l\u2019élévation de la température demeurent les principaux inconvénients de l\u2019administration du sérum antilymphocytaire par voie intramusculaire.Les critères sur l\u2019évaluation du SAL dans son utilisation en clinique ont été tellement variables d\u2019un centre à l\u2019autre, qu\u2019il nous a été impossible d\u2019établir ou de nier son efficacité comme agent immunosuppressif dans les transplantations cardiaques.Source of ALG: The ALG preparations came from fourteen different laboratories.All but two of these preparations were produced in horses.Six different sources of human cells were used as antigens for the immunization: spleen, spleen and lymph nodes, spleen and thymus, thymus, peripheral lymphocytes, and thoracic duct lymphocytes.The mode of immunization, the time of bleeding, as well as the use of adjuvant varied from one laboratory to another.Altogether, 31 patients were treated with anti-thymus serum (3 sources) and 11 patients with anti-thoracic duct serum (2 sources).The remaining 13 patients received ALG produced with antigens from cells of the other sources listed above.Evaluation of the immunosuppressive activity of ALG: Of the 14 ALG preparations used, three were tested for their capacity to maintain skin grafts in monkeys.Five of the 14 preparations abolished delayed hypersensitivity type reactions to various antigens in vivo, including PPD, toxoplasmin, coc- cidiomyein, DNCB, measles, ete.Two of these ALG were tested for their ability to stimulate blastogenie transformation in vitro, and both were found to be positive.Four ALG preparations were not tested at all for their immunosuppressive activity before use.Rules for the administration of ALG: ALG was given from the time of transplantation in 92 per cent of the 56 cases and in 8 per cent for the rejection episodes only.In 10 of the patients, administration of ALG was discontinued for various reasons : development of anti-horse antibodies (3 patients) ; termination of the planned course of treatment (2 patients); pain, infection, allergic reaction, thrombocytopenia, and lack of ALG (1 patient in each instance).Sensitivity to horse serum proteins prior to ALG treatment: Sensitivity to horse serum proteins was tested prior to the injection of ALG in 45 patients, but not in the remaining 11.Among those treated, three patients (7 per cent) gave a positive response.One patient not tested prior to the first injection of ALG died of anaphylactic reaction 90 minutes after the injection.Symptoms caused by ALG: Table 1 summarizes the percentage of patients presenting symptoms due to injection of ALG.On the whole, pain and fever developed mainly in the TaBLE I Symptoms caused by injection of ALG TIME AFTER INJECTION SYMPTOMS 0-6 hrs 6-12 hrs 73% 46% 50% 35% Local erythema 29% 44% Lymphopenia RE 62% 66% Leucocytosis 10% 31% Thrombocytopenia .__\u2026 6% 11% Loreal Vol.4I- firs i dng, pent tin | rs | fregue at fe Cutan iy to dig Were ] voie \u2018nat hy i fédicoi bn, 197 a mae nisin douleur ang: ramus: nique possible il dans a, {ls w.Ou Jf AL \u201cet \"le \\ Laval Médical Vol.41- Fév.1970 first six hours following the administration of the drug, while local erythema and thrombocytopenia appeared mainly six hours or more after the injection.Liymphopenia was observed shortly after or more than six hours after the injection with equal frequency.It evolved from the data that the pain and fever produced by the intramuscular or subcutaneous route of administration were mostly seen during the first weeks of treatment and then tended to disappear.Presence of anti-horse and anti-sheep antibodies after the administration of ALG: Tests to detect anti-horse or sheep antibodies were performed in 22 of the 56 patients studied, using the immuno-diffusion or the passive hemagglu- tination technique.These tests were performed from one to 32 weeks after the first injection of ALG.Of the 22 patients tested, 6 were positive (27 per cent) and 16 were negative (73 per cent).Rejection episodes during treatment with ALG: The rejection episodes were classified as doubtful, weak, strong, or no rejection at all.Table II shows the percentages of the rejection episodes, according to their type, that occurred in the first twelve weeks following heart transplantation and more than twelve weeks after transplantation.The number of rejection episodes was much higher in the first twelve weeks than afterwards and there were 20 deaths during this 12-week period.Among the remaining 36 patients that survived for more than TasLe II Classification of the rejection episodes totalling 111 in 56 cases of heart transplantation THE USE OF ALG IN 56 CASES TIME Typ F REJECTION E OF REJECTION EPISODE AFTER TRANSPLANTAION 1-12 weeks 12 weeks Doubtful 111110000000 10% >3% Weak een 12% 2% SErong oe 44% 13% No rejection 9% 9% 241 three months, 9 per cent showed no signs of rejection, even nine months after transplantation.Survival time in 46 heart transplantations: Table IIT summarizes the survival time, in weeks, in the 46 cases documented in response to this question.Among the nine patients that died during the first week following transplantation, rejection was not found to be the cause of death, with one exception.If the immediately postoperative deaths are excluded, number of deaths occurring during the first twelve weeks was similar to the number of deaths occurring between 12 and 24 weeks after transplantation.It is very encouraging to see that nine patients (17 per cent) out of the 56 patients studied altogether survived for longer than six months.Was ALG a potent immunosuppressive drug in heart transplantation ?The data reported in the present study do not permit an evaluation of the immunosuppressive activity of ALG.Too many factors were involved at the same time: the type of ALG used, its lack of standardization, its association with the other immunosuppressive drugs, the lack of appropriate controls, etc.ALG was employed together with the other immunosuppressive agents in all cases, in order to increase the chances of a successful treatment rather than to test the immunosuppressive TasLE III Survival time in 46 * heurt transplants performed before January 1969 and treated with ALG SURVIVAL TIME IN WEEKS 0tol 1 to 12 12 to 24 > 24 Deaths .9 (19%) |15 (33%) |11 (24%)| 2 (4%) Alive \u2014 \u2014 \u2014 9 (19%) * Data on 10 additionnal cases unavailable. 242 activity of ALG.The heart transplantation was an experiment in itself; it was obvious from the questionnaire that no real attempt was made in any centers to assess in human, the immunosuppressive activity of the ALG preparation used, per se.On the whole, the preparation of ALG employed were all accepted from the start as being potent immuno- suppressive drugs.Three main sources of antilymphoeytic serum were used for heart transplantation: horse anti- human thymocyte serum produced in Houston and used for treating 17 cases ; horse anti-human thymo- cyte serum produced in Montreal and used in Gilles LAMOUREUX Laval Médical Vol.41- Fév.1970 Canada in the treatment of 14 cases; and horse anti-human thoracic duct lymphocyte serum produced in Munich that was used to treat nine cases.With the Houston serum, as with the Montreal serum, 40 per cent of the patients survived for more than three months, while with the Munich serum, 50 per cent of the patients survived for more than three months.The means of the rejection episodes, per patient, during the first three months was as follows: 1.6 for patients treated with the Houston serum, 1.7 for patients treated with the Montreal serum, and 1.5 for patients treated with the Munich serum.LES HAUT fédical &, 1 à Ir LES AVANTAGES D\u2019UNE GLOBULINE ANTILYMPHOCYTAIRE : HAUTEMENT PURIFIEE * ; li pry i?(HES.wil Maurice CARRAZ, M.D., rl i Vmieh ul Lr Service d'immunologie, Institut Pasteur de Lyon, France.De nombreuses recherches sont faites en vue d'obtenir du sérum antilymphocitaire et des immunoglobulines pourvus du minimum de ca- ractéres antigéniques.Des |gG ont été obtenues chez le lapin et le mouton par chromatographie sur DEAE-cellulose et DEAE-sephadex.L'auteur a obtenu un bon rendement soit par le procédé d\u2019électro-décantation, soit par le procédé Rivanol-alcool, d'une IgG de mouton antilymphocytes humains.Le but de ces études est de perfectionner le sérum antilymphocytaire = humain de façon à isoler et augmenter au maximum l\u2019activité immuno- suppressive pour un minimum de protéines hétérologues injectés.Outre le sérum, il faut également fournir les IgG présentant un maximum d'effets immunosuppresseurs pour un minimum d'effets toxiques.Au deuxième congrès sur la transplantation, sir Peter Medawar nous invitait à garder à l\u2019esprit que l\u2019administration de sérum antilymphoeytaire est une thérapeutique de conception archaïque, puisque l\u2019injection de protéines de cheval à l\u2019homme demeure un non-sens.Or, en trois ans, les nécessités de la transplantation humaine ont fait de la sérothérapie habituelle une thérapeutique continue et prolongée avec parfois des reprises et tous les risques que cela comporte.D'autre part, la transplantation du cœur a certainement ouvert à la sérothérapie la pratique presque continue de la voie intraveineuse.Après trois ans d\u2019applications humaines, on peut constater que les incidents dramatiques de cette thérapeutique n\u2019ont pas été ce que l\u2019on pouvait prévoir d\u2019une thérapeutique par sérum hétérologue, sans doute grâce aux immunosuppresseurs chimiques associés mais également aux propriétés mêmes du sérum antilymphoeytaire capable d\u2019induire une tolérance aux protéines de cheval à condition toutefois, contrairement à ce que l\u2019on pouvait penser, d\u2019aug- * Travail présenté au Deuxième symposium mondial sur la transplantation cardiaque, Montréal, 6-8 juin, 1969, menter considérablement les doses (Brendel).Cependant, 11 est même certain, comme Balner et Van Bekkum l\u2019ont indiqué au cours d\u2019études expérimentales sur des singes, que de nombreux sérums antilymphoeytaires et des préparations plus pures, telles que des IgG, ne présentaient pas, bien qu\u2019elles fussent appliquées à l\u2019homme, les caractères de non- toxicité et d\u2019activité immunosuppressive que nous étions en droit d\u2019admettre.C\u2019est chez la souris que nos connaissances sur les sérums antilymphocytaires ont été bien définies au moyen de sérums préparés chez le lapin.Tl a été prouvé que l\u2019IgG pure obtenue chez cet animal, généralement par chromatographie sur DEAE-cellulose, est très satisfaisante quant à son activité immunosuppressive (Woodruff, Lewey et Medawar, Lance, Jeejeebhoy).Monaco a montré très tôt par la greffe de peau chez l\u2019homme et la négativation de réaction d\u2019hypersensibilité retardée que chez le lapin immunisé contre les lymphocytes humains l\u2019essentiel de l\u2019activité lympho- agglutinante et immunosuppressive était concentré dans l\u2019anticorps TS obtenu pur par fractionnement au sulfate d\u2019ammonium à 33 pour cent suivi d\u2019un passage sur DEAE-cellulose. 244 Maurice CARRAZ Chez le mouton, il est relativement facile de produire et d\u2019extraire des IgG antilymphocytaires par DEAE-sephadex (Halpern).Dubost nous a signalé tout l\u2019intérêt d\u2019une telle immunoglobuline de mouton lorsque les malades sont sensibilisés aux immunoglobulines de cheval.Récemment, dans notre laboratoire, nous avons obtenu et avec bon rendement, soit par le procédé d\u2019électrodécantation, soit avec le Rivanol et l\u2019aleool, une IgG de mouton anti- lymphoeytes humains dont nous étudions actuellement les qualités immunosuppressives.Les le G de bœuf ont été séparées par Lamoureux et utilisées à Montréal comme relai thérapeutique chez un sujet sensibilisé au cheval, Toutefois, nous voudrions faire remarquer qu\u2019il existe des réactions croisées entre les anticorps de ces différentes espèces.L'utilisation prolongée chez l\u2019homme de sérum de cheval antilymphoeytaire nous a incité à n\u2019utiliser que des IgG, dans le but de concentrer les anticorps par rapport aux taux de protéines injectées et de diminuer ainsi les incidents de la sensibilisation aux protéines de cheval.Les protéines éliminées au cours des purifications sont principalement l\u2019albumine, les œ-globulines et les B-globulines.L'intérêt de cette purification réside dans le fait que les protéines éliminées (œ-globulines et 8-globulines) sont très immunogènes par rapport aux IgG.Le Laval Médicul Vol.41- Fév.1970 taux de préeipitine anti-alpha et anti-béta s\u2019éléve régulièrement chez l\u2019homme au cours des traitements alors que le taux de précipitine anti-IgG reste faible, comme l\u2019ont montré Kashiwagi et Starzl.Nous pouvons apporter ici une expérience que nous avons effectuée sur le singe.Deux groupes de singes sont traités: d\u2019une part, les singes 1, 2 et 3 par du sérum de cheval antilymphoeytes humains préparé par le sulfate d\u2019ammonium durant un mois ; d'autre part, les singes 4, 5 et 6 par du sérum normal de cheval purifié par la méthode au sulfate d\u2019ammonium.Ces deux sérums sont ajustés à 50 mg de protéines par ml.Les précipitines titrées nous montreni (tableau I) que les animaux traités par le sérum antilymphoecytaire présentent durant le traitement un titre plus élevé en précipitines que les animaux traités par du sérum normal de cheval non antilymphoeytaire.Nous constatons également que les précipitines des animaux traités par du sérum de cheval antilymphoeytaire humain disparaissent plus rapidement que celles des animaux traités par du sérum normal de cheval.Ces faits ont été observés également chez l\u2019homme, comme l\u2019a montré Træger.Pour éviter les réactions de sensibilisation, il devenait intéressant de fabriquer des TABLEAU 1 Taur de précipitines antiprotéines de cheval SINGES * 15 0 0 1:2 1:32 1:16 1:16 \u2014 0,7 ml s.-cut./kg 1 injection/jour * Singes 1, 2 et 3: SAL purifié au sulfate d\u2019ammonium (lymphe) (lot : 2048) (protéines totales : 50 mg/ml) ; singes 4, 5 et 6 : Sérum de cheval normal purifié au sulfate d'ammonium (protéines totales : 50 mg/ml).Lod Ya 4 leu \u20ac Bile Is f td sy.aus à fin li lag.tity lig ly Tent leg \u201cil wl de q UE nig lity It ls g \u201célu tee tr lig Thy la \u2018aire, Diy ye Ii Uy hy ly, lédicol di élève «rai Heh vai & Ji que pes | od [aint 1: J allie Salm es LOTS tés par rat ies b pl ened Laval Médical Vol.41 -Fév.1970 IgG extrêmement pures vis-à-vis desquelles l\u2019organisme s\u2019immunise moins qu\u2019avee des œ-globulines et des B-globulines.De nombreuses méthodes de préparation des IgG pures ont été successivement utilisées.Terasaki utilise des précipitations successives au sulfate d\u2019ammonium, la précipitation à l\u2019alcool à froid, méthode (6 + 9 Cohn) que nous avons utilisée, ainsi que la précipitation par le Rivanol des a-globulines et de l\u2019albumine suivie d\u2019une précipitation par l\u2019aleool à froid.Mais c\u2019est surtout la méthode de traitement par passage sur DEAE- sephadex préconisée par Perper qui est actuellement la plus utilisée, Nous avons fait des essais de purification au moyen de la méthode M.M.E.D.(multi-membranes electro decanter) avec un appareil à électrodécantation qui permet la séparation des différentes fractions du sérum de cheval avec un excellent rendement.On a également essayé, après extraction de ces IgG, de les concentrer par différentes méthodes: ultrafiltration, mais également concentration par lyophilisation.Dans tous les cas les IgG produites très pures sont leuco- agglutinantes, leucoeytotoxiques et blastogéniques.Si les chimistes ont obtenu des IgG antilymphoey- taires extrêmement pures, on a oublié trop souvent de vérifier leur activité immunosuppressive, étant donné les difficultés de mise en œuvre et le prix des techniques de titrage chez le singe.Dans cet effort d\u2019obtenir des IgG antilymphoey- taires pures de cheval, il fut oublié que le cheval produit en cours d\u2019immunisation un constituant appelé constituant T, une globuline plus rapide à l\u2019électrophorèse que les IgG.Ce constituant peut apparaître après deux mois d\u2019immunisation par les lymphoeytes et persister très longtemps chez l\u2019animal.Starzl nous l\u2019a rappelé et la suppression du bloc des B-globulines où se situe ce constituant T (B, @) par une purification plus poussée entraîne une diminution de l\u2019activité immunosuppressive.Ces faits furent observés par Starzl sur un assez grand nombre de transplantés du rein où les cerises de rejet furent plus fréquentes après traitement par une IgG pure obtenue sur DEAE-sephadex qu\u2019avec une préparation au sulfate d\u2019ammonium contenant le constituant T du cheval.Ceci fut confirmé chez LES AVANTAGES D\u2019UNE GLOBULINE ANTILYMPHOCYTAIRE 245 le chien par Kashigawi qui observe que la lymphopénie avec un sérum de cheval anti-chien est au moins aussi importante avec le constituant T qu\u2019avec l\u2019IgG.Starzl nous a également signalé que l\u2019activité lympho-agglutinante est liée au constituant T du cheval.Faut-il préparer une IgG extrêmement pure mais peut-être moins active qu\u2019une préparation contenant également des globulines 8 et des globulines y pouvant plus fréquemment provoquer des accidents de sensibilisation chez l\u2019homme?Une longue expérience d'utilisation de préparations de sulfate d\u2019ammonium contenant des B-globulines et des IgG fut réalisée chez l\u2019homme en transplantation rénale, mais aucun incident grave n\u2019a été signalé au cours de traitement chez les malades (Træger).Ces sérums au sulfate d\u2019ammonium ont été préconisés par voie intraveineuse chez l\u2019homme pour les transplantations cardiaques.Kaplan utilisa chez un transplanté du cœur, pendant près de deux mois, uniquement ce sérum antilymphoeytaire, sans Imuran et sans cortisone, sans avoir pour autant des phénomènes d\u2019intolérance chez le malade.Les rejets furent parfaitement contrôlés durant cette période.Ceci confirme que l\u2019activité de cette préparation contenant le constituant T du cheval et des IgG antilymphocytaires était bonne.Si les IgG antilymphocytaires pures du cheval, du lapin ou du mouton permettent de limiter les effets sensibilisants, voire anaphylactisants des sérums de ces espèces, il n\u2019en reste pas moins que ces méthodes nous donnent des préparations qui, en plus de leur activité lymphoeytotoxique, peuvent garder une activité antiprotéique humaine (d\u2019où la nécessité d\u2019absorption sur plasma humain) et également une activité antiplaquettaire avec effet throm- bopénique par production d\u2019anticorps parasites antiplaquettaires qui se situent avec les IgG anti- lymphocytaires.Ces effets thrombopéniques des IgG extrêmement pures ainsi préparées sont particulièrement importants avec certains sérums obtenus à partir de lymphocytes sanguins ou de lymphocytes en provenance de la rate, ce qui d\u2019ailleurs a bien souvent limité leur production.Nous avons trouvé un moyen de déceler ces effets thrombopéniques 246 Maurice CARRAZ généralement révélés chez le singe qui est très sensible (hémorragie) ou chez l\u2019homme, ce qui entraîne parfois l\u2019arrêt immédiat du traitement.Le test de l\u2019appréeiation de l\u2019effet thrombopénique des sérums antilymphoeytaires est obtenu par injection à la souris des sérums antilymphoeytes humains (0,5 ml par voie sous-eutanée en une seule injection).Les souris soumises à cette thérapeutique ne meurent pas, mais après 48 heures on peut déceler à l\u2019autopsie des hémorragies sous-cutanées avec des sérums provoquant des hémorragies chez l\u2019homme.Si l\u2019on fait le décompte des plaquettes de la souris on s\u2019apercoit que ces préparations abaissent le nombre des plaquettes en dessous d\u2019un million par mm?de sang.C\u2019est peut-être une réaction croisée que l\u2019on observe entre les sérums antilymphocytes humains et les plaquettes de la souris.Des études à ce sujet sont en cours.Nous avons pu constater que les sérums de mouton provoquent beaucoup moins de thrombopénie chez la souris que les sérums de cheval.Il est à remarquer que les sérums anti- lymphocytes humains (lymphe) provoquent également une chute des plaquettes chez la souris, mais cette chute n\u2019est pas aussi importante que la chute provoquée par des sérums en provenance de sang qui cause une thrombopénie et des hémorragies chez l\u2019homme.Il est également à noter que les 1lzG extrêmement pures préparées par diverses méthodes de purification peuvent avoir néanmoins des effets pyrogènes et des effets d\u2019intolérance.Nous avons fait des recherches sur ces différentes préparations en ce qui concerne l\u2019effet pyrogène chez le lapin.Afin de vérifier cet effet, nous injectons deux ml par voie intraveineuse chez le lapin.Nous observons avec certaines préparations des augmentations de température jusqu\u2019à 1,7° C.Cependant, ces préparations sont des préparations d\u2019IgG pure.La source de ces pvrogènes peut être, par exemple, les bactéries qui se développent au cours des méthodes de préparation (DEAE-sephadex).Par contre, les méthodes à l\u2019aleool à froid, les méthodes au sulfate d\u2019ammonium et l\u2019électrodécantation produisent peu de bactéries contaminantes ayant des effets pyrogènes.Laval Médical Vol.41- Fév.1970 Les effets pyrogènes peuvent être également dus à l\u2019agrégation d\u2019immunoglobulines, comme l\u2019a montré Ishizaka pour les immunoglobulines humaines injectées par voie intraveineuse.En effet, les 1gG pures peuvent donner dse agrégats moléculaires de 108, 15S.Ces agrégats non seulement peuvent produire de la température par injection intraveineuse mais également de l\u2019anaphylatoxine ayant des effets sensibilisants chez l\u2019homme et le lapin.Ces protéines agrégées ont la propriété de fixer le complément mais elles sont peut-être moins réactives, Ces phénomènes d\u2019intolérance par des IgG extrêmement pures agrégées peuvent se produire notamment au cours d\u2019injection intraveineuse.On admet pour les immunoglobulines humaines qu\u2019au moins cing mg de protéines injectées doivent fixer deux unités de complément (50 pour cent).Ces essais peuvent être faits soit avee un complément de cobaye, soit avec un complément humain.Nous avons essayé de relier ces essais anticomplémentaires des IgG anti- lymphoeytaires à l\u2019effet pyrogène observé chez le lapin (tableau IT).Donc beaucoup de méthodes de préparation d\u2019IgG extrêmement pures conduisent sans doute à des agrégations de protéines ayant une activité anticomplémentaire.Il ne faut pas oublier non plus qu\u2019une mauvaise conservation peut conduire à des effets de cet ordre.En étudiant différents procédés de production des IgG nous avons constaté que les méthodes de préparation d\u2019IgG à l\u2019aleool conduisent rarement à des préparations ayant des effets hyperthermisants chez le lapin, dont l\u2019élévation de température n\u2019a jamais dépassé 1° C dans ce cas.Nous avons également constaté que l\u2019éleetrodécantation (M.M.E.D.) conduit à des préparations aussi acceptables que les préparations produites par l\u2019alcool à froid.Par contre, les méthodes au sulfate d\u2019ammonium donnent souvent des préparations ayant des effets hyperthermiques chez le lapin et ayant également des activités anti- complémentaires.Nous avons aussi constaté que les méthodes de précipitation par le Rivanol et l\u2019alcool ou les méthodes de précipitation par le Rivanol suivies d\u2019une ultrafiltration conduisent également à des préparations à activité anticomplémentaire à effet pyrogène, Lael Ya.dl itil 5.Ir I Il male: kb \u201cpes de ing D pures dé Laval Médical Vol.41- Fév.1970 LES AVANTAGES D'UNE GLOBULINE ANTILYMPHOCYTAIRE Lo 5 TasLEAU 11 Étude comparative du pouvoir anticomplémentaire et du pouroir pyrogène chez le lapin du sérum purifié ; ; EFFET PYROGÈNE SÉRUM PURIFIÉ TITRE L.C.T.C\u2019 COBAYE C\u2019 LAPIN C\u2019 HUMAIN SUR LAPIN ANTILYMPHOCYTES (intraveineuse) Origine : lymphe K 3105 2048 7,7 mg 7,7 mg 7.7 mg 0,9° C K 0303 1024 0,28 mg 9,2 mg 1,2 mg 1,6° C T 3001 1024 0,47 mg 15,0 mg 1,9 mg 1,4° C T 2202 1024 0,60 mg 18,0 mg 2,4 mg 1,3° C R 2202 2048 1,2 mg 18,0 mg 2,4 mg 1,7° C R 0402 2048 0,6 mg 18,0 mg 1,2 mg 1,1° C Origine : sang P 0404 1024 7,4 mg 29,0 mg \u2014 0,7° C CONCLUSIONS Nous devons établir des techniques de controle Nous devons perfectionner les sérums antilympho- cytaires de façon à atteindre les objectifs suivants: 1.Isoler et augmenter au maximum l\u2019activité im- munosuppressive pour une quantité minimum de protéines hétérologues injectées.2, Diminuer au maximum des effets toxiques qui ne sont pas négligeables surtout par voie intraveineuse (activité antiprotéique, activité anti- plaquettes, activité antiglobules rouges) ; c\u2019est le traitement de l\u2019antigène qui nous permettra d\u2019arriver à de tels résultats.3.Éviter les agrégats moléculaires, tant au cours de la préparation qu\u2019au cours de la conservation, ces agrégats pouvant être la source d\u2019acei- dents hyperthermiques et d accidents de sensibilisation.Nous devons également essayer de produire des sérums sur d\u2019autres espèces animales de façon à relayer les thérapeutiques lorsqu'elles ne deviennent plus utilisables.et échanger nos sérums, créer des étalons et des standards aussi bien pour la lymphocytotoxicité que pour le pouvoir immunosuppresseur.En effet, il est nécessaire de fournir pour la transplantation du cœur des sérums antilymphoeytaires purifiés ou des IgG présentant un maximum d'effet immunosuppresseur pour un minimum d'effet toxique.Il ne faut pas oublier, cependant, que chaque individu réagira différemment et que c\u2019est aux cliniciens d'étudier les doses et les posologies à partir d\u2019un produit présentant des caractères connus.Il serait utile, étant donné l'importance des effets toxiques de différentes préparations utilisées pour la transplantation du cœur, de vérifier au préalable tous les lots de sérums employés.L'épreuve peut se faire chez des transplantés du rein pour lesquels l'application de ces sérums thérapeutiques pose des problèmes moins graves.C\u2019est à ce prix que nous obtiendrons de bons résultats en transplantation du cœur, en prévenant le rejet par des préparations d'immunoglobulines actives et non toxiques. IN VIVO TESTING OF ANTIHUMAN LYMPHOCYTE SERA * D.W.VAN BEKKUM and H.BALNER, Radiobiological Institute TNO, Rijswijk (ZH), The Netherlands.Le test de la survie des greffes de peau chez les singes inférieurs et les chimpanzés demeure à l'heure actuelle la méthode de choix pour évaluer l\u2019activité immunosuppressive d\u2019un SAL.Cependant, la valeur im- munosuppressive de grands pools de SAL testés chez les primates demande encore à être confirmée par les essais cliniques chez l\u2019homme.INTRODUCTION Early in 1967 already, the discussions at the Ciba Study Group on Antilymphocyte Serum (ALS) made it clear to all involved in clinical and fundamental ALS research, that this agent held high promise for use in clinical organ transplantation and possibly in other conditions requiring effective immune suppression (i.s.) (5).This conclusion gave rise to concentrated efforts in many countries aimed at the production of sufficiently large amounts of effective antihuman LS, not only to meet the demands of the clinicians, but also to permit at the same time a more exact evaluation of its 1.s, properties in controlled clinical trials.During the past year these efforts have been markedly intensified \u2014 especially those at the production level \u2014 following the introduction of elinieal heart transplantation, when it became gradually apparent that rejection of cardiac allografts is more diffieult to prevent by conventional i.s.treatment than that of kidney allografts.Additional stimuli were provided by the intensified attempts to transplant other organs, e.g.lungs and liver, and by the recent discovery of a favourable effect of recipient pretreatment with ALS in diminishing the severity of the graft versus host * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.reaction following allogeneic bone marrow transplantation in mice as well as in monkeys (4).In his introduction to the Ciba meeting on ALS, J.H.Humphrey pointed out that \u2018\u2018One of the important things which ought to emerge from the discussions here is a sharing of experience regarding the practical steps needed to get a therapeutically effective serum, and what methods of assessment sm vitro will enable its therapeutic efficiency to be predicted.\u201d\u2019 It was indeed logical at that time to envisage a fast evolution of in vitro methods of testing, because work on the in vitro properties of ALS, involving a number of different systems, had already been initiated.However, none of the in vitro methods that seemed promising two years ago were subsequently found to possess dependable quantitative predictive value for the i.s.poteney of ALS preparations.In vivo test: Instead, in vivo testing in chimpanzees and macaques has been, thus far, the only available means of evaluating and comparing antihuman lymphocyte sera.Such a development was certainly not within expectation because a high species specificity of heterologous antilymphocyte preparations had been observed by several investigators.The susceptibility of subhuman primates to anti- human lymphoeyte sera was discovered when we decided to use one of our chimpanzees to assess an Jie] Yi] d- Laval Médical Vol.41- Fév.1970 IN VIVO TESTING OF ANTIHUMAN LYMPHOCYTE SERA 249 3 Nous discutons la valeur des tests in vitro ayant une corrélation positive entre la valeur immunosuppressive de SAL chez les primates, et ces analyses.Nous cherchons à savoir si la valeur immunosuppressive obtenue BALNER chez le primate à la suite de greffes de peau est un bon indicateur du pou- inte THO, voir immunosuppressif de ce sérum quand il s\u2019agit de la greffe de d'autres ele organes comme le rein, le foie, le cœur.Nous discutons de la possibilité d\u2019induire chez l'homme la tolérance immunologique vis-à-vis les immunoglobulines normales, avant l\u2019emploi du sérum antilymphocytaire.Le but de ce procédé est d\u2019empêcher la for- eus dl mation d\u2019anticorps circulants dirigés contre les protéines actives du SAL.sit pour Nous discutons, enfin, la nécessité de produire de grands poolis de SAL Jol ir pour faire, sur un seul lot, toutes les analyses essentielles in vivo ainsi que demande des essais cliniques chez l'humain, avant l'utilisation de ce SAL dans les gr Trés ilk the iru J i pel a ae offen oa fe Ah f | potes ps il tie i cid! at greffes d'organes.ALS preparation before making it available for patients.It was then found that chimpanzees not only respond to several of the toxic side effects but also that a significant prolongation of skin allo- graft survival as well as suppression of a delayed- type skin test (DNCB sensitivity) following the administration of certain antihuman lymphocyte sera could be obtained (2).These studies were then extended to lower monkeys and it was found that M.rhesus and M.speciosa also respond to anti- human lymphoeyte sera, be it with a less pronounced immunosuppressive effect.This unexpected interspecies susceptibility is ascribed to the fact that chimpanzees, and to a lesser extent macaques, share a number of leukoeyte antigens with man (3 and 9).During the past two years we have been engaged in comparing the properties of more than 30 anti- human lymphocyte sera and globulins in chimpanzees and monkeys, using the effect on free skin allograft rejection time and the DNCB reaction (in chimps only) as an index for is.potency.The results (Table I) show that there is a rough correlation between the responses of macaques and those of chimpanzees, in the sense that the sera that show strong i.s.in chimps always give rise to a clearcut response in monkeys.Sera having no activity in monkeys show no or only a weak activity in chimpanzees.It seems reasonable to assume, and to use as a working hypothesis, that this trend will extend to man, so that sera with outspoken i.s.potency in chimpanzees will probably be also highly active in humans.It has to be stressed however that the final proof of this assumption is still lacking and in fact seems difficult to obtain.There are at least two reasons for this gap in our knowledge.The first is the difficulty to get a reliable guan- titative assessment of the Ls.effects of ALS in clinical situations, where the disease itself as well as the simultaneous administration of other is.agents tend to cloud the picture.Only by the use of rigid protocols in a series of controlled clinical trials can we hope to overcome this obstacle.The second difficulty is caused by the limited amounts of anti-human LS available for simultaneous clinical use and laboratory assessment.Very large pools of sera are obviously required for such eriti- cal studies and as long as clinical demands for ALS continue to exceed supplies, such pools will not be made available.Fortunately Medical Research Councils and other government organizations in a number of countries have recently taken steps to assure such critical evaluations in the future.Another reason for urgently establishing the relation between the responses of chimpanzees and humans to the same anti-human LS preparation is the development and perfection of in vitro assays which could proceed much more efficiently and faster by comparing them with the standardized results of tests in subhuman primates and monkeys. 250 D.W.VAN BEKKUM and H.BALNER In vitro tests: For routine testing, required for several steps in the large scale production of anti-human LS, in vitro assays are obviously to be preferred to the elaborate, time-consuming and expensive im vivo testing.Already duringt he past year, two in vitro assays have emerged that seem to offer good possibilities.Among many of the tests that were proposed, the rosette inhibition assay (1) and the Laval Médical Vol.41- Fév.1970 opsonisation test (8) showed an excellent correlation with the an vivo i.s.activity in experiments involving rodents.Both are being tested with many of the anti-human agents that have become available for in vivo testing and suggestive positive results have already been obtained with one of them (rosette inhibition, J.F.Bach et al, Transplantation, in press).A number of other \u2018\u2018candidate\u2019\u2019 in vitro tests have been found to bear insufficient relation to the results of the in vivo tests (Table IT).TABLE 1 Horse anti-human lymphocyte sera and globulins CODE AND ORIGIN SUPPRESSION OF ALLOGRAFT REACTIVITY ANTIGEN In In Clinical impression monkeys chimps IX Louvain \u2014 Favorable XII Paris \u2014 Favorable v* London \u2014 \u2014 Spleen VI* London \u2014 \u2014 xI* London \u2014 (+) II Leiden \u2014 + VII Denver + Favorable I Amsterdam + ++ XIII Lyon \u2014 XVII * Los Angeles \u2014 Blood XXVI-1 Bilthoven \u2014 lymphocytes XXVI-2 Bilthoven \u2014 XXVI-3 Bilthoven \u2014 XXVI-4 Bilthoven \u2014 XXVI-5 Bilthoven \u2014 III Leiden \u2014 (+) XVI* Montreal \u2014 XXIV * Toronto + ++ Thymus XVIII Kalamazoo \u2014 + XX Kalamazoo + ++ XXVIII Houston + Favorable XXXIII Marburg ++ IV Lyon + ++ Favorable .Xv Lyon + Favorable Thoracic duct VIIa Munich + Favorable cells VIIIb Munich ++ Favorable XXXII Marburg + Node x Nijmegen \u2014 Lymph.leuk.VIII Munich + Favorable Cult.cells XIX Minneapolis \u2014 Favorable * Pool of sera from 2-5 horses.hr Vil.4l- hum Sin La .i ing I bi \u201cWg Lédicol -Pér, Lely Hels it ma De aval Sie 14 i the gla did\u201d suite Tif] alk Lanal Médical Vol.41- Fév.1970 IN VIVO TESTING OF ANTIHUMAN LYMPHOCYTE SERA Tape II Correlation between assays for 1.8.efficacy of anti-human L.S.IN VIVO IN VITRO \u2014 chimp (skin graft) macaque (skin graft) good rosette (J.F.Bach) (Greaves, Roitt) opsonisation other cytotoxicity agglutination inhibition of various lymphocyte reactivities Significance of im vivo tests: Free skin allografts have been widely employed to measure the degree of suppression of the homo- graft reaction.It should be noted, however, that the two agents most widely employed in clinical organ transplantation today, Imuran and pred- nisolone, have little if any effeet on skin allograft survival, unless the histocompatibility barrier between host and donor is very low mdeed.The question might be asked whether the results obtained with skin grafts may be interpreted quantitatively to predict the degree of suppression of organ allograft rejection.In the rejection pattern of organ allografts two components have recently been recognized to respond differently to Ls.agents (10).One, represented by the damage of Tape III Kidney homografts in rats (M.J.de Vries et al., 1968) GRADE OF GLOMERULAR DAMAGE INCIDENCE OF VASCULAR REJECTION % 1.8.TREATMENT Severe Slight/moderate Slight (10) large vessels, seems to be more susceptible to inhibition by Imuran, the other, represented by lymphoid cell infiltration and damage of parenchymal cells, seems to be more specifically inhibited by ALS (Table III).retical basis for the combination therapy of ALS These observations provide a theo- and Imuran, which has been found to yield superior results in a rat model of kidney allografting by de Bruin of our group (7).The damage of large vessels, one of the characteristic aspects of rejection in organ allografts, is not an integral part of the rejection process in skin allografts, the information obtained from assays involving skin grafts may therefore be incomplete.The i.s.potency of ALS as determined by these tests may still require correction before being applicable to the organ allograft situation.To clarify these complicated and highly practical problems in vivo studies involving comparison between responses of skin grafts and organ grafts are needed, because organ grafting is too elaborate a procedure to ever become a routine test method by itself.In this respect it should be noted that it is not even justified, a priori, to extend the findings obtained with grafting one particular organ to other organs, since striking differences have been observed between for instance heart and kidney grafts with 52 regard to their response to 1.s.agents under standard conditions in the rat (Table IV), (6).Needless to say that in vitro assays will never be able to provide an answer to this type of question.Defining optimal application of ALS: In devising optimal treatment schedules for ALS at least two factors have to be taken into account.One is the influence of the agent on the rejection process, the complicated nature of which has been pointed out above.The second is the reaction of the recipient to the agent, this is immunological in nature and may result in the production of antibodies against the active principle, thereby preventing or minimizing its further efficacy as well as creating the hazards of allergic reactions following its continued administration.Suggestive evidence is accumulating that the simultaneous administration of other i.s.agents, in particular of Imuran, may inhibit or even prevent the immunological reaction of the recipient against ALS.If that would prove to be of critical importance and if the combined administration of ALS and Imuran would become indicated on the grounds discussed in the previous section, the current procedure of in vivo testing of anti-human LS may need modification.The development of less immunogenic or even non- immunogenic anti-human LS preparations would of course simplify matters considerably, not only from TABLE IV Effect immunosuppressive regimens in rats Per cent graft survival beyond 30 days IMURAN ALS WITH OR WITH OR TYPE OF ALLOGRAFT WITHOUT WITHOUT STEROIDS IMURAN Free Skin No effect 90% (9) Kidne 53 32 8 Large vessels y % (32) 0% (34) anastomosed .Heart 10% (21) 26% (19) Kidneys orthotopic, hearts heterotopic (From de Bruin et al, 1968, and van Bekkum et al., 1968).D.W.VAN BEKKUM and H.BALNER Laval Médical Vol.41-Fév.1970 the point of view of testing, but chances that this could soon be accomplished seem to be remote.On the other hand the induction of tolerance to heter- ologous anti-human lymphocyte gamma globulin may prove to be feasible in patients and such developments would probably necessitate similar adaptations of the in vivo testing procedure.Finally, the establishment of optimal modes and routes of administration still presents many problems, which will only be solved by systematic in vivo experiments, preferably in subhuman primates.Side effects: Apart from the hazards arising from sensitization to ALS mentioned above, antilymphocyte preparations have already shown a rather discouraging variety of other undesirable side effects (Table V).Some of these can be avoided or diminished to acceptable levels by absorption and purification.Others, e.g.the induction of thrombocytopenia seem to be inherent properties, to a certain extent probably inseparable from the i.s.activity.It is clear that in vitro tests will at best provide only partial information concerning toxic effects of ALS preparations and that therefore in vivo toxicity studies will be indispensable for some time, to provide the ultimate safeguards required for all preparations before their routine clinieal application is justified.Presently available information on the predictive value of the various in vitro and in vivo tests for toxicity of anti-human LS is summarized in Table VI.Because of the close biological TABLE V Main hazardous side effects of ALS IMMEDIATE : Thrombopenia Hemolysis LATER : due to nephritis ; AB formation Serum anaphylaxis } arthritis (high doses) : Infections (virus) LONG TERM : Malignant lymphomas Love Vol 4 Pre si iE) In Lu fin lige Ig hi dng iy Nigg ly ir, ty of i ig gy Sib [edie fr.18 it thi in Bir cobalt 1 devel steph 15 dd 5 pri le i Fle.aI 7 pr igi Be.pied al pl y aveu : Ji je ef à ply ju in il gpl jouit pl pos pa lei wo pi Laval Médical Vol.41- Fév.1970 TasrLE VI Predictive value of toxicity tests for anti-human L.S.IN VIVO IN VITRO human chimp macaque rodents antibodies | : against: i ?partial | i ! some ; i suggestive : red cells i suggestive | 7 platelets ! (in progress) I ; en eel serum proteins similarity of chimpanzees to man, the chimp remains the subject of choice for these toxicity checks.However, practical considerations are severely limiting the use of these animals so that maximal efforts have to be made to devise other systems for toxicity evaluations.As regards the assessment of the long-term effects of ALS and of the effects of long continued administration, for the time being there seems to be no reliable substitute for the subhuman primate.The long-term hazards of ALS are clearly not the main concern at present, because the conditions for which treatment with ALS is required are all of a rather urgent nature.As with many other promising therapeutic agents even their large scale application will not be prevented by the absence of reliable information concerning the long-term hazards.One can only hope that governmental agencies will have the foresight to promote initiation of programs for the evaluation of Long term studies on ALS in animal models.It seems advisable to include studies on the effect of antihuman LS in subhuman primates into such projects.CONCLUSION In vivo testing of antihuman LS in apes and monkeys is as yet the only reasonable possibility of predicting its i.s.potency.The exact value of the results of these tests urgently needs to be established by a systematic comparison with the results of controlled clinical trials using large pools of ALG.IN VIVO TESTING OF ANTIHUMAN LYMPHOCYTE SERA 253 It is to be expected that reliable in vitro tests for use in the various steps of ALS production will soon become available, so that in vivo testing could be restricted to a final assay of each large pool before it is made available for clinical application.The study of the rejection mechanisms for skin and organ allografts and their respective suseep- tibility to i.s.agent has shown important differences and similar but less significant differences have been found between various types of organ grafts e.g.between kidneys and hearts.Consequently, the interpretation of in vivo assays based exclusively on skin allograft rejection, in terms of their predictive value for the suppression of organ allografts will have to be reinvestigated.There are indications that the clinical application of ALS may in the future be predominantly in combination with Imuran.The latter drug may not only enhance the i.s.effect by an action of its own but also indirectly by inhibiting antibody formation by the recipient to the ALS preparation.Alternatively, the successful induction of tolerance to the effective principle in ALS preparations may become feasible.In both cases, the i vivo testing procedure could be perfectionated accordingly, although the current unmodified 4» vivo testing would still be a valuable screening procedure.For the assessment of toxicity, in vivo assays remain essential but replacement of chimpanzees and monkeys by lower animals has to be sought.The late effects of ALS administration and the effects of long term administration will have to be carefully studied in view of the prospects for increased use of ALS.It seems advisable to obtain pools of anti-human lymphocyte preparations large enough to do all the essential in vivo studies in subhuman primates as well as clinical trials with the very same agent.REFERENCES 1.Bach, J.F., DARDENNE, M., DorMoONT, J., and ANTOINE, B., A new in vitro test evaluating anti-lympho- cyte serum potency, in Proceedings of the Second International Congress of the Transplantation Society, H.M.Stratton Inc., Publ, New York, p.403-407, 1969. 254 2.Banner, H., Eysvoocrr, V.P,, and Crrron, F.J, Testing of anti-human lymphocyte sera in chimpanzees and lower primates, Lancet, 1: 19\u201422, 1968.BALNER, H., LEEUWEN, A.VAN, DERSJANT, H., and Roop, J.J.VAN, Defined leukocyte antigens of chimpanzees : use of chimpanzee iso-antisera for leukocyte typing in man, Transplantation, 5: 624-642, 1967.BEkkUM, D.W.vax, (To be published).BEKKUM, D.W.vAN, LEenney, G.D., BALNER, H, Pvrren, L.M.VAN, and Vries, M.J.DE, Suppression of secondary disease following foreign bone marrow grafting with antilymphocyte serum, in Antilymphoeytic serum, Ciba Foundation Study Group Nr.29, Churchill, London, p.97-110, 1967.BEKKUM, D.W.vAN, HEYSTEK, G.A., MARQUET, R.L., Bruix, R.W.bE, and TiNBERGEN, W.J., Comparative studies on immunosuppression of heart and kidney allograft rejection in rats, in Proceedings of D.W.VAN BEKKUM and H.BALNER Laval Médical Vol.41- Fév.1970 the International Symposium on Pharmacological Treatment in Organ and Tissue Transplantation, Milan, 1969, (To be published).Bruin, R.W.vx, Thesis, (To be published).GREAVES, M.F., TUrsi, A., PLAYFAIR, J.H.L., Tor- RIGIANI, G., ZAMIR, R., and Rorrr, I.M., Immuno- suppressive potency and in vitro activity of anti- lymphocyte globulin, Lancet, 1 : 68-72, 1969.METZGAR, R.S., SEIGLER, H.F., and ZMIJEWSKI, C.M.The cross-reactions of primate tissue antigens with human leukocyte isoantibodies, in Cross-reacting antigens and neoantigens, John J.Trentin (ed.), The Williams and Wilkins Co., p.98-104, 1967.Vries, M.J.br, TINBERGEN, W.J., and WESTBROEK, D.L., The effect of various immunosuppressive agents on the histology of the homografts reaction, Abstract to The Seventh International Congress of the International Academy of Pathology, Milan, 1968.NTR lédival el À ological mm, INTRAVENOUS USE OF HIGH DOSAGE OF ALG * Walter BRENDEL + i Tike Department for Experimental Surgery, University of Munich, Germany nmin if atk L'auteur décrit une méthode de traitement avec des doses élevées de globulines antilymphocytaires associées à l'Imuran et à la Cortisone.Au cours des transplantations, les doses recommandées sont de 20 ml par jour au cours de la première semaine.Le premier jour, on donne la moitié de la dose avant l'opération.Les doses de corticostéroïdes et =} mis d\u2019lmuran sont diminuées plus tard, alors que le traitement aux globulines 4 all antilymphocytaires se poursuit pendant trois mois.Si une crise de rejet esl se manifeste des semaines apres l'arrét des globulines antilymphocytai- reiting in ed.BLE : Nil, res, un nouveau traitement identique aux mêmes doses est institué.Les manifestations du traitement aux globulines antilymphocytaires sont : 1.Une lymphopénie, qui porte le plus souvent sur les petits lymphocytes.On note cependant l\u2019apparition, après quelques jours, de lymphocytes plus grands, et de formes irrégulières, dont la présence signe l'action des globulines antilymphocytaires ; 2.Une destruction des granulocytes ; Yesterday we heard of the clinical results obtained with heart transplantations round the world.You will agree with my general statement that these results are not yet optimal.The mean survival rate is low even if we exclude those patients who died from surgical complications and caleulate only such cases who died from rejection.On analysing all heart transplants one particular group does not fall within this picture.The survival rate in those patients that were treated with high doses of high grade ALG and then by the Intravenous route was significantly higher.I cannot give you the exact details of those patients that were treated with ALG by other teams, but Tables I and II will show vou the results in nine cases \u2014 with the last case in London, ten \u2014 that were treated with our ALG according to a schedule worked out by us.Our ALG was raised * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.$ Institut fiir Experimentelle Chirurgie, Nugbaum- strasse 20, 8 Miinchen, Germany.(suite du résumé en page suivante) in cooperation with the Behring Company, Mar- burg.Two of the patients were treated with our ALG after the appearance of a rejection crisis, eight were treated from the very beginning of the operation.Eight of these ten patients are still alive and did not show signs of serious rejection as long as the ALG-therapy was continued.One patient died four months after the operation on account of a brain embolus, but no histological signs of rejection of the heart could be detected.One patient died after three months of sepsis.Those results were obtained in spite of the fact that most of these patients had a mismatch in two or three transplant antigens.These results as well as our experience in the treatment of kidney transplants and autoimmune diseases seem to indicate that our scheme of treatment with high doses of ALG additional to Imuran and cortison will be the method of choice.I would like to describe now the criteria and the side effects involved.Mostly we used antilympho- cytic globulin which had a high agglutinating and Walter BRENDEL Laval Médical Vol.41- Fév.1970 3.Une thrombopénie qui retourne à la normale malgré le traitement continu aux globulines antilymphocytaires.une agglutination des leucocytes et lymphocytes qui ment dû à Ceci est probable- englobent les thrombocytes, ou plus encore à l\u2019action des substances produites par la destruction des leucocytes ; 4.Une augmentation de la température, de la fréquence cardiaque, et parfois une légère chute de la tension artérielle, au cours des premiers jours.la première semaine.Ces réactions diminuent et disparaissent après Elles sont également produites par les substances toxiques de destruction des leucocytes.Les doses élevées de corticostéroïdes données au cours des premiers jours sont nécessaires pour leur effet immunosuppressif, mais également pour supprimer les réactions dues aux substances toxiques libérées par la destruction des leucocytes.En vue d'éviter le syndrome de Cushing et l'ulcére de stress, on substitue une partie des glucocorticoides par des doses élevées d\u2019Aldostérone et de Spironolactone, qui se sont avérés efficaces chez l\u2019animal d\u2019expérimentation et dans les transplantations rénales humaines.cytotoxic titre of about 1:2000 to 1:4000 respectively.This ALG was raised by using lymphocytes from the thoracic duct, lymphocytes from leukemic patients or thymocytes.The immunesuppressive effect of this ALG was tested on primates by Doctor Balner.We recommend in the first week of the transplantation 20 ml of ALG daily, starting already before the operation, then 10 ml.In the first few days high doses of corticosteroids up to 500 mg per day should be given.Later on the dosage of corticosteroids and Imuran can be diminished as long as the treatment with ALG is continued.In cases with a pronounced sensitivity against Imuran this drug could be omitted for one or two weeks without serious complications.This therapy was usually carried on over a period of three months.There were no rejection crises as long as the ALG therapy lasted.If there was a rejection crisis weeks Tape 1 Adjuvant therapy in rejection episodes following heart transplantation * AVERAGE DOS.T ALG ITER OF TYPE OF (ml/day) CLINICAL SURGEONS PATIENT INJECTION RESULTS PHYSICIANS DURATION OF leuko- ¢ TREATM.(days) aggl.cytotox.5-75 Dr.Ph.B.acute Ch, Barnard Cape Town (cellular) 7 1 : 4096 1 : 4096 reversal S.C.W.Bosman 10 M.E.P.acute ; - 4096 I J.Caplan Vina del Mar (cellular) 15 1 : 4096 1 : 409 reversa R.Eberhard * Heart transplant treated with ALG (intravenously), corticosteroids and Imuran.Lord fol 4l ite It Wis tinal tons iti Dent fee À Ho, \u2018a 33, (Cap sde À sn event | able | ès qui à sus | diaque, rs des api ar les remiers Jement es Dar ass, ON d'Aldor qn ge ed y a Judd a TE ul hf ons pe JI 3 qi À pote Le yt (3 git pi Laval Médical Vol.41-Fév.1970 after the interruption of the ALG therapy, then it was easily suppressed by increasing the conventional therapy.In order to avoid serious complications one should test for an eventual high sensitivity against horse serum proteins before treatment by injecting 0.1 ml ALG intradermally.If there is no reaction within one hour, we start the treatment by infusing the first half of the ALG in 250 ml physiological saline in a slow drip over one hour.The second half are given in the evening.INTRAVENOUS USE OF HIGH DOSAGE OF ALG 257 The following effects of ALG should be kept in mind : 1.A lymphopenia involving mostly the small lymphocytes which fall to 5 to 10% in the peripheral blood (Figure 1).After some days there appear, however, bigger, sometimes bizarrely formed lymphocytes which must be counted separately in order to avoid errors.Those cells have à pronounced ergastoplasma and look somehow like plasma cells.We assume that these cells are Tapue II Adjuvant therapy from day of operation in heart trans plantation * AVERAGE DOS.TITER OF ALG CLIN.RESULTS .(ml/day) PATIENT PAT.SURVIV.PHYSICIANS TO DATE ] ; x duri ter DURATION OF leuko- cytotox.uring aîter TREATM.(days) aggl.treatm.treatm.10 - ; H.O.10 15 no reject no E.J.Zerbini (Sao Paulo) months 1 : 4096 1 : 4096 pericard reject E.Antonaciu 180 effusion 10 J.S.10 no no Ch.Barnard (Cape Town) months 100 1: 256 1:512 reject reject S.C.W.Bosman 10-15+ N.O.8 no J.Caplan (Valparaiso) months 200 1: 4096 1 : 4096 reject N.Adriasola 10-15 C.P.3 no + E.J.Zerbini (Sao Paulo) months 80 1: 4096 1 : 4096 reject septic, E.Antonaciu 5-10 W.K.2 5 no Ch.Barnard (Cape Town) months t 1 : 4096 1 : 1024 reject \u2014 S.C.W.Bosman cont.D.F.2 10-20 no Ch.Barnard (Cape Town) months 30 1 : 2048 1 : 8000 reject \u2014 S.C.W.Bosman EH 2 10 - 20 A.Senning na 0 F.Largiardèr Zuri 1 : 2048 1 : 8000 no \u2014 (Zurich) months cont.reject B.Linder * Heart transplants treated with ALG (intravenously), corticosteroids and Imuran (case 10, London, operated by Dr.Ross, not on table).+ Patient treated also with Lyon serum (Carraz-Tracger). 258 transformed lymphocytes.We tend to consider the appearance of such cells as a positive sign of the ALG treatment.In the thoracic duct lymph they may represent 50 per cent of the existing lymphoid cells.2.Since ALG destroys the granulocytes with the same intensity as the lymphocytes, we normally find young forms of polymorphous cells.This is à normal reaction.3.In spite of the fact that our ALG has no titre against thrombocytes, a thrombopenic effect can always be observed (Figure 2).The lower curve shows the mean thrombocyte values of nine patients.It can be seen that in the beginning the values decrease.When the therapy is continued, the values return gradually to normal in spite of continued high ALG quantities.Only twice we experienced such a heavy thrombopenia that ALG had to be discontinued for one or two days.This phenomenon might be due to an aggregation of leucocytes and lymphocytes which enclose thrombocytes.Furthermore, we have some indications that some substances of the destroyed leucocytes produce a thrombocytopenia.4.In the first days we observed an increase in temperature and heart rate and sometimes a slight fall in blood pressure in most of the patients.Si- bord 15000 leucocytes 100001 5000 lymphocytes Î 1 1 À i 1 Walter BRENDEL Laval Médical Vol.41-Fév.1970 multaneously rigor appears (Figure 3).Those reactions diminished from day to day to disappear usually after the first week, This too is caused by The speed of infusion also plays an important role.toxic products of the destroyed leucocytes.Therefore, we recommend to give the ALG diluted in saline in a slow drip over one hour.Even this cannot prevent the reactions entirely, but anti- pyretica and antihistaminica help considerably.In some of the patients the mentioned ill effects were not observed at all.In 70 patients including kidney transplants, leukemia and autoimmune diseases we observed in about 10% urticaria and three times signs of an- aphylactic shock.Only in the latter ease ALG had to be discontinued.This shows the advantage of the intravenous route, as only by this method ALG administration can be stopped instantaneously.In the first days high doses of corticosteroids are not only required because of their immune- suppressive effect, but they are also indispensible in order to suppress the reactions due to the toxie substances which are released by the destroyed leucocytes.In order to prevent a Cushing syndrome and stress ulcera we prefer now to substitute part of the glucocorticoids with high doses of aldo- sterone and spironolactone which have proved to [r] 120 | hemoglobin 100 platelets ALS on 5 10 15 20 25 days Figure 1 \u2014 Mean values of WBC and lymphocytes in 8 heart transplants during ALG treatment.ALS on 10 20 30 days Figure 2 \u2014 Mean values of Hb and platelets in 8 heart transplants during ALG treatment.Lure Vel.4 x iM: bee Kil Sr ty hy ay ling a ère [ding] , 190 se D \u201cper nel br + The ii tile.(ited il tis li avai I of ik prod pige À pi Al qi, sels pL que fe 05 ne dm y pi i lie in id Li Laval Médical Vol.41- Fév.1970 bloodpressure 1/mm 130 mmHg 110 120 1s'day gg LT 10 | b\u2014* INTRAVENOUS USE OF HIGH DOSAGE OF ALG 239 pulse rate °C temperature n 39 | Le 2 > / em 0=\u2014C ! I / 371 e vof} shiver.ng 36 OQ mmm OQ mm 100 | 50 x infusion | | = infusion | , ; | + infusion ; .) 130 F | 39H 110 e 0-0 th 100 È e /\\ 38 | of 7° 4 day 100 | .e ° O_o Joe\u201d Ye se / 371 70 so Ÿ oo\u2019 \\/ ie L infusion ; ; «+ infusion L , ; + infusion ; ; CL 130 TS ol ~~ © 120 t es No.0\u2019 \u201co 39} 6''da 100 F | | y no | / 38, ° 70 + 100 F 07 37 + Ir + infusion ) .= | infusion £ infusion J J de No TN 11th day 100 | 80 | 80 o 0 0 qe / 0 Ne7 \u2018e-0-0-0.0 - e 70F Er \u2014 70 E [infusion ] 38 H Sd 37H OO O+O+O+0\" x infusion À 1 À \u201c1 A À -60 -30 0 30 60min -60 -30 +0 30 60 min -60 -30 *0 30 60 min Figure 3 \u2014 Blood pressure, puise rate, temperature and rigor in one patient under ALG infusion.be efficient by us in animal experiments and human kidney transplants.Symptoms of serum nephritis were seen in onc case of an autoimmune disease, who did not receive Imuran or corticosteroids and in one heart transplant.In the last case the batch of ALG used contained a certain amount of precipitating antibodies against human serum proteins, which were apparently not sufficiently absorbed.We apply such high doses of ALG intravenously additional to the conventional Imuran and steroid therapy not only to increase the immunesuppressive effect.Much more we believe that with such high doses of ALG one can prevent a sensitizine of the host against at least some transplant antigens.This can only be achieved if important cloni of lymphocytes can be destroyed immediately before and maybe also a few days following the transplantation.Therefore we recommend now high doses of ALG already one or two days before the operation.With other words, the aim of this therapy is not only the suppression of the sensitized lymphocytes, but also a partial prevention of sensitizing.It seems to us that one might achieve a partial tolerance against some transplant antigens at least in some cases.Otherwise we cannot explain the phenomenon of the long time survival of the transplants even after the ALG therapy had been discontinued and the patients were maintained on relatively low doses of Imuran and corticosteroids. SUCCESSFUL TREATMENT OF ACUTE CARDIAC HOMOGRAFT REJECTION WITHOUT ANTILYMPHOCYTE GLOBULIN * H.M.KAUFFMAN, Jr., M.D.\", Derward LEPLEY, M.D., Dudley JOHNSON, M.D., and Donald KUBAN, M.D.Les auteurs relatent le cas d\u2019une malade qui a subi une homotrans- plantation, et qui a présenté un phénomène de rejet au sixième jour.Alors qu\u2019elle recevait 3 mg/kg d\u2019Isotiaprine et 200 mg de Methyl prednisone par jour, on augmenta au moment de la crise de rejet la Methyl prednisone a 300 mg/jour.En plus, on administra 100 microgrammes d\u2019'Actenomyci- ne C par voie intraveineuse et des radiations du cœur avec une dose de 150 r aux sixième, huitième, dixième et douzième jours après la transplantation.On nota que le voltage du QRS s\u2019améliorait, de même que le retour à la normale de la tension artérielle et de la pression veineuse.Ultérieurement, le dosage de la Methyl prednisone fut réduit.Après sept mois et demi, la malade présente une activité complètement normale.Elle reçoit 3 mg/kg d\u2019Isotiaprine et 30 mg de Methyl prednisone par jour.Since most investigators performing clinical cardiac transplantation have used antilymphocyte globulin as part of the immunosuppressive therapy, it is important to document the successful treatment of cardiac homograft rejection in a patient who has received no antilymphocyte globulin during her entire postoperative course.The patient is a 49 year old white female with a ten year history of chronic myocarditis of un- know etiology.Catheterization data revealed profound left ventricular failure with no evidence of valvular disease or coronary artery disease.Because of inhability to control the patient\u2019s congestive heart failure in the hospital environment, transplantation was recommended.The patient was started on Azathioprine, 1 mg per kg, while a search was made for a suitable cadaver donor.She remained on this dose for three weeks before a cadaver heart was available.Histocompatibility test was performed by Doctor * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.1.8700, West Wisconsin Ave, Milwaukee, Wisconsin, 53226.Kuban who obtained a B match and by Doctor Terasaki who obtained a D match.Unfortunately, because of the cadaver situation, a retrospective checking of this discrepancy in the two matches was impossible.Cardiac homotransplantation was performed on October 21, 1968 and no technical difficulties were encountered.The patient received Azathioprine 3 mg per kg and 200 mg of methyl prednisone, which is approximately 4 mg per kg on the day of transplantation.The initial function of the cardiac transplant was quite satisfactory.On the fourth postoperative transplant day a diagnosis of acute ilio-femoral venous thrombosis of the right leg was made.Rather than re-explore the patient\u2019s right inguinal incision, it was elected to perform a vena caval clipping and treat the patient\u2019s thrombosis with heparine.This surgery was tolerated well but on the 6th post-transplant day a decrease in the voltage of the QRS complex was noted.Concurrently with this decrease in voltage there was a decrease in systolic blood pressure and a rise in venous pressure.There was also a decrease in the creatinine clearance as well as an increase in weight. rans Hors § \u20ac par ison mo sq pa ge le usé: ip Mae.Jour Luval Médical Vol.41- Fév.1970 The rejection episode was treated by increasing the dose of methyl prednisone to 300 mg per day, by the administration of 100 micrograms oË actino- mycin C intravenously and by the administration of 150r of radiation to the heart on the 6th, 8th, 10th and 12th post-transplant days.The QRS voltage was noted to improve along with a return of systolic blood pressures and venous pressures to more normal levels.At the same time the patient\u2019s creatinine clearance again improved and she underwent a diuresis.The methyl prednisone was subsequently tapered and the patient had no other manifestations of rejection episode.The patient was discharged from the hospital on the 33d postoperative day but returned on the 55th day with symptoms of malaise.She was readmitted with a questionable rejection episode that was never proven and it was suspected that the patient had a flux-like syndrome without undergoing a true rejection episode.She was subsequent- H.M.KAUFFMAN, Jr., D.LEPLEY, D.JOHNSON and D.KUBAN 261 ly discharged for outpatient follow-up but was readmitted a third time on the 14219 post-transplant day with a tender right groin mass.This was drained under general anaesthesia and resulted in the development of a right groin lymphatic fistula.This lymphatic fistula drained for 21 days during which time the patient developed a mild lymphopenia in spite of reduction of her Azathio- prine dosage.It was also noted at this time that her QRS voltage improved.The significance of this lymphatic fistula is still not clearly understood.The patient was again discharged on the 170th post- transplant day.The patient is currently thirteen months and a half post-transplantation and has returned to a completely normal activities.There have been no further clinical or laboratory data suggestive of rejection episodes and she currently is receiving 3 mg per kg of Azathioprine per day and 20 mg of methyl prednisone per day. DIAGNOSTIC CRITERIA OF REJECTION IN HUMAN HEART TRANSPLANTATION * Ihor DYRDA Cet article relate les critères de diagnostic du rejet cardiaque chez 57 transplantés cardiaques, parmi lesquels on observa 64 épisodes de rejet, dont 30 pour cent furent fatals.Trente pour cent des premiers épisodes furent diagnostiqués entre le cinquième et le quinzième jour.Après quoi, la fréquence diminua fortement mais persista de façon constante et proportionnellement au nombre de patients survivants.|! est impossible de dire si la fréquence de rejet diminuera après six mois.La sensation de malaise est très souvent le signe précoce du rejet, tandis que le tableau de « grippe » est généralement un signe tardif.The aim of this presentation is to summarized the known facts about the diagnosis of rejection of the human heart allograft and thus clear the field for more thought provoking presentations by the panelists that will follow.With this in mind a questionnaire was sent to the different transplant groups that so far have grafted a total of 130 human hearts.We received information about 57 that is 45 per cent of the total.The source of this data is analysed in Table TI.[t may be summarized as follows: 34 from the U.S.A; 14 from Canada; 5 from Europe; 3 from South America and 1 from Australia.The sample appears to be quite representative of the world experience.The mean survival time was 80 days: 25 per cent of the patients had survived 150 days and 10 per cent were surviving more than 210 days.During the first month after surgery there was a mortality of 40 per cent (most of it during the first 15 days) and during the following months the mortality ranged from 12 to 22 per cent of the survivors per month.Rejection was the main cause of death in 50 per cent of the cases.Figure 1 shows the distribution of the rejection * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.episodes.ln 37 heart allografts 64 rejection episodes were diagnosed of which 30 per cent were fatal.Twenty-nine other rejection episodes were suspected.These were not included in the data that will follow.Thirty per cent of the episodes were diagnosed between five and fifteen days after transplant that is during the first set rejection period.Thereafter, the incidence sharply decreased and remained constant being proportional to the numbers of surviving patients each month.From the data available it is not clear if the incidence of rejection will decrease after six months.57 patients 64 rejection crisis 22 fatal 29 suspected rej.crisis No.of rejection crisis 120 150 180 210 240 270 Days after transplant [54 | 45 | 35 | 34| 27 | 22| 8/14 |9 | 5 | 4 |3 No.of patients alive Figure 1 \u2014 Distribution of the rejection episodes.bocal Vol.4 1 DYRDA © chez des de s entre 103 fore y nom ce de | reel al atte pra al! of a il il call sil = jt Laval Médical Vol, 41-Fév.1970 DIAGNOSTIC CRITERIA OF REJECTION 263 Les signes et symptômes de défaillance cardiaque sont peut-être parmi les premiers notés, mais ils signent déjà une atteinte myocardique fonctionnelle et anatomique importante.L'augmentation de l'indice cardio-thoracique peut être secondaire à la dilatation du cœur et à l\u2019épaississement des parois myocardiques, secondaires à l\u2019œdème.|| n\u2019y a pas moyen de dissocier ces deux facteurs.Les signes électrocardiographiques du rejet sont certainement parmi les premiers qui apparaissent.On note une réduction du voltage de l\u2019onde QRS, une déviation de l'axe du QRS et une augmentation de la fréquence cardiaque.Parmi les données hématologiques, on peut noter une modification de la formule blanche, avec augmentation des lymphocytes.La vitesse de sédimentation et le nombre de plaquettes ne sont pas des indices valables.Les modifications enzymatiques sont tardives, et l'augmentation initiale peut bien être secondaire à la thérapie et à la nécrose, tandis que l'augmentation tardive peut être secondaire a la défaillance cardiaque.Signs and symptoms during rejection: The systemic changes during rejection (Table II) are very non specific and may in some cases be secondary to the therapy.The feeling of not being well is sometimes a very early manifestation of re- jeetion, on the other hand the complete \u2018flu like\u2019\u2019 picture is usually a late sign.The signs and symptoms of heart failure during rejection are shown in Tables III and IV.These may well be among the first to be noted but they are certainly not early since their presence means that enough functional if not anatomical myo- cardial damage is present to nullify the cardiac reserve and produce overt failure.The incidence Is quite impressive but one must remember that during a fatal rejection crisis sooner or later all these signs will be present.Since in this serie 30 per cent of the episodes were fatal one must substract 30 per cent from these values in order to have the picture during reversible episodes of rejection.Table V shows the X-rays signs.The increased C/T index may be secondary to heart dilatation and to an increased thickness of the myocardial wall secondary to œdema.We have no means to dissociate these two factors since ultrasound measurements of the myocardial wall are not vet generally done.The electrocardiographic signs of rejection (Table VI) are certainly among the first to make their TaBLE I Information was received regarding 57 patients with transplanted heart from the following centers ANN ARBOR USA 3 CHICAGO (Kittle) USA 1 DALLAS USA 2 HOUSTON (Cooley) USA 19 LYON FRANCE 1 MONTREAL (Dobell) CANADA 1 MUNICH GERMANY 2 PITTSBURG USA 1 TORONTO (Baird) CANADA 3 SIDNEY AUSTRALIA i BORDEAUX FRANCE 1 CHICAGO USA 1 DENVER USA 1 JOHN HOPKINS USA 1 MILWAUKEE USA 1 MONTREAL (Grondin) CANADA 9 PARIS (Cabrol) FRANCE 1 RICHMOND USA 4 TORONTO (Bigelow) CANADA 1 VALPARAISO CHILE 3 264 appearance thus making the E.C.G.the most important tool in rejection diagnosis and follow-up.The reduction in QRS voltage, the shift of the QRS axis and the acceleration of the heart rate are the most frequent and the most easily measured changes.This is well illustrated in Figure 2.This patient died of rejection 47 days after transplant.Tape IT General signs and symptoms during rejection Asthenia i, 78% Myalgia \u2014 malaise oc en recanesecercenrvree 48% DAC dE PET 46% ANOTeXIa ET 46% NEIL RIT 28% TaBLE III Signs and symptoms of heart failure during rejection Ihor DYRDA Decreased work tolerance nier 90% Fall in blood Pressures coi 83% Tachycardia.rer are rare 71% Dyspnea 72% Weight gain _.0 nine een ere een ereere 65% Peripheral edema 60% Distention of jugular veins \u2026 55% Congestive rales 52% Hepatomegaly i.52% Pleural effusion rer ere cre eee 26% TABLE IV Cardiac examination in rejection Tachycardia LL ee one ere inserer enr ere 77% Arrhythmia ere ere e rare are are en ee 55% IIT heart sound ee aérien ere 57% Muffled heart sounds _.0 0e a ins 57% Pericardial friction rubs ere ere 35% Loud SP cernes 17% Mitral insufficiency murmur 0% TaBLE V X-rays signs of rejection Increased C/T index Pulmonary congestion \u2026 Pleural effusion Laval Médical Vol, 41- Fév.1970 You will notice the first change in the axis and voltage beginning at the 5th day, the second change at the 25th day and the final change at the 40th.The questionnaire regarding the biochemical and hematological changes during rejection was inadequate for this reason we have no cumulative TasLE VI E.C.G.signs during rejection Decreased in QRS voltage Tachycardia .Right axis deviation ce Left axis deviation .eee QRS duration increase .coiiiin R.B.B.B.Lee eee eeae serrer ae ere eee nr PR internal increase PVCs eener serrer scans Atrial flutter \u2014 Fibrillation \u2026 P, ST-T, QT Y.T.21-X-68 7-XII-68 150° \u2018 Pa ?100° .i QRS axis od e « .o 2 Avg lS 50° £8 oA 7 7 .\u2019 + odd 0d © 3 oe Lo\u201d 0, Veet * 5 50 | i FEN 40 - i + wn.QRS voltage ne sol °° .\\ 120 | \\ 110 | Pulse/min./ 100 Flo A 90 F \\/ os WN 80 ! 1 L \u20184 1 L 1 1 + 0 5 10 15 20 25 30 35 40 45 50 Days after transplant Figure 2 \u2014 Changes of the E.C.G.after heart transplantation.This patient died of rejection 47 days after transplant.[nial Ya] il lédical i, 140 is change | i, | al uid | ml tie Laval Médical Vol.41- Fév.1970 25 20 WBC 1000/ mnt / Sr eue Pra 0 [oo \u2014\u2014\u2014\u2014 ar\u201d a Lymph.Mono 100/mnÿ 15 | = ON 10 mi \\ 7 TIN ov o 28° sk Platelets 100,000/mnÿ 4H Somes Smt \u2014 7 2F - \\ .1 Le _ Cor.sed.rate mm 25 om 0 m= 7 / 20 | © Na \\/ of A \\/ .QRS voltage mV 25 DWN Nome.20 = \\ \u201c\\ RE 15 LmV \\, 15 1413 12 1 109 8 7 6 54 32 1 + Days before death (5 pts with rejection) Figure 3 \u2014 Changes of the blood before 5 fatal rejection crisis.data to present.Figures 3 and 4 will illustrate our own experience with five fatal rejection crisis.The WBC changed only six days before death (Figure 3).Note the rise in the lymphocyte count between the 14th and the 7th day.The drop at this point is secondary to increased therapy.The platelet count and the sedimentation rate were of no value.DIAGNOSTIC CRITERIA OF REJECTION 265 150 HU ==: SGOT PER 100 L co SGPT 01 LP 50 acces LPS O L'amant .2000 Lu o-=e LDH 0 1500 | »\u2014: HBD i 1000 }- Jas.500 porsimsenn a oom 5 Re NT 20 Fmg/kilo *\u2014: Prednisone AU 15H s\u2026\u2026\u2026 Imuran o/ 10 | ome ALG.RN 0.5 [=> mm Eee 8 ae 8 wn Sem © 25 L NAN QRS voltage mV Seaeg .20 L mV Ney SR 15\u20ac ° 1514 13121 109 876 5 4 3 2 1 + Days before death (5 pts with rejection) Figure 4 \u2014 Enzymatic changes before 5 fatal rejection crisis.Figure 4 shows the enzymatic changes.Note that these changes are late and the initial rise may well be secondary to the therapy and only this final sharp increase may be secondary to necrosis and heart failure.In summary it would not be wrong to say that after twelve years of animal experience and eighteen months of human experience there still is no good way to make an early diagnosis of heart allograft rejection and that the electrocardiogram is still the only trustworthy tool at our disposal. fend Ya #1 2 CLINICAL AND HEMODYNAMIC CHANGES DURING REJECTION OF THE 2 TRANSPLANTED HUMAN HEART * James J.NORA, M.D.,' Michael R.NIHILL, M.D., M.R.C.P.,?and Robert D.LEACHMAN, M.D.* Les données cliniques les plus souvent rencontrées au cours des épisodes de rejet sont dans l'ordre de fréquence : la défaillance cardiaque, le frottement péricardique et le malaise.Parmi les examens de laboratoire quotidiens : les LDH, l\u2019électrocardiogramme, l'examen hématologique, la détermination du débit cardiaque, l'examen radiologique du thorax, I'étude des stimulations leucocytaires phytohémaglutiniques.Du point de vue histocompatibilité, trois facteurs sont déterminés : la compatibilité du système ABO, le cross-match des lymphocytes pour la recherche des anticorps préformés, et la détermination des antigènes lymphocytaires utilisant la méthode de Terasaki.Au cours de la thérapie immunosuppressive, trois agents furent utilisés, ce sont I'Azathioprine, les adrénocorticostéroides et les globulines antilymphocytaires.Les signes typiques de rejet cardiaque précoce, c'est-à-dire dans les quatre premières semaines, sont: la réapparition ou l'augmentation du frottement péricardique, l\u2019augmentation radiologique du volume du cœur, Reliable indices of cardiac rejection in the human formed in 18 patients at the Texas Heart Institute tal subject must be defined to provide optimal clinical of St.Luke's Episcopal and Texas Children\u2019s Ilos- bog management.Methods for recognizing the acute pitals in Houston, Texas.A number of clinical and li episode at the earliest stages are required to pre- laboratory variables were selected as potential in- 8 vent irreversible destruction of the allograft.Epi- dices of cardiac rejection on the basis of previous ; sodes of chronie rejection must also be appreciated canine and murine studies, and on theoretical .as early as possible to arrest progressive changes grounds.These indices were modified as our clinical si, which could compromise the physiologic competence experience increased (3, + 11 and 12).h | of the transplanted heart.Clinical and laboratory indices.Clinical findings hy encountered repeatedly during cardiac rejection .CLINICAL MATERIAL AND METHODS episodes have been evaluated in terms of their fre- bl qe .by Nineteen human cardiac allografts have been per- quency of association with rejection: 1) congestive In heart failure; 2) pericardial friction rub; and fy * Paper presented at the Second world symposium 3) malaise.Laboratory indices were monitored pro- \u201cou on heart transplantation, Montreal, June 6-8, 1969.: .: : \u201clig; 1.Associate Professor of Pediatrics, Baylor College spectively to guide immunosuppressive therapy.I | of Medicine and Associate Cardiologist, The Texas Heart Most of these indices have also been reviewed retro- lig, Hf Texas Children\u2019s and St.Luke's Episcopal spectively, and a judgment made as to when each 0] 2.Fellow in Pediatric Cardiology, Texas Children\u2019s Parameter taken independently should be accepted iy Hospital.» as diagnostic of rejection : i 3.Associate Professor of Medicine, Baylor College 1.Lactate dehydrogenase isozymes, studied daily Wy, of Medicine and Director of Cardiology, St.Luke's Hospital, Houston, Texas 77025.for the first two postoperative weeks and reduced ROA ND! | il rs des cardié- o aber émald- je du res la jour 18 gènes i ul pings aps les ion 80 | cal poil jf al jl | ie pri?arid fi gud li wr | purl?TE gi al pi gent d LU ol a eff Jil A Laval Médical Vol, 41 -Fév.1970 I'augmentation du volume du foie avec œdème périphérique.CLINICAL AND HEMODYNAMIC CHANGES NURING REJECTION 267 D\u2019habitude, il y a une température qui s\u2019éléve a 101°, une augmentation de la fréquence cardiaque et des malaises sous forme d\u2019anorexie, parfois des nausées et douleurs généralisées.Deux ou trois jours avant les signes cliniques, on constate une augmentation des LDH.L\u2019électrocardiogramme montre une ischémie souvent sous-endothéliale et une diminution du voltage du QRS.Parfois, on note une arythmie et une déviation axiale droite du vectocardiogramme dans le plan frontal.Ces signes électro- cardiographiques précèdent les signes cliniques, mais apparaissent après les modifications des LDH.On note une augmentation subite des globules blancs, allant jusqu\u2019à 25 à 40 000.Si l'épisode ne peut être contrôlé par les immuno-suppresseurs, on note une chute de la pression sanguine qui sera contrôlée avec de l\u2019Iso- proterenol.À l\u2019autopsie, il y a une infiltration interstitielle du myocarde, avec des lymphocytes, un petit nombre d\u2019histiocytes et un nombre variable de leucocytes polymorphonucléaires.Cette infiltration est plus marquee dans la région périvasculaire et se rencontre également dans l'intima, épaissie, des artéres coronaires.Parmi les signes de rejet tardifs, on note a I'électrocardiogramme une diminution progressive du voltage du QRS, de méme que des changements ischémiques sous-endothéliaux.Le malade ne se sent pas bien.On notera progressivement une augmentation du volume du cœur, une augmentation du poids, une diminution de la tolérance à l'exercice, gradually to twice weekly by the end of the second month, using mierozone electrophoretic separation (13).2.Daily electrocardiograms.3.Daily hematological evaluation, including routine complete blood count, alkaline phosphatase.stain of peripheral smear, periodic Rebuck window (13), and bone marrow aspiration when indicated.4.Hemodynamic evaluation, beginning with a baseline dye dilution cardiac output 24 hours after transplantation and followed by sequential cardiac outputs and full cardiac catheterization studies including response to exercise and cardioactive pharmacological preparations (7).5.Daily chest roentgenograms, for the first two weeks, then reduced in frequency as indicated.6.Weekly phytohemagglutinin leukocyte stimulation studies (10).Histocompatibility.Prospective histocompatibil- (11) {suite du résumé en page suivante) ity studies performed locally at Texas Children\u2019s Hospital have been compared with retrospective studies on the same patients obtained through a collaborative study with Doctor Paul I.Terasaki (6).The three constituents of the donor-recipient mateh are: 1) ABO red blood cell compatibility; 2) lym- phoeyte cross-matching for preformed antibodies: 3) lymphocyte antigen matching using the Terasaki microdroplet lymphocyte cytotoxicity testing technique and grading scale.Immunosuppressive therapy.Three basic im- munosuppressive agents have been employed in the management of patients in this series.Several modifications in the earlier reported use of these agents (3, 4 and 11) have been made on the basis of increasing clinical experience (12).Azathioprine.This agent is still considered to be corner-stone of the immunosuppressive program.At the time of decision for cardiac transplantation (usually only hours before the procedure), 4 mg/kg body weight is administered orally.This dose is Laval Médical M jun Vol.41- Fév.1970 Yi, 4 James J.NORA, Michael R.NIHILL and Robert D.LEACHMAN et des malaises.caractéristiques.On note une diminution du débit cardiaque et une augmentation pro- 8 bi gressive de la pression télédiastolique du ventricule droit et de la pression M im de l'oreillette droite.À l\u2019examen clinique il y a une diminution de la pres- I k ; sion artérielle et une augmentation du rythme cardiaque.Les LDH sont 1 augmentés, mais non de façon significative.La leucocytose est aux | de environs de 10 à 15 000.§ oi À l\u2019autopsie, les artères coronaires présentent un épaisissement de gs l\u2019intima et une fibrose avec une infiltration de lymphocytes, plasmocytes et histiocytes contenant des vacuoles lipidiques.On trouve souvent une infiltration d\u2019érythrocytes par rupture des petits vaisseaux.On trouve également des foyers de nécrose myocardique.Il y a donc cinq indices principaux dans le rejet cardiaque, ce sont la défaillance cardiaque, le frottement péricardique, les malaises, les mo- RO lu difications des LDH et du tracé électrocardiographique.Parmi ceux-ci, 8 vin trois constituent des indices fiables dans la détection du rejet tardif : ce É tu sont la défaillance cardiaque, les malaises et les modifications électro- | La fièvre et le frottement péricardique ne sont pas Yet are by ge | lip fhe re cardiographiques.Prévention du rejet : 1.Histocompatibilité.L\u2019histocompatibilité tissulaire des groupes C et D a un pronostic très réservé ; 2.Thérapie immunosuppressive : Azathioprine, adrénocorticostéroi- des et globulines antilymphocytaires.reduced to 3 mg/kg for the next two days and further reduced to 2 mg/kg, which is maintained throught the first postoperative month.The final maintenance dose has been dependent on bone marrow and systemic tolerance of the drug, and has varied from 25 mg to 100 mg per day in adults discharged to return home and to work.Cyclo- phosphamide has been used intravenously as a supplement to azathioprine during the most severe acute rejection crises.Adrenocorticosteroids.At the time of decision for transplantation prednisolone, 1 mg/kg is administered orally and 5 mg/kg of hydrocortisone is given intravenously.These two agents are administered in the same dosage every six hours throughout the first postoperative day, at the end of which the prednisolone is reduced to 0.75 mg/kg per dose and the hydrocortisone to 2 mg/kg per dose each every six hours.The hydrocortisone is then discontinued and reserved for use during rejee- tion crises in doses as high as 10 mg/kg every two hours.Preduisolone is given orally throughout the first two weeks at a level of 0.5 mg/kg every six hours.At the end of the first month prednisolone has been gradually reduced to 0.25 mg/kg every six hours and before discharge from the hospital the adult patients have been further reduced to levels between 15 mg and 30 mg daily, divided into three or four doses.Other synthetic adrenocortico- steroid preparations have been used for maintenance therapy in doses comparable to the above prednisolone schedule.Antilymphocytic globulin.ALG prepared in Houston for the patients in the present study is produced in horses against human thymus and purified to a final product which consists entirely of IgG fraction.This agent is given daily for two weeks, intravenously or intramuscularly, and then administered every other day.The dosage is determined by the cytotoxic titer of the product and the rate of clearance of the isotopically labeled doses.fin y ing [il Hla lo gh fit ] Jee, Pri édical 5, 470 È pas pre sion | pres | sonl {alk it poyles NL Une House 2 sont 5 m0 a) if 0 lectro- pes 0 stéro arte i sis ale eld tl pel pl à iti ile itt ul wt paie jt it » (pl Laval Médical Vol.41- Fév.1970 RESULTS Before reviewing the clinical and laboratory findings of rejection from the point of view of assessing the validity of each individual parameter as an indicator of cardiac rejection, it would be useful to describe what might be called the typical findings in early rejection (first four weeks) and late rejection (over four weeks).These deseriptions are based on the observation of 26 episodes of cardiac rejection (Table 1) occurring in 14 of the 18 patients in this series.Early human cardiac allograft rejection.What we interpret as a first set rejection is clinically detectable as early as the fifth postoperative day with the reappearance or increase in the pericardial friction rub, roentgenographic increase in heart size and often an increase in liver size, with peripheral edema.There is usually a temperature elevation to about 101°, and increase mm heart rate and a distinct malaise with anorexia, sometimes nausea and generalized aching.Prior to the appearance of these clinical findings, CLINICAL AND HEMODYNAMIC CHANGES DURING REJECTION 269 as early as the second or third day, serum LDH-1 is significantly elevated (see LDH-1 criteria in subsequent section).The electrocardiogram shows ischemia, often subendocardial injury, and loss of QRS voltage; occasionally arrhythmia and rarely a right axis shift of the frontal plane QRS vector.These ECG changes may precede the clinical findings of rejection, but usually occur later than the LDH-1 abnormality.At about the same time the pericardial friction rub, fever and malaise begin, the white blood count is suddenly increased, often rising to levels of 25-40,000 WBC/mm?.The cells are almost all poly- morphonuclear, mature and have a normal alkaline phosphatase stain count.The Rebuck window shows persistence of polymorphonuclear cells rather than normal transition to mononuclear.The phyto- hemagglutinin leukoeyte stimulation is usually normal, without ever having reflected suppression.If the episode cannot be adequately controlled by the immunosuppressive program, the pulse pressure drops and an intravenous isoproterenol drip (and recently glucagon) may be required to maintain the Tape 1 Clinical experience with cardiac transplantation TISSUE No.or CasE DATE OF AGE FIRST REJECTION CAUSE oF No.OPERATION (Yrs) Sex DIAGNOSIS MATCHING REJECTION EPISODE BEGAN SURVIVAL DEATH GRADE EPISODES 1.a) 5- 2 68 47 M Rheumatic c 2 8 days 200 days _ @st op.) Multivalvular b) 11-21-68 5 Cardiac rejection c 1 Immediately 3 days Rejection (2nd op.) 2.5- 5-68 48 M Coronary 0 \u2014 3 days Infection 3.5- 7-68 62 M Coronary C 0 \u2014 8 days Pre-existing diseases 4.5-21-68 54 M Coronary Cc \u2014 2 50 days 145 days Rejection 5.7- 2-68 46 M Coronary D 6 6 days 149 days Rejection 6.7-20-68 58 M Coronary C + 1 \u2014 267 days Rejection 7.T-23-68 57 M Coronary Cc 3 13 days 170 days Rejection 8.7-29-68 49 F Coronary Cc 1 11 days 55 days Infection a.8-18-68 5 F Endocardial D 1 5 days 8 days Rejection Fibroelastosis 10.8-19-68 50 M Coronary ec \u2014 5 days 68 days Infection 11.9-15-68 2 m, F A-V Canal (cardio- ce 0 \u2014 14 hours Pulmonary pulmonary insufficiency transplant) 12.10-25-68 52 M Coronary Cc 3 23 days 126 days Rejection 13.11- 5-68 50 M Cardiomyopathy D 1 5 days 7 days Rejection 14.11- 9-68 55 M Coronary c 0 \u2014 48 days Infection 15.11-16-68 50 M Coronary D 1 7 days 188 days Living 16.11-29-68 54 M Coronary D 1 6 days 13 days Rejection 17.3- 4-69 56 M Coronary D 2 5 days 80 days Living 18.4- 7-69 47 M Coronary D 0 \u2014 3 days Infection no cardiac output.In three patients an acute first set rejection could not be reversed by aggressive immunosuppression and cardiovascular support.Death occurred in these patients between the seventh and thirteenth postoperative days.The findings of acute rejection at autopsy (9) show a myocardial interstitial infiltrate consisting of lymphocytes, a small number of histiocytes and varying numbers of polymorphonuclear leukocytes.The infiltrate is more concentrated in perivascular areas.A similar infiltrate is found in thickened intima of coronary arteries.Late human cardiac allograft rejection.It is most important to appreciate that late rejection begins with a gradual loss of QRS voltage, which is not clearly recognized as a trend for several days, because of the day to day variability in this parameter.Ischemic changes increase and subendo- cardial injury may appear.The patient often insists that he feels well.These electrocardiographic abnormalities may be reversed by one or two days of massive intravenous hydrocortisone supplementation of the immumnosuppressive regimen.If the electrocardiographie changes are not recognized early, further progression occurs which includes increase in roentgenographic heart size, increase in weight with peripheral edema, decrease in exercise tolerance and malaise.Fever and pericardial frie- tion rub are not charaeteristic of late cardiac allo- graft rejection.The hemodynamic changes encountered during episodes of clinical rejection include decrease in cardiac output as measured by indicator dye-dilution technique.There is progressive increase in right ventricular end-diastolic pressure and right atrial pressure.A consistent clinical reflection of the failing myocardium and decreased cardiac output is drop in systemic blood pressure accompanied by narrow pulse pressure and inereased heart rate.LDH-1 is inereased, but not diagnostically so, and LDH-1 is not greater than LDH-2.The white blood cell count may become slightly elevated (10,000-15,000 WBC/mm?) which is not to the extent found in early acute rejection.Immature 70 James J.NORA, Michael R.NIHILL and Robert D.LEACHMAN Laval Médical Vol.41 -Fév.1970 granulocytes and atypical mononuclear cells are found.The Rebuck window may show a normal migration of cells with some decrease in mono- nuclear elements.Phytohemagglutinin leukocyte stimulation frequently returns to normal before the onset of a rejection episode.The findings at necropsy of chronic rejection (9) reveal coronary arteries exhibiting intimal thickening and fibrosis with an infiltrate of lymphocytes, plasma cells, and histiocytes containing lipid vacuoles.There are varying degrees of luminal compromise, Acidophilic degenerative change may be present in the tunica media of the medium and small coronary arteries.There is a myocardial interstitial infiltrate of lymphocytes, plasma cells and histiocytes.Extravasation of erythrocytes due to rupture of small vessels is common.Focal areas of myocardial necrosis are found.RECOGNITION OF REJECTION Congestive heart failure.All patients, except one, required digitalis in the immediate postoperative period, and fluid retention with peripheral edema has been experienced by all patients in the first weeks after surgery.However, florid congestive heart failure with increasing cardiomegaly, hepato- megaly, peripheral edema and dyspnea is what is more characteristic of patients having cardiac re- Jeetion.Severe congestive heart failure was obvious in all patients with early rejection (Table IT) and was prominent in all but two late rejection episodes.The specificity of this sign increases with the number of postoperative weeks to the point that an episode of congestive heart failure beginning after four weeks must be regarded as cardiac rejection.Pericardial friction rub.Table IT shows that nine of eleven patients having rejection episodes during the first four weeks had a reappearance or significant increase In a pre-existing pericardial friction rub.After four weeks, a pericardial rub rarely accompanied cardiac rejection.It may be argued that many patients have the recrudescence of a pericardial friction rub following other types of open heart surgery, but this does not depreciate Laval Vol.41 the mn card drone direct mo Ya Hl deg pin Drum wil sith lity id y Ty Wal fy tly ii 4 te / Up Em [idiot § br 160 Iv ire B wi À ie phocrte ne fle al! bicker Jules, 1 vate al ol i qu al dial gs anl ue tr as il ant ue.pele | ed fie di pif pi ali b lite I ie pal qe Jp J far pe ft! jo Ï gs a gil?pp ÿ al | at pr} jar i i\u201d ref ! \" i Laval Médical Vol.41 -Fév.1970 the immunological implication of this finding in cardiac rejection or the post-pericardiotomy syndrome.We regard the pericardial friction rub as a direct and clinically detectable sign of host-graft immunologic interaction.Malaise.Although malaise may sound vague and non-specific, we have come to regard it as a reliable index of cardiac rejection.Loss of appetite, nausea, pain in muscles, joints, chest and abdomen, and progressive lethargy has been found in all patients with acute rejection, whose sensorium permitted such an assessment.Heart transplant patients are not inclined to complain over minor discomforts, and we become deeply concerned when they say they \u2018feel sick\u2019.Infection is also accompanied by malaise, but is distinguishable by the detection of findings supporting infection, such as positive blood culture, abscess and clinical and roentgenographic evidence of pneumonia.A word of caution should be offered regarding the use of malaise as an index of rejection.In the early stages of chronic rejection there is apparently no malaise, and even in later stages there is a tendency to deny the presence of symptoms.In aretro- spective analysis of clinical and laboratory para- CLINICAL AND HEMODYNAMIC CHANGES DURING REJECTION 271 meters, we concluded that one of our patients had begun chronic rejection of his heart approximately three months before he died.Yet during that time he was working a full day as a salesman and swimming daily up to one week before his death.Lactate dehydrogenase (LDH) isozymes.LDH isozymes, specifically LDH-1, which predominates in myocardium, have been studied as an independent index of cardiac rejection (13).During the first month following surgery the mean level of LDH-1 is significantly higher in patients rejecting than in those not rejecting.After one month the difference is no longer significant.The percentage of LDH-1 always exceeded 35 per cent of total LDH during the first four weeks after surgery.After four weeks, however, clinical rejection was not accompanied by LDH-1 levels in excess of 35 per cent.LDH-1 was greater than LDH-2 in nine of eleven patients with cardiac rejection during the first four weeks, but after the sixth postoperative week, 13 out of 15 episodes of clinical rejection occurred without this finding.The criteria we derived from this study as suggestive, if not diagnostic, of human cardiac rejection during the first post-transplant month are: Tape II Five most reliable indices of cardiac rejection and their occurrence in rejection episodes (Rej) or in apparent absence of rejection (Non) 11 Episoprs 15 EPISODES 0-4 WEEKS > 4 WEEKS Rej.Non Rej.Non CHF | Present 11 3 (12) 0 Absent 0 4 (3) 10 Present 9 0 (3) 1 Rub Absent 2 7 (12) 9 Malai Present 10 2 (12) 4 alaise Absent ?3 6 Î Present 10 1 2 0 LDH- Absent 1 6 (13) 10 ECG Present 11 4 (15) (4) abnorm.Absent 0 3 0 7 ( ) = more than one episode in the same patient. LDH-1 > LDH-2; LDH-1 > 35 per cent of total LDH ; LDH-1 > 100 International Units.Using these criteria LDH-1 was elevated in 10 of 11 acute rejection episodes during the first four weeks and in only one patient was there a diagnostic LDH-1 elevation without obvious clinical rejection, After four post-transplant weeks, LDI-1 ceases to be a useful index of rejection.Lactate de- hydrogenase isozymes are most reliable as an index of rejection in the early postoperative period, at a time when the electrocardiogram is least reliable due to non-specific changes related fo heart surgery obscuring signs of rejection.Electrocardiogram.The electrocardiographic findings consistent with cardiac rejection are listed in what we would consider to be the order of importance and specificity : 1.Progressive decrease in QRS amplitude; 2.Sub-endocardial injury; 3.Ischaemia.The ECG tracings were studied daily as a guide to immunosuppressive therapy and were later studied in a retrospective analysis of this parameter as an independent index of rejection.During the first four weeks all patients surviving more than three days, whether or not they had other findings of cardiac rejection, had electrocardiograms diagnostic of rejection (Table II).However, after four weeks the electrocardiogram became more diseriminating and the frequency of false positive diagnoses of rejection (based solely on ECG criteria) decreased.What is perhaps the most specific ECG index of rejection, right QRS axis, is not listed in the above three criteria, because it does not occur as frequently as the other signs, which lessens its diagnostie importance.Arrhythmias are also useful but not consistent clues to rejection.The two deficiencies in the use of the electrocardiogram as a clinical guide to rejection are: its lack of discrimination in the first postoperative weeks between rejection and non-specific changes related to open heart surgery; and its rather wide range of variability, day to day.and even hour to hour.These deficiencies are compensated for by James J.NORA, Michael R.NIHILL and Robert D.LEACHMAN Laval Médical Vol.41 -Fév.1970 relying on another parameter in the first weeks after surgery (LDH-1), and by plotting ECG changes daily searching for the earliest evidence of an established trend.At this time, despite the above-noted inadequacies, we consider the electrocardiogram to be the most useful guide we are currently employing to judge rejection of the transplanted human heart.Other laboratory parameters.The results of the hematological and phytohemagglutinin studies are still being evaluated to determine their prognostic value as independent parameters of rejection.As soon as conclusions are possible these data will be reported.A certain number of other clinical and laboratory indices of rejection suggested in earlier reports from this and other transplantation centers (1, 3, 4, 5 and 11) have not been discussed because they have not proved useful.For example, erythrocyte sedimentation rate appears to be of no value as an index of rejection, at least in the presence of our usual immune suppressive program.Enzyme determinations other than LDH-1 have not shown consistent and reproducible patterns as yet.At the present, there appear to be five reliable indices of early acute cardiac rejection: 1) congestive heart failure; 2) pericardial frietion rub; 3) malaise; 4) elevated LDH-1; 5) ECG changes.Three of these parameters are reliable in the detection of late or chronic rejection: 1) congestive heart failure; 2) malaise; 3) ECG changes.Supporting evidence for both acute and chronic rejection is found in the hematological, hemodynamic and phy- tohemagglutinin studies, but their reliability as independent parameters of rejection is still being assessed.PREVENTION OF REJECTION Histocompatibility.The relevance of tissue typing to remal allograft survival was predictable from the extensive background of mammalian investigations (16) and confirmed in clinical studies involving related and unrelated donors (14 and 18).However, a number of years of experience with 7 te La Hy [ i, pe (diel [rl weeks ea § fan ratory report 13 i tT rst pth of lf ie Foul 3 elle 1 wl M; 0 i: ! Jn | N jetée ple! | pir Laval Médical Vol.41- Fév.1970 human renal transplantation has been required to reach the conclusion that lymphocyte typing is correlated with clinical outcome.The length of time required to establish this correlation has been related to the development of methods for leukocyte typing and antigen identification which are reproducible.The relative immunologic incompetence of the uremic patient may also have delayed the appreciation of histocompatibility differences by permitting survival of patients with degrees of mismatch which eannot be tolerated in cardiac transplantation, Recognizing the limitations in analysis of small samples, a trend is nonetheless becoming apparent.Length of survival and quality of survival of human cardiac allografts appear to correlate directly with the closeness of histocompatibility match detectable by present methods.Table 111 summarizes our observations on histocompatibility and clinical out- The decrease in mean survival and mean survival without come in patients surviving seven days.a rejection episode with decrease in grade match from C+ to D is shown.Also documented is the relationship between matching grade and rejection episodes per patient day with one rejection episode per 29 patient days being found in D grade matches and one episode per 267 patient days being found in C + grade matches.Immune suppression.The results of immuno- suppressive therapy were highly satisfactory in the carly course of the patients of this series.The regimen of azathioprine, adrenocorticosteroids and antilymphoeytie globulin was patterned after the CLINICAL AND HEMODYNAMIC CHANGES DURING REJECTION 273 use of these agents in unrelated donor-recipient renal allografts (17).An effort was made to reduce immune suppression to levels which would permit full employment and restoration of activity.Four patients returned home to a high level of activity including swimming and hunting.Two were fully employed, one as a certified public accountant and one as an automobile salesman.No patient discharged from the hospital on the immunosuppressive level which we required for discharge has developed a significant infection.These doses (see Methods) were based on the adequacy of suppression of clinical and laboratory evidence of cardiac rejection achievable with bone marrow and systemic tolerance of the medications.Antilymphoeytic globulin was first introduced into human cardiac transplantation in the patients in this series, and its effectiveness and optimal methods of use are still being assessed.We do not feel that maximal benefit has yet been achieved from this agent, if it fulfills an early prediction by Sir Peter Medawar (8) of being \u201c\u2018 most powerful but also the only true immuno- .not only the suppressive agent.\u201d\u201d We are making efforts to discover optimal dosage, route and frequency of administration, and to devise methods of preventing increasing Immunologic clearance.Presently our dosage regimen is based on cytotoxic titer and rate of clearance of isotopically labeled doses (2) and no patient has yet had his treatment with this medication discontinued.However, by all routes of administration, the plasma half-life of 125; labeled ALG decreases, in some patients very slowly over Tape III Clinical course related to histocompatibility grade in 14 human cardial allografts surviving 7 or more days C+ C C\u2014 D Mean survival (days) 267 106 98 69 Mean survival without rejection (days) 267 225 19 57 Rejection episodes per patient day 1/267 1/92 1/65 1/29 274 a period of months, and in others very rapidly over a period of weeks (2).These data suggest that ALG is antigenic in man and that there is need to develop methods to prevent formation of antibodies against ALG to prolong its effectiveness as an im- munosuppressive agent.An encouraging observation has been made in one of our patients who began to demonstrate an increasing ALG half-life in his eighth postoperative month after first manifesting the customary decrease in 125; plasma half-life of ALG.This may represent the development of tolerance to ALG.DISCUSSION Human cardiac allograft rejection is a real and dramatic event, the clinical features of which may be readily described.An important difference between cardiac and renal rejection which is becoming apparent is that there does not seem to be the quiescent period of graft tolerance after three postoperative months in poorly matched heart patients as there is in kidney patients.The rejection of the heart appears to be inexorably progressive in pa- Far from being a privileged organ, the heart seems even tients with poor histocompatibility matches.more vulnerable to rejection than the kidney.Several factors contribute to this vulnerability.The critical physiologie function of the heart will not permit periods of shutdown without death as in the transplanted kidney.Nor can a rejected heart be removed and the patient maintained for many weeks by extracorporeal support while seeking another organ.In addition, the cardiac patient may not have the recognized diminished immunologic competence of the uremic patient.It must be appreciated that human cardiac transplantation is an investigative procedure which has minimal present clinical application.Those who may derive enough benefit from the procedure at our present level of understanding to justify the enormous expenditure of human and fiscal resources would seem to be patients with excellent histo- compatibility matches and all other presently accepted clinical criteria for heart transplant reecip- James J.NORA, Michael R.NIHILL and Robert D.LEACHMAN Laval Médical Vol.41- Fév.1970 ients (3 and 4).compatibility matching may be found through re- Opportunities for better histo- gional and national pooling of prospectively-typed donors and recipients, with emergency transportation of patients to selected centers.Recipients of histocompatible hearts should hopefully receive both genuine clinical benefit and provide a background of needed immunologic and physiologic information concerning long-term graft survival.From this series we have learned that rejection and infection in patients with grades C and D histo- compatibility matches constitute significant deterrents to immediate clinical application of cardiac transplantation, However, if cardiac transplantation is going to have wide clinical application in the future, new methods will have to be devised for overcoming poor histocompatibility matches.Present methods of immune suppression have not proved to be as adequate as anticipated.A logical next step would be vigorous investigation into possible methods for induction of tolerance.Further frontiers worthy of consideration are long-term organ preservation and possibly, at some distant time, crossing the formidable species barrier.REFERENCES {.BARNARD, C.N., Human heart transplantation : the diagnosis of rejection, Am.J.Cardiol, 22: 811- 819, 1968.2.BurLer, W.T., et «l.Antilymphocyte globulin turnover rates in heart transplant patients, (Abs.), Clin.Research, 17 : 72, 1969.3.CooLry, D.A., BLoonwELL, R.D, HALLMAN, G.L., and Nora, J.J., Transplantation of the human heart, J.A.M.A., 205.479-486, 1968.CooLky, D.A., HALLMAN, G.L., BroopwELL, R.D., Nora, J.J., and Leacamax, R.D., Human heart transplantation : experience with twelve cases, Am.J.Cardiol., 22 : 804-810, 1968.Dvsosr, C., and CACHERA, J.-P., Un cas de greffe allo- génique du cœur chez l\u2019homme (II), Presse Méd., 76 : 1713-1716, 1968.fi.FERNBACH, D.J., Nora, J.J, and CooLEY, D.À, Prospective tissue-typing for heart transplants, Lancet.1: 425-426, 1969.LEacHMAN, R.D., et al.Physiologic responses of the transplanted human heart (Abs.), Circulation, 38 : (Supp.VI-123), 1968.~~ Tu ~2 JA Tl 4 Da \u201cM WW [EY died! «lin lise jh ne 11 arti Ay if ve bith rill iin 1-1 Hite er rie plat qui Jel hes ie ul hg ji pas order jeter fiston ou de y: «il ja I Ash wt Laval Médical Vol.41- Fév.1970 $ 10.MivaWar, P.B., Quoted by HumpHREY, J.H., in Antilymphoeytic serum, Ciba Foundation Study Group No.29, Boston, Little, Brown and Company, 1962, p.2.Miam, J.D, BroonwErL, R.D., Nora, J.J., SHIPKEY, F.H., Jr, HALLMAN, G.L., and Coorery, D.A, Morphologic findings in human cardiac allografts, In preparation.MonTeoMERY, J.R., SourH, M.A.Rawrs, W.E., MELNICK, J.L., Orson, G.B., and Goop, R.À, Viral inhibition of lymphocyte response to phytohemag- glutinin, Science, 157 : 1068-1070, 1967.Nora, J.J., Recognition and prevention of rejection of the transplanted human heart, Med.Rec.& Ann., 61 : 386-390, 1968.Nora, J.J., CooLEY, D.A., FERNBACH, D.J., ROCHELLE, D.G., Miram, J.D., MoNTGOMERY, J.R., LEACH- MAN, R.D., BUTLER, W.T., RossEN, R.D, Bzoop- WELL, R.D., HALLMAN, G.L., and TRENTIN, J.J., Rejection of the transplanted human heart : Indexes of recognition and problems in prevention, New Engl.J.Med.280 : 1079-1086, 1969.CLINICAL AND HEMODYNAMIC CHANGES DURING REJECTION 13.16.IN.Parry, Lo \u20141 Lt Nora, J.J., CooLey, D.A., JoHNsoN, B.L., WATSON, S.C., and MrzaMm, J.D., Lactate dehydrogenase isozymes in human cardiac transplantation, Science.(In press), 1969.R., Mickey, M.R., and TrrAasAKI, P.1, Serotyping for homotransplantation.XVI.Analysis of kidney transplants from unrelated donors, New Engl.J.Med.279 : 501-506, 1968.Resvcek, J.W., and CrowLey, J.H., A method of studying leukocyte functions in wvivo.Ann.N.Y.Acad.Sci., 59: 757-805, 1955.SxuLL, G.D., and SrtimprLiNG, J.H., Genetics of tissue transplantation, in Biology of the Laboratory Mouse, Second edition, Editor, E.L.GREEN, New York, McGraw-Hill.1966, pp.457-492.STARZL, T.E., MArcHIORO, T.L., HUrcCHIsoN, D.E., Porrer, K.A., CErRELLI, G.J., and BRETTSCHNEIDER, L., The clinical use of antilymphocyte globulin in renal homotransplantation, Transplantation (Supp.), 5: 1100-1105, 1967.TKRASAKI, P.I, VrEbEVoE, D.L., and Mickey, M.R,, Serotyping for homotransplantation.X.Survival of 196 grafted kidneys subsequent to typing, Transplantation (Supp.), 5: 1057-1070, 1967. ELECTROCARDIOGRAPHIC AND VECTOCARD!OGRAPHIC SIGNS OF REJECTION * J.-P.LACASSAGNE and J.-P.CACHERA à Les auteurs présentent les modifications électrocardiographiques rencontrées au cours du rejet chez deux malades qui ont bénéficié d'une transplantation cardiaque.Parmi ces signes, on notait : 1.Des arythmies sous forme de bloc sino-auriculaire et auriculo- ventriculaire ; 2.Des troubles de conduction auriculo-ventriculaires sous forme d\u2019une augmentation de l\u2019espace PR, et des signes de troubles de conduction intramyocardiques, sous forme d\u2019un élargissement du QRS, puis du QT.Analysis of the E.C.G.tracing following heart transplantation in the dog (4) has enabled us to recognize the following signs of rejection : Arrhythmias; Troubles of the intramyocardial conduction; Low voltage ; Troubles of repolarization.Since the beginning of our experimentation, the most important E.C.G.variations announeing rejection seem to be arrhythmias and intramyocardial conduction troubles; low voltage comes later and its pronostie is very bad.This is due to the very disseminated character of the histological lesions as observed on acute or chronic myocarditis (5 and 6).These data have been verified on two human cases.A.The first case concerns a 59 year old man transplanted on May 12th 1968, for ischemic disease (1, 2 and 3).1.The E.C.G.survey and its comparison to the titration of serum enzymes derived from heart muscles (7), has been normal from the first to the 204th day, where abruptly occurred a sino-auricular * Paper presented at the Second world symposium on cardiac transplantation, Montreal, June 6-8, 1969.i Hopital Broussais, Department of cardiac surgery (Professor Ch.Dubost) and Centre d\u2019étude des techniques chirurgicales (Professor J.P.Cachera), 96, rue Didot-75, Paris XIV, France.2/1 block which was registered for only one minute This arrhythmias has not been followed by any more with a left rotation of the ventricular axis.troubles during a month (Figure 1).2.The second E.C.G.change, on the 240th day gave more evidence of rejection, by the increase of the PR interval; of the QRS and QT duration, and a variation to the left of the ventricular axis; but there were no arrhythmia, nor low voltage ; and at the same time fever occurred and the myocardial enzymes increased.The adjustment of therapy was followed in a few days by restitution to normal data.Then during three months we observed no ECG changes.3.On April 25th, eleven months after the transplantation, for a four hour period an arrhythmia occurred.It consisted first on a sino-aurieular 2/1 block then a 3/1 block which reduced the heart rate to about 38/mn, then occurred an auriculo- ventricular block of variable degrees until it reached a complete auriculo-ventricular block.Diffused repolarization troubles, as seen in pericarditis, were present for a week.Enzymes derived from heart increased in the same period.Then the E.C.G.returned to normal.4.Troubles of repolarization have occurred between the second and the third E.C.G.changes, ll EE AIRE Lol fol 4 N Laval Médical ih Vol, 41- Fév.1970 SIGNS OF REJECTION 277 : Quant au rejet s\u2019annongant par une diminution du voltage, les auteurs H considèrent ce facteur important, mais il faut tenir compte qu\u2019il peut ap- | paraître dans le cas d\u2019un épanchement péricardique et qu\u2019en fait, ce signe À est tardif et précédé par d\u2019autres modifications électrocardiographiques.di | Son apparition signifie un rejet actif.Les changements ischémiques, lorsqu'ils sont localisés et d'apparition brutale, peuvent être le fait d'un rejet.Des modifications diffuses, telles que dans les péricardites, peuvent se rencontrer également au cours du rejet ou dans le syndrome post-péricar- dotomie.Les changements progressifs et diffus de l\u2019onde T, conséquence du traitement à long terme et à haute dose aux corticoïdes, disparaissent avec une thérapie au potassium.|| semble que les signes prémonitoires du rejet soient les arythmies et les troubles de conduction intramyocardi- ques, tandis que la présence d\u2019un bas voltage signe la présence du rejet.Notons que dans l\u2019évaluation du bas voltage, il est important que le tracé soit pris sur la même machine, avec le même technicien, à la même heure, sien | d'une 8 feller due 8 onde: | #1 et en disposant les électrodes de la même façon.ik while an osteoporosis was noted with an hypo- crease of voltage following minor variations of the Thi kaliemia due to cortisonic treatment.With po- zymogram (Figure 2).gt tassium per os, all repolarization troubles disap- On the end of the fourth month, progressively peared.appeared a variation of repolarization on leads V5 The actual B.C.G.is like the first B.C.G.after and V6 which might be interpreted as subepicardic 4 ' transplantation, with a 90/mn sinusal rate and an ischemia.No more E.C.G.change was noted.nt | incomplete right bundle branch block, as shows the it vectocardiogram, DISCUSSION ist We must note that the voltage has never changed, got even during the most important rejection erisis These facts suggest some comments.pol (204th day) out of normal variations due to posi- 1.Arrhythmias occurred twice, during registra- | tion, breathing.The three E.C.G.changes were tion of the E.C.G.This calls for a daily E.C.Gnu arrhythmias on the first and third erisis, and survey and a program of continuing E.C.G.tracings f auriculo-ventricular and intra-myocardial conduction troubles on the second crisis.B.The second case concerns a 48 year old man once the patient has returned home.We try to realize such a program.Such arrhythmias occurred, in a patient trans- lnk | transplanted on November 24th 1968, for ischemic planted in Bordeaux (Pr.Fontan).The adminis qu} disease and complete heart failure.tration of heparine was followed by the suppres- nN The first E.C.G.after transplantation shows a sion of arrhythmia (access of auricular fibrillation le vertical position and a dextrorotation of the heart, which called for several electric shocks during a two ut an incomplete right bundle branch block, and signs month period).This fact, and the knowledge of J il of posterior infarction, as confirmed by vectocardio- histological coronary thrombosis with rejection are a gram.We believe that a coronary air embolism an argument for the anticoagulant therapy.y oceurred.9.The most important crisis of rejection has \u2019 Cp During the four first days, voltage was low, and given multiple signs of rejection, such as in myo- ve it then increased to normal values, 25-30 mv, where carditis: auriculo-ventricular conduction time in- it remained until now (seven months).creased (PR interval from 0.16 to 0.20 see.), intra- yrl ¥ However, on three times, we noted a slight de- myocardial conduction troubles (enlargement of JF 278 J.-P.LACASSAGNE and J.-P.CACHERA Laval Médical ue Vol.41- Fév.1970 | 271 12 BOU.CHARLES nate 3160 71 i Co 120 ten \u2014e \u2014 ® 100 So ne FREQUENCE el.eo of th o +0 BSA2/1 > 020 22 0,18 C.AN : 9 \u2014 FO gore AV eg \"eo na 1012 nl a10 QRS.gee glos D.I D.-\u2014\u2014\u2014o00%% 0000p D.l.G.- o\u20140\u20140-0-6-0-0 (94 A.P - .w i M0 ws - on A.QRS 0° | -30° | 0° P| 35] or, & 10° 10° o° 10° 1 - | of AT .\u2014\u2014\u2014 | \u2014|æ]|- \u2014 i ° 0° | © 45° > 25 off |.BARNARD 20 \u20ac 2 say A 10 : .I.ALZU 5 : à [ 25 | R6-S2 20 * °° Pope 15 | 10 W-BOCK ba A QTC ; NLE.S_P 4 fs i IMMURAN ay G.A-L.Ye CORTICOIDES Figure 1 \u2014 Diagram of the first transplanted man.On December 4, 1968, occurs a sino auricular block 2/1 and the axis of QRS turns to the left.No more changes on the following E.C.G.On January 7, 1969, rejection crisis with increase of PR interval (from 0.16 to 0.20 sec), of QRS duration (0.08 to 0.10), and of QT duration by comparison to QT IN corrected time while QRS axis, turns to the left.In four days the E.C.G.returns to normal. fii Laval Médical SIGNS OF REJECTION 279 150 Vol.41 -Fév.1970 QRS) and later repolarization troubles (QT dura- mentation we have given both the E.C.G.and his- 1» tion increased).We believe that all these variations tologie proof.\" are the reflect of the very disseminated character 3.We have not observed rejection erisis an- 9 i a - .0 of the lesions seen on histology.In animal experi- nounced by low voltage.We have often seen in Û +k FOR.JOSÉ n a4 + ot nt (019 1 I pt A ° 4 5-5 ose k -e- / eS ® + © à 8-0 © 7 2000 4-46 0 Neue eo ot TTT TN ee qd ues?wi +004 MOY.-004 70 1 | 1 1 1 1 1 ] 10 15 20 25 30 35 40 45 Figure 2 \u2014 Diagram of second transplanted man during the first 45 days.Normal data except variation of repolarization due to surgery. 280 J.-P.LACASSAGNE and J.-P.CACHERA dogs, and found on the second case, an immediate postoperative low voltage which increased to normal values a few days later.This immediate low voltage seems to be due to surgery and not to rejection.We followed the voltage on three indexes: on leads I, II and ITI (Barnard\u2019s Index), on aVL- aVR-aVF (Alzu\u2019s Index) and on horizontal plan (sum of R5-S2 or R6-S2).We think that a low voltage is present if encountered in the three indexes.It must be known that, position, breathing, location of precordial electrodes may be responsible of voltage variations.As a matter of fact we did require the following precautions: same E.C.G.set, same technician, same hour of tracing, and marking of the position for precordial electrodes.We believe that low voltage is a most important sign of rejection.But two remarks must be made : it can be the fact of an intrapericardial effusion such as in postpericardotomy syndrome.In our experimentation on dogs, we noted it as a late sign occurring at the terminal period of evolution, and usually preceeded by other E.C.G.changes, even minor.Its appearance signs an evolutive rejection.After this we never waited to induce the adequate therapy.4.The repolarization troubles call for discussion : a) Ischemic changes, when localizated and abruptly occurring, can be the sign of a rejection crisis, as shown by histology (coronary thrombosis).b) Disseminated changes, as in pericarditis may be seen, even in the course of a rejection crisis (intramyoeardial conduction troubles) or a post- pericardotomy syndrome.e) Progressive and disseminated changes of T wave, may be related to au important and prolonged decrease of serum potassium and to high Laval Médical Vol.41 \u2014 Fév.1970 corticoid therapy doses.Return to normal might be attained by a potassic therapy.CONCLUSION Analysis of animal experimentation and survey of two human cases show that the most important signs of acute rejection are arrhythmias and intra- myocardial conduction troubles.The low voltage is mostly always present on rejection crisis but appears to be a later sign, and a very bad prognosis.Preceeded by other E.C.G.changes, even minor ones must not wait to increase therapy.Isolated troubles of repolarization must be analysed by eomparison to metabolic changes of serum.REFERENCES {.CACHERA, J.P., LACOMRE, M., BU1-Monc-Hune, LACAS- sAGNE, J.P., CrEPIN, Y., and HATTEWAY, A., Allo- genic grafts of the heart in dogs treated with an anti-dogs lymphocyte serum q-globulin, Europ.Surg.Res., 1: 26, 1969.DuBost, C., and CACHERS, J.P., Un cas de greffe allo- génique du cœur chez l\u2019homme compatible dans le système HL-A et traitée par une globuline anti- lymphocytaire hétérologue, Presse méd., 76 : 1651 and 1713, (Sept.21 and Sept.28) 1968.3 LACASSAGNE, J.P., Évolution électrocardiographique après transplantation cardiaque chez l\u2019homme, Arch.Mal.Cœur, 62 : 772, 1969.4.LACASSAGNE, J.-P, CREPIN, Y., HALPERN, B., and Ca- CHFRA, J.P., Séméiologie électrocardiographique des transplantations orthotopiques du cœur chez le chien.Recherche des signes électriques de rejet, Path.Biol.17 : 261-268, 1969.LEANDRI, J., Some histological features of canine cardiac transplants, Thorax, 22 : 397, 1967.wo = 6.LEANDRI, J., CACHFRA, J.P., LACOMBE, M., BUI-MONG- Hrwna, ViGANo, N., and HARADLA, S., Étude histologique des transplants cardiaques orthotopiques chez le chien, Path.Biol, 15 : 501, 1967.CLAUVEL, M, SCHWARTZ, K., CRFPIN, Y., CACHERA, J.P., Enzyme profiles after heart transplantation, Nature, 220 : 483, 1968.-2 (LN D) Veil Pr, 1950 ù might 1 sire porta nd nite vide bat ar pst : mnt be dl (AN UNOS IL AMOI ad A da a Go CLINICAL RECOGNITION OF REJECTION OF THE TRANSPLANTED HEART * Velva SCHRIRE 7 L'auteur étudie le diagnostic clinique du rejet dans la transplantation cardiaque : 1.Modifications générales sous forme d'anoxie, fièvre, augmentation de la vitesse de sédimentation, malaises et fatigue.2.Changements subjectifs sous forme de dyspnée d'effort avec diminution de la tolérance à l\u2019effort.3.Données objectives : augmentation du volume du cœur, arythmies, extrasystoles ventriculaires et élévation de la pression veineuse jugulaire.Les modifications des bruits cardiaques apparaissent tardivement, tandis que le frottement péricardique paraît précocement.|| est difficile de dire si ce frottement est dû à la chirurgie ou au rejet.4.Modification radiologique : cardiomégalie.5.Modifications électrocardiographiques : réduction du voltage et altérations des ondes ST et T ; la réduction du voltage des complexes QRS semble être secondaire à une détérioration de l\u2019état clinique.La réduction du voltage est probablement en relation avec le rejet, bien qu'il faille tenir compte de l'épanchement péricardique possible.L'interprétation est compliquée en raison de la péricardite postopératoire et de l\u2019administration de la digitale.As of the present moment, clinical recognition of rejection of the transplanted heart is primitive to say the least.Evidence at present available sug- pe\u2019 13169 gests that complete tolerance with no histological or functional abnormality does not exist and that a modified but continuous rejection is to be ex- das Figure 1 \u2014 Serial X-rays in patient P.B.show progressive increase in heart size * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.t From the Cardiac Clinie, Groote Schuur Hospital, the Department of Medicine, University of Cape Town and the Council for Scientific and Industrial Research Cardiovascular-Pulmonary Research Group, supported in the Department of Medicine, University of Cape Town.pected.Rejection can thus be encountered in varying degrees of severity and probably in one and the same patient, peaks and troughs in the active rejection process commence with the insertion of the allograft and continue unabated thereafter.Superimposed on these acute and chronic episodes Velva SCHRIRE 13169 Laval Médical Vol.41- Fév.1970 Figure 2 \u2014 No significant change in heart size (patient P.S.) are the effects of immunosuppressive therapy and incidental infection.Systemic changes noted have been fever, anorexia and raised E.S.R.Subjective complaints have been loss of sense of well-being, fatigue and dypneea.Elevation of jugular veins and hepatomegaly are difficult to elicit at the bedside because of steroid effects.Cardiomegaly is best recognized radiolo- gically.Arrhythmias have been strikingly absent.Alteration in heart sounds and murmurs have only appeared at a late stage in our longest surviving patient.Triple rhythm, however, was an early sign in our last subject.The significance of a pericardial rub in the early postoperative period is difficult to determine.Long persistence of pericarditis suggests rejection.Radiological evidence of cardiomegaly with or without pulmonary congestion appears to be an important sign.This occurred early in our second transplant patient and never subsided although some fluctuation in size with acute rejection episodes occurred (Figure 1).Cardiomegaly soon after surgery was noted also in our last patient, but this was associated with triple rhythm and signs of cardiac failure.The absence of cardiomegaly throughout the course of our third patient parallels his smooth trouble-free course (Figure 2).Electrocardiographie changes should be looked for both from the point of view of voltage changes and changes in configuration of the ST-T waves (Figure 3).In our second patient (P.B.) daily oscilloscopie records showed gradual reduction in voltage in all leads, most likely due to rejection 13-2:68 263-68 6568 14668 26668 97-68 PRE-OP 161-68 : 1 69-68 24-10-68 25-11-68 2-12-68 31-69 3-2 69 103-69 11469 14469 eeprom = : - FORT \u2014 Figure 3 \u2014 Serial ECG tracings in patient P.B.showing progressive changes in the ST-T waves over 15 months with the development of RAD.pol fii 4 alt boli Tigre Int lay \u201cA ly I diël Fer, IN Laval Médical Vol.41\u2014 Fév.1970 although the effects of pericardial effusion cannot be excluded.The voltage promptly increased when more steroids were administered.In the early stages after operation fluctuation in voltage is common however and interpretation difficult.Marked fluctuation from hour to hour and day to day may be significant.Interpretation is complicated by postoperative pericarditis and the HO 68 212.68 3160 326 7369 28469 Figure 4 \u2014 Serial records early in postoperative course of patient D.F.showing fluctuation in voltage and progressive ST-T wave changes.12) CLINICAL RECOGNITION OF REJECTION 283 administration of digitalis.This applies even more to the ST-T changes but persistence of T wave inversion In the left chest leads is probably significant (Figure 4).Once the acute effects of operation and possibly acute rejection have disappeared voltage changes may be more meaningful.After an initial fall associated with rejection, there was a rapid return to normal when the steroid dosage was increased (patient P.B.) and this pattern was repeated during the subsequent major clinical rejection episode.Our third patient (P.S.) who has remained well throughout has showed no significant major change.Similarly in our second patient progressive ST-T wave changes developed (Figure 3) whereas in our third patient these abnormal changes regressed (Figure 5).2449 254-69 28460 2560 3569 4-569 556 Figure 5 \u2014 Serial ECG changes in patient P.S.The initial tracing shows severe left ventricular hypertrophy with progressive restitution and return towards normal. SUMMARY The diagnosis of rejection after transplantation of the human heart is extremely difficult.This is not only due to the complex nature of rejection but also to the difficulty between distinguishing changes caused by rejection, those following the use of drugs, those resulting from common com- 84 Velva SCHRIRE Laval Médical Vol.41- Fév.1970 plications of cardiac surgery such as pericardial effusion and the post-cardiotomy syndrome not to mention the effects of superadded infection.Repeated, regular and careful examination of the patient with special reference to cardiac function is essential.Changes in the electrocardiogram particularly in voltage and in the ST-T segments may be important.PREV The fry Ring, a ey ll ay, ly li die.ir.1% ui À PREVENTION OF INFECTION AFTER CARDIAC TRANSPLANTATION * mt: Luiz V.DECOURT and E.J.ZERBINI, bit i: Sao Paulo, Brasil.L\u2019infection au cours de la transplantation cardiaque constitue la complication la plus fréquente et la plus sévère.Parmi les facteurs prédisposants l\u2019on note l\u2019acte chirurgical lui-même, l\u2019environnement hospitalier et la thérapie immunosuppressive.Les corti- coïdes favorisent la dissémination de l'infection, et inhibent la phagocytose cellulaire.Les globulines antilymphocytaires augmentent le degré d\u2019infection virale.Notons également l\u2019administration intraveineuse des liquides et médicaments comme facteur prédisposant.Les agents infectieux les plus courants sont les Staphylococcus aureus, type 3, qui sont les staphylocoques d'hôpital, les Pseudomonas aeruginosa, les mycoses, notamment le Candida albicans et d\u2019autres agents comme le Pneumocystis carinii.Au cours d\u2019une infection antérieure par des streptocoques B-hémoly- tiques, certains composants capsulaires et membraneux peuvent produire des réactions d\u2019immunisation croisée avec les tissus cardiaques et avec les constituants musculaires artériels.De sorte que les agents bactériens sont non seulement capables d\u2019avoir une action directe, mais aussi capables de déterminer un processus de rejet dû à un phénomène d'immunisa- tion croisée.The experience of heart transplantation in different surgical centers throughout the world demonstrates that infection is one of the most frequent and severe postoperative complications.In this presentation we will discuss the prevention and the treatment of infection in three patients submitted to heart transplantation.A.PREDISPOSING FACTORS 1.Surgical handling of the patient.In spite of every precaution, surgical management offer every opportunity for contamination.Therefore, it seems advisable to restrict surgery to a minimum.For instance, direct aortic cannulation * Paper presented at the Second world symposium on heart transplantation, Montreal, June 6-8, 1969.i From the Institute of Cardiopulmonary Disease, Hospital das Clinicas, University of Sido Paulo, Medical School.(suite du résumé en page suivante} for the arterial blood return, avoiding the inguinal incision, is probably a wise step.2.Hospital environment.It is a widely known fact that general hospitals, where many heart transplantations were performed, are contamined by pathogenic agents, specially staphylococei and Gram-negative bacteria.Infee- tious processes, in order to be eliminated, are counterattacked by hypersensitivity phenomena.3.Immunosuppressive therapy.Immunosuppressive agents depress the immunological process that regulates the hypersensitivity phenomena.Their action is less marked on early hypersensitivity and more intense on delayed hypersensitivity.Immunosuppressive agents, specially corticosteroids, present prominent inhibitory action on cellular phagocytosis.Furthermore, cortico- steroids favor the spread of infection due to its 286 protective action on the lipoproteic lisossomic membrane.Bacterial infection oceurring early after cardiac transplantation is controlled mainly by reactions related to early hypersensitivity phenomena.Im- munosuppressive agents, including antilymphocytic globulin, inhibit delayed hypersensitivity and, probably, immediate hypersensitivity in the level of IgM and IgG.Furthermore, ALG enhances viral As a high doses of infections.consequence, administration of immunosuppressive agents in the early postoperative period is a contributing factor in the spread of bacterial infection.Greater danger, however, is the appearance of infection in the late postoperative period, due to the depressive action of the immunosuppressive drugs on delayed hypersensitivity phenomena.+.Intravenous fluid administration.Intravenous administration of fluids and drugs kept in refrigerators must be always regarded as a possible source of infection.B.INFECTIOUS AGENTS The agents listed below are capable to produce infection in any phase of the cardiac transplantation postoperative course, but there is a tendency for some of them to start earlier than others.Among the infectious agents appearing early after surgery are: 1.Staphylococcus aureus, type 111 (\u2018\u2018hospital staphylococcus\u2019).Luiz V.DECOURT and E.J.ZERBINI Laval Médical Vol.41-Fév, 1970 Certaines mesures prophylactiques sont envisagées : éliminer les foyers infectieux, protéger la peau et les muqueuses, confiner le malade dans un espace restreint, et sélectionner le personnel non infecté.Parmi les mesures pour enrayer l'infection, notons l'emploi des antibiotiques, et parmi ceux-ci le Céphalotin, qui est également administré au donneur.Dans le cas où le Céphalotin ne peut être utilisé, d\u2019autres antibiotiques tels que la Gentamycine et la Cloracilline sont utilisés.Notons en outre l'isolement dans une chambre stérile, la stérilisation des aliments et les cultures du sang, des urines et des expectorations.2.Pseudomonas aeruginosa, Gram-negative bacteria with the following characteristics: a) resistant to routine methods of sterilization ; b) able to grow even in low temperatures, for instance in fluids kept in refrigerators; ¢) frequent in patients with indwelling urinary catheters, and d) present in the tracheo-bronchial tree of tra- cheostomy patients.3.Other Gram-negative agents of the Entero- bacteriaceae family (Klebsiella, Aerobacter, Serra- tia) and the Proteus and coli groups.Among the most frequent infection agents responsible for the late appearing processes are: 4 Fungi, such as Candida albicans, whose proliferation is aided by the combined use of antibiotics and corticosteroids, as well by prolonged intravenous administration of glucose solutions.>.Other agents, such as Pneumocystis carinii, responsible for severe respiratory infections, and cyvtomegalic virus, present sometimes in extra- corporeal equipment, ('.INDIRECT CONSEQUENCES OF PREVIOUS INFECTIONS (Biological mimicry phenomena) Certain capsular (1) and membrane (3) components of B-hemolytic streptococci, such as M protein, C carbohydrate and glycoprotein, are able to produce cross immunization reactions with heart tissues (myocardium, valves, endocardial smooth muscle), as well as with arterial muscular components.Pas bal Told i] rs hater col: The Cours tem fin der Gin Vas, | Ga Hay \u201ci Pity lédient ir.Ji er les Malade 5 anf iré al 5 anf ons en enis & ire Var ILE ps, für prit ai al pri np a 1 fll n° afd pie I Laval Médical Vol.41- Fév.1970 On the other hand, Rapaport and collaborators (2) demonstrated the possibility of certain bacterial antigens, specially staphylococcal, to be comparable to transplant organ antigens.Therefore, bacterial agents are able not only to course direct attack on the patient but also to determine rejection process through cross immunisation phenomena.D.PROPHYLACTIC MEASURES According to the aforementioned considerations, certain prophylactic measures were observed in our cases.1.Preoperative care.The preoperative care included: a) removal of infectious foei elicited by clinical and laboratorial investigation; b) care of skin and mucosae; c) confinement of the patient to a restricted area, to avoid contact with other patients or with contaminated surrounding; d) selection of non-infected personnel, taking care to treat or remove infectious foei in the individuals involved in the patient\u2019s care.2.Postoperative care.Among the measures to avoid infection in the postoperative period were: a) Use of antibiotics.The characteristics of the \u2018\u201cideal\u2019\u2019 antibiotic in the prophylaxis of infection after cardiac transplantation were considered to be: 1) wide spectrum of action against frequent infections agents; it) bactericidal activity; à) reduced possibility of developing bacterial resistance.Taking in account these points, cephalotin was one choice.This antibiotie, derived from the ce- phalosporanie acid, presents some advantages : 1) intense bactericidal action, interfering with the bacterial membrane synthesis ; 1) good control of different strains of staphylo- coeci, even penicillinase producers; PREVENTION OF INFECTION 287 wi) active against Gram-negative bacteria, except Pseudomonas aeruginosa ; ww) possible to administer even in patients with poor renal funetion.Cephalotin was administered in doses of 1.0 g every six hours, during four days.Administration started before extracorporeal circulation.The antibiotic was discontinued after four days in order to avoid superinfection.Cephalotin was given to the heart donor (2.0 g before surgery).In cases where cephalotin cannot be used, the alternatives are gentamycin and cloxaecillin.Gentamyecin has the following characteristics: 4) good activity against Gram-negative bacteria and against penicillin \u2014 resistant staphylococci; b) small likelihood of inducing superinfection.Cloxacillin is active against penicillinase producing staphylococci.b) Confinement to sterile area.After cardiac transplantation the recipient was kept in a sterile unit during one week.After that period of time, confinement of the patient was gradually released.¢) Sterile diet by antoclaving was instituted in the period of confinement.Special care was dispensed to vegetables and fruits during this period.d) Routine check of blood, urine, sputum and feces was instituted in order to detect early infee- tion.Repeated blood cultures were performed, Blood cultures for anaerobic agents, fungi and « Li » forms without waiting for the previous results.of bacteria were likewise performed.E.TREATMENT OF INFECTION In three cases of heart transplantation, in spite of the prevention, infection was present in two cases.1.In Case I there was no infection.2.In Case II the following infections processes were observed : a) Staphylococcal pyodermitis in the fingers.This complication appeared 100 and 135 days after transplantation.Serum enzymes increased only when the infectious process was well established. 288 Treatment was drainage and administration of cloxacillin.b) Genital herpes simplex.3.In Case III the following events were observed : a) The inguinal incision disrupted in consequence of infection.Positive cultures were obtained for Escherichia coli and Proteus vulgaris, sensitive to cephalotin ; b) Mycotic arteritis of the left femoral artery, followed by rupture and hemorrhage.The femoral artery was ligated; ¢) Infection in the inguinal incision persisted, and the patient had septic embolization to the right lung; d) Suggestive signs of bacterial endocarditis; e) Necrotizing papilitis ; Luiz V.DÉCOURT and E.J.ZERBINI Laval Médical Vol.41- Fév.1970 f) Bilateral pyolonephritis and renal failure; ¢) Pulmonary artery thromboembolism, followed by irreversible cardiac arrest.REFERENCES I.KarLaN, M.H., and SucHY, M.L., Immunologic relation of streptococcal and tissue antigens.II.Crossreaction of antisera to mammaliae heart tissue with a cell wall constituent of certain strains of group A streptococci, J.Exp.Med., 119: 643, 1964.2.Rapaport, F.T., CHASE, R.M., Jr, and SoLEWEY, A.C,, Transplantation antigen activity of bacteriae cells in different animal species and intrecellular localization, Ann.N.Y.Acad.Sci., 129 : 102, 1966.3.ZABRISKIE, J.B,, and FREIMER, E, H., An immunological relationship between the group A streptococcus and mammalian muscle, J.Exper.Med., 124: 661, 1966.LET UM lung re à uty by UT I fégicni ir {0 lure; silowel ge cl Jular I it JH log oa tot: bi | t \\ J | i LE TRAITEMENT DES INFECTIONS VIRALES PENDANT L\u2019IMMUNOSUPPRESSION * Jean FONTAINE, M.D., Montréal, Canada.Au cours des transplantations, les infections virales sont a craindre, d'autant plus que leur prévention est aussi difficile que leur traitement.Ce sont avant tout des virus de la famille des Herpès-viridae : Herpès- virus-varicellae responsable autant de la varicelle que du zona, Herpès- virus-hominis à l\u2019origine des différentes formes cliniques de l\u2019herpès, et cytomegalia-virus.Étant donné l\u2019utilisation de sang au cours des transplantations, le risque d\u2019hépatite sérique n\u2019est pas négligeable.Mesures prophylactiques et thérapeutiques : 1.Application rigoureuse des techniques d\u2019asepsie et isolement dans une unité stérile ; 2.Sélection du personnel hospitalier.Dans le domaine de la prévention spécifique, il n'existe pas de vaccin efficace contre ces virus.Les conditions actuelles des thérapeutiques immunodépressives font courir à l\u2019opéré d\u2019une greffe d\u2019organe un risque infectieux aceru.Outre les infections bactériennes, mycotiques et parasitaires, des infections virales sont à craindre, d'autant plus que leur prévention est aussi difficile que leur traitement.Chez ces opérés, les virus les plus opportunistes sont ceux auxquels nous ont habitués les malades atteints d\u2019hémopathies ou de réticulopathies malignes traités par corticoïdes et antimitotiques.Ce sont, avant tout, des virus de la famille des Herpès- viridae : Herpès-virus varicellae responsable autant de la varicelle que du zona, Herpès-virus hominis à l\u2019origine des différentes formes cliniques de l\u2019herpès, et Cytomegalia-virus.C\u2019est ainsi que parmi les neuf malades qui ont subi une transplantation cardiaque à l\u2019Institut de cardiologie de Montréal, l\u2019un d\u2019eux a présenté un * Travail présenté au Deuxième symposium mondial sur la transplantation cardiaque, Montréal, 6-8 juin 1969, (suite du résumé en page suivante) zona qui a grandement contribué à assombrir le pronostie.Ce malade a subi la greffe d\u2019un cœur le 26 septembre dernier ; le 16 octobre, est apparue l\u2019éruption érythémato-vésiculeuse d\u2019un zona au niveau de l\u2019hémithorax moyen gauche, deux jours après que des signes de rejet aient nécessité l\u2019utilisation de doses massives de corticoïdes.Les lésions cutanées, très extensives, sont rapidement devenues bulleuses, ecchymotiques, hémorragiques, nécroti- ques et, malgré la corticothérapie, elles étaient ex- trémement doulourcuses.Des vésicules varicelloides sont apparues à distance sur les téguments et la muqueuse buccale ; le malade présentait des céphalées, il était fébrile, asthénique, réellement déprimé.Malgré l\u2019isolement en unité stérile et des techniques d\u2019asepsie aussi rigoureuses que possible, en dépit du traitement local et de l\u2019antibiothérapie générale, une surinfection par le Pseudomonas s\u2019est greffée sur les lésions eutanées.À son décès, le 2 décembre, outre les lésions cutanées qui persistaient, il existait de multiples abcès pulmonaires et cérébraux à Pseudomonas et Candida albicans, 290 Jean FONTAINE Laval Médical Vol.41- Fév.1970 L'utilisation des immunoglobulines a été un échec probablement parce que leurs titres d\u2019anticorps contre le virus varicelle-zona sont constamment très faibles, alors que ces mêmes titres sont suffisants contre les virus de la rougeole, de la rubéole, de la poliomyélite et de la vaccine.La plupart des inhibiteurs viraux connus à ce jour n\u2019ont qu'un intérêt expérimental.Les interférons n'ont jusqu\u2019alors pas répondu aux espoirs qu\u2019ils avaient suscités, pas plus que les nombreux agents chimiques et les antibiotiques qui ont été expérimentés.La 5-iodo-2-desoxyuridine (l.D.U.) a été utilisée sans succès dans le zona.Trois autres greffés ont présenté des éruptions d'herpès périlabial et des uleérations disséminées dans toute la cavité buccale et sur la langue.Voici les maladies virales que nous avons observées chez les greffés de l\u2019Institut de cardiologie.Nous savons, par nos collègues d\u2019autres équipes de transplantation, que nous ne sommes pas les seuls à avoir eu à faire face à ces infections par Herpès- viridæ.Il faut remarquer aussi que les transplantations cardiaques, nécessitant l\u2019utilisation de sang, le risque d\u2019hépatite sérique n\u2019est pas négligeable.Cinq de nos opérés ont franchi le cap de l\u2019ineubation minimum de l'hépatite sérique, soit deux mois; aucun d\u2019eux n\u2019a présenté d\u2019hépatite.Quelles sont les ressources prophylactiques et thérapeutiques que nous avons actuellement à opposer à ces infections virales ?Il va de soi que les méthodes générales de prophylaxie \u2014 isolement dans une unité stérile et application rigoureuse des techniques d\u2019asepsie \u2014 permettront d\u2019éviter un certain nombre d\u2019infections virales, de la même façon qu\u2019elles protègent contre les infections bactériennes d\u2019origine exogène.Tout membre du personnel hospitalier atteint ou suspect d\u2019infection virale \u2014 syndrome grippal.herpès.\u2014 sera évincé de l'entourage de l\u2019opéré.ainsi que tout sujet vacciné contre la variole, durant la phase de contagiosité de la lésion vaceinale.(La fréquence actuelle des voyages exigeant cette vaccination rend nécessaire le rappel de cette précaution.) Par contre, les méthodes générales de prophylaxie seront sans action sur les infections qui.comme le zona et l\u2019herpès, peuvent être d\u2019origine endogène.Il est très probable.en effet, que le zona soit dû à la réactivation de l'Herpès-virus varicellae demeuré sous une forme inactive dans un ganglion sensitif, depuis la varicelle remontant à l'enfance.Le zona apparaît lorsque la réactivation du virus survient alors que le taux d'anticorps circulant tombe à un niveau trop bas pour neutraliser le virus régénéré.Le virus du zona.tout comme celui de l\u2019herpès ou de l'hépatite sérique, peut donc pénétrer clandestinement avec le malade dans la chambre stérile, débordant ainsi les méthodes générales de prophylaxie.Dans le domaine de la prévention spécifique, on sait qu\u2019il n\u2019existe pas de vaccin efficace contre ces virus-ci.On sait également que les immunoglobulines ont été largement essayées, dans la prévention de la varicelle, notamment chez des enfants, contacts soumis à la corticothérapie pour diverses affections.Ces essais se sont soldés par des échecs dont la cause peut être due au fait que.si les immunoglobulines standards utilisées habituellement ont des titres suffisants et assez homogènes contre les virus de la rougeole, de la rubéole, de la poliomyélite et de la vaceine, leurs titres d'anticorps contre le virus Varicelle-Zona sont constamment très faibles.(C\u2019est tout au moins ce qui ressort d\u2019une étude faite sur les titres de ces anticorps dans 26 préparations commerciales d'immunoglobulines, par Netter et ses collègues, au Laboratoire nationale de la santé publique à Lyon.) Laon Ts yy \u201cté lili | in 1 \u201cparce | ment Sis § | inéré cspois ies ¢f | gs | pl, jp à Joelle ail Le oll rit pe à 0 sp [lop Jp tl ie ltr li le! jy.ll re Joh ii ll kit pré J i AIL i aa | Laval Médical Vol.41-Fév.1970 T1 paraît done souhaitable que nous puissions disposer d\u2019immunoglobulines spécifiques préparées à partir de sérums de convalescents de zona ou de varicelle.Un projet est en cours a cet effet: il permet d\u2019espérer que nous serons mieux en mesure de prévenir des zonas du type de celui que nous avons observé.La valeur préventive des immunoglobulines pour l\u2019hépatite sérique est très controversée.Cependant, dans un travail portant sur 1 500 transfusés, Mirrick, en 1965, a trouvé que les immunoglobulines diminuaient de facon significative le risque d\u2019hépatite qui est passé de quatre pour cent à un pour cent.Quant au traitement des maladies virales chez les greffés, il n\u2019est pas différent de celui des maladies virales en général; c\u2019est dire qu\u2019il est encore très pauvre.La plupart des inhibiteurs viraux connus à ce jour n\u2019ont, à de rares exceptions près, qu\u2019un intérêt expérimental.Les interférons n\u2019ont pas jusqu'alors répondu aux espoirs qu\u2019ils avaient suscités, pas plus que les nombreux agents chimiques LE TRAITEMENT DES INFECTIONS VIRALES 291 et les antibiotiques qui ont été expérimentés.La- 5-1odo-2-desoxyuridime (IDU) a donné de bons résultats dans le traitement de la kératite herpétique, mais elle a été utilisée sans succès dans celui du zona, comme l'a été aussi l\u2019ABOB, un dérivé diguanidé.Aussi, a-t-on recours aux immunoglobulines à de très fortes doses, Elles n\u2019ont pas entraîné chez notre malade d\u2019amélioration notable.Des immunoglobulines spécifiques auraient peut-être donné de meilleurs résultats.comme c\u2019est le cas dans le traitement des vaccines généralisées.En somme, il n\u2019est pas facile de protéger les greffés des infections par les micro-organismes les plus opportunistes.Soubaitons que des agents anti- viraux et spécifiques efficaces soient découverts, mais nos espoirs vont également vers la découverte de méthodes moins débilitantes et moins déprimantes que celles dont nous disposons actuellement, pour rendre tolérant l\u2019organisme du receveur au cœur greffé. COMPLICATIONS OF PROLONGED CORTISONE THERAPY * J.KAPLAN, H.AGUIRRE, R.EBERHARD, and N.ADRIAZOLA t Les complications que l\u2019on rencontre avec le traitement aux corticoi- des sont en relation avec le dosage et la durée de la thérapie.Dans le but d\u2019éviter ces complications, de nombreuses approches sous forme de dosages intermittents, doses élevées pour une courte durée, ont été utilisées.N.B.Les complications en elles-mêmes, présentées en diapositives, n\u2019ont pas été reproduites dans le manuscrit.In the management of rejection, the value of glucocorticoids as an adjunct to cytotoxic drugs has been well documented (4, 6 and 7).Steroid hormones play a major role in the immunosuppressive therapy utilized by most transplantation centers.Although the experimental and clinical evidence indicate that glucocorticoids acts in several ways inhibiting the antibody formation and the transplantation immune response (3, 5 and 9), the mechanisms of action of these steroids in producing an immunosuppressive effect, is only fragmentarily understood.However, the use of glucocorticoids in man, for prolonged periods of time, has by no means been free of complications.The incidence of undesirable side effects varies from series to series (1, 2 and 8) (Figure 1), the general consensus being that these complications are related principally to dosage and duration of therapy.In organ transplantation the use of eytotoxie drugs and ALS with their side effects add new problems to the use of glucocorticoids and very often, the need of diminution or suppression of them is life-threatening to the patient.Figure 2 shows the complications due to prolonged glucocorticoid therapy in a patient submitted to cardiac transplantation.Figure 3 refers to a post-transplantation lung syndrome * Paper presented at the Second world symposium on cardiac transplantation, Montreal, June 6-8, 1969.i Instituto de Torax y Transplantes, Hospital Naval, Valparaiso, Chile.Departamento de Ciencias, Univer- sidad de Chile, Valparaiso.occurred in the 95th postoperative day with good remission (clinical and radiological) after reassuming cortisone treatment.In the search to avoid complications due to the use of glucocorticoids various approaches have been attempted: intermittent dosage; large doses for short terms.Reduction of dosage has its schemes according to experience of different centers.Advanees in biochemical and other investigative technics focus the influence of adrenal corticoids on metabolic functions of single cell and their constituents.Furthermore, actions of glucocorticoids must be considered in the light of their ability to COMPLICATIONS MOONINS ZIT TTT 7 7 222 TT IO 2 2772 02 Baus 77 DYSPEPSIA (61 4.20%) 7777777772277727727270 HIRSUTES | WEIGHT GAIN 7777272 OEDEMA 777777227772 MENSTRUAL [P2700 NFECTION aus -YPERTENSION 7 ZMOTIONAL INSTABILITY 2 AC NE OSTEOPOROSIS ZZ CATARACT == GLYCOSURIA THROMBOEMBOLISM 2 PIGMENTATION 2 ZZ2 mid or moderate EE severe OTHERS HYDROELECTROLYTE- IMBALANCE ELECTROCARDIOGRAM ALT.BLOOD ALTERATIONS Figure 1 \u2014 Complications of prolonged treatment with corticosteroids (six months to twelve years).Low Ro SP ST LIL HEN REC M SE Fat Hg uy My hy Qu - ried ans me nt él ives te pial A fini ifr a if HEART TRANSPLANTATION.DEPARTMENT OF THORACIC SURGERY AND TRANSP UNIT COMPLICATIONS IN N.0.S.4 21 YS.H.N.V.- CHILE 68/4012 ( OP.OCT 1a 1968 ) CORTISONE THERAPY DYSPEPSIA GASTROINTESTINAL ZZ) mis or moderate HEMORRHAGE a BEE severs HEMORRHAGIC RECTOSIGMOIDITIS 22 URINARY INFECTION ABCESS rz ad ZENERALIZED HERPES 7] \u201cOONING \u2014\u2014rZ\"3 \u201c+ PERGLYCEM: A 7777777 E7727] -VFIKALEMIA 7777777777 CEZEMA es PREDNISONE (Mg) a.s caraaz | veme \\[|[[TTMMCCCOCCCCD TC MIMEET FEET C0 00 Fd INTOLERANCE 300 ACT-C 200 MURAN (Mg) 7 im wor] | 04 u T T T T 4 Days Post op Q | 30 | 60 Jor 120 | | 150 180 | R [210 240 REJECTION CRISIS Figure 2 \u2014 Complications in prolonged cortisone therapy HEART TRANSPLANTATION.DEPARTMENT OF THORACIC SURGERY AND TRANSP.UNIT MEP ¢ 24 YS.HNV.-CHILE 68 2059 (OP.JUNE 28 1968) POST TRANSPLANTATION LUNG SYNDROME E KG 100 HEART RATE 60 VENTR.EXTRASIST.0D0O00O0000O0O0OO6O0O0OOosoosensensecsoncennsencsesseneseennee NODAL RHYTHM LerLocLLLLLe LL LL ele LOC Ces OC 00 CC eme eee CCC me TO 000 C0 SAM MNT FLUTTER PORST VOLTAGE D, 1 ) | | | { milivolts ) 0 A LA rm 0-T Dy ( sec) 1 \u2014\u2014 \u2014\u2014\u2014\u2014\u2014 ST \u2014_\u2014 TS AXIS OF QRS rn sos Bh DD DAAANDAD ALL Pr unit 50% hemol.of BR à à | mu | | 2 - Les \u2014\u2014 TEMPERATURE (°C) 3°10.TT S TTT DYSPNEA COC) COUGH COE) SPUTUM _ oo _ COE antibiotics EE als ooooocoogaoon @ @ @ PP PB @ 2 D @ 200 corticoids (mg) POST OP, TIME (doys) 61 7 81 8 10 m 121 294 J.KAPLAN, H.AGUIRRE, R.EBERHARD and N.ADRIAZOLA Laval Médical stimulate molecular functions in certain cells while simultaneously inhibiting those of other cells.These investigations, undoubtedly will be oË great value in finding drugs with greater potency and fewer undesirable effects to be used in transplantation of organs.REFERENCES J.ACKERMAN, G.L., and NoLAN, C.M., Adrenocortical responsiveness after alternate-day corticosteroid therapy, New Engl.J.Med., 278 : 405, 1968.2.Briser, W.R., and Rapaport, M.I., Adrenocortical functions and infectious illness, New Engl.J.Med., 280 : 596, 1969.J.DovaHARTY, T.F., BERLINER, M.L., and BERLINER, D.L., Hormonal influence in lymphocyte differentiation from RES cells, Ann.N.Y.Acud.Sci, 88 : 77, 1961.4 ~2 Vol.41-Fév.1970 GERMUTH, F.G., OrriNGer, B., and Ovamg, J, Influence of cortisone on experimental hypersensivity and circulating antibody in the guinea pig, Proc.Soc.Exp.Biol.Med., 80 : 133, 1952.GLENN, E., MILLER, W.L.and SCHLAGEL, C.A, Metabolic effects of adrenal steroids in vivo and in vitro : relationship to anti-inflamatory effects.Recent Prog.Hormone Res, 19 : 107, 1963.HAMBURGER, J., CORSNIER, J., and DorMoNT, J., Experience with 45 renal homotransplantation in man, Lancet (London), 1: 985, 1965.MEpawaRr, P.B., and Sparrow, E.M., The effects of adrenocortical hormones, adrenocorticotrophic hormone and pregnancy on skin transplantation immunity in mice, J.Endocr., 14 : 240, 1956.SAUER, W.G., and Maks, S.W., Withdrawal of adrenal steroids and corticotropin, Arch.Int.Med., 107 : 88, 1961.TREADWELL, B.L.J., SEVER, C.D., SovaGE, O., and CorEMAN, W.S.C., Side effects of long term treatment with corticosteroids and corticotrophin, Lancet, 7343 : 1121, 1964.Ie tL IE i TOK édicai i, 1970 Jr «i: TOXICITY OF AZATHIOPRINE * Pi ; James C.PIERCE, M.D.,t and David M.HUME, M.D, F.A.C.S,, A ; nl Department of Surgery, dis Medical College of Virginia, | Health Sciences Division, 8 ; Virginia Commonwealth University.bp [Er .too iI feux di , ., ., sel L\u2019azathioprine (Imuran), substifut dérivatif de la 6-mercaptopurine (6- in MP), constitue l'agent immunosuppressif de base pour les transplantations | rénales chez l'homme.arent Pharmacologie.L'azathioprine est très facilement réabsorbée par le ur tractus gastro-intestinal.Sa voie d'élimination est rénale.Sa période d\u2019action est d'environ quatre jours.Dans la transplantation d'organes, la dose sera de 4 mg/kg au cours des quatre à sept premiers jours.Après quoi, la dose sera réduite à trois mg par kg de poids.Mécanismes biochimiques de la toxicité.Les manifestations cliniques de la toxicité de l\u2019azathioprine sont parrallèles à celles de la 6-MP.Il y a deux modes d'action : d'une part la transformation de la 6-MP en 6-MP- ribotide, qui bloque de novo la synthese des purines, et d'autre part l\u2019activité de neuf substituts de la 6-MP.Toxicité hématologique.La complication la plus souvent rencontrée est la leucopénie.La dose d'azathioprine sera en fonction de cette formule leucocytaire.La vitesse avec laquelle les leucocytes diminuent est (suite du résumé en page suivante) ti, au 0 (read in, fie INTRODUCTION mized dog treated with 6-MP had survived for over .; 0 Le one year (46).As the result of these studies, the In 1951, Elion, Hitchings, and Vanderwerff (21) i oo .; .major modality of immunosuppression for organ reported that 6-mercaptopurine (6-MP), which had 20° | ; ; b thesized + of temati h transplantation in man was changed from irradia- een synthesized as a part of a systematic searc ; à .y .p _.y ; tion to chemotherapy.Unfortunately, 6-MP de- for purine antagonists, inhibited the growth of bac- 20 ; : j oo _ pressed hematopoiesis, caused jaundice and pro- 9 teria in culture.In 1958, Schwartz, Stack, and .A Lo \u2018 .i duced denudation of the epithelium of the intes- Damashek (52) demonstrated that 6-MP prevented .; A ; ; ; .tinal tract in experimental animals (9 and 44) and the formation of antibodies to bovine serum albu- 2 A 1; ; LE ; .these complications were frequently observed at min in rabbits.Within two years, it was discovered 1, ; © that it a 1 oh val of skin all ft dosage levels used for the prevention of rejec- hat it would prolong the survival of skin allografts | \u2018 © prolong = tion (6, 46 and 60).Azathioprine (Imuran), the S-imidazolyl substituted derivative of 6-MP (Figure 1), was less toxic and immunosuppressive at in rabbits (39 and 51) and renal allotransplants in dogs (5 and 59).In 1961, it was reported that a renal 1 transplant in a bilaterall hrecto- ; ; ; nal homotransplant in a bilaterally nephrecto lower doses in mice (1 and 20).In dogs, it also * Paper presented at the Second world symposium on appeared to be more effective than 6-MP in pro- cardiac transplantation, Montreal, June 6-8, 1969.longing the survival of renal allotransplants (11) Supported in part by grants from the National Institu- oo .tes of Health (HE 08203 : FR 0065), the Atomic Energy and it was subsequently universally adopted as Commission (AT 40-1), and the American Cancer So- the basic immunosuppressive agent for renal allo- ciety (T-166D).+ Box 95, Medical College of Virginia, Richmond, ; .Virginia 23219, U.S.A.nical experience, it has been established that at transplants in man.As the result of extensive cli- Laval 296 James C.PIERCE and David M.HUME Laval Médical vu ol.Vol.41- Fév.1970 plus importante que son nombre absolu.Lorsqu'il existe une leucopénie, il faudra prendre des précautions en vue d'éviter les infections.On donnera de l'acide folinique et des préparations multivitaminiques.La throm- bocytopénie est rare en l\u2019absence de leucopénie comme complication de la thérapie à l\u2019azathioprine.On surveillera également le nombre des globules rouges et le taux d\u2019hémoglobine.Toxicité hépatique.Elle se caractérise par l\u2019apparition d\u2019un ictère dans 20 pour cent des homotransplantations rénales.Toxicité gastro-intestinale.Les doses élevées provoquent de l'anorexie, perte de poids et diarrhée.On rencontre également des ulcères des membranes muqueuses, des lèvres, de la langue et de la bouche.Les effets duodénaux que l'on rencontre sont attribués à la thérapie aux corticostéroïdes.Sensibilité accrue pour les tumeurs malignes.L\u2019azathioprine, en association avec la Prednisone, favorise l\u2019implantation de métastases et de tumeurs malignes transplantées avec l'organe.Ces complications peuvent être évitées en sélectionnant les donneurs et receveurs.Même dans ce cas, on a rapporté que l\u2019azathioprine et les globulines antilymphocytaires therapeutic levels azathioprine also has significant 2.4 per cent as 6-MP, and O to 2.25 per cent un- A st toxic effects, but that careful management can lar- changed in 24 hours (18).In addition, approxima- al gely eliminate deaths from these effects.tely 7 per cent is exereted as 5-mercapto-1-methyl- | Hi Pharmacology 4-nitroimidazole in 24 hours (8).Because the urine ly Azathioprine is readily absorbed from the gastro- NH, SH intestinal tract.The sodium salt which is available A A for investigational use may be administered intra- NZ \u2014\\ Na \"\\ venously.Once absorbed, the imidazole group is .| 7 = | 7 split off to yield 6-MP which is probably responsi- NT H NT H ble for most if not all of the toxic and immuno- ADENINE 6 - MERCAPTOPURINE suppressive actions of the drug, and because of this, data on both drugs will be discussed.This cleavage is promoted by sulfhydryl compounds and not en- zymatically mediated (18).The drug has a relati- S T N-CHz HN N vely long period of action, approximately four days.: : NT N À Cumulation of successive doses over this period | > 0 readily occurs and unless this possibility is appre- q a N ciated, a toxic level of drug may easily be reached.N \" IMIDAZOLYL Also, when azathioprine is discontinued because of leukopenia, it is often four days before an appre- AZATHIOPRINE big, ciable recovery of the leukocyte count is observed.(IMURAN) 1 The chief route of elimination of azathioprine is Figure 1 \u2014 6-Mercaptopurine (6-MP) is an analogue of ; ; adenine.Azathioprine (Imuran) is an analogue of 6-MP He in the urine.In man, 13.0 to 21.4 per cent of an and after absorption, the imidazole moiety is cleaved to : by oral dose was excreted as 6-thiourie acid, 1.3 to release 6-MP.by gical Laval Médical TOXICITY OF AZATHIOPRINE 297 BR Vol.41 - Fév.1970 pine.| n dor 4 tron: § jon de À Û pouvaient en effet promouvoir l\u2019induction de tumeurs malignes inhérantes à la thérapie immunosuppressive.La fréquence de ces tumeurs spontanées n'est pas suffisamment large pour abandonner la thérapeutique, mais elle souligne l'importance d\u2019une surveillance continue de ces patients.Toxicité du système reproducteur.L'azathioprine a un effet térato- 6 taux génique sous forme de rupture des chromosomes et autres anomalies.Complications squelettiques.On rencontre des nécroses aseptiques ite de la hanche, du genou et de I\u2019épaule, ostéodystrophie, ostéoprose et autres lésions squelettiques.Il semble que ces lésions squelettiques soient en relation avec la maladie rénale, l\u2019'hyperparathyroidisme secondaire et la thérapie corticostéroïde, plutôt qu\u2019avec la toxicité de l\u2019azathioprine.Sensibilité accrue pour les infections.Celle-ci est en relation avec la suppression des mécanismes immunologiques cellulaires et humoraux.[an jicères hé, réa L'administration concomitante des corticostéroïdes, notamment aux doses élevées, augmentera fortement cette sensibilité.S\u2019il se développe une ms infection en l'absence d\u2019une dépression de la moelle osseuse, insuffisance sd rénale ou atteinte hépatique, la dose d\u2019azathioprine sera maintenue aux a doses thérapeutiques.Le traitement de l'infection bactérienne se fera ans avec un antibiotique à spectre étroit, étant donné le développement de ps mycoses avec les antibiotiques à large spectre.A Ur is the principal route of excretion of azathioprine and its degradation products, the dose should be biochemical level, there are two possible pathways observation that 6-MP binds tightly to RNA (29).i reduced if renal function is impaired.Also when of action of 6-MP (45).In the first of these, 6-MP i allopurinol is given concomitantly, the dose of is initially converted to 6-MP ribotide and in the azathioprine should be reduced because the conver- second, this step is not required.In the first path- sion of 6-MP to 6-thiouric acid, which is one of the way the 6-MP ribotide blocks purine de novo syn- chief degradative pathways, is blocked (19, 49 thesis at a number of sites, the most important of à, and 57).which are the initial step in purine synthesis, the | For immunosuppressive in organ transplantation, formation of phosphoribosylamine from phospho- | the dosage schedule of azathioprine which we em- ribosylpyrophosphate and glutamine; the conver- ! ploy is 4 mg per kg which is given for four to sion of inosinate to suceinoadenylate; and the a à seven days after which it is tapered to approxi- dehydrogenation of inosinate to form xanthine- mately 3 mg per kg.The dose is then adjusted monophosphate (17).A second possible pathway according to the patient\u2019s leukocyte count.By of action of 6-MP has been suggested by the observa- 120 days after transplantation, 33 per cent of the tion that 9-substituted 6-MP\u2019s are still active (30, patients are receiving from 2.28 to 2.87 mg per kg, 33 and 34).Although one explanation for the 33 per cent of patients are receiving less, and activity of these analogues has been that they were 33 per cent are receiving more.converted to 6-MP, 9-arabinosyl-6-mercaptopurine, prolonged skin allograft survival in rats despite Biochemical mechanisms of toxicity the absence of 6-MP and its breakdown produets The clinical manifestations of toxicity of azathio- in the urine (35).The activity in vivo of these prine closely parallel those of 6-MP and it is likely 9-substituted 6-MP derivatives may be related to the iy that they result in a large part, if not entirely, When the SH group of 6-MP was blocked by a ol from the release of 6-MP by azathioprine.At the methyl group, binding was prevented. 298 Hematological toxicity The most common complication of azathioprine therapy is leukopenia (leukocyte count less than 2,000 per mm?) which occurred one or more times in 40 per cent of the renal homotransplant recipients at the Medical College of Virginia.The oceur- rence of leukopenia in patients with à blood urea nitrogen greater than 30 per cent which usually indicated that significant rejection had occurred was a particularly ominous sign because less than 30 per cent of these patients were alive with fune- tioning transplants four months later.Terminal depression of the bone marrow characterized by severe leukopenia, thrombocytopenia (platelets less than 100,000 per mm?), and decreased reticulocytes (less than 1.5 per eent) occurred in 22 per cent of leukopenic patients.This usually occurred in patients with significant pre-existing infections who were receiving doses of prednisone greater than 30 mg per day.Severe rejection reactions occurred in other leukopenic patients when azathioprine was discontinued, especially if previous rejection episodes had already damaged the transplant.In still other patients leukopenia was only one manifestation of au debilitated state associated with progressive downhill course.The first episode of leuko- penia was most likely to occur during the initial two months after transplantation (50 per cent of the patients) but did occur as late as 18 months after transplantation.It was twice as likely to occur in splenectomized as in unsplenectomized patients, but it was no more likely to oceur in recipients of kidneys from living related donors than in recipients of cadaver kidneys.The management of leukopenia consists first of all in preventing a fall to dangerous levels by daily monitoring of the leukoeyte count and tapering the dose of azathioprine gradually as the leukocyte count falls.This might have prevented the leukocyte depression illustrated in Figure 2.The rate of fall of the leukocyte count is more important than the absolute level.Many patients have been maintained on azathioprine for years with leukocyte counts less than 5,000 per mm?except when James C.PIERCE and David M.HUME Laval Médical Vol.41- Fév.1970 infection or operation stimulated a leukocytosis.When the leukocyte count falls as much as 40 per cent in one day or to a level below 3,000 per mm?it is advisable to discontinue azathioprine entirely.The patient is placed on gown and mask reverse precautions when the leukocyte count falls below 2,000 per mm?and in a sterile room (48) when the leukocyte count falls below 1,000 per mm?The lowest total leukocyte count which a patient has had followed by recovery was 225 per mm*.In addition to a standard multivitamin preparation, it is also our custom to administer folinic acid to severely leukopenic patients because increased urinary formiminoglutamic acid after histidine administration has been observed in a leukopenic renal transplant recipient on azathioprine who had normal serum folate and vitamin B;, concentrations suggesting that reduction of folic acid was blocked (40).Thrombocytopenia of a significant degree rarely ae BLOOD UREA 25 NITROGEN (mq%) ° [ 16,000 12000 8000 4000 0 800,000 400,000 PLATELETS LEUKOCYTES PER MMS PER MM 200000 24 RETICULOCYTES (%} 8 OO RRNNNNNNNINNNNANNIREUI 150 A scam NTT IIRNL all L do 104004 AI 8 53 S55 5 5 6 65 6 69 7 73 75 77 DAYS AFTER TRANSPLANTATION Figure 2 \u2014 Leukopenic episodes such as the one illustrated in this renal transplant recipient usually respond promptly to a decrease or discontinuance of azathioprine.If the organ transplant is functioning well as in this case, the azathioprine may be discontinued temporarily without precipitating rejection, but if it has already been impaired by rejection, the transplant or the patient is often lost, Although thrombocytopenia often accompanies leukopenia as in the case illustrated here, it rarely occurs in the absence of leukopenia as a result of azathioprine toxicity.if ie ihe A mi nt alter had lo tré wil | to if ring Ho die! ér 1 its, per oT LL irl.§ HET ili jan he TH out lis ald LS ltl wr UNIT rill il un Ril pelt pee Laval Médical Vol.41 -Fév.1970 if ever occurs in the absence of leukopenia solely as the result of azathioprine therapy.Anemia (Hb less than 11.0 g per 100 ml) oceur- red in 18 per cent of kidney recipients with normal renal function who were more than four months after transplantation.One of these patients who had a megaloblastic anemia responded dramatically to treatment with folinie acid and not with folie acid, but the remaining patients failed to respond to either drug.Cautious reduction of the azathio- prine dosage may be helpful in this latter group.Hepatic toxicity In toxicity studies in normal animals, 6-MP caused hepatic necrosis in rats and intracanalicular bile stasis, jaundice, and bromsulphalein retention in dogs (44).In rats, 6-MP increased the urinary excretion of d-amino levulinie acid and copropor- phyrins and it also increased the d-amino levulinie acid and or porphobilinogen in the liver (23).Eales observed significant disturbances in porphy- rin metabolism in two heart transplant recipients, both of whom were receiving azathioprine (15).In adults with acute leukemia treated with 6-MP, the incidence of jaundice was 34 per cent.At postmortem examination, a variety of lesions were found in different patients: bile stasis in canaliculi, hemo- siderosis, cirrhosis, periportal fibrosis, central fatty changes, infiltration with leukemic cells or tumor, and hepatoma (4).In another study of leukemic patients, 42 per cent developed jaundice while taking 6-MP, but only 9 per cent developed it who were not receiving it (16).In renal homotransplant recipients at the Medical College of Virginia the incidence of hepatitis was 20 per cent.The incidence in recipients of cadaver transplants, however, was 35 per cent while in recipients of kidneys from living donors, it was only 8 per cent.Because cadaver kidney recipients were often on dialysis for prolonged periods of time while awaiting a suitable kidney, they received more blood transfusions than recipients of kidneys from living related donors and were, therefore, more likely to be exposed to serum hepatitis.Also the possibility of transmission of hepatitis by the transplant is greater when the (13) TOXICITY OF AZATHIOPRINE 299 donor is a patient dying from a head injury from whom a complete medical history may be unavailable.Both recipients of kidneys from a common cadaver developed jaundice in two instances in our series.Frozen section examination of the cadaver liver would probably have detected hepatitis which was not evident upon gross examination.The extent to which azathioprine and 6-MP directly cause liver disease and the extent to which they predispose to viral infeetions which in turn cause liver damage is unknown.Regardless of the exact mechanism, it is necessary to reduce or discontinue these drugs in the face of impaired liver function.The bromsulphalein test has been the most sensitive mode of detecting dysfunction and the serum total bilirubin and serum glutamic oxal- acetic transaminase levels have proved useful in following such patients subsequently.When the function of the transplant was good, i.e.when it was not undergoing chronic rejection, it was possible to stop azathioprine for periods up to eight months without precipitating rejection of the organ in such patients.However, if the funetion of the kidney was impaired as the result of chronic re- Jection, discontinuation of azathioprine in the face of jaundice usually resulted in early rejection of the kidney just as in leukopenic patients.After recovery from hepatitis it was often necessary to reduce the maintenance dose of azathioprine to the range of 25 to 50 mg per day for many months to avoid recurrence of jaundice.Gastrointestinal toxicity Large doses (6.3 to 50 mg per kg per day) of 6-MP in dogs caused anorexia, weight loss and diarrhea.There was extensive denudation of the epithelium, capillary congestion in the tips of denuded villi, and leukocytic infiltration throughout the mucosa 1 the small intestine.In the large intestine, there was only moderate glandular atypia and some mucosal hemorrhages (9 and 44).In adults with acute leukemia treated with 6-MP at dosage levels of 4.0 mg per kg or more, gastrointestinal symptoms of anorexia, nausea, and vomiting were common (16 to 32 per cent of patients). 300 But with lower doses and in children, the incidence was much lower.Stomatitis occurred in 24 per cent of patients (28).in renal homotransplant recipients (up to 4.0 mg At the doses of azathioprine used per kg) anorexia, nausea, vomiting, and diarrhea have not been significant problems in the absence of other complications.Uleers of the mucous membranes of the lips, tongue, and mouth have been frequent problems, however.When these have been extensive they were usually accompanied by denudation of the esophageal epithelium which on occasion involved virtually its entire surface.Duodenal ulcers have occurred in 22 per cent of renal homotransplant recipients at the Medical College of Virginia who did not have a prior history of ulcer (36), but this complication is probably attributable to the corticosteroid therapy which these patients also received rather than to azathioprine.Other lesions of the small intestine and colon have been insignificant.Fatal pancreatitis has oceurred in one patient in the Medical College of Virginia series and two cases have been reported (31 and 55).Pancreatic pseudocysts occurred in three of 55 patients reported by Ginn (24).Increased susceptibility to malignant tumors Azathioprine together with prednisone has very likely promoted the transplantation of malignant tumors in organs transplanted from patients dying of tumors (37 and 38).The effectiveness of im- munosuppressive therapy in promoting the implantation and metastasis of malignant tumors transplanted with organs was confirmed in two other instanees in which the tumors were rejected along with the organ transplant when immunosuppressive therapy was discontinued (24, 58 and 61).Aza- thioprine may also contribute to the recurrence 2?of \u2018\u2018naturally\u2019\u2019 occurring neoplasms in transplant recipients (31 and 53).Although these untoward effects of azathioprine can be avoided by selecting donors and recipients who have not had cancer, there have been recent reports suggesting that azathioprine and anti- lymphocyte globulin may actually promote the induction of malignant tumors and that this is in- James C.PIERCE and David M, HUME Laval Médical Vol.41- Fév.1970 herent in all immunosuppressive therapy.Both 6-MP (14) and azathioprine (7) have been reported to induce lymphomas in mice.À malignant primary lymphoma of the lung developed in a cadaver kidney recipient in our series two years after transplantation, who had received azathioprine, cortico- steroids, and actinomyein C, but not antilympho- cyte serum.Eight other cases of lymphoma occurring in renal homotransplant recipients while on immunosuppressive therapy have been reported (12, 13 and 43).In addition, one of our patients developed à carcinoma in situ of the cervix three years after receiving a renal homotransplant from her sister.Her immunosuppressive therapy consisted of azathioprine, corticosteroids, actinomyein C, and local irradiation of her kidney.A squamous cell carcinoma of the ear occurring two and one half years after transplantation (31) and an anaplastic carcinoma of the lung occurring seventeen months after transplantation (61) have also been reported.The incidence of spontaneous tumors in these recipients on immunosuppressive therapy is not large enough to negate the present therapeutic advantages of renal transplantation.They do indicate the importance of a continuous surveillance of these pa- patients have been apparently cured by timely treatment (12, 31 and 43).Reproductive system toxicity When administered to pregnant rats early in gestation, azathioprine caused a high percentage of fetal reabsorption and those fetuses which survived were usually severely stunted.Although azathio- prine was less toxic than 6-MP for the mothers, it was more toxic for the fetuses (54).Azathioprine was also teratogenic in mice (25), rabbits (56), and dogs (41).In patients treated with azathio- prine, chromosome breakage and other abnormalities were observed in bone marrow aspirates (32), and in patients treated with 6-MP, polyploidy and chromatid breaks were observed in peripheral blood leukocytes (42).These observations suggest that azathioprine is teratogenic in man as well.Nevertheless, two patients in our series, of whom one has been reported (2), carried infants to term with no Lost Vol, 41- ten Were fined a, woutls ben Dre V'édical LSU 8 i, Bath pret puis ver bd VI Jor lyuphs- etl 5hile on pel pun ae ul ph nls uel tire I pot lire pillage: ip 1 fu g ls | i Laval Médical Vol.41- Fév.1970 interruption of azathioprine therapy.The children were completely normal at birth and have continued to develop normally, one and three years later.One patient had a miscarriage at three months.In addition, eight normal children have been sired by fathers who were on azathioprine and prednisone.Despite these and normal offspring of patients in other series who were conceived while one of the parents was receiving azathioprine therapy, it would still seem prudent to warn patients of the potential teratogenic effects of azathioprine.Skeletal complications Aseptic necrosis of the hip, knee, and shoulder, osteodystrophy, osteoporosis, and other skeletal lesions frequently complicate renal homotransplanta- tion (11, 26 and 27).In weanling rats, azathioprine caused irregularity of the cell columns, an extended hypertrophied zone, and cellular distortion in the epiphysial plate of the proximal tibia, but it did not significantly increase slippage of the plate when it was subjected to shear stress (3).These skeletal lesions in patients are probably related to renal disease, secondary hyperparathyroidism, and cortico- steroid therapy rather than to azathioprine toxicity.Increased susceptibility to infection Because of the capacity of 6-MP and azathioprine to suppress both cellular and humoral immunological mechanisms \u2014 see the excellent review article by Schwartz (50) \u2014 infections by bacterial, fungal, and viral organisms frequently complicate the use of these drugs (10, 22, 24, 31 and 47).The addition of corticosteroids, especially in high doses, greatly increases susceptibility to infection.Broad spectrum antibiotics such as the tetracyclines and chloramphenicol are particularly likely to induce overgrowth of fungal organisms in the gastrointestinal tract with subsequent systemic dissemination and, therefore, treatment of bacterial infections is limited to antibiotics with a narrow spectrum of activity whenever possible.If bone marrow depression, or renal failure, or liver dysfunction do not occur simultaneously with an infection, and TOXICITY OF AZATHIOPRINE 301 if the invading organism is sensitive to an anti- biotie, the dose of azathioprine is usually maintained unchanged during treatment.SUMMARY Azathioprine (Imuran) is cleaved to 6-mercapto- purine (6-MP) after absorption and therefore the toxic manifestations of these two drugs are very similar.In organ transplant recipients, increased susceptibility to infection is the most serious untoward effect of these agents.More specific toxic effects include: leukopenia, which occurs in 40 per cent of renal homotransplant recipients; thrombo- eytopenia; normoeytie and macrocytic anemia ; hepatitis which occurs in 20 per cent of recipients; and ulceration of the mucous membranes of the lips, tongue, mouth, and esophagus.In addition, aza- thioprine has promoted the metastasis of tumors which were transplanted together with renal transplants and it appears to have induced lymphomas de novo in some recipients.Although there have been no reported cases, experiments in animals and the observation of chromosome damage in man suggest that it may also be teratogenic.The incidence of toxic manifestations may be reduced by careful adjustment of dosage in relation to the total leuko- eyte count and by the use of lower doses in patients with renal failure and patients receiving allopurinol.REFERENCES 1.Bieger, S., Erion, G.B., HrrcrINGs, G.H., HOOPER, D.C., and NATHAN, H.C., Suppression of the immune response by drugs in combination, Proc.Soc.Exp.Biol.Med., 111 : 334, 1964.Boarp, J.A, LEE, H.M, DRAPER, D.A, and HUME, D.M., Pregnancy following homotransplantation from a non-twin, Obstet.Gynec., 29 : 318, 1967.3.BriGHT, R.W., and ELMoRE, S.M., Some effects of immunosuppressive drugs on the epiphysial plate of rats, Surg.Forum, 18 : 485, 1968.9 4.BURCHENAL, J.H., and ErLisoN, R.R., The pyrimidine and purine antagonists, Clin.Pharmac.Ther.2: 523, 1961.CALNE, R.Y., The rejection of renal homografts, Inhibition in dogs by 6-mercaptopurine, Lancet, 1; 417, 1960, =e ~2 19.oo ~~ 302 6.10.11.12.13.16.17.18.Erion, G.B., HircHINGS, G.H., and VANDERWERFF, H James C.PIERCE and David M.HUME CALNE, R.Y., Inhibition of the rejection of renal homografts in dogs by purine analogues, Transplantation Bull., 38 : 65, 1961.Casey, T.P., The development of lymphomas in mice with autoimmune disorders treated with azathioprine, Blood, 31 : 396, 1968.CHALMERS, A.H., KN1cHT, P.R., and ATKINSON, MR., Conversion of azathioprine into mercaptopurine and mercaptoimidazole derivatives in vitro and during immunosuppressive therapy, Aust.J.Exp.Biol.Med.Sco., 45 : 681, 1967.CLARKE, D.A, Pururies, F.S., STERNRERG, S.S., Stock, C.C., ELonN, G.B., and HrrcHiNgs, G.H., 6-Mercaptopurine : Effects in mouse sarcoma 180 and in normal animals, Cancer Research, 13 : 593, 1953.CRAIGHEAD, J.E., HANSHAw, J.B., and CARPENTER, C.B., Cytomegalovirus infection after renal allo- transplantation, J.A.M.4., 201 : 725, 1967.CruEss, R.L., BLENNERHASSETT, J., MACDONALD, F.R., MacLraN, L.D., and Dosseror, J., Aseptic necrosis following renal transplantation, J .Bone and Joint Surg., 50A : 1577, 1968.DropHar, S.D, KUKLINCA, A.G., Vint, D.G., Ro- BERTSON, A.L., and Hazarp, J.B., Reticulum-cell sarcoma at site of ALG injection, New Eng.J.Med., 280 : 1104, 1969.Doak, P.B., MONTGOMFRIE, J.Z., NORTH, J.O.K, and SMITH, F., Reticulum cell sarcoma after renal homotransplantation and azathioprine and pred- nisone therapy, Brit.Med.J., 2 : 746, 1968.Doe, R.G.,, DEVAUX ST.Cyr, C., and GRABAR, P., Immune reactivity prior to development of thymic lymphoma in C,-B1 mice, Int.J.Cancer, 2: 103, 1967.5.BALES, L., in Experience with human heart transplantation, Proceedings of the Cape Town Symposium, 13-16 July, 1968, Ed.H.A.Shapiro, pp.178-182, Durham, Butterworths, 1969.BINHORN, M., and DavipsoHN, I., Hepatotoxicity of mercaptopurine, J.A.M.A., 188 : 802, 1964.Erion, G.B., Biochemistry and pharmacology of purine 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l\u2019administration de 6-mercaptopurine sur la porphyrino- genèse chez le rat blanc, Comptes Rend.Soc.Biol, 157 : 42, 1963.GiNN, H.E., Late medical complications of renal transplantation, Arch.Internal Med, 123 : 537, 1969.GITCHENS, J.H., ROSENKRANTZ, J.G., and TUNNOCK, S.M., Teratogenic effects of azathioprine (Imuran), J.Pediut., 66 : 959, 1965.Harr, M.C., and Humr, D.M.Bone changes in patients with renal transplants, J.Am.Med.Women's Assoc, 23 : 1040, 1968.Haur, M.C., IRey, R., ELMORE, S.M, Pierce, J.C., BricuT, R.W., and HuME, D.M., Skeletal problems encountered in a series of human renal allografts, J.AM.A., 208 : 1825, 1969.Harr, B.E., RicHARDs, M.D., Wivrerr, F.M, and FEICHTMEIR, T.V., Clinical experience with 6- mercaptopurine in human neoplasia, Ann.N.Y.Acad.Sci, 60 : 374, 1954.HANSEN, H.J., BENNETT, S.J., and NADLER, S.B., Studies on the binding of 6-mercaptopurine by ribonucleic acids in the presence of metals, Arch.Biochem.Biophys.\u2026.98 : 379, 1962.HANSEN, H.J, Gires, W.G., and NADLER, S.B., In vivo metabolism of 9-methyl-6-mercaptopurine-S% and 9-ethyl-6-mercaptopurine-S* by the rat, Cancer Res., 22: 761, 1962.Humr, D.M., Progress in clinical renal homotrans- plantation, Advances in Surg.2 : 419, 1966.JENSEN, M.K., Chromosome studies in patients treated with azathioprine and amethopterin, Actu Medica Scand., 182 : 445, 1967.Kerrey, G.C., WHEELER, G.P.,, and MONTGOMERY, J.A, The effects of a series of 9-alkylpurines on the growth of sensitive and 6-MP resistant H.Ep.#2 cells, Cancer Res., 22 : 329, 1962.KimBaLL, A.P.,, LEPAGE, G.A., and BowymaN, B., The metabolism of 9-arabinosyl-6-mercaptopurine in normal and neoplastic tissues, Canad.J.Biochem., 42 : 1753, 1964.Kimsarr, A.P., LEPAGE, G.A., BOWMAN, B., and HrrrioT, S.J., Suppression of the homograft response by purinethiol nucleosides, Proc.Soc.Exp.Med.Biol, 119 : 248, 1965.LEE, H.M., LINEHAN, J.D., and Hume, D.M, Peptic ulcer disease in renal homotransplant patients receiving immunosuppressive therapy, In preparation.MACLEAN, L.D., DossETor, J.B., GAULT, M.H, OLIVER, J.A., INGLIS, F.G., and MACKINNON, K.J., Renal homotransplantation using cadaver donors, Arch.Surg., 91 : 288, 1965, Land Tol.4t- A Man ibdical és.10 PLIS, Pos, ciplents 0a : [ali hyring- Bil.| Af sl.n° 5, [N30 za JU probleurs ogres Laval Médical Vol.41- Fév.1970 38.39.42.> bh 48.49.Martin, D.C., RuBini, M., and Rosen, V.J., Cada- veric renal homotransplantation with inadvertent transplantation oË carcinoma, J.A.M.A., 192 : 752, 1965.MEEKER, W., CoNDIE, R., WEINER, D., Varco, R.L., and Goon, R.A., Prolongation of skin homograft survival in rabbits by 6-mercaptopurine, Proc.Soc.Exp.Biol.Med., 102 : 459, 1959.Mowsray, J.F., CoHEN, S.L., Doak, P.B., KENYON, J.R., Owen, K., PERCIVAL, A., PorTER, K.A., and Peart, W.S., Human cadaveric renal transplantation, Report of twenty cases, Brit.Med.J., 2: 1387, 1965.Murray, J E., SHrir, A.G.R., MoSELEY, R., KNIGHT, P., McGavie, J.D, and DAMMIN, G.J., Analysis of mechanism of immunosuppressive drugs in renal homotransplantation, Ann.Surg., 160 : 449, 1964.NAsgLETI, C.E., and Spencer, H.H., Chromosome damage and polyploidization in human peripheral leukocytes in vivo and in vitro with nitrogen mustard, 6-mercaptopurine, and A-649, Cancer Res.26 : 2437, 1966.PENN, I, HAMMOND, W., BRETTSCHNEIDER, L., and STARZL, T.E., Malignant lymphomas in transplantation patients, Proc.Transplantation Soc, 1: 106, 1969.PnrsLIPs, F.S., STERNBERG, S.S., HAMILTON, L., and CLARKE, D.A., The toxic effects of 6-mercaptopurine and related compounds, Ann.N.Y.Acad.Sci, 60 : 283, 1954.5.PIERCE, J.C., The Modification of Biological Factors in the Rejection of Canine Allotransplants by 6- mercaptopurine, Ph.D.Thesis, University of Minnesota Graduate School, 1966.PIERCE, J.C., VARCO, R.L., and Goon, R.A., Prolonged survival of a renal homograft in a dog treated with 6-mercaptopurine, Surgery, 50 : 186, 1961.Rirkinp, D., MarcHIORO, T.L., SNECK, S.A, and Hi, R.B., Systemic fungal infections complicating renal transplantation and immunosuppres- sive therapy, Am.J.Med, 43 : 28, 1967.RITTENBURY, M.S., Humr, D.M., and HEencH, M.E,, \u2018Pathogen-free\u201d patient care area, Antimicro Agents and Chemotherap., 197 : 51, 1962.RunpLES, R.W., WYNGAARDEN, J.B., HircHiNGgs, G.H., Erion, G.B., and SILBERMAN, H., Effects of xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia, and gout, Trans.Assoc.Am.Physicians, 76 : 126, 1963.Ct Tn Th 56.~2 a8.00.GI.54.TOXICITY OF AZATHIOPRINE 303 .ScHWARTZ, R.S., Immunosuppressive drug therapy.Chapter 28, pp.440 in Editors : Rapaport, F.T., and Dausset, J., Human Transplantation, Grune and Stratton, New York, 1968.SCHWARTZ, R.\u2026, and DAMESHEK, W.The effects of 6-mercaptopurine on homograft reactions, J.Clin.Invest., 39 : 952, 1960.SCHWARTZ, R., STACK, J, and DAMESHEK, W., Effect of 6-mercaptopurine on antibody production, Proc.Soc.Exp.Biol.Med, 99 : 164, 1958.STARZL, T.E., BREITSCHNEIDER, L., PENN, I., BELL, P., GrorH, C.G., BLANCHARD, H., KaswIwaer, N., and PurNAM, C.W., Orthotopic liver transplantation in man, Transplantation Proc.1: 216, 1969.THIERSCH, J.B., Effect ot 6-(1\u2019'methyl-4\u2019-nitro-5\u2019-imida- zole) \u2014 mercaptopurine and 2-amino-6-(1\u2019-methyl- 4\u2019-nitro-6\u2019-imidazole) \u2014 mercaptopurine on the rat litter in utero.J.Reprod.Fertil., 4 : 297, 1962.TiuwEy, N.L., CoLLINS, J.J., Jr, and WiLsoN, R.E., Hemorrhagic pancreatitis : A fatal complication of renal transplantation, New Eng.J.Med., 274 : 1051, 1966.TUCHMANN-DUPLESSIS, H., and MERCIFR-PAROT, L., Induction of limb defects in rabbits by administration of the metabolite, azathioprine, Comptes Rendus Acad, Sci, (Paris), 259 : 3648, 1964.VocLER, W.R., Bain, J.À.Huvaurey, C.M, PALMER, H.G., and Lowrey, M.E., Metabolic and therapeutic effects of allopurinol in patients with leukemia and gout, Am.J.Med., 40 : 548, 1966.WiLson, R.E., HAGER, E.B., HAMPERS, C.L., CORSON, J.M., MERRILL, J.P., and MuRrray, J.E.,, 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COMPTE RENDU DE LA DEUXIÈME RÉUNION PLÉNIÈRE \u2014 PROCEEDINGS OF THE SECOND GENERAL SESSION : \u2014 Role of ALG in heart transplantation ; \u2014 Clinical and laboratory diagnosis of rejection ; \u2014 Infection and other complications of immunosuppression.Chairman : Denton COOLEY, Houston.Reporters ; H.E.TAYLOR, Ottawa, and Gilles LAMOUREUX, Montréal ; Edward B.STINSON, Palo Alto, and Ihor DYRDA, Montréal ; Donald ROSS, London, and André LEDUC, Montréal.Transcript Editor : Gilles LEPAGE.We will first call on Doctor Taylor and Doctor Lamoureux to report on the session regarding the role of ALG in heart transplantation.Doctor Taylor : Doctor Cooley, ladies and gentlemen.1 feel rather like a medical student right now, my mind is full of facts but I am not sure how they are going to drop-out in this oral exam.It really is very difficult at the present time to scientifically evaluate the effectiveness of ALG as an immunosuppressive agent since we have as yet no method of accurately standardizing it.One of the most urgent problems to be solved is the development of an in vitro or in vivo method of defining the potency of ALG and thus to develop a standard international unit which would allow valid comparisons between one center and another.Another difficulty is related to the variety of antigens used for its preparation.This was discussed by several people this morning.On the one hand Doctor La- moureux, from the answers to a questionnaire that he had distributed to all centers doing heart transplants, came up with figures that suggested an ALG prepared either against human thymus cells or against thoracic duct lymphocytes might be more effective than ALG prepared against other lym- On the other hand, Doctor Starzl reported experiments in his laboratory where his phoid tissues.model was the intra-abdominal heart transplant in which he used ALG prepared from three antigens, one using spleen, one using the spleen and lymph- node cells, and the third one using thymus.And he found no difference in the survival time of the heart transplant as far as these three were concerned and concluded that the type of antigen may not be quite as important as we presently think.However, contamination of the antigenic material with other cells, such as red cells and platelets, will of course give rise to antibodies against these two cell types and therefore one may encounter the problem of having a high titer hemaglutinin or a high titer anti-platelet antibody which would result in the production of hemolytic anemia and/or thrombocytopenia.I gathered the general impression, from the clinicians who have used ALG in significant number of patients, that thrombocytopenia certainly may occur, particularly if the titer is over 1/32.In the Medical Research Council of Canada ALS program about which IT may speak briefly later, we now have a highly immunosuppressive ALG prepared against human thymocytes.This had a lymphocytotoxic titer of 1/9 000 and after fractionation, absorption with red cell stroma, ultraconcentration and lyo- phylization, it still had a hemaglutinin titer of 1/256.Doctor Starzl did the platelet antibodies for us and this was 1/32.This particular product has been highly immunosuppressive in the hands of Doctor Balner when tested in both the speciosa monkey and the chimpanzee.In the latter it significantly prolonged the four allografts from other chimps and one human heterograft.However the We nial: font: gh du qf fe ong tl lig) poll Ji os od die \u201cre OK ï high le lain pt i gi pal?gir 0 | nied pre por bi 8 pp pots pi fie gd jt d lis fu duet bs ob d gai sf fief fie ol pd aud Laval Médical Vol.41 -Fév.1970 chimpanzee on the 15\" day had a hematocrit of 26 and a platelet count of 40 000.Although this did not come out in the meeting this morning, I have been told by other colleagues that one cannot positively make a correlation between the effect of these agents in the chimpanzee directly to the human.Doctor Van Bekkum did speak of this this morning and he believes that there is some degree of correlation although further experimental work has to be done along that particular line.So I think we can conclude then, as far as antigen is concerned, that the contamination of these other cells 1s a very important factor in the methodology used to get the most pure form of cell or cell fraction and there is evidence, again not discussed this morning, that the cell membrane fraction may be possibly the best antigen.Speaking of the species of animals used to produce the ALG, horses are the common ones, simply because they give masses of serum and also are good antibody producers.Other workers have used rabbits, goats, sheep, and cows.And I think the important point concerning this is to have sufficient quantities of ALG prepared in a variety of species so that if one encounters the clinical problem of serum sickness or anaphylaxis, then one can immediately change over to one of the other species ALG.Various protocoles for immunization have been used for a considerable length of time.I think the groups that are interested in the mass production of ALG were perhaps influenced by the work of Medawar and Levey with the two-pulse method and their statement that any ALG produced with Freund\u2019s adjuvant was likely to be toxic.This does not seem to be borne out in the human work.I think that everybody now agrees that the most effective ALG can be produced by the initiation of immunization with adjuvant therapy, followed by intravenous whole cell or membrane fractions.Methods of fractionation were discussed at some length by Doctor Carraz and here again there is a tremendous variation from one center to another.In his earlier work, he found the ammonium sul- PROCEEDINGS OF THE SECOND GENERAL SESSION 305 phate method of preparing his gammaglobulin gave him a very sound immunosuppressive product.On the other hand we know that DEAE-sephadex methods, either the batch or columns method, also give a very sound immunosuppressive agent.And from this general discussion, without too much chemistry involved, on the preparation of ALG, it became obvious that the immunosuppressive aet- ivity from the stand point of prolongation of skin grafts is largely in the IgG fraction but also in the T equine fraction.Now this had not been recognized and therefore, at one stage in the development of ALG, there was a tendeney to over- purify and so to speak, throw the baby out with the bath water.With the present methods of using batch DEAE-sephadex and two fractiona- tions you do end-up with a 90 per cent pure gamma- globulin IgG and T fraction.It is interesting that the mass producers such as Connaught Laboratories and the Institute of Microbiology who have been making tetanus and diphteria antitoxin for years, have known this.In fact Cinader showed this some years ago with tetanus antitoxin.When you acutely immunize a horse, you tend to have almost all your immunosuppressive activity in the IgG fraction.When you chronically immunize and drain-off by plasmaphoresis over a period of months or even years, as in the case of tetanus antitoxin producers, then you get a shift towards the T frae- tion.Doctor Starzl pointed this out in a paper originally given I think in Vancouver at the Royal College meeting and he emphasized this point again today.So I think it is of some importance that in fractionation, one must be aware of losing the immunosuppressive activity by over-purification.We came to the different therapeutic regimens that have been used in the various centers.And again there is a great deal of controversy.I gathered from the papers given by Doctors Trea- ger, Starzl and Brendel, that long term maintenance therapy is probably a must.I think each of these speakers emphasized the fact that if you stop ALS, an escape occurs very rapidly from its effect.Doctor Treager, in experiments using skin allografts, showed us very nicely that as long as 306 COMPTE RENDU DE LA DEUXIÈME RÉUNION PLÉNIÈRE he maintained the dose, the skin allograft was beautiful.Stop the ALG therapy and very rapidly the rejection phenomena set-in.For heart transplantation, it became very obvious that ALG is probably a must in the immunosuppressive therapy of such patients.This may not necessarily apply as far as renal transplants are concerned.The intravenous versus the intramuscular methods of introducing the serum were discussed by Doctor Brendel and also by Doctor Monaco from the audience.Doctor Brendel is convineed that the intravenous method is the one of choice: a high dose can thus be given rapidly and painlessly.Doctor Barnard also spoke of his own patients in South Africa who had been treated in this manner for rejection crises.The synergistic effect of the other immuno- suppressive agents, Imuran and the steroids with ALG led, not to a controversy, but to some differences of opinion.It has always been assumed that ALG and cortisone worked synergistically, but Doctor Lamoureux showed preliminary experiments that suggested that administration of cortisone with ALG may in fact not be synergistic in the mouse skin allograft model.In his experiments anyway, the survival time of the grafts when he used cortisone and ALG together was shorter than with ALG alone.However, this was not agreed to by other members of the panel.This brings up the next problem, that of the toxicity of ALG.In relation to this, we have already mentioned the effect upon the hemopoietic system, particularly platelets, with thromboeyto- penia.the possibility of a bleeding tendency, purpura, internal hemorrhage, and so on.This can be overcome by adequate absorption of the ALG by using platelets, a difficult problem.You can also diminish significantly the hemaglutinins by absorbing with either whole red cells or red cell stroma.Now theoretically serum sickness should be a real problem: we are chronically administering to a patient a foreign serum protein and yet, for some peculiar reason, this does not seem to have reared its ugly head in the clinical use of ALS over long periods of time.It has been reported that one can demon- Laval Médical Vol, 41- Fév.1970 strate a binding of the horse gammaglobulin to various basement membranes, particularly the glom- erular basement membrane and yet 1 gathered this morning that so far, there have been no significant examples of serum sickness nephritis.Is this related to the simultaneous immunosuppression using steroids and Imuran along with the ALG?This I do not think anybody can answer at the moment.When one thinks of giving the large doses that Doctor Brendel spoke of intravenously, where you have a mass of antigen confronting your immune system, one would suspect, one would expect in fact, that one would rapidly get immune complexes and deposition of these complexes when you get certain states of equivalence between antigen and antibody, and this should give rise to the lesions of serum sickness.These are the classical experiments of Frank Dixon many years ago.And yet I understood that, while you can demonstrate by immuno- fluorescence methods the binding of the protein to basement membranes, this does not seem to be of any significant pathogenetic significance at the moment.No one mentioned neoplasia this morning.However this is a real hazard and at the Brook Lodge ALS conference held about a month ago, there was given incontrovertible evidence that ALS or ALG in experimental models not only will increase the incidence of transplantable tumors or virus induced tumors, but that spontaneous tumors will appear in highly significant numbers in animals usually not susceptible to the appearance of tumors.In my own laboratory, we have a trans- plantable myeloma tumor.If you put in a fragment of the tumor, it grows beautifully.But the injection of a suspension of the myeloma cells showed no apparent growth.Then by accident, testing ALS for another purpose, we used these animals that apparently were not producing tumors, they were given two doses of ALS a week apart and on the 215t day, the tumors at the site of the original injections were 1.25 em in diameter.So here is evidence that ALG can indeed stimulate a latent tumor to become typically malignant and invasive.This is somethting that we have to bear in mind. Védicni Pé Fi in | i il i A ampicilline :ÿ a-t-Il entre mpicine 3: ood 1: J | -1 etleprixdesbananes?{li | Pp nu GTi Seulement ceci: D\u2019après les récentes statistiques, La marque de distinction Bristol est aussi évi- une | les bananes sont l'une des rares choses qui coû- dente dans la grande variété de formes posolo- wil tent moins cher aujourd\u2019hui qu\u2019il y a cinq ans.giques d\u2019Ampicine, pour recontrer tous les be- wl Cette affirmation s\u2019applique aussi à Ampicine.En soins du patient.L\u2019Ampicine est présentée en A effet, si l'on considère la récente baisse de prix capsules de 250 mg.et 500 mg.; suspension ur annoncée récemment, le coût de l\u2019Ampicine a été orale de 125 mg.et 250 mg.par 5 ml.L\u2019Ampicine iv | réduit de plus de 39% depuis son lancement est aussi disponible sous forme parentérale\u2014 agi sur le marché en 1964.et est devenue, selon Ampicine pour Injection (ampicilline sodique).ai les études sur le prix au patient, un traitement Canad revere Cb ] presque aussi économique que les plus impor- BRISTOL Bristol Laboratories ot Canada où .| tantes marques de tétracycline et d'érythromycine.Pionnier dan la découverte et le développement des antibiotiques - se - peus J 1 ler J jn ote hed > Al te ÿ.How i Lil 1B ; gl + os 9 8 plus par Quel rapprochement + # MARQUE DEPOSEE Laval Médical Vol.41- Fév.1970 dans le choc rebelle.S0lu-Gortef A DOSES PHARMACOLOGIQUES \u201cQuelle qu'en soit la cause profonde, l\u2019état de choc sévère devrait toujours être traité au moyen d\u2019une dose d'hydrocortisone (500 à 2000 mg) donnée par voie intraveineuse sur une période variant de quelques minutes à plusieurs heures.\u201d Blalock, A.and Harrison, T.R., eds.: Principles of Internal Medicine.McGraw-Hill Book Co., N.Y., Ed.5, p.728, 966.\u201cDes corticostéroïdes devraient être administrés aux malades qui ne réagissent pas à des transfusions sanguines suffisantes ou qui sont en état de choc septique, assez tôt et à fortes doses intraveineuses, soit une dose initiale de l ou 2 g d\u2019hydrocortisone ou son équivalent, à renouveler toutes les 2 à 6 heures, selon le besoin.Robins, J.: Obstet.Gynecol., 28:130-138 (July) 1966.\u201cDepuis un an et demi, nous avons couramment administré à des malades souffrant de choc septique des doses quotidiennes correspondant à 4,000 jusqu\u2019à 6,000 mg d\u2019hydrocortisone, et les résultats de ce traitement: .ont été très satisfaisants.Chez plus de 20 des malades traités par une corticothérapie massive, la proportion de survie a été d'environ 90%.\u201d Rigby, R.A.and Christy, J, H.: Amer.J.Med., 45:959-966 (Dec.) 1968.\u201cLes glucocorticoïdes ont une valeur indéniable dans le choc, qu'il soit d\u2019origine hémorragique, toxémique ou cardiogéne.Pour être efficaces, ils doivent être donnés à des doses infini-; ë ment supérieures aux doses physiologiques, soit des doses de l\u2019ordre de 1000 mg d'hydrocortisone ou son équivalent.\u201d Forsham, P.: The Adrenals.R.H.Williams\u2019 Textbook of Endocrinology, W.B.Saunders Co., Phila., 372-373, 1968.Lat Sal py Eu &lg tell Pug tat bei Gi Dig dint toy Li Sa Br Ti Up Seth gy iy tg Hg [Edi im oi Laval Médical Vol.41-Fév.1970 pour augmenter le taux de survie d0lu-Gortel disponible en Mix-O-Vial renfermant: Hydrocortisone (à l'état de succinate sodique d'hydrocortisone) 100 mg, 250 mg, 500 mg et 1 g, pour rendre plus commode et plus économique I'administration des doses pharmacologiques.Posologie: Adultes\u2014 Dans les urgences médicales telles que les réactions d'hypersensibilité et la pneumonie par aspiration, la dose initiale est de 100 à 500 mg, selon le degré de gravité de la pathologie, à être administrée par voie intraveineuse sur une période d'au moins 30 secondes.Cette dose peut être renouvelée à intervalles d'une, de trois, de six et de dix heures, selon la réaction du malade au traitement et son état clinique.Devant toute forme de choc rebelle et dans les cas critiques, spécialement chez les malades âgés dont le choc est causé par des endotoxines ou une infection accablante, on recommande d'injecter, par voie intraveineuse, une dose d'un gramme ou plus, suivie d'une dose de 500 mg toutes les 4 ou 8 heures, pendant une période de trois à cinq jours, si nécessaire.!-3 Le Solu-Cortef peut aussi être administré par voie intramusculaire ou en perfusion intraveineuse.Nourrissons et enfants- La dose peut être réduite chez le nourrisson et l'enfant, mais elle doit dépendre plus de la gravité de la pathologie et de la réaction du malade au traitement que de son âge ou de son poids.Avertissement: Les précautions générales et les contre-indications inhérentes à la corticothérapie par voie générale s'appliquent également au Solu-Cortef.Cependant, employé dans des cas d'urgence médicale ou des états apparentés au choc, il serait sage de mettre en parallèle, d\u2019une part la possibilité de sauver la vie du malade et d'autre part les effets hormonaux défavorables du médicament.Dans le traitement du choc, le Solu-Cortef doit être considéré comme un adjuvant des traitements classiques, tels que la sérothérapie, etc.Une documentation complète est envoyée sur demande.Références: 1.Thal, A.P., and Wilson, R.F.: Shock, Current Problems in Surgery.Year Book Med.Pub., Inc., Chicago, 1965.2.Lillehei, R.C., et al.: Ann.Surg., 160:682-710 (Oct.) 1964.3.Sambhi, M.P., et al.: Internatl.Anesthesiol.Clin., 2:421-433 (Feb.) 1964.MEMBRE LA COMPAGNIE UPJOHN DU CANADA DON MILES, ONTARIO 699 MARQUE DÉPOSÉE; SOLU-CORTEF MARQUE DE COMMERCE: MIX-O-VIAL CF 5631.1 asthénies gérontologies psychasthénies formule: premier tube second tube Vitamine C 1000mg.Cortico-surrénale 19.33 Glande orchitique 3g.Substance grise 3g.posologie adulte: pour Smt 1 JUMO-TUBE ~ > ar jour.présentation: pari Boites de 12 JUMO- posologie entant: TUBES de 5 + Smi.- 1 JUMO-TUBE à tous les deux jours.LABORATOIRES A MEMBRE: AFQPP LABORATORIES Laval Médical Vol.41-Fév.1970 Lin il. édical =, 10 Luval Médical Vol.41- Fév.1970 I know Doctor Starzl and his group have drawn together certain figures from around the world and I think that one has to accept this as a very definite hazard in the long term use of ALS.I would like to conclude, Mister Chairman, with just a few remarks about our own Canadian program and this is based on my starting premise here that you cannot at the present moment scientifically compare anything that is going on in one center with that in another.A committee of the Medical Research Council was formed about a year and a half ago and they drew up a careful protocol.Last summer we started to prepare for this clinical trial using renal transplantation as the method of assessment.What we are attempting to do is to produce a common pool of ALG that has met all the criteria that we can presently use such as lymphoeyto- toxicity, various in vitro tests, and the Balner chimpanzee test (in other words standardizing at least on the basis of the available 1m vitro and in vivo tests) and then utilize this standard product in 100 patients with renal transplants and compare these with another group of patients who will not receive ALG.We will immunize 24 horses, starting one group of 12 here at the Institute next week and then another group in Connaught Laboratories.Human thymus will be used as antigen.This will give us a pool of some 500 liters of crude ALS which will be tested for cytotoxicity.Satisfactory samples will then be pooled, absorbed and fraec- tionated and finally tested by Balner.This mass production of a common pool of ALG has raised many problems, however it should be ready for the clinical trial early in 1970.Doctor Cooley: Thank you Doctor Taylor, would Doctor Lamou- reux care to add anything to this?No?I have been impressed personally with Doctor Kahn's results in three consecutive myocardiopathy patients in which he did not use ALG.Is there any significance to the fact that his program did not include ALG, did it have any relationship to the success of his cases?(15) PROCEEDINGS OF THE SECOND GENERAL SESSION Doctor Taylor: Mister Chairman, this was mentioned by Doctor Sarzl.I had posed the question: in what way can we prove that ALG is really effective anyway?Doctor Starzl pointed out there are many experimental models and now human cases, particularly in the kidney transplantation field, in which there is a great deal of argument.Should you use ALG anyway ?They are doing fine without it.However the general impression was that the cardiac transplant really should have ALG and in particular, of course, 1f there is any evidence of any rejection.I believe there was no sign of any rejection at any time in those three cases Doctor Kahn mentioned yesterday.Doctor Cooley: Any question or contribution from the floor?I would like to announce the arrival of two other outstanding surgeons in this field.I see Doctor C.Walton Lillehei, from New York, and Doctor Henry Bahnson, from Pittshurg, have just arrived.The next report will be that of Doctor E.B.Stinson from Palo Alto and Doctor Dyrda, from Montreal, on clinical and laboratory diagnosis of rejection.Doctor Stinson: In response to Doctor Dyrda\u2019s questionnaire which was sent to all transplantation centers, 57 cases were reported back.In these 57 cases a total of 64 definite rejection episodes were reported.The highest incidence of diagnosed rejection oceur- red in the first two postoperative weeks with a gradual decrease in incidence after this time until about four months postoperatively.However, rejection was reported out to about 200 days.Of these total 64 episodes, 30 per cent were fatal and all in all, rejection caused approximately 50 per cent of postoperative deaths.The clinical and laboratory manifestations of cardiac rejection can be categorized in three broad groups.The first would include the manifestations of local organ dysfunction.The second would 308 include the primary immunologieal factors, and third, the systemic consequences of either or both of these.dysfunction of the graft can be subdivided into Furthermore the manifestations of local those of electrophysiology, anatomical changes, physiological changes, biochemical changes, including myocardial enzymes, and alterations in physical cardiovascular examination.It is apparent that most people have been more successful in utilizing these parameters for the diagnosis of rejection than in utilizing either the immunological or systemic alterations.It is somewhat gratifying to find one point of uniform agreement in the Symposium, and that is that the electrocardiogram is of paramount importance in the diagnosis of re- Jection.In both early and late acute rejection the most common changes encountered include decreasing electrocardiographic voltage, deviation in the mean frontal plan axis, usually toward the right, and various atrial arrhythmias.These include paroxysmal atrial tachycardia, simple atrial premature beats, atrial flutter and atrial fibrillation.A gradual decrease in voltage may oceur with chronic rejection changes.It was mentioned that a transient decrease in voltage occurs commonly during the first postoperative week.Unfortunately, very little control data are available on this.It is apparent however that more and more centers are willing to initiate therapy for rejection on the basis of electrocardiographie changes alone.Some of the physiological alterations that occur with acute cardiac rejection, including diminished cardiac output and arterial pressure, cannot be demonstrated until nearly the terminal episode.However with various provocative tests, earlier myo- cardial changes can be demonstrated.With both heterotopic and orthotopic transplantation, one can, by controling heart rate either through linear or coupled pacing document a diminished ability of the rejecting heart to increase its stroke volume.Doctor Heimbecker presented data with the hetero- topic preparation showing changes in left ventrie- ular function during rejection as measured by force development during isometric contraction from varying ventricular volumes.But in the early post- COMPTE RENDU DE LA DEUXIÈME RÉUNION PLÉNIÈRE Laval Médical Vol.41- Fév.1970 operative period, measurement of cardiac hemo- dynamies has contributed very little to either diagnosis or clinical management.Later on, in the course of chronic rejection, clinical impressions can be confirmed by alterations in resting cardiac output or the myocardial response to exercise.As will be demonstrated in the session on the pathologic changes that occur with cardiac rejection, there are early alterations in cardiac anatomy.The plain chest X-rays serve only to confirm changes in size of the cardiac silhouette which are greater than systolic-diastolie variations, but these changes do not generally oceur early during rejection, By ultra-sound cardiographie measurements of various cardiac dimensions, however, more early changes can be detected.These include measurement of wall thickness, presumably contributing evidence of myocardial edema, changes in chamber size predominantly right ventricular diameter, and changes in overall heart size.In addition, ultrasound cardiographic measurements can show diminished amplitude and rate of systolic movement during rejection (similar to the fluoroscopic observations described by Doctor Lower).In terms of the physical diagnosis of rejection, there is some disagreement because of the non- specificity of many of these signs.However, the earlier signs apparently include a pericardial frie- tion rub.Doctor Nora from Houston was more It should be noted however that pericardial friction rubs are enthusiastic about this than most.common following all types of heart surgery.In our own experience early physical evidence of rejection has included changes in the character of right ventricular contraction (palpation) and also an increase in the amplitude of the neck vein pulsations without an increase in venous pressure (V waves).Later on more severe changes include obvious venous distension, right and left ventricular heaves and/or a murmur of mitral insufficiency.Abnormal heart sounds do tend to occur earlier than the other signs, particularly the S-3 or early diastolic gallop.There was a significant dichotomy of opinion regarding the enzyme diagnosis of cardiac rejection.fain Vil.4 hi slr beat fied dora thr ail édieal 6, 1970 em 1 ling in the js en ae oll Laval Médical Vol.41 -Fév, 1970 I think this results primarily from theoretical considerations, namely that immunologic damage to the heart severe enough to cause cellular necrosis or even damage to cellular membranes sufficient to elevate the serum levels of myocardial enzymes must theoretically be a relatively late event.Doctor Nora again was more enthusiastic than others about the fast moving fraetions of lactic acid dehydrogenase as an index of rejection, and presented evidence that in the great majority of their cases alterations in the first band of LDH were quite suggestive.In regard to primary immunological factors in cardiac rejection, I think the situation is similar if not identical to that obtaining in renal transplantation.Doctor Botha from Cape Town defended very elegantly the negative results that have been recorded and indicated that a detectable level of circulating eytotoxie antibodies has omnious prognostic significance.In particular, though, he urged continuation of the studies that have been initiated mostly for the sake of obtaining more data.Most of the systemic consequences of cardiac rejection are non specific and serve as suggestive phenomena.The most common occurrence in response to Doctor Dyrda\u2019s questionnaire was a decrease in exercise tolerance as reported by the patients or as observed clinically, occurring in more than 90 per cent of definite rejection episodes.Other symptoms and signs include malaise, fever, anorexia and fatigue.The clinical relevance of all these considerations is significant only in so far as they permit the early diagnosis of cardiac rejection and the application of effective therapy.In summary, it appears that there is nearly uniform agreement that the electrocardiogram serves as the primary index of acute cardiac rejection.Other early phenomena inelude a diastolic gallop rhythm, changes in cardiac dimensions as determined by ultra-sound techniques, and possibly the elevation of the myocardial fractions of lactic acid dehydrogenase.It should be emphasized that short of biopsy, none of these indices is entirely specific and this consideration has pointed out the need for controlled studies which at this point do not exist.PROCEEDINGS OF THE SECOND GENERAL SESSION 309 Doctor Cooley: Thank you Doctor Stinson.Doctor Monties from Marseille had asked to be permitted to make some remarks at this time.Doctor Monties.Doctor Monties: La ressemblance anatomo-pathologique des lésions de rejet et de coagulation intravaseulaire disséminée d\u2019une part, la fréquence des phénomènes thrombo-emboliques lors des transplantations d\u2019autre part, nous ont amené, au cours de l\u2019évolution d\u2019un malade opéré depuis six mois, à surveiller de très près sa coagulation sanguine.Nous avons fait deux constatations.La première, une hyper- coagubilité très importante qui est apparue au troisième jour et qui a nécessité des doses très importantes d\u2019héparine (415 mg) dans les 24 heures.La deuxième, c\u2019est l'apparition, lors d\u2019un épisode de rejet aigu le 31 décembre 1968, de signes biologiques de coagulation intravaseulaire disséminée avee une chute des plaquettes à 70 000, un épistaxis, et un thrombo-élastogramme qui montrait un aspect typique de coagulation intravaseulaire disséminée.Cette chute des plaquettes a été interprétée comme signe de rejet, car nous avons à ce moment-là augmenté la globuline antilymphoeytaire et traité le malade par l\u2019héparine.En six heures les plaquettes sont revenues à un taux normal, l\u2019état eli- nique du malade s\u2019est amélioré, en particulier l\u2019épistaxis, les douleurs thoraciques ont disparu, et l\u2019amplitude du QRS a augmenté.Ces deux constatations nous amènent à faire deux commentaires.Tout d\u2019abord, le phénomène d\u2019hypercoagubilité postopératoire que nous avons vu cadre très bien avec tous les phénomènes thrombo-emboliques qui ont été décrits après transplantation en particulier par Starzl.D\u2019autre part, les rapports tant anatomo- pathologiques que biologiques entre la coagulation intravaseulaire disséminée et le rejet paraissent dans cette observation avoir été établis.Ceci nous amene a deux conclusions.Dans la surveillance du transplanté cardiaque, une appréciation régulière des tests de coagulation, en particulier le thrombo- élastogramme et la numération des plaquettes, 310 peut être un apport intéressant dans le dépistage d\u2019un rejet et, à posteriori, nous nous sommes aper- eus que sur le thrombo-élastogramme, on aurait pu depuis dix jours prévoir l\u2019apparition des signes de rejet.Deuxièmement, le traitement à l\u2019héparine a permis vraisemblablement, en évitant des lésions de thrombose intracardiaque ou intracoronaire, de laisser au traitement classique le temps d'agir.Doctor Cooley: Is Doctor Lower here?Would you make a remark to this question about whether heparin might protect the allograft from developing these occlusive changes in the coronary circuit?Doctor Lower: We have no experience, but Doctor Kahn is using heparin.Perhaps he could tell us.Doctor Cooley: We are getting off the main subject but I think we would like to hear what Doctor Kahn will say.Doctor Kahn: We studied the effect of heparin on coronary blood flow in pig heart using *!'Cesium chloride.Heparin markedly increased coronary blood flow mn the transplanted heart producing less vascular changes than in control pigs.This fact led us to clinically use heparin in our three human cardiac transplants.Doctor Cooley: I think this is an interesting observation.I know from our two longest survivors which Doctor Milam will present today in the pathology session, that there was extensive evidence of coronary ocelusive disease as a principal sign of rejection.It seems that this might be one area where we could use preventive measures and if heparin would be one of the preventive measures, I think it should be used more liberally.Are there any other questions or comments that someone would like to make at this point?COMPTE RENDU DE LA DEUXIÈME RÉUNION PLÉNIÈRE Laval Médical Vol.41- Fév.1970 Doctor C.Barnard: For the past nine months we have studied the value of the impedance electrocardiogram in the diagnosis of rejection, as suggested to us by Doctor Kubicek and his group in Minneapolis.It is a little early to come to any definite conclusions, but my impression is that it is not going to be of value in the diagnosis of acute rejection.However, it seems to be of value in studying the gradual deterioration in the cardiac muscle of the patient, the chronie damage, the reduced reserve of the heart.We have seen in some of our patients that there is a gradual deterioration in the various parameters studied with impedance electrocardiogram.So this may be a useful way to follow the chronic damage that takes place in the myocardium, due to sub- clinical rejection that goes on all the time.Doctor Stinson: Doctor Cooley, I think this is an important point, for the diagnosis of chronic rejection is extremely unsatisfactory.We, and other centers, have seen patients coming to autopsy with severe narrowing of nearly all the coronary arteries.Yet, until the last few days of life, these patients were apparently normal in terms of cardiovascular examination, exercise tolerance, exercise electrocardiograms and balistocardiograms.The diagnosis of chronic rejection is an area that surely needs intensive investigation.Doctor Cooley: Our longest survivor, who went for nine months, had not a single recognizable epsidoe of rejection, yet he died rather abruptly and the autopsy revealed classical findings of graft rejection and a good deal of evidence of coronary occlusion.We are inclined to believe that he died from a Stokes-Adams attack, which would be a coronary type of death rather than the usual type of chronic rejection.Let us now move on to the next report which will be given by Mister Donald Ross on infection and other complications of immunosuppression.\u2018en \u2014_ \u2014 Laval Médical 27 Vol.41-Fév.1970 Lilie a I Tic, Ii - N ç Lt Eau minérale alcaline naturelle 5 Décor salé diététique, ry légèrement thérapeutique.CE Le tonique minéral tout indiqué mère, = .5 .he dans les soins post-opératoires.Sap, 1h ur FOIE [] VOIES BILIAIRES [] cas VOIES DIGESTIVES [/] sans EQUILIBRE DE LA NUTRITION [] shi , PT sm Souvent recommandée par le corps médical n y a Méfiez-vous des substitutions Prescrivez CELESTINS La seule véritable eau de Vichy vendue au Canada nr Importée directement br , de l\u2019établissement so thermal de Vichy, re France.ni wl pt?pi pu que se v puis pie} quil pi mi A a i F i ue pl! - ping cen itl Pd | Si Importateurs : rue Viau, Montréal.(16) D | Les symptômes de l'ulcère et des troubles gastro-intestinaux peuvent varie d'un patient à l\u2019autre.Mais \u2018Stelabid' permet de traiter les trois catégorie les plus importantes de malades.\u2018Stelabid' No 1 pour les patients chez qui le trouble psychique est minim@ \u2018Stelabid\u2019 No 2 pour la plupart des patients accusant de l'anxiété, deg l'hypersécrétion et des spasmes \u2019 \u2018Stelabid\u2019 Forte un moyen additionnel de soulager les spasmes et l'hy persécrétion Trois catégories de malades\u2014trois combinaisons de symptômes\u2014trois fo mules de \u2018Stelabid'\u2014assurant une protection de 24 heures contre le spasmes, l'acidité, l'anxiété et les nausées, avec une posologie biquotil dienne commode.K CE Smith Kline & French, Montréal 379, QUÉDEC \u2018Marque déposée au Gand we < .» lee Lavul Médical 29 Vol.41- Fév.1970 Comprimés \u2018Stelabid\u2019 renseignements généraux Pour tous renseignements, veuillez consulter la monographie correspondante figurant dans le Vademecum International.Composition \u2014 Chaque comprimé \u2018Stelabid\u2019No1 renferme 1 mg de Stelazine (trifluopérazine, SK&F), sous forme de chlorhydrate, et 5 mg de Darbid* (iso- propamide, SK&F), sous forme d\u2019iodure.Chaque comprimé \u2018Stelabid\u2019 No 2 renferme 2 mg de \u2018Stelazine\u2019, sous forme de chlorhydrate, et 5 mg de \u2018Darbid\u2019, sous forme d\u2019iodure.Chaque comprimé \u2018Stelabid\u2019 Forte renferme 2 mg de \u2018Stelazine, sous forme de chlorhydrate, et 7,5 mg de \u2018Darbid\u2019, sous forme d\u2019iodure, Indications \u2014 Traitement d\u2019une vaste gamme de troubles gastro-intestinaux, y compris ulcère gastro-duodénal, hyperchlorhydrie, gastrite et duodénite, pylo- risme, spasmes gastro-intestinaux, dystonie biliaire, cholélithiase chronique, entéro-colite muco-membraneuse, diarrhée fonctionnelle et constipation spasmodique.Contre-indications \u2014 Etats comateux, glaucome, cardiospasme, obstruction pylorique d\u2019origine organique, hypertrophie de la prostate et obstruction du col de la vessie.Effets secondaires \u2014 Les effets secondaires possibles dus à l'action anticholi- nergique sont la constipation, la xéros- tomie, les troubles visuels et la dysurie.Etant donné la faible dose du composant \u2018Stelazine\u2019, les symptômes myoneuraux (extrapyramidaux) ne sont pas à craindre mais ils peuvent se manifester chez des patients sensibles aux composés phénothiaziniques, Précautions à prendre \u2014 Doit être administré avec précaution aux cardiaques et aux femmes enceintes, surtout durant le premier trimestre.En raison de sa puissante action antiémétique, \u2018Stelabid\u2019 peut masquer des signes de doses de médications toxiques trop fortes ou obscurcir le diagnostic d'affections comme l\u2019obstruction intestinale ou la tumeur du cerveau.Posologie \u2014 Un comprimé \u2018Stelabid\u2019 toutes les 12 heures.Bien que l\u2019emploi des comprimés No 2 soit recommandé pour la majorité des malades, on pourrait préférer les comprimés No 1 lorsque le trouble psychique est minime.\u2018Stelabid\u2019 Forte est spécialement indiqué dans les cas où l\u2019on désire un effet antispasmodique et antisécrétoire plus puissant.Présentation \u2014 Comprimés (No 1 et No 2) en flacons de 100 et de 500; (Forte) en flacons de 100.Renseignements complets sur demande, * SI4 SMITH KLINE & FRENCH &F MONTREAL 379, QUEBEC * Marque déposée au Canada NORMES NATIONALES RELATIVES À LA QUALITÉ DE L\u2019EAU POTABLE Des critères, couçus pour venir en aide aux autorités provinelales et municipales et assurer une meilleure protection des approvisionnements en eau potable ont été rendus publics par l'honorable John Munro, ministre de la Santé nationale et du Bien- être social.Ces critères sont le résultat du travail du Comité conjoint pour les normes de l'eau potable, organisme formé par le Comité consultatif sur le génie sanitaire et par l'Association canadienne d'hygiène publique.Les normes disponibles en vertu de nos connaissances actuelles ont été réunies dans un document publié par le Ministère de la santé nationale et du bien-être social, intitulé: Normes et objectifs de l\u2019eau potable au Canada.« En recommandant ces normes à la communauté dans son ensemble », déclarait monsieur Munro, «et en ajoutant des échelles graduées et des explications détaillées, nous espérons que les autorités compétentes seront capables de les appliquer avec intelligence, jugement et discrétion ».« L'évolution constante de la technologie, les progrès de la science médicale et une meilleure connaissance de l'influence de l\u2019environnement de l'homme », terminait le ministre, « nécessiteront des révisions périodiques de ces normes et objectifs En conséquence, «e document sera révisé et mis à jour chaque fois que les circonstances l'exigeront ».Nous espérons que les gouvernements provinciaux et municipaux utiliseront largement ces critères pour établir leurs propres normes de qualité de l'eau potable.protégeant ainsi la santé de tous les Canadiens.C'ette formule est la première qui ait été spécifiquement mise au point pour répondre aux conditions canadiennes en établissant des normes de qualité en ce qui a trait à l'eau potable. 30 Laval Mdédicul Vol.41- Fév, 1970 DURGENCE Æ et D'ENTRETIEN CRISES ANGINEUSES DOULEURS ARTÉRITIQUES ANGIO-SPASMES ARTERIO-SCLEROSE INSUFFISANCES VASCULAIRES ACROCYANOSE-CEPHALEE COMPOSITION: N.P.S.-10: \u2014 Chaque comprimé contient: Acide nicotinique 10mg Papavérine 10 mg N.P.S.-50: \u2014 Chague comprimé contient: Acide nicotiniquè 50 mg Papavérine 50 mg N.P.S.INJECTABLE: \u2014 Chaque ampoule de 3 cc S.C.ou |.M.contient: Acide nicotinique 45 mg Papavérine 45 mg POSOLOGIE: N.P.S.-10: 1 à 3 comprimés 2 ou 3 fois par jour aux repas.N.P.S.-50: V2 à 1 comprimé 3 ou 4 fois par jour aux repas.N.P.S.AMPOULES: Y> à 1 ampoule S.C.ou I.M.que l\u2019on peut répéter selon l\u2019avis du médecin.Prévenir le malade que la réaction vaso-dilatatoire ui s\u2018extériorise parfois par une rougeur cutanée visible au niveau de la tête et du cou ne doit pas être interprétée comme une manifestation d'intolérance.DOCUMENTATION ET ÉCHANTILLONS SUR DEMANDE | WELCKER & CIE LIMITÉE, 1775 boul.Edouard Laurin, MONTREAL 9, Qué.PLUS DE CENT ANS AU SERVICE DE LA MÉDECINE J.-E.LIVERNOIS, Limitée PHARMACIENS EN GROS Produits chimiques et pharmaceutiques Instruments et accessoires de chirurgie \u2014 Produits biologiques Articles de photographie \u2014 Ciné-caméras 1200, rue Saint-Jean, Québec Téléphone : 522-5214 AE ron Laval Médical Vol, 41 - Fév.1970 Mister Donald Ross: Mister Chairman, I would like to ask your indulgence because I am strictly a surgeon and not an expert on infection, bacteriology or immunosuppres- sion.All I can do is try and report as objectively as 1 can what was discussed at this morning\u2019s meeting.I think there was general agreement among all transplanters that we should get rid of immuno- suppressives if we can, or keep them to a minimum, but that they are here to stay for some time in the future.It is clear also that all the immunosuppressives contribute to the general problem of infection in one way or another.Infection of course can be of à specific nature, the one we are usually confronted with in surgery is due to pathogenic organisms of gram positive and particularly of gram negative type.These we can do something about.This is what Doctor Zerbini spoke about, and he emphasized the importance of prevention of infection in cardiac transplantation.He spoke about the need to minimize surgical trauma, and one of the points that was brought up yesterday in connexion with this was the avoidance of groin incisions.In other words one should limit skin incisions as much as possible, There was a vogue for cannulating the venea cavea from the groin in the past.This is a bad region for infection and it has been shown in transplantation of the heart to be somethig to avoid.Discussing sources of infection which were not normally considered, Doctor Zerbini warned us about intravenous fluids even if kept in a refrigerator, and also emphasized the dangers of indwelling urinary catheters and tracheostomy tubes.He spoke about the need to clean up foci of infection particularly in skin, and to exclude from the operating environment all infected personnel, whether they had overt sepsis or a history of infection in the last days or weeks before the transplant.He discussed the question of antibiotie cover in the postoperative period?There was general agreement among all the people in the room that antibioties should be used, although I thought I (17) PROCEEDINGS OF THE SECOND GENERAL SESSION 311 heard Doctor Dubost yesterday say that he had never used antibiotics in any of his transplants.The generally recommended antibiotic was ceph- aloridine, and Doctor Zerbini suggested its use for four days postoperatively.He also mentioned the need to give it to the donor if possible.That is perhaps a point that most people do not remember in the heat of the moment.As an alternative antibiotic regime, he mentioned the possibility of using gentamycin and cloxacillin, All speakers agreed that they used antibiotic cover, and I think Doctor Cooley suggested that he would use it for a longer period of time than four days.Our own policy has also been to use it for three to four days only.The other infective organisms that have come into prominence in relation to immunosuppression in transplantation are the so-called opportunist organisms, which include all the viruses, the eyto- megalic virus, the pneumocystis carinii and the fungi.Doctor Fontaine spoke to us about those and gave a rather gloomy prognosis in that we are unable, at present, to control the viruses very adequately.The non specific gammaglobulin fractions which are available are not very helpful, but he raised some hope for the future by suggesting more specific preparations.He discussed the experience of the Montreal group and pointed out that four of their nine patients had had important viral infections, one of them a Herpes Zoster infection, which he showed pictures of, and which had become secondarily infected and certainly contributed to the death of the patient.He warned us also about the risk of serum hepatitis from the use of blood during the by-pass and postoperatively.I imagine that would please Doctor Cooley who has long ago proposed a non-blood prime.He also again emphasized the need to avoid all infected personnel, particularly those who have had recent viral infection.He mentioned that immunoglobulins were of doubtful value as prophylaxis against serum hepatitis.He did however show that there was a diminished risk among general cases, not necessarily transplant cases, who had had immunoglobulin therapy, the risk being reduced from 4 per cent to 1 per cent.So there may be a case for using immunoglobulins 312 COMPTE RENDU DE LA DEUXIÈME RÉUNION PLÉNIÈRE as a prophylactic measure, although we certainly need to have more specific types of globulins.Doctor Kaplan spoke about the problems associated with the use of cortisone and again there was general agreement that cortisone is probably the most useful immunosuppressive we have, although it is also felt that its mode of action is not entirely clear.It certainly contributes to infection.He did point out that it was the second killer, second only to rejection as a cause of death in transplanted patients.He also listed the long list of complications which most people recognize in relation to the use of cortisone including gastrointestinal hemorrhage, osteoporosis, particularly of the hip and of the vertebral bodies, and so on.Fluid retention in relation to heavy immuno- suppression with cortisone has been a problem with our patients, and as Doctor Marius Barnard has mentioned it is also a problem with the Cape Town patients, Other effects of immunosuppression with cortisone include diabetes, hypertension, euphoria and the depression which comes when the dose is reduced and this can present a serious management problem.Doctor Kaplan suggested that withdrawal of immunosuppression with cortisone could be a cause of so-called transplant lung and pseudo- rheumatism.but I do not think there was general agreement on this.Doctor Pierce spoke at length and with considerable expertise on the toxicity of Imuran, relating his experience mainly to his knowledge of the use of Imuran in renal transplantation.He pointed out that Imuran is broken down to 6-Mercaptopurine and that the toxic manifestations may in fact be related to this drug.Imuran, of course, contributes like the other drugs to infective problems, particularly viral infection.He also discussed its toxicity in relation to the liver and here again there is no general agreement, some believing that there is a direct toxic effect of Imuran on the liver, others believing that it is a viral hepatitis facilitated by the use of Imuran.He believed that there was a 20 per cent incidence of liver problems in cases receiving Imuran suppression.He spoke about its effect on the bone marrow, the gastro-intestinal Laval Médical Vol.41 - Fév, 1970 tract and the incidence of tumors.He did point out that in relation to the bone marrow, the inei- dence of leucopenia was higher in patients without splenectomy although I do not think this is likely to have much effect on the heart transplantation program.In relation to gastro-intestinal toxicity, he had noted extensive ulceration of the mouth, nose and throat even extending down into the ceso- phagus with long standing Imuran therapy.He brought up the important question of malignancy in relation to Imuran.This has been discussed in relation to ALG, but he pointed out that Imuran could also promote the incidence of tumors in a number of ways: it could promote the transplantation of cancer from a donor, it could promote its growth or it could promote the recurrence of a tumor, for instance in cases which had been operated on for hepatoma or Wilms\u2019 tumor.This of course would relate more to liver and kidney transplantation, He also emphasized that it could induce tumors, for instance lymphoma tumors, even in patients not reveiving ALG.He also said that there were sporadically mentioned cases of carcinoma developing in patients on Imuran.And so there seems to be littie disagreement that Imuran is a definite source of tumor formation.Ile mentioned something which I believe is not generally recognized, that Imuran has potential effects on the fetus and that perhaps it should not be used in pregnant patients, or conversely, patients who had received a transplant and were on Imuran therapy should perhaps be dissuaded from becoming pregnant.However, he showed a picture of a young woman with a baby in her arms having successfully completed her pregnancy during therapy with Imuran without any ill effects on the baby.In the general discussion, there was a question about how long people should be kept in sterile conditions following a transplant.According to Doctor Barnard\u2019s group they should be kept in sterile conditions until they leave hospital and I think we would agree with this.We believe that one of the most dangerous places for a patient to be is inside a general hospital in relation to infection.There was talk on the recommended doses Jute Yi] ! (ly Monondonedoc , ete a oan édirai Laval Médical 31 4, Vol.41-Fév.1970 | mo 02 2 2 ni | 0 Co _ i \u2014 Ligh _ _ _ lito - - LS == \u2014 sut \u2014 5 - , \u201cART og ont.I Je se y fr opt Lo ° 7 .ui toute la journée.toute la nuit À rt ) ; 5 .\\ soulagement de la sinusite, JE | qe i * e ju de la rhinite, du coryza jt ! ; 3 + i /et du rhume des foins\u2014 y op pis avec une absence remarquable qi 7 ° .or de réactions secondaires pp ere wa FORMULE : POSOLOGIE : 3 wll Chaque tabule renferme : Adultes: 1 tabule deux fois par jour.il Tannate de Phényléphrine .25,0 ma.Enfants : De 12 ans et plus, 1 tabule Tannate de Prophenpyridamine.37.5 mg.par jour.De 6 à 11 ans \u2014 14 tabule deux | ou Tannate de Mépyramine.37.5 mg.fois par jour.ag La dose peut être augmentée ou diminuée, gl 1 INDICATIONS : selon l\u2019avis du médecin.pif | Sinusite, rhinite, coryza, rhume des foins, Seat api nas | et une variété d\u2019affections allergiques ou SSENTATION ald associées.Flacons de 30 et 500 tabules.Jp ] w AVANTAGES I il + Procure 10 à 12 heures de soulagement avec une seule dose orale.pd » Dégage les voies respiratoires Soulage les maux de têtes sinusaux.oh | * Enraye le larmoiement et le picotement des yeux et du nez.rh Arrête l'écoulement nasal.4 FRACAU liôis Doit être employé sur le conseil du médecin seulement.fl qui Echantillon envoyé aux médecins sur demande.pe ll ae Préparé par NEISLER LABORATORIES, INC., Decatur, lllinois, U.S.A.kf al! Représentants exclusifs au Canada a Herdt :Charton Inc.pl Ç Fe 2245 RUE VIAU + MONTREAL, P.Q.pI J ei *Marque déposée au Canada (18) Luval Médical Vol.41- Fév.1970 Pourquoi il est logique de prescrire du Fero-Grad-500* dans le traitement de l\u2019anémie ferriprive.Si, d'après vous, le traitement oral par excellence de l'anémie ferriprive consiste en 100 mg de fer métal (Fe) sous forme de sulfate ferreux pris à jeun \u2014 alors un comprimé par jour de Fero-Grad-500* (105 mg de fer métal) répond à cette définition.Le grand avantage de notre Fero-Grad-500* provient de ce que le sulfate ferreux n'est libéré qu'en quantité minime au niveau de l'estomac, diminuant de beaucoup la possibilité d'une irritation gastrique.Presque tout le fer thérapeutique se dégage là où il est le mieux absorbé \u2014 dans la partie supérieure de l'intestin grêle.Et l\u2019action anti-oxydante d'une forte dose d'acide MEMBRE ! ACER / a50769F ascorbique (500 mg) contribue à une absorption maximale.Prescrire le Fero-Grad-500° c'est réduire sensiblement l'intolérance gastrique \u2014 facteur qui restreint souvent le succès d'une thérapie ferrugineuse orale \u2014 et accroître l'assimilation du fer.Ibéret*-500 Aussi: Ibéret\u2018-500 (fer à dégagement différé avec vitamines du complexe B et vitamine C) pour le traitement de l'anémie ferriprive et de l'anémie nutritionnelle.Précaution: Conserver les Fero-Grad-500 hors de l'atteinte des enfants afin de prévenir l'intoxication accidentelle par le fer.Documentation médicale envoyée sur demande.MARQUE DÉPOSÉE 3 LABORATOIRES ABBOTT, LIMITÉE 190 fabrets Ko 2238 Fretabs\" 3 LOT RETIRE ASCORBIC ACID AND DELAYED RELEASE IRON, ABBOTT \u201cdie 5], ~~ Laval Médical Vol.41- Fév.1970 of steroids in heart transplantation patients and Doctor Kaplan advocates starting on a dose of 120 mg per day whereas Doctor Barnard mentioned their massive initial dosage of about 500 mg a day.That, mister Chairman, was the main burden of the message.I did not hear any discussion, although 1 would have liked to, on tissue typing and whether improved tissue typing methods and better matches could enable us to reduce our immunosuppression dosage, but perhaps this will come out in the general discussion.Thank you.Doctor Cooley: It is interesting that of all the viruses that might affect the recipient, the Herpes virus is the most difficult to control once it starts.Also remarkable to me is the low incidence of hemologous serum jaundice in these patients and one wonders if the Prednisone is not masking the presence of hepatitis or whether it is just the fact that some of the patients do not live long enough to go through the incubation period for this complication to appear.I would now like to ask Doctor Lillehei if he would comment on their series in New York since he was not here yesterday for the report on the world experience.I would like to hear impressions of the importance of histocompatibility and immuno- suppressive therapy.Doctor Lilleher: We have done six cardiac transplants in the period since May 1st 1968.One aspect that, I think, is unique about our series is that in the group of six donors, there were 29 organs that were transplanted along with the heart at the same time.This is a point we think of some significance for the future because of the obviously limited supply of donors.The surgical technique utilized in the first cardiac transplant involved the use of coronary perfusion.That heart was the only one that did not take over and support the circulation postoperatively.I hasten to add, however, that this donor was in very (19) PROCEEDINGS OF THE SECOND GENERAL SESSION 313 poor condition at the time because I was attending a meeting in California when he was admitted and 1 had, of necessity, to take a devious route back home so that the donor\u2019s cardiovascular status was preserved inordinately long and he had several arrests before the heart could be harvested.In the next five, we used the technique of moderate hypothermia in the donor and recipient (30°C) with non-coronary perfusion.The hearts were placed in Ringer\u2019s lactate at 6°C immediately after removal from the donor and for transport to the recipient\u2019s operating room.All of these hearts took over well with excellent blood pressure and no instances of heart block after implantation.There were two deaths in the second week, one from infection in a patient who had a pre-existing purulent empyema which had been undiagnosed prior to the transplant procedure.He was thought to have a pleural effusion and had not been tapped because he had gone into shock with the previous tap some months earlier while hospitalized on the cardiology service.Immediately after the transplantation operation, in the LOU.we did tap it and got 1400 ce of pus with a positive culture of mixed gram negative organisms and thus treated this patient rather conservatively with immuno- suppression, but by the eighth day, he had both septicemia and rejection.The other patient who succumbed early, at nine days, was a patient with very severe pulmonary hypertension associated with terminal failure due to a chronic myopathy.She also had had a ventricular septal defect closed twelve years earlier.Two other patients died of rejection, one after 115 days and the other after 63 days.I think knowing what we know now, we simply did not observe these patients closely enough.They had been discharged from the hospital and were seemingly doing very well.Both had had a very benign postoperative course and we were lulled into a false sense of security.The patient succumbing at 63 days was one in whom the donor heart was removed in another hospital three blocks away, placed in Ringer\u2019s lactate at 6°C, and carried by a surgical fellow to the recipient\u2019s operating room where it was sutured in without coronary perfusion. 314 The total ischemia time was 35 minutes for removal and transportation and 53 minutes for suturing.The heart resumed beating spontaneously and the patient made a completely uneventful recovery.He was discharged from the hospital 52 days post- operatively, There is then, currently one patient alive at approximately one month postoperatively.I might comment on the tissue matching which was done prospectively in all by our laboratory.The one patient who is alive now was a D match, he has had one severe episode of rejection just recently, approximately one month postoperatively, which is currently being treated.There were in the six, 3 B matches, 2 C matches and 1 D match.Of the three liver transplants that were done from these donors, two of them are still alive, at approximately five months and three months.I think that summarizes our experience.Doctor Cooley: Thank you Doctor Lillehei.Doctor Bahnson, would you like to make a remark about your case?Doctor Bahnson: I am sure that the one case we had would not allow one to make or draw any sort of conclusion.He has been treated like all the rest and I think operated upon like most of the rest.He has received ALG and I suppose the only difference is that ALG was made from a horse in our back yard that had previously dumped Doctor Cooley when he came to visit us.Although we often have heard of instances in which the recipient has rejected the transplant, I think this is the only instance in which a transplanter had been rejected.Thank you.Doctor Cooley: Would anyone like to make a comment about infection or some other point that should be raised at this time?Doctor Botha?Doctor Botha: Doctor Cooley, I did not attend the session on anti-lymphocyte globulin this morning.I had to COMPTE RENDU DE LA DEUXIÈME RÉUNION PLÉNIÈRE Laval Médical Vol, 41- Fév.1970 take part in another session at the same time.Therefore, I would like to make a comment now, particularly since T am not altogether happy about your categorie statement, when introducing this general discussion, that complications from ALG such as might affect the kidneys for example, have not vet been observed.We should consider a very recent observation made in one of our patients which may be relevant and important.A diagram which I showed at the International Symposium on pharmacological treatment in organ and tissue transplantation, held in Milan during February demonstrated a rather remarkable drop in complement level at the time when ALG was given intravenously to a heart transplant recipient.As some of you know, this patient improved rather dramatically at the time when he received ALG.Doctor Turk from London, who had previously commented on the effect of ALG on complement levels, suggested in Milan that our patient\u2019s rapid clinical improvement was possibly due to the fact that ALG was a binding complement, either through its antibody action against the lymphocyte antigens, or perhaps by some other means; and this resulted in relief for the graft itself in the sense that complement could not longer damage the graft by participation in a rejection process.Another observation emerges from this diagram; we note that really low levels of complement were first measured at the time when this patient developed demonstrable antibodies to horse globulin.We should consider the possibility that antigen- antibody reactions between horse serum and human serum, in either of two possible directions, may bind complement.This is relevant to the serological and clinical course of another heart recipient.A remarkable event in the early post-transplant course of our fifth patient was the almost total disappearance of complement approximately seven days after the heart transplant.This observation caused me considerable concern.In this instance, the precipitous fall of eomplement level did not prevent the patient, who had rather an unsatisfae- tory leucocyte antigen match in my opinion, from LT édien! r.There.| Als ado | © {fi ) AL à Dave Ate atients at 14 où À during p dnp ff VE à pial ther A sos) Joel ; ail je fa pra fige il at eo hr par era y lt jus pol\" pt juil if ii a al 1, il © Laval Médical Vol.41- Fév.1970 SUPPOSITO!RES SHONCHO-GRIPPOL Adultes \u2014 enfants \u2014 bébés INDICATIONS : Médication de choix pour le traitement des états fébriles, de la grippe, des refroidissements saisonniers, des laryngites, des trachéites, des bronchites, du status postopératoire, des pneumonies et des broncho-pneumonies, en tant qu'adjuvant des traitements par les antibiotiques et les bactériostatiques.FORMULE : Adultes enfants bébés Acétylsalicylate de Ca.0.40 gm 0.200 gm 0.050 gm Dihydroxypropylthéophylline .0.15 gm 0.100 gm 0.015 gm Sulfate de Quinine.0.05 gm 0.030 gm \u2014 Racine d\u2019aconit pulv.0.02 gm 0.005 gm 0.001 gm Gaiacol .2222 ol 0.05 gm 0.030 gm 0.002 gm Eucalyptol .0.05 gm 0.030 gm 0.020 gm Camphosulfonate de Na.0.05 gm 0.020 gm 0.010 gm Excipient spécial q.s.INDEX THÉRAPEUTIQUE : De par la synergie entre ses composants, le Bron- cho-Grippol est doué des propriétés les plus efficaces comme antipyrétique, comme antiseptique des voies respiratoires, comme eupnéisant et comme cardio- protecteur.Seuls distributeurs au Canada Mrowrdt «7 Mnarton Inc.2245, rue VIAU \u2014 MONTRÉAL, P.Q.Échantillon et documentation envoyés sur demande.(20) Le NOUVEAU SIROP pour la toux BRONCHO-GRIPPOL INDICATIONS ; Sirop béchique agréable au goût pour soulager les symptômes accompagnant les affections de l'appareil respiratoire supérieur tels que la bronchite, la laryngite, la pharyngite, le coryza, l'asthme, la rhinite allergique, l'influenza, la sinusite et le rhume des foins.Avantages : décongestionne la muqueuse nasale sans produire d\u2019excitation cérébrale; soulage les symptômes allergiques sans entraîner de somnolence; diminue le réflexe tussigène sans entraîner les effets secondaires de la codéine : constipation, accoutumance, etc.; favorise l\u2019expectoration soutenue en fluidifiant le mucus.FORMULE : Chaque cuillerée à thé (5cc) contient : Phényléphrine HCI.Diphénylpyraline HCI Dextrométhorphan HBr Citrate de Sodium Gaiacolate de Glycéryl.\u2026.33 Laval Médical Vol.41-Fév.1970 COMPOSITION: Capsules: 50, 25, 10 mg de chlorhydrate d'hydroxyzine.Sirop: 10 mg/5 ml de chlorhydrate d\u2019hydroxyzine.CONTRE-INDICATIONS: Aucune connue.EFFETS SECONDAIRES: Aucun effet secondaire sérieux rapporté.Une somnolence chez certains patients, généralement transitoire.Possibilité de sécheresse buccale à doses élevées.PRÉCAUTIONS: Peut potentialiser la mépéridine, les opiacés, les barbituriques et l'alcool: en tenir compte lorsque administré avec des dépresseurs du SNC.Bien qu\u2019on ait constaté une certaine amélioration chez certains épileptiques traités à l\u2018Atarax, on a observé dans quelques rares cas une augmentation de la propension aux crises ainsi qu'une activité motrice involontaire chez les patients hospitalisés qui avaient reçu de fortes doses de la médication.POSOLOGIE: Varie selon l\u2018intensité des troubles émotifs plutôt que le poids du patient.ADULTES: 25 mg t.i.d.à 100 mg q.i.d.ENFANTS: Moins de 6 ans: 30 à 50 mg par jour: plus de 6 ans: 50 à 100 mg par jour, en doses fractionnées.ATARAX EST AUSSI DISPONIBLE EN SOLUTION IM/IV.tBasé sur 2 milliards de doses prescrites et 500 mémoires publiés comportant 15,000 patients.RENSEIGNEMENTS COMPLETS FOURNIS SUR DEMANDE.MEMBRE peo Pfizer LA COMPAGNIE PFIZER LTEE, MONTRÉAL, QUÉBEC.: ACFP ages ATEN SSLIOUNE GBESA\u2014SHSOdPp ONDIENS bars Va: exh] ng flr sin d: dise belo fone al fron fm Laval Médical Vol.41- Fév.1970 exhibiting two early episodes of cardiac rejection in spite of enjoying what was probably the most energetic regime of prophylactic immunosuppres- sion employed to date.This patient received 20 ml of ALG intravenously daily, in addition to high doses of steroids and azathioprine.Another unusual feature of this case is that before the transplant operation (and therefore before ALG was administered) the patient had a weak antibody to horse globulin.This antibody titre rose from 1 in 2 after ALG was commenced, to a titre of 1 in 16 at the time when the complement level commenced falling precipitously.We were not initially aware of the presence of this antibody, since we were not able at any stage in this patient to demonstrate antibodies to horse protein with our regular test method, i.e.the latex fixation test.Retrospectively the antibody could be demonstrated readily with the passive haemagglutination method.Thirty days after ALG was commenced, the clinical picture of serum sickness emerged.Retrospective analysis then revealed that from about the tenth day onwards (1.e.approximately three days after the complement level had reached a very low peak), there is a slow rise in serum creatinine, and a more notable rise in the total protein excretion per 24 hours.This patient is now seriously ill with serum sickness.Finally, I want to mention just briefly that the batch of ALG given the latter patient contains a precipitating antibody to human serum, demonstrable by the Ouchterlony method.Therefore, in theory we are dealing here with at least two possibilities: the formation of antigen-antibody complexes either between horse antibody and human antigen, or between human antibody and horse antigen.Perhaps this is too early a stage to make any really valuable comment on the possible effect of ALG on the clinical course of this recipient.However, I think we should very certainly bear in mind that we may here be witnessing serious deterioration in kidney function as a direct result of ALG.Thank you.(21) PROCEEDINGS OF THE SECOND GENERAL SESSION 315 Doctor Cooley: Thank you, Doctor Botha.Are there any others who would like to comment before we adjourn?Doctor Barrett: I would like to draw attention to some work in another field which might have applicability in the assessment of the future of ALG.It has been known for some time that one can use a human fraction of factor 8 in the treatment of hemophilia.Some years ago Biggs and Bidwell developed sheep and pig factor 8, and they used it in a crude form in humans and in every instance it was found that the factor 8 in the patient was subsequently inactivated.In a few instances, there was frank anaphylaxis.One of the commercial firms developed this product further, purified it and the same results were obtained.I make these remarks to draw attention to the fact that perhaps this work has not been fully realized by people who are working on ALG.Doctor Cooley: Are there other comment?Doctor Aguirre from Chili.Doctor Aguirre: I think of interest to say something about discontinued periods of use of ALG.In one of our patients, we had problems because of a bleeding peptic ulcer and a subcutaneous abcess.Then we discontinued Prednisone and Imuran therapy.In this period of six weeks, we maintained our patient only with ALS from l\u2019Institut Pasteur de Lyon, Professor Carraz, and in this period we had no signs of rejection.Only in the few last days did we see ST and T alterations and these were transitory and improved by using ALG exclusively.Afterwards we saw a sensitization to the ALG and had to again use Imuran and Prednisone therapy.Doctor Cooley: Than you, Doctor Aguirre.Doctor Treager, would you like to make a remark? 316 Doctor Treager: Was this ALG used by the intravenous route or by the intramuseular route?Doctor Aguirre: Intravenously.Doctor Treager: I must say that in more than 70 patients using the same ALG that was used in Valparaiso, we had only one serum sickness and it was necessary in only one case to stop ALG.Maybe using the intravenous route, you may have more serum sickness and more anaphylactoid reactions of this type.Doctor Carraz: Au sujet de l\u2019observation du docteur Botha, je voudrais signaler ici ce que j'ai signalé ce matin sur les différentes méthodes de préparation des ALG.Certaines peuvent former des aggrégats moléculaires qui fixent le complément, et ces faits sont très connus en ce qui concerne les immunoglobulines humaines utilisées par voie intraveineuse.Ces immunoglobulines peuvent abaisser le taux de complément sérique de manière extrêmement importante.Cela a également été démontré chez le lapin.J\u2019ai présenté ce matin le problème que posent les aggrégats moléculaires suivant les différentes méthodes de préparation.Ces aggrégats peuvent amener une intolérance à l\u2019ALG qui n\u2019est pas due uniquement aux anticorps antiprotéiques mais à la forme moléculaire de l\u2019ALG présenté.COMPTE RENDU DE LA DEUXIEME REUNION PLENIERE Laval Médical Vol.41 -Fév.1970 Doctor Cooley: Doctor Brendel, would you like to make a remark?Doctor Brendel: I only want to say that in this batch of ALG about which Doctor Botha was talking, we had a certain amount of precipitating antibodies which were not absorbed sufficiently, due to a technical error.In those cases we had serum sickness with high doses of intravenous ALG.In 55 other patients with organ transplantation, we did not see yet any signs of serum sickness.In some other patients not with organ transplantation, we had anaphylactic reactions, but these were cases with auto-immune diseases, and we know that those patients have a special allergic hypersensitivity.In such cases we never will use ALG alone without high doses of steroids and Imuran.Of course, if you stop ALG treatment after several injections, you first have to look if you have antibodies against your ALG in the serum before you ean start ALG again.But if you do not find any antibodies, then you can use ALG from the same batch twice or three times as we and our group of surgeons have done several times.Doctor Conley: Thank you Doctor Brendel.We have not heard from our colleagues from the Soviet Union and I would like to invite Doctor Vishnevsky or one of his associates to make a remark if they would care to.No?Are there any other comments?Well then, we will adjourn./ / dic! dû jn ai] put À jf y Laval Médical 35 Vol.41- Fév.1970 CONSULTANTS PROFESSIONNELS (QUEBEC) INC.PLANIFICATION FINANCIÈRE ET ADMINISTRATIVE RÉORGANISATION D'ENTREPRISES COMMERCIALES ET INDUSTRIELLES MANDATAIRES POUR L\u2019OBTENTION D'AVIS LÉGAUX, FISCAUX ET COMPTABLES.2835, Chemin Gomin, Ste-Fov, 1\u2019.Q.Téléphone: 651-5074 LAXATIF DOUX (sans accoutumance) comprimés par jour ETHICA LIMITÉE 12250, Albert Hudon \u2014 MONTRÉAL 462, P.Q.Membre de l\u2019Association des Fabricants du Québec des Produits Pharmaceutiques (22) RE mw il i ; | i 36 Laval Médical Vol.41- Fév.1970 _\u201c ME 7 eon | H =, id i | 3) i be He de fi Py it I Mens a det 7 iy he Hi lus 1% 1p des rly Dy Ue ¢ 4 ly ly by rh lt | 4e Ur | 5 | mm re \u201cegy te ig de \" | i M4 ds, 2 Ca [st J Us) ny A 2 po 2 i Es Iv i # de ] \u2018ei Dy anilone\u201d Parions qu'il écrit D te comprimés de phénylindanedione BP dit \"anticoagulant oral le plus prescrit fey Documentation compléte sur demande \u201caly OO 1S PHARMACEUTIQUES DF QUALHT li EFwsst at Cla canine AU CANADA LA 1006 ha = \u2018y fh Wi | hy ly, Et \u201cy Vi Te % 50e Hele: ie Bis 13 \u2014 Vestibulométrie clinique, par G.F.GREINER, C.CONRAUX et H.Collard.Un livre 21 X 26 de 336 pages avec 79 figures et 43 planches.Editions Doin Deren et Cie, 8, Place de l\u2019Odéon, Paris (VI°), 1969.Il s\u2019agit là, croyons-nous, d\u2019un volume d\u2019un immense intérêt pratique qui était sûrement attendu de tous les otologistes versés en vestibulométrie eli- nique, Nous savons qu\u2019il a été rédigé par des auteurs de grande expérience et sommes assurés que ce volume est le fruit de longues années de recherches et d'expérience clinique.Cet ouvrage comporte cinq parties à peu près d\u2019égale valeur.Dans la première partie, les auteurs mentionnent une citation de Dolhman qui recommande, en vesti- bulométrie clinique, l\u2019uniformisation et la standardisation des méthodes d\u2019examens, tout en signalant que cette uniformisation est difficilement réalisable pour l'instant, à cause de la grande multiplicité des examens et de l\u2019interprétation qui n\u2019est pas encore sans recours.Dans un historique de grand intérêt, on passe en revue la naissance des diverses épreuves de vestibulométrie clinique, L'auteur attache ici beaucoup d\u2019importance aux commentaires sur les tests caloriques et mentionne surtout l\u2019intérêt de ne pas nous limiter aux seules épreuves froides.Il rejette l\u2019épreuve de Kobrak comme donnant une réaction trop vive qui entraîne, en plus de la stimulation vestibulaire, des réactions physiques et psychiques violentes chez le sujet.La première partie se termine par une revue des bases d\u2019anatomie de physiologie et d\u2019expérimentation concernant le vestibule.Dans la deuxième partie, les auteurs, passent en revue les différents tests d'investigation vestibulaire.On en donne a chaque reprise le principe de stimulation, l\u2019appareillage, la technique d\u2019application ainsi que l\u2019interprétation des résultats obtenus.Les épreuves rotatoires, linéaires et sinusoïdales ainsi que les épreuves caloriques sont toutes évaluées.Les auteurs décrivent également l\u2019épreuve de stimulation galvanique et le test de position.La technique en est revisée et on signale ici l\u2019avantage d\u2019une table inclinable pour la réalisation de l\u2019épreuve.Il est également mentionné qu'il n\u2019existe pas actuellement de corrélation entre le caractère sé- méiologique du nystagmus de position et la topographie ou l\u2019étiologie de l\u2019atteinte vestibulaire.(23) Revue des livres Finalement, l\u2019épreuve cervicale, le fauteuil ascen- tionnel, la contre-rotation oculaire, l\u2019épreuve du pendule et la recherche du nystagmus optocinétique sont passés en revue.Dans la troisième partie du volume, ils nous expliquent la technique d\u2019enregistrement et la conduite de l\u2019examen.La séméiologie vestibulaire est complètement passée en revue.Enfin, les deux dernières parties, soit la quatrième et la cinquième partie, sont d\u2019un grand intérêt pour le clinicien qui revoit de facon claire et concise les différents syndromes périphériques et centraux tels qu\u2019ils apparaissent en vestibulométrie.Nous avons grandement apprécié la lecture de cet ouvrage et nous le recommandons fortement à tous ceux qui s\u2019intéressent à la vestibulométrie.Cette synthèse mérite une mention honorable à toute l\u2019école de vestibulométrie de Strasbourg pour nous avoir présenté un volume d\u2019un aussi grand intérêt.Paul FUGÈRE, M.D., et Jacques DIONNE, M.D.Bases statistiques pour la recherche médicale et biologique, par F.GREMY, professeur à la Faculté de médecine, Centre de caleul et de statistique de la Faculté de médecine de Paris, et D.SALMON, chargée de recherches au C.N.R.S., Centre de caleul et de statistique de la Faculté de médecine de Paris.Un volume 10 X 6,5 de 412 pages avec de nombreux tableaux et figures.Dunod éditeur, 92, rue Bonaparte, 75 - Paris (VI°) 1969.Les auteurs initient d\u2019abord les lecteurs aux principes et aux méthodes qui sont à la base de la pratique statistique ; ils donnent de nombreux exemples pratiques, escomptant que le lecteur acquerra une connaissance suffisante pour lui permettre d\u2019adapter ses méthodes aux problèmes quotidiens avec lesquels il est confronté.La première partie de l'ouvrage expose la base des méthodes; la deuxième parle de leur emploi; chaque sujet traité dans la première partie réapparaît done dans la deuxième.Sans prétendre à un exposé complet des méthodes statistiques, les auteurs ont cependant insisté sur certains points d\u2019usage plus courant, dont la statistique descriptive, les lois de probabilité, les possibilités offertes en statistiques pour les ordinateurs ses ue me Le ae Fu a def 1 Sn 318 REVUE DES LIVRES Laval Médical et la procédure séquentielle de certains tests en dehors de l\u2019emploi d\u2019un ordinateur.La première partie, théorique, traite de statistique descriptive, de valeurs typiques d'une distr1- bution, des éléments du caleul des probabilités, des lois de probabilités théoriques, des problèmes d'estimation du test de x\u201c.des fréquences relatives observées, des moyennes observées de remarques sur les tests de la régression linéaire, de statistiques doubles tirées d'une population guassienne de tests non paramétriques de comparaison de plusieurs échantillons.Dans la deuxième partie, les auteurs disent comment utiliser les données pratiques; ils parlent d\u2019histogrammes, de diagrammes, de moyennes et variances, de tables, de nombres de tables de Laplace- Gauss de normalité d\u2019une distribution, des exercices de probabilité, des lois de probabilités discrètes, du test du x\u201c des fréquences et des moyennes observées de la régression et des tests non paramétriques ; toutes ces têtes de chapitre sont un langage compris des unités à la science des statistiques et permettront au lecteur de s\u2019v trouver facilement.J,-B.JOBIN, M.D.Physiopathologie et pathologie aéronautiques et cosmonautiques, par L.TABUSSE, médecin général et professeur agrégé du Corps de santé de l\u2019armée de l'air, et R.PANNIER, médecin commandant et professeur agrégé du Corps de santé de l\u2019armée de l\u2019air.Un volume 8,5 X 7 de 399 pages avec 69 figures.Éditions Doin Deren ct Cie, 8, Place de l\u2019Odéon, Paris (VI*°) 1969.Les docteurs Cabusse et Pannier sont des méde- «ins professeurs agrégés du Corps de santé de l\u2019armée de l\u2019air de France.Ce livre, le premier de son genre, est l'œuvre de cliniciens qui ont une expérience pratique dans le traitement des navigateurs.Il s'agit d\u2019une discipline nouvelle dans l\u2019ensemble de la science médicale.Les deux auteurs ont été successivement chefs du Service de médecine aéronautique à l'hôpital d\u2019ins- rruction des armées Dominique-Larry qui recoit tous les aviateurs militaires, tant pour traitement que pour exercices d'aptitude ; ils reçoivent également des aviateurs civils.Parallèlement à leurs observations cliniques, les auteurs ont fait des études d'exploration fonctionnelle des systèmes cardio- rasculaire et respiratoire.De nombreuses observations et statistiques ont permis de dégager une pathologie médicale de Vol.41- Fév.1970 l\u2019aviateur, spécifique et liée aux facteurs agressifs du vol, de la vitesse et de l\u2019altitude.Les auteurs ont mis au point les problèmes phy- siopathologiques posés par le vol en avion et rédigé la nosographie de la pathologie aéronautique.Tout individu s\u2019intéressant à l\u2019aviation aura intérêt à consulter ce livre, étant donné que 50 pour cent des accidents d\u2019avion sont fonction d'un facteur humain et que les aviateurs doivent pouvoir compter sur les services d'un médecin parfaitement informé.J.-B.JOBIN, M.D.Cahiers de biologie pratique, destinés aux laboratoires et à la préparation de l\u2019internat en pharmacie, cahier I, par M.DUMONTET, interne en pharmacie des hôpitaux de Paris, O.G.EKIND- JTAN, interne en pharmacie des hôpitaux de Paris, et E.NEUBERG, interne en pharmacie des hôpitaux de Paris.Un volume broché 21 X 27 de 194 pages avee 4 figures et 10 tableaux: 34 f.Masson et Compagmie, Paris (VI°).Devant d\u2019incessants progrès, le biologiste, dans son laboratoire d\u2019analyses médicales, se trouve confronté à trois grands problèmes : \u2014 avoir une connaissance approfondie des bases fondamentales de la biologie ; \u2014 critiquer puis choisir les techniques de dosage ; \u2014 replacer les données du laboratoire dans leur contexte clinique.De même, le clinicien doit savoir ce qu\u2019il peut attendre de la biologie et quelles sont les limites des résultats qui lui sont rendus.C\u2019est dans cet esprit que les auteurs de ces cahiers se sont attachés à présenter de manière claire, schématique et illustrée, d\u2019une part les bases fondamentales de la*biologie, d\u2019autre part les méthodes de dosage employées.Une courte bibliographie sélectionne, pour chaque question traitée, les ouvrages approfondis, les articles spécialisés, les techniques détaillées de dosage.L\u2019ouvrage s'adresse donc non seulement aux étudiants puisqu\u2019il traite la totalité du nouveau programme de biologie de l\u2019internat en pharmacie et, de manière partielle, les programmes des Certificats d\u2019études supérieures et spéciales de biologie des Facultés de médecine et de pharmacie, mais encore à tout ceux, biologistes et cliniciens, qui désirent être tenus au courant de manière claire des progrès de la biologie.Lan, Ya: bn Li ugh He Re Heyy Pug ky fy Tui qi Pa Tél I= ciel will Hi ai oh lr iN ui mi i ells we 2 our Laval Médical Vol, 41- Fév.1970 SOMMAIRE Hématologie.Métabolisme du fer.\u2014 Dosage dans le sérum du fer et de la sidérophiline.Porphyrines.Hémoglobines.\u2014 Séparation, identification, dosage.\u2014 Identification et dosage de la méthémoglobine et de la carboxyhémoglobine.\u2014 Recherche de l\u2019hémoglobine dans les urines.\u2014 Recherche du sang dans les matières fécales.Rôle du laboratoire dans le diagnostic et le traitement de l\u2019intoxication oxycarbonnée, Pigments biliaires et dérivés.Rôle du laboratoire en cas d\u2019ictères.Recherche et dosage des pigments biliaires et de leurs dérivés.Examen hématologique standard.\u2014 Hémoglobinémie.\u2014 Numération-formule sanguine.\u2014 Numération des plaquettes.Rôle du laboratoire dans le diagnostic et le traitement des principaux types d\u2019anémies.Cytogenèse des éléments figurés du sang circulant.Moelle osseuse.\u2014 Myélogramme normal et pathologique.Détermination des groupes À B O et du facteur rhésus.Hémostase et coagulation.Bactériologie.Virologie.Immunologie.Liquide céphalo-rachidien.\u2014 Examen chimique et cytobactériologique.Examen cytobactériologique des urines.Hémoculture.Recherche du bacille diphtérique dans un prélèvement rhino-pharyngé.Bacilles tuberculeux.Recherche d\u2019un bacille tuberculeux.Micrococcaceæ.Dosage des antistreptolysines.Entérobactériacées.\u2014 Genres Escherichia, Salmonella.Méthodes générales d\u2019études des virus.Diagnostic sérologique de la syphilis.Parasitologie.Examen parasitologique des selles.Examen cytologique du sang au cours du paludisme.Traité de radiodiagnostic, tome X., os, pathologie générale.par Raymond TRIAL, professeur agrégé du Val-de-Grâce.chef de service au Centre médieo-chirurgieal Foeh, et Ÿ.M.ALLAIN, H.BER- ToJo, R.CALLE, G.CHAVANNE, R.P.DELAHAYE, A.Durm, J.M.Ducuoux, H.Fournier, P.La- CROIX, G.LEpoux-LEBARD, À.MAZABRAUD, R.PEREZ, À.VINCENT et À.WEBER.Un volume cartonné toile 19.5 X 26 de 634 pages avec 993 figures et 9 tableaux: 300 f.Masson «t Compagnie, Paris.REVUE DES LIVRES 319 Le Traité de radiodiagnostic doit comprendre environ 20 tomes.Il se situe entre les Encyelopédies \u2014 battues en brèche par le progrès incessant des connaissances \u2014 et les monographies spécialisées \u2014 approfondies mais limitées, Ce sera le grand traité de la spécialité.Un livre de radiodiagnostic se ramène à un commentaire d\u2019images radiographiques.L\u2019impression d\u2019un tel ouvrage entraîne donc le transfert des détails du film radiographique original sur un papier à surface très régulière, et fait appel à l'intervention d\u2019une trame qui décompose les demi-teintes en points.Malgré les progrès de l'imprimerie, le transfert des détails implique une certaine perte d\u2019information au cours des opérations se succédant entre la copie, la photogravure et l\u2019impression.Récupérer ces informations perdues constitue le souci principal des Éditeur et de la Direction du Traité.C\u2019est dire que la qualité du film original conditionne celle de l'illustration du livre, seuls les détails visibles sur la page entrant en ligne de compte pour le lecteur.Les auteurs ont essayé de répondre aussi bien aux préoccupations des anciens, soucieux à juste titre d'un radiodiagnostie précoce, évolutif et différentiel, épuré des éponymies et synonymies, qu\u2019aux sollicitations des jeunes radiologistes, désireux d'acquérir un radiodiagnostie libéré de certaines formules des premières décennies de la radiologie et largement ouvert sur des sources inédites.Ils ont voulu tenir compte des tendances et des nouvelles acquisitions dans lesquelles la radiologie d\u2019au- jourd\u2019hui doit s'intégrer : \u2014 L\u2019exploration radiographique, en effet, ne constitue plus la seule exploration morphologique sur l\u2019homme vivant ; l\u2019endoscopie, les radio-isotopes, les ultra-sons, la thermographie, arrivent avec leurs propres images ; \u2014 L'image radiographique, toujours plus fine, n\u2019acquiert sa signification diagnostique et étiologique que dans un contexte clinique, biochimique, anatomo-patho- logique, génétique et écologique ; \u2014 Grâce enfin à sa définition accrue et à sa précision topographique, l\u2019image radiologique, multipliée dans ses formes d\u2019expression, du film isolé à la bande de radio- cinéma, de l'écran de télévision au magnétoscope, acquiert un contexte fonctionnel ; le radiologiste doit bien connaître les fonctions d\u2019élimination du rein qu\u2019il rend visible, comme il ne peut ignorer l\u2019endroit où les messages visuels, partis d'un seul œil, se séparent pour parcourir les deux hémisphères, à travers des voies anatomiques explorables par les rayons-X.Car si le signe radiographique provient d\u2019une altération morphologique, le symptôme clinique traduit une fonction perturbée ; les deux ne sont plus dissociables.Les auteurs ont choisi les images évocatrices, si non spécifiques, et les données sur lesquelles un accord assez général devient possible.Des références bibliographiques peu nombreuses, mais récentes et fondamentales, se trouvent en fin des principaux chapitres.Le Traité de radiodiagnostic trouvera sa place dans les Bibliothèques universitaires et dans celles des Services de radiologie. 320 Radiologistes praticiens ou hospitaliers, jeunes médecins des C.E.S.de radiologie, cheïs de clinique et candidats aux grandes responsabilités, enseignants, médecins, chirurgiens et spécialistes, trouveront dans les différents tomes, un consultant, un interlocuteur toujours disponible, pour les aider dans les situations embarrassantes et répondre aux questions difficiles.Les tomes X, XI et XII consacrés à l\u2019os, aux articulations et aux parties molles des extrémités se proposent de faire le point dans ce domaine, qui a commencé en 1895 avec la radiographie de la main de Mme Roentgen.Le tome X traite de l\u2019os et de sa pathologie générale radiologique : la pathologie générale radiologique constitue un concept nouveau dû à l\u2019interférence du radiodiagnostic avec des discipilnes aussi récentes que la génétique, la biochimie, l\u2019endocrinologie et le métabolisme général de l\u2019organisme.La solitude du radiologiste, dans son cabinet particulier, dans un service central et méme dans un service de radiologie de haute technicité, mène à un radiodiagnostic symptomatique ne s\u2019intégrant que partiellement dans un diagnostic final centré sur l\u2019étiologie et les mécanismes lésionnels.Textes, images radiographiques, pièces osseuses, schémas et tableaux différentiels s\u2019éclairent mutuellement et REVUE DES LIVRES Laval Médical Vol.41- Fév.1970 facilitent la prise de connaissance visuelle du radiodiagnostic.Après un rappel admirablement illustré de microradio- graphie et d\u2019histopathologie des lésions osseuses, sans lesquelles l\u2019image radiographique surgit comme l\u2019ombre dans la caverne de Platon et après un chapitre de sémiologie générale, les grandes divisions du diagnostic osseux sont passées en revue : Les dysplasies osseuses pour lesquelles un exposé concis, s\u2019oriente vers une classification tenant compte de la génétique, de la biochimie, de l\u2019endocrinologie et des manifestations viscérales, du système nerveux central ou de la peau ; Les lésions traumatiques avec, entre autres, des chapitres originaux comme l\u2019erreur du diagnostic de fracture et ses incidences médico-légales ou les fractures de fatigue ; Les tumeurs osseuses avec une classification nouvelle inspirée d\u2019Ackerman, une iconographie riche en détails et des images obtenues avant et après radiothérapie.Les autres osthéopathies (carentielles, hémopathies, maladie de Paget) complètent \u2014 dans le même esprit \u2014 ce tome X qui s\u2019adresse à tous les médecins \u2014 radiologistes ou non \u2014 intéressés par la vie normale et pathologique de l\u2019os. Lédies Fé 1% radiof: ierorad § es, er ¢ l'ont de sémi- ie ques posé pte de je et 2 TE es i Je rad cures: D0 a di aple pote sp aides paul NOMINATIONS DE PROFESSEURS TITULAIRES ET DE PROFESSEURS AGREGES À la suite d\u2019une séance régulière du Conseil universitaire, Monseigneur Louis-Albert Vachon, reec- teur de l\u2019université Laval, a annoncé la nomination de plusieurs professeurs de la Faculté de médecine au titre de professeurs titulaires et de professeurs agrégés : Le docteur Jean-Paul Dechène, chef du Service d\u2019anesthésie à l\u2019hôpital Laval, a été nommé professeur titulaire d\u2019anesthésie ; Le docteur Jean Delâge, directeur du Centre médico-social pour enfants et professeur auxiliaire à la Faculté des sciences sociales, a été nommé professeur titulaire de psychiatrie ; Le docteur François Gagné, chef du Service d\u2019anatomie pathologique de l'hôpital de l\u2019Enfant- Jésus, à été nommé professeur titulaire de pathologie; Le docteur Paul-J.Lupien, professeur au département de biochimie, a été nommé professeur titulaire de biochimie ; Le docteur R.Venkatachala Murthy, professeur au département de biochimie, a été nommé professeur titulaire de biochimie ; Le docteur Pierre Potvin, professeur au département de physiologie, a été nommé professeur titulaire de physiologie ; Le docteur Mircea Stériade, professeur au département de physiologie, a été nommé professeur titulaire de physiologie ; Le docteur Claude Catellier, membre du Service de médecine de l\u2019hôpital de l\u2019Enfant-Jésus, a été nommé professeur agrégé au département de médecine ; Le docteur Jacques Gaudreau, membre du Service de médecine du Centre hospitalier de l\u2019université Laval, a été nommé professeur agrégé au département de médecine ; Le docteur Harry Grantham, membre du Service de psychiatrie de l\u2019Hôtel-Dieu de Québec, a été nommé professeur agrégé au département de psychiatrie ; Le docteur Raoul Roberge, membre du Service de médecine de l\u2019hôpital du Saint-Sacrement, a été nommé professeur agrégé au département de médecine ; Nouvelles Le docteur Pritam Singh, membre du département de pharmacologie, a été nommé professeur agrégé au département de pharmacologie.NOMINATION AU CONSEIL DE LA FACULTÉ À la suite de la réunion annuelle de l\u2019Assemblée des professeurs de la Faculté de médecine, les représentants des professeurs au Conseil de la Faculté ont été élus.Les docteurs Jacques Brunet, Clément Jean et Louis Poirier ont été élus comme représentants des professeurs titulaires: les docteurs Paul- J.Lupien, André Moisan et Yves Warren, comme représentants des professeurs agrégés, et les docteurs Harry Grantham, Gilles Julien et Picard Marceau, comme représentants des professeurs adjoints.Par ailleurs, à la suite de la réunion de leur groupe respeetif, les étudiants inserits à l\u2019École des gradués ont élu monsieur Gaston Boucher pour les représenter et les étudiants en médecine ont élu messieurs O\u2019Donnell Bédard et Martin Lemay.En plus de ces représentants élus, le Conseil de la Faculté est formé du doyen, des vice-doyens, du secrétaire de la Faculté, des directeurs des départements et des directeurs des écoles affiliées.NOUVEAU CONSEIL D\u2019ADMINISTRATION DE L'ASSOCIATION DES MÉDECINS DE LANGUE FRANÇAISE DU CANADA Le Conseil général de l\u2019Association des médecins de langue française du Canada a élu son nouveau conseil d\u2019administration pour l\u2019année 1969-1970 à l\u2019occasion de sa réunion annuelle à l\u2019hôtel Reine Elisabeth, de Montréal, le 15 novembre dernier.Le docteur Charles Lépine, de Montréal, a été élu président de l\u2019Association et le docteur Roger Du- fresne, de Sherbrooke, vice-président.Le secrétaire et le trésorier sont respectivement les docteurs Raymond Caron et Jacques Léger, de Montréal.Les autres membres du conseil sont les docteurs Paul David et André Leduc, de Montréal, les docteurs Pierre Jobin et Raoul Roberge, de Québec, les docteurs Jean Laframboise.Bernard Lefebvre et Henri de Saint-Victor, d\u2019Ottawa.Le directeur administratif de l\u2019Association est le docteur Antonio Lecours, de Montréal. 322 COMMUNIQUÉ DE L\u2019ASSOCIATION DES BUREAUX MÉDICAUX DES HÔPITAUX DE LA PROVINCE DE QUÉBEC Lors de la réunion du 22 novembre dernier, le Conseil exécutif de l\u2019Association des Bureaux médicaux des Hôpitaux de la Province de Québec a procédé au choix de ses officiers pour l\u2019année 1969- 1970.Les docteurs Robert Lavigne, de Ville Saint- Laurent, et Jean-Guy Parent, de Ville Lasalle, ont été réélus respectivement président et secrétaire de l\u2019Association.Aux postes de premier vice-président et de deuxième vice-président, les docteurs Henri Robinson, de Hull, et Lionel Montminy, de Québec, ont été également réélus.Le docteur Maurice Campbell, de Trois-Rivières, demeure membre du Conseil à titre d\u2019ex-président.La composition du Conseil exécutif est complétée par les directeurs suivants: les docteurs Pierre Ar- chambault (Greenfield Park), Gérard Boudreault (Chicoutimi), (Gilles Brunet) Contreeœur, Robert Carrier (Sainte-Foy), Lucien Gendreau (Luce- ville), Raymond-Marie Guay (Lévis), Claude Lan- glois (Montréal), Claude Paulin (Montréal) et André Poisson (Grand\u2019Mère).JOURNÉE ANNUELLE SUR LES STAGES D\u2019ÉTÉ EN RECHERCHE La Journée annuelle sur les stages d\u2019été en recherche à eu lieu le mercredi 5 novembre dernier au grand amphithéâtre de la Faculté de médecine.Au cours des mois d\u2019été, cent étudiants ont travaillé dans les laboratoires de la faculté et des hôpitaux affiliés, grâce à des bourses d\u2019été.Vingt-sept de ces bourses ont été accordées par le Conseil des recherches médicales, quarante-quatre conjointement par le Ministère de la santé et le Ministère du travail, et les autres payées à partir des subventions des chercheurs.Soixante-dix de ces boursiers ont rédigé un rapport sur leurs activités et vingt-deux d\u2019entre eux ont présenté une communication lors de cette journée.Un jury composé de dix professeurs et présidé par le docteur André Collet, du département d'anatomie, à choisi quatre de ces communications comme étant les meilleures.T1 s'agit des présentations de mademoiselle Nacia Faure, de deuxième année (laboratoire du docteur Yves Warren, Hôtel-Dieu de Québec), M.Jean-Pierre Deschénes, de troisième NOUVELLES Laval Médical Vol.41-Fév.1970 année (laboratoire du docteur Marcel Lacerte, Hôpital du Christ-Roi).M.Jean-Roch Lapointe, troisième année (laboratoire du docteur Maurice Bé- langer, Hôtel-Dieu Saint-Vallier de Chicoutimi), et M.Jean-Louis Boucher, deuxième année (labora- toiré du docteur Ernest Rioux, Hôpital de l\u2019Enfant- Jésus).Le vice-doyen à la recherche, le docteur Carlton Auger, ainsi que le président du jury, le docteur À.Collet, ont félicité les étudiants choisis et ont souligné la valeur des autres travaux.Ils ont également exprimé leur appréciation aux professeurs pour leur collaboration à ce programme et aux étudiants, en particulier, pour l\u2019intérêt qu\u2019ils ont manifesté et leur assiduité au travail.Un dîner, groupant professeurs et étudiants ainsi qu\u2019un représentant du Ministère du travail, a clôturé cette journée, UNITÉ D'ENSEIGNEMENT EN PSYCHIATRIE À L'HÔPITAL ST-MICHEL-ARCHANGE L\u2019Tnité d\u2019enseignement de l\u2019hôpital Saint-Michel- Archange a ouvert ses portes, comme prévu, au début du mois de septembre.Cette unité comprend un service de 33 lits pour les hommes et un service de 36 lits pour les femmes.Il s'agit principalement d\u2019une unité de soins intensifs pour patients à court terme.Néanmoins, au cours de l'année, des cas a long terme seront également admis, afin d'élargir l\u2019éventail de l\u2019expérience des résidents.Cette unité est sous la responsabilité du docteur Jacques Labrie, lequel est secondé par les docteurs J.A.Bury, G.Pomerleau et N.-H.Montgrain.Plusieurs professeurs viennent d'autres milieux, régulièrement tel le docteur Y.Rouleau, professeur agrégé à l'université Laval et directeur du Service de psychiatrie de l'hôpital Saint-Sacrement ou, périodiquement, tel le docteur G.Sarwer-Foner, assistant- professeur à l\u2019université MeGill et directeur du Service de psychiatrie de l'hôpital Queen Elizabeth de Montréal.L\u2019Unité d'enseignement a accueilli, pour toute d'année 1969-70, tous les résidents de psychiatrie de première année de l\u2019université Laval, L'orientation de l\u2019Unité d'enseignement est centrée sur l'apprentissage des notions générales de psychiatrie et l\u2019évaluation des patients psychiatriques.Chaque résident a la responsabilité des soins d'un petit nombre de patients seulement, afin de permettre une supervision individuelle poussée et régulière.Les techniques d\u2019entrevue et la supervision en psycho- pharmacothérapie, ainsi que l\u2019organisation d\u2019un Liv Ta, dit i I [iy di a Hi lie IH ti tout fi CI ur ie rept po lie 3 nl! Qu Laval Médical Vol.41- Fév.1970 club de lecture et la projection de films psychiatriques sont les principaux autres aspects du programme d\u2019enseignement à l'hôpital même.Les cours théoriques organisés par le Département de psychiatrie de l\u2019université Laval s\u2019ajoutent à ce programme.Les enseignants de l'Unité préparent actuellement un programme, pour des résidents de troisième et de quatrième années, pouvant entrer en vigueur dès l\u2019année 1970-71, Ce programme individualisé, comprenant des postes à la Division de recherches, offrira un choix d'activités utilisant toutes les ressources hautement spécialisées de l\u2019hôpital Saint-Michel-Archange.DEPARTEMENT DES SCIENCES NEUROLOGIQUES À L'HÔPITAL DE L'ENFANT-JÉSUS Le docteur Gérard Leblanc, mn.(Laval 1955), C.S.P.Q.(neurochirurgie), F.r.C.s, (C), diplômé de \"American Board of Neurosurgery, est entré en fonction comme membre actif du Département des sciences neurologiques de l'hôpital de l\u2019Enfant- Jésus et chef du Service de neurochirurgie de ce département le 15 juillet dernier.Le Département des sciences neurologiques compte également parmi ses nouveaux membres actifs le docteur Jacques Francœur, neurochirurgien depuis juillet 1968, et le docteur Michel Drolet, neurologue depuis janvier 1969.Le docteur Denis S1- mard, boursier McLaughlin, est aussi devenu tout récemment un nouveau membre; il ira se spécialiser dans les maladies vaseulaires cérébrales à Copenhague.LE DOCTEUR DUFOUR À MEXICO Le docteur Didier Dufour, professeur titulaire de biochimie et directeur du (entre de biomédecine, donnera du 18 au 22 février 1970, à Mexico, un cours intensif sur les nouveaux concepts d'allergie et d\u2019immunologie.Ce cours sera donné sous les auspices de lu Société mexicaine d'allergie.ÉLECTIONS À L'HÔPITAL SAINT-FRANÇOIS D'ASSISE Au cours de l'assemblée annuelle tenue le 2 décembre dernier, les membres du Conseil des médecins de l'hôpital Saint-Francois-d\u2019Assise de Québec ont procédé à l\u2019élection de leur Bureau (comité exécutif) pour l\u2019année 1970.Le Bureau (1970) sera désormais composé des officiers suivants: pré- NOUVELLES 323 sident, docteur Roger Brault; vice-président, docteur Raymond Ruelland ; secrétaire-trésorier, doe- teur Robert Carrier ; directeurs, les docteurs Euclide Dechène, André Gilbert, Louis Levasseur et Robert Potvin; directeur général, M.Jean-Jacques Minguy ; directeur médical, docteur Gérard Roy.De plus, le docteur Clément Jean, ex-président, a été désigné pour remplir la fonetion de délégué du Conseil des médecins au Conseil d\u2019administration de l'hôpital Saint-François-d'Assise.ÉLECTIONS À L\u2019HÔTEL-DIEU DE QUÉBEC Au cours de la première partie de la réunion générale annuelle, le Bureau médical de l\u2019Hôtel- Dieu de Québec s\u2019est constitué un nouvel exécutif pour l\u2019année 1970.Les officiers du Comité exécutif et du Bureau médical sont: président, docteur Jean-Ls Bonen- fant ; président désigné, docteur Jacques Houde ; vice-président, docteur Robert Lessard; président sortant de charge, docteur Louis Coulonval ; secrétaire-trésorier, docteur Yvon Ouellet ; assistant- secrétaire-trésorier, docteur Paul Savary.MAITRISE ES SCIENCES MÉDICALES AU DOCTEUR BERTRAND VILLENEUVE Après avis d\u2019une commission particulière du Conseil de la Faculté et avis d\u2019une commission supérieure au Ministère de l\u2019éducation nationale français, la Faculté de médecine de l'université de Paris vient de décerner, en date du 4 septembre dernier, le titre de maitre és sciences médicales au docteur Bertrand Villeneuve, hématologiste à l\u2019hôpital Saint-Sacrement.Cette nomination fait suite à la présentation et à l\u2019étude de ses récents travaux.T]l a consacré trois années de travail à l\u2019Institut de recherches sur les leucémies de la Faculté de médecine de Paris, à l\u2019hôpital Saint-Louis dans le Service du professeur Jean-Bernard.Ses recherches ont porté surtout sur le lymphocyte.Le docteur Villeneuve a pu apporter la premiére description de la circulation des lymphocytes dans la leucémie lymphoide chronique humaine et découvrir une série de faits jusque-là inconnus, en particulier l'allongement considérable au cours de cette maladie du temps de passage de la lymphe au sang.De façon plus générale et en dehors des états pathologiques, la physiologie des lymphocytes, 1\u2019étude de leur cireulation, tant dans le ganglion lymphatique lui-méme que dans le canal thoracique, et l\u2019étude du mécanisme de déplétion 324 lymphocytaire sont beaucoup mieux connues depuis ces travaux.Une série de vingt notes, communications et rapports témoignent de l\u2019activité de ce chercheur.Ses travaux ont recueilli une très large approbation sur le plan international.Le docteur Bertrand Villeneuve est actuellement hématologiste à l\u2019hôpital Saint-Sacrement dans le Service d\u2019hématologie dirigé par le docteur Jean- Marie Delâge où il consacre son temps à la clinique et à la poursuite de ses travaux de recherche dans l\u2019étude du comportement des lymphocytes dans diverses maladies hématologiques, en particulier dans les lymphosarcomes et la leucémie lymphoïde chronique.CONFERENCIER INVITE Le docteur Guy Perdoncini, professeur à Wichita State University et chargé de cours à l\u2019université de Nice en pathologie du langage, a été l\u2019invité du département d\u2019oto-rhino-laryngologie et d\u2019ophtalmologie de la Faculté de médecine de l\u2019université Laval.Le 8 décembre dernier, il s\u2019adressait aux orthophonistes, audiologistes et rééducateurs du trouble de langage, au Centre de l\u2019ouïe et de la parole, à Québec.Le 9 décembre, il donnait une conférence 3 la Faculté de médecine, ou il exposait les bases psychophysiologiques de la rééducation de l\u2019enfant sourd, les éléments techniques et les résultats eli- niques.Le docteur Perdoncini est directeur d\u2019un centre médical de rééducation du langage à Wichita, au Texas, et directeur de deux centres de rééducation en France, l\u2019un à Villefranche et l\u2019autre en banlieue de Paris.Docteur en médecine, spécialiste en oto-rhino- laryngologie, audiologiste et phoniatre, le docteur Perdoncini est également lauréat de l\u2019Académie de Médecine de Paris.BOURSE DU CONSEIL DE LA RECHERCHE MÉDICALE DU QUÉBEC Le doyen de la Faculté de médecine annonce que le Conseil de la recherche médicale du Québec a accordé une bourse de $600 à deux étudiants en médecine, afin de leur permettre de continuer, durant l\u2019année universitaire, les travaux de recherche qu\u2019ils avaient entrepris au début de l\u2019été.Ces bourses ont été attribuées à monsieur Jean- Louis Boucher, étudiant de deuxième année, qui NOUVELLES Laval Médical Vol.41- Fév.1970 travaillera sous la direction du docteur Ernest Rioux, et de monsieur René Pouliot, étudiant de troisième année, qui travaillera dans le laboratoire du docteur Guy Pelletier.LA FONDATION UNIVERSITÉ LAVAL A DÉJÀ RECUEILLI PLUS DE $885 000 La Fondation Université Laval, incorporée en 1966 par les Anciens de Laval en collaboration avec les autorités universitaires, à reeu en souseriptions plus de $885 000, dont $435 000 sont présentement déposés en fiducie.C\u2019est là ce qu\u2019a révélé le recteur de l\u2019université Laval, Monseigneur Louis-Albert Vachon, alors qu\u2019il s\u2019adressait aux quelque 700 convives qui partiei- paient au déjeuner annuel offert par l\u2019Université à ses professeurs et amis.La Fondation, à dit Monseigneur Vachon, compte 70 membres gouverneurs (souscription de #5 000) et le travail de sollicitation actuellement en cours permettra vraisemblablement aux organisateurs d'atteindre leur premier million de dollars en 1970.Les revenus des capitaux reçus serviront à mettre à exécution des projets chers à l\u2019Université, tels que recherches, bourses, ete.Plusieurs invités de marque assistaient à ce déjeuner, dont le chancelier de l\u2019Université, le cardinal Maurice Roy, qui présidait le repas; Son Excellence Monsieur Hugues Lapointe, lieutenant- gouverneur du Québec; le ministre des Institutions financiéres et représentant du premier ministre du Québec, M.Armand Maltais, et le chef de l\u2019Opposition, M.Jean Lesage.PREMIÈRE COLLECTION DE DIAPOSITIVES POUR L'ENSEIGNEMENT MÉDICAL Medical Communications, Inc, annonce la mise en vente d\u2019une première série de diapositives pour l\u2019enseignement médical.Il s\u2019agit des syndromes pédiatriques, première partie, une collection de plus de cent diapositives en couleur qui a été préparée à partir de l\u2019excellente collection de réputation mondiale des docteurs Sydney Gellis, professeur de pédiatrie et directeur du département de pédiatrie à la Faculté de médecine de l\u2019université Tufts, et Murray Feingold, professeur de pédiatrie et directeur du Boston Floting Hospital for Infants and Children au New England Medical Center Hospital.Un livret préparé par les docteurs Gellis et Lu Ya.Fan an Bly ill tip ft fie [; wat | wl sal dvi du! ir, 155 Enes ll Rate ol die: pine tale frit sill pati ill ab jena Ti | jstlé hi A ne Es à pi vs pi ol i \u201d pré qui ga ; Ai qi al dir gps jap plis à | Laval Médical Vol.41 -\u2014 Fév.1970 Feingold donne une description détaillée des syndromes présentés sur les diapositives et l\u2019ensemble est présenté avec une petite visionneuse pour utilisation facile.D\u2019autres séries portant sur l\u2019endocrinologie, la biopsie du foie, les sédiments urinaires et les manifestations buccales des maladies systémiques seront bientôt mises sur le marché.La première partie des syndromes pédiatriques est offerte au coñt de $65 pour l\u2019ensemble de la collection.Pour tout renseignement additionnel, s\u2019adresser à Medical Communications, Ine., 280 Park Avenue, New York, N.Y.10017.LE CONGRES DU TRAVAIL DU CANADA ET LES CENTRES COMMUNAUTAIRES DE SANTE Plus de 250 syndiqués, rassemblés peudant trois jours à Sault-Sainte-Marie (Ont.).et venant de toutes les régions du Canada sont rentrés chez eux.le 4 décembre dernier, bien décidés à voir à ce que les soins médicaux prodigués dans leurs localités soient améliorés, 11 s\u2019agissait des délégués à une conférence sur l\u2019assurance médicale, tenue du 2 au 4 décembre sous les auspices du Congrès du Travail du Canada.La conférence avait pour objet de promouvoir l\u2019établissement d\u2019un plus grand nombre de centres communautaires de santé du genre de ceux qui, avec l\u2019aide du mouvement syndical, existent déjà à Sault- Sainte-Marie, St.Catharines, Régina, Saskatoon et Prince- Albert, Dans son allocution inaugurale, monsieur Donald MacDonald, président du CTC.a qualifié la conférence de « coup de départ d\u2019une campagne qui donnera aux Canadiens une conception nouvelle et différente de ce que signifie l\u2019assurance-santé », enchaînant : « J\u2019aimerais imaginer que cette conférence donnera le signal à l\u2019établissement d\u2019un véritable réseau de centres communautaires de santé à travers le Canada, fournissant à des centaines de milliers de familles canadiennes des soins médicaux de première qualité et servant d\u2019exemple à suivre par d\u2019autres.» Les délégués écoutèrent un orateur après l\u2019autre souligner les défauts du régime actuel d\u2019assurance- santé et les moyens à prendre pour y remédier.Selon les orateurs (professeurs d\u2019université, directeurs de centres médicaux et autres experts canadiens et américains), les défauts du système actuel sont nombreux: inégalités injustes entre les provinces et entre les régions urbaines et rurales; man- (24) NOUVELLES oo Lo Qt que de coordination entre les services, les professions et les institutions de soins médicaux; importance attribuée aux services coûteux, au détriment de services plus économiques et plus efficaces.Ils critiquèrent, par ailleurs, le système d\u2019honoraires individuels payables aux médecins, système décrit en ces termes par le docteur Samuel Wolfe, professeur à l'université Meharry de Nashville (USA): «Plus on voit de patients par heure, plus on gagne d\u2019argent.Plus on enlève d\u2019organes et plus on à le portefeuille garni.Pour les syndiqués, le travail à la pièce a disparu depuis déjà longtemps.Pourtant, en médecine, la plupart des médecins se font encore payer de cette manière.» Au cours des nombreuses discussions en groupe, auxquelles ils ont participé, les délégués ont appris que la réponse à beaucoup de ces problèmes réside dans l\u2019établissement de centres communautaires de santé, Ces centres, a déclaré monsieur Tommy Douglas, chef du Nouveau Parti démocratique, permettent le rassemblement, sous un même toit, des médecins et des spécialistes de toutes sortes; ils permettent aux médecins plus jeunes de travailler avec des collègues plus expérimentés; ils permettent, enfin, aux médecins d\u2019interrompre leur travail de temps en temps, pour suivre des cours de recyclage et de perfectionnement.Il a ajouté que les centres communautaires de santé permettent la pratique d'une médecine préventive, « gardant les gens en bonne sauté plutôt que d'attendre qu\u2019ils tombent malades pour les guérir ».En Chine ancienne, a-t-il expliqué, la coutume voulait que tous les habitants d\u2019une localité paient à leur médecin un salaire mensuel tant qu\u2019ils restent eu bonne santé.Mais dès que l\u2019un d\u2019eux tombait malade, le salaire du médecin s\u2019arrêtait.Parmi les autres avantages que comportent les centres de santé, monsieur Douglas a cité le fait que le nombre de services de santé connexes qu\u2019ils peuvent abriter est illimité; qu\u2019ils permettent de réaliser des économies considérables en réduisant le nombre de soins prodigués à l\u2019hôpital et la longueur de la moyenne des hospitalisations; et qu\u2019ils permettent aux patients de collaborer avec les médecins dans l\u2019administration du centre.Le mot de la fin est venu du docteur Wolfe, qui a déclaré : « I] est temps que le mouvement syndical se réveille et qu\u2019il prenne l\u2019initiative de protéger le consommateur de services de soins de santé, au moyen d\u2019un plus grand nombre de centres de santé tout à travers le Canada.» 326 RAPPORT DU COMITÉ D'ÉTUDE SUR LE COÛT DES SERVICES SANITAIRES La Conférence fédérale-provinciale des ministres de la Santé s\u2019est réunie à Ottawa en novembre dernier, en vue d\u2019analyser le rapport du Comité sur le coût des services sanitaires, dont la formation avait été autorisée par les ministres à leur dernière réunion, en novembre 1968.La préoccupation immédiate s\u2019inspire de facteurs, définis en détail dans le rapport, comme la hausse constante de plus de 10 pour cent par an du coût des services sanitaires et celle de 14 pour cent du coût des services hospitaliers.On dit dans le rapport: « Le coût des services sanitaires a tellement augmenté au Canada au cours des dernières années que nous avons aujourd\u2019hui à choisir l\u2019une des trois solutions que voici : \u2014 réduire les normes de soins médicaux que nous connaissons ; \u2014 augmenter encore les taxes, les primes ou le coût des services, ou \u2014 trouver dans une meilleure gestion la formule qui permettra d\u2019enrayer la hausse du coût des services sanitaires, ou songer sérieusement à repenser tout le système.» On constate également que la seconde solution \u2014 hausse des taxes, quelles qu\u2019elles soient \u2014 comporte en elle-même des objections.La perspective même d\u2019être taxé répugne au contribuables, comme d\u2019ailleurs au fise d\u2019avoir à le faire.Le Comité d\u2019étude formé par les ministres était présidé par le docteur John N.Crawford, ancien sous-ministre de la Santé nationale, qui a pris sa retraite récemment.Ce comité comprenait des sous- ministres et d\u2019autres hauts fonctionnaires de tous les ministères provinciaux de la Santé.Les travaux des sept groupes d\u2019experts ont porté sur les domaines suivants : Services hospitaliers : l\u2019utilisation des services hospitaliers, l\u2019efficacité de gestion, les traitements et salaires, les lits et les installations d\u2019hôpitaux.NOUVELLES Laval Médical Vol.41- Fév.1970 Services sanitaires: les méthodes de dispensation des soins médicaux, le coût des services médicaux, le coût des services sanitaires.Les groupes d\u2019experts ont été conduits par des spécialistes du domaine sanitaire désignés par des dirigeants d\u2019universités, d\u2019hépitaux, d\u2019associations professionnelles et de l\u2019État, assisté d\u2019un certain nombre de conseillers en matière de santé et d\u2019économie, Le ministre de la Santé nationale, monsieur John Munro, président de la Conférence, a fait remarquer que l\u2019étendue du rapport exige que d\u2019importantes décisions soient prises par les gouvernements et les spécialistes des professions de la santé, Il a suggéré qu\u2019il soit considéré comme un rapport d\u2019activité et qu\u2019il revienne au groupe d\u2019étude de faire les propositions ultérieures de mise en application.Monsieur Munro a aussi fait ressortir les réalisations remarquables des groupes d\u2019experts et du comité de coordination depuis leur création, au début de l\u2019année.Les trois volumes de leur rapport comptent près de 1 000 pages imprimées et portent sur des domaines de services sanitaires qui n\u2019ont Jamais été étudiés au Canada.Les propositions du rapport ont été soumises sous les seize titres suivants: \u2014 Coordination de la planification gouvernementale \u2014 La régionalisation \u2014 L'utilisation des services hospitaliers \u2014 Planification des accommodations hospitalières \u2014 Facilités d\u2019enseignement \u2014 Efficacité de gestion \u2014 Mesures d\u2019encouragement d\u2019ordre financier \u2014 Utilisation de la main-d\u2019œuvre \u2014 Classification des soins aux malades \u2014 Normes des soins médicaux aux malades \u2014 Services pour malades sur pied \u2014 Soins à domicile \u2014 L\u2019administration des soins médicaux \u2014 Les barémes d\u2019honoraires - Le dépistage collectif - L'enseignement de la médecine \" : css Q\u201d \\Viaman wy, ve cs wy 39) er Wédici Fr, = She >\" = 2 = A > æ.re 7 Inc 5 a F VUS Dé ES x Ÿ 3 Ye > Se des = x Fo >a 2 ve, A: 7.> VER A 25 Fr par \u20ac. a 3 nd {i = fel i 7 * pla 's : 3, ses Jos Ted + > * oo age 13 di Ji Pv ge 2, fis Ev Se ia H \u201cig, rape pe 3 seas a + ME por (i Hw +2 x £15 i ol aE >>, i 1ÿ 1 = qu\u201d 25 \u201cvat se\u201d = - ar RAN 1 Rass rere =i Fld yh 5 \u201c> if Hy LA = Un Con whe ET A i i?3 PE Bn = a joel 2) Sa 2 : FF, Bh LE # x 2 ple vi owe RN ds = & ih tt 1 2.3 - 7 % # oF, & 5 => \u201ca 5 = » I % à > A Le > # = x ve } n a > ta - .=\" ik Fi Sa i [Va .ann ee DUIIMAMAN hais seulement lorsque psychologiquement nancièrement, le temps sera propice 1e LA ( ah \\ x LL RSS SE présentation pratique, De la maison Desbergers, un des pionniers dans la recherche des substances oestrogéniques, nous vient le nouvel anovulant oral Novinol.Si les femmes sont différentes, Novinol l\u2019est aussi.Novinol est présenté en régimes de 21 ou de 28 comprimés.Le nouveau Novinol, par sa composition (mestranol et nore- thynodrel), a fait ses preuves depuis plus de dix ans.Novinol = NOUVEAU NOVINOL féminine, différente \u2026 Novinol est présenté dans un étui-compact exclusif et des plus attrayants, équipé d'une roue dentée à sens unique qui minimise les risques d'oubli ou de confusion.Novinol s\u2019es révélé non seulement efficace mais extrêmement bien toléré dans le traitement des syndrômes de la ménopause.NOVINOL.démontre l'incidence de grossesse la moins élevée de tous les contraceptifs connus.POSOLOGIE Novinol-21: un comprimé par jour pendant 21 jours consécutifs commençant le 5ièzme jour du cycle menstruel, que le flot menstruel soit arrêté ou non.Arrêter.7 jours, puis recommencer un nouveau traitement.Novinol-28: débuter le premier cycle en prenant Je premier comprimé blanc le Sième jour du cycle menstruel, que le flot menstruel soit arrêté ou non.Après 21 jours de traitement (21 comprimés blancs) prendre un comprimé bleu pendant 7 jours, puis recommencer un autre traitement le jour suivant (jour 29).INDICATIONS THERAPEUTIQUES Novinol peut être utilisé: 1) dans le contrôle de la conception, comme anovulant oral Renseignements thérapeutiques sur demande.9) dans le traitement du syndrôme de la ménopause.COMPOSITION ET PRÉSENTATION Novinol est présenté dans un distributeur contenant 21 comprimés (Novinol-21) ou 98 comprimés (Novinol-28).Novinol-21: Chaque comprimé blanc contient: \u2014\u2014un oestrogène: le mestranol à une dose de 0.1 ms.\u2014Un progestatif: le noréthynodrel à une dose de 2.5 ms.Novinol-28: Aux comprimés blancs de la formule Novinol-21 sont ajoutés 7 comprimés bleus contenant des ingrédients inertes.CONTRE-INDICATIONS L'administration de Novinol est contre- Pour une protection virtuellement optimale, prescrivez indiquée chez les femmes en période lactation, de même que chez les person présentant des troubles fonctionnels h tiques ou des tumeurs malignes des s@ et des organes génitaux.Novinol est lement contre-indiqué chez les patie présentant des antécédents de throm phlébite, de maladies thrombo-embolia d'accidents cerdiovasculaires et de lési neurovasculaires ou oculaires.Cet and lant est aussi contre-indiqué dans les de saignement vaginal non diagnostiq d'exophtalmie, de migraine, de grosse ou de soudure incomplète de l'épiph DESBERGER# LIMITÉE MONTH in | ir uni: Hingis fol: fre LE PREMIER CONGRÈS INTERNATIONAL DE MÉDECINE DE GROUPE Le premier congrès international de médecine de eroupe aura lieu à Winnipeg, dans la province du Manitoba, au Canada, du 26 au 30 avril 1970.Ce congrès ouvrira, sur le plan mondial, une discussion sur les méthodes permettant d\u2019offrir des services complets d\u2019hygiène et de santé sur le thème « Horizons nouveaux dans le domaine des services de santé ».Le rôle du médecin et celui des professions auxiliaires y feront l\u2019objet d\u2019une évaluation.Des personnalités marquantes des secteurs gouvernemental, médical et administratif et des professions auxiliaires des services de santé ont accepté de participer à des séances plénières sur les sujets suivants: Philosophie socio-économique des services de santé ; Médecine de groupe et services de santé; La médecine de groupe dans différents pays; Organisation et administration de la pratique en groupe ; Recherche groupe; et formation dans la pratique en Université et communauté comme bases possibles de la médecine de groupe; Les professions auxiliaires des services de santé et de la médecine en groupe; L\u2019aspeet économique des soins fournis dans le cadre de la pratique en groupe.Des visites de cliniques privées sont prévues le 29 avril à Winnipeg.Un programme varié d\u2019activités mondaines a été organisé, dont certaines avec participation des dames, ainsi que des excursions avant et après le congrès, entre autres une visite de la clinique Mayo.Pour de plus amples informations, prière de s\u2019adresser au Secrétariat du congrès: Congress Secretariat, First International Congress on Group Medicine, 425 St.Mary Avenue, Winnipeg 1, Manitoba, Canada.CONGRÈS DU COLLÈGE DES MÉDECINS DE FAMILLE DU CANADA Le XIIIe congrès du Collège des médecins de famille du Canada avait lieu & Toronto, du 29 sep- (25) Congrès tembre au 3 octobre 1969, sous le thème de « Nouvelles perspectives pour la prochaine décennie ».Huit cents congressistes environ assistaient à cette convention ; il est à noter qu'un groupe de deux cents médecins de médecine familiale de l\u2019Angleterre, dont des conférenciers, s'étaient rendus à ces assises.(Il était intéressant de coudoyer des confrères de pays étrangers et d\u2019échanger des idées sur divers modes de pratique médicale).Les autres congressistes étaient des médecins canadiens, en grande partie de l\u2019Ontario et de quelques provinces de l\u2019Ouest.Il a été remarqué et déploré qu\u2019un très petit nombre de médecins québécois (environ dix) assistalent à ce congrès, Est-il nécessaire de rappeler, pour expliquer la non-participation des médecins du Québec, l\u2019opposition qui existe entre là « Fédération des omnipraticiens de la Province de Québec » et « Le Collège des médecins de famille du Canada ».Quelle que soit la valeur des deux organismes, je dois souligner en passant qu\u2019un des buts primordiaux du Collège de médecine familiale du Canada qui est l\u2019éducation médicale permanente de ses membres, la qualité des soins médicaux donnés aux malades me paraît, dans le contexte médical d\u2019aujourd\u2019hui, d\u2019une valeur authentiquement incontestable.Plusieurs travaux scientifiques médicaux furent présentés aux congressistes ; quelques-uns traitèrent de l\u2019aspect particulier de médecine familiale.Je me contenterai de rappeler quelques aspects diseu- tés ou mntionnés dans ces travaux.1.Le médecin de famille survivra-t-il?Est-il nécessaire qu\u2019il survive ?A-t-il réellement un rôle spécifique et utile à jouer dans la société?Il fut de l'avis des conférenciers tant de l\u2019Angleterre que ceux du Canada, des spécialistes autant que des omnipraticiens, que le médecin de famille a une entité propre dont la tâche diffère de celle du spécialiste, à cause de sa façon d\u2019envisager et de traiter un malade, une famille.2.L\u2019omnipraticien qui fait, non de par sa qualité mais de par sa nature, une médecine différente de celle de son confrère tel le néphrologue, l\u2019endo- crinologiste, le cardiologue, doit-il recevoir une formation, une préparation différente spécialisée ?Si oui, de quelle façon, à quel moment ?Cette question ouvre la discussion à de multiples possibilités, d\u2019autant plus que l\u2019enseignement médical, à plusieurs endroits aujourd\u2019hui, est sujet à une réforme 328 CONGRÈS profonde.Plusieurs hypothèses sont émises : a) l\u2019enseignement médical devrait offrir dans son programme ou ses cycles des cours de médecine familiale dès la première ou au moins dès la deuxième année d\u2019enseignement comme préparation éloignée, ce qui en plus aurait l\u2019avantage de rappeler à l\u2019étudiant qu\u2019il existe une possibilité d\u2019option en médecine familiale; b) d\u2019autres ne préconisent la formation du médecin de famille qu\u2019après le cours médical régulier, complétée par une deuxième année de résidence seulement, alors que le médecin s\u2019oriente avec certitude dans cette pratique; ¢) certains en font une spécialité comme toute autre spécialité, s\u2019étendant sur une période d\u2019études prolongées aboutissant à des connaissances plus étendues avec accent en médecine familiale.3.Un autre point abordé au cours du congrès dans le domaine de l\u2019omnipratique fut celui de la recherche clinique.L\u2019omnipraticien doit faire de la recherche parce que celle-ci le force à une plus grande précision, l\u2019oblige à se poser des questions, à faire des distinctions.L\u2019effort à définir des termes le conduira à une meilleure compréhension des concepts.La discipline d\u2019observations exactes conférera un sens de précision nullement atteint auparavant.Un médecin ne peut s\u2019enrichir intellectuellement qu\u2019en développant l'habitude d\u2019analyser, de réfléchir sur ses expériences personnelles et de comparer avec les expériences des autres.Impressions et réflexions personnelles : Le médecin de famille doit survivre à cause de son rôle propre, différent de celui du spécialiste.qu'il a à jouer dans la société auprès des malades.Après une formation de base complète, l\u2019omnipraticien doit être préparé à sa future tâche par un enseignement spécial lui permettant d\u2019offrir à ses futurs patients un travail de qualité, de compétence; formé au cours de trois années, peut-être, de spécialité en médecine familiale, à cause de sa valeur médicale, son autorité dans sa discipline, il ne sera plus l\u2019objet de mésestime, l\u2019enfant pauvre Laval Médical Vol.41- Fév.1970 de la médecine; il jouira d\u2019une égale considération avec ses confrères et méritera la parité salariale (D\" Paul David).La nouvelle génération de praticiens, pour survivre d\u2019une façon plus humaine, devra envisager d\u2019une façon réaliste et comme une condition presque sine qu@ non la pratique de groupe.Il ne devrait exister que par exception, dans un avenir assez prochain, une pratique individuelle, isolée, à des postes éloignés où le sujet est inévitablement voué à la routine, l\u2019assèchement professionnel et la déception.Une tâche à laquelle devra s\u2019atteler le médecin de famille compétent est celle de l\u2019éducation populaire médicale concernant les croyances absurdes, les tabous, les superstitions que semblent entretenir, cultiver certains professionnels parce que favorisant leurs intérêts personnels.Le médecin de famille ayant reçu une formation d\u2019homme de science, de connaisseur, ne saurait perpétuer dans la masse des idées préconçues, des mythes qui deviennent des dangers, des pièges non seulement pour les profanes mais encore pour les médecins eux-mêmes.Les services d\u2019assurance-santé universelle seront bientôt en vigueur.Il est à prévoir qu\u2019une demande accrue de soins médicaux en résultera.À ce moment, il m\u2019apparaît que les Services de consultations externes devront résoudre en partie la surcharge prévue.Ils seraient en mesure de le faire s\u2019ils comptaient dans les rangs de leur personnel médical des médecins préparés à cette fin, plusieurs médecins de famille compétents capables de donner des solutions immédiates, traiter les malades en consultation, faire un tri judicieux des malades pour les orienter, si tel est le cas, vers les spécialités concernées, hospitaliser à bon escient ou retourner chez lui le malade qui doit l\u2019être, tout ceci à la lumière souvent des services de laboratoires.Philippe BOULIANE, M.D.Service de médecine (médecine générale) Centre hospitalier de l\u2019Université Laval = = NOUVEAU PRÉSIDENT À FRANK W.HORNER LIMITED M.Kirby Peake, président du Conseil d\u2019administration de Frank W.Horner Limited, annonce la nomination de M.Joel R.Brown, fils, au poste de président de la compagnie.Cette nomination entrait en vigueur le 1°\" décembre dernier.Monsieur Brown, qui a déjà résidé à Montréal, possède une vaste expérience dans le domaine pharmaceutique, ayant passé quelque vingt-deux ans au service de l\u2019American Cyanamid Company.Le dernier poste qu\u2019il occupa, au sein de cette maison, fut celui de directeur général adjoint, division des laboratoires Lederle, à Pearl River, New York.Entre-temps, de 1956 à 1960, il détint le poste, au Canada, de directeur général du département des produits médicaux et, en 1960, de retour aux États-Unis, il prit la direction de la division Davis & Geek, a Danbury, au Connecticut.Davis & Geck est un des principaux fabricants de produits de suture et de spécialités d\u2019hôpitaux.Monsieur Brown est un ancien administrateur de l\u2019Association canadienne des fabricants de produits pharmaceutiques, ancien administrateur de la Medical-Surgical Manufacturers Association et an- clen administrateur de la Health Industries Association.Jusqu\u2019a cette nouvelle nomination, il demeurait au Connecticut, ol il était membre actif du Comité exécutif du Council for Equal Employment Opportunity, du Associate Board of Directors of the State National Bank et du Conseil d\u2019administration de l\u2019hôpital Danbury.Natif de Beggs, Oklahoma, monsieur Brown a obtenu son baccalauréat ès sciences biologiques de l\u2019université de ce même État en 1937.Il fut par la suite pilote dans l\u2019Aviation américaine, de 1940 à 1946, et obtint le grade de major.Monsieur Brown est père de deux filles mariées.NOUVEAU VACCIN VIVANT CONTRE LES OREILLONS Le premier vaccin à virus vivant, atténué, contre les oreillons est maintenant à la disposition des médecins.À la suite de l\u2019autorisation accordée par la Direction des aliments et drogues, la compagnie Merck Sharp & Dohme Canada Ltd.annonce la mise en marché du vaccin provenant de la souche Jeryl Nouvelles pharmaceutiques Lynn, mis au point par les laboratoires de recherche de la compagnie.Monsieur Donald H.Burgess, président de MSD Canada, parlant de ce nouveau vaccin, a déclaré : « Les résultats d\u2019études cliniques étendues permettent d'espérer qu\u2019une immunité durable contre les oreillons puisse être conférée par une seule injee- tion du vacein à virus vivant.Au cours d'essais cliniques pratiqués en milieu externe, plus de 6 500 personnes susceptibles à ce virus, dont 206 hommes, ont été soumises à cette vaccination.Depuis que le vaccin a été mis sur le marché aux Etats-Unis, il y a environ dix-huit mois, quelque 4,2 millions de personnes ont été immunisées.» Le vaccin à injection unique est recommandé pour les enfants de plus de 12 mois ainsi que pour les adultes susceptibles de contracter cette maladie infectieuse.Il a été mis au point par les docteurs Maurice R.Hilleman et Eugène B.Buynak après plus de cinq ans de recherche dans les laboratoires Merck Sharp & Dohme.On considére généralement les oreillons comme une des maladies bénignes de l\u2019enfance.C\u2019est vrai dans les cas ordinaires.Toutefois, chez un très petit nombre d\u2019enfants et dans une plus grande proportion chez les adultes, les conséquences cliniques de l'infection virale peuvent être très graves et, dans des occasions relativement rares, les complications peuvent inclure l'atteinte d\u2019organes vitaux tels que le cerveau, les oreilles, les yeux, le cœur et les vrga- nes génitaux.UN NOUVEAU PRODUIT STELABID Smith Kline & French Canada Ltd.vient d\u2019ajouter un élément important à la gamme des produits Stelabid \u2014 11 s\u2019agit de Stelabid forte.Stelabid forte renferme une dose de Darbid (anti- cholinergique) supérieure de 50 pour cent à celle des autres présentations de Stelabid (Stelabid n° 1, Stelabid n° 2 et élixir Stelabid) et est indiqué pour les patients dont l\u2019état nécessite un effet anti- cholinergique ou antispasmodique supplémentaire.Stelabid forte contient en outre 2 mg de Stelazine en plus de ses 7,5 mg de Darbid.Comme les deux composants de Stelabid forte exercent une action prolongée inhérente, le médicament peut être administré selon une posologie biquotidienne commode et économique.À l'instar des 330 autres formes de Stelabid, il est indiqué dans une grande variété de troubles gastro-intestinaux.Stelabid forte n\u2019est dispensé que sur ordonnance, en flacons de 100 comprimés maïs monogrammés.Stelabid, Stelazine et Darbid sont des marques déposées par Smith Kline & French Canada Ltd.TOURNIQUET STÉRILE JETABLE Un tourniquet pneumatique stérile et jetable est maintenant offert par Orthopedic Equipment Company, Bourbon, Ind., sous le nom de Redi-Cuff.Ce tourniquet pneumatique est préstérilisé, ce qui élimine complétement les dangers de contamination et le besoin de le recouvrir séparément.Il est présenté en formats pour les extrémités supérieures et inférieures et est particulièrement bien adapté au champ chirurgical lorsque l\u2019espace entre le tourniquet et le champ opératoire est limité.Il existe également un format pédiatrique.Le tourniquet Redi-Cuff assure très efficacement NOUVELLES PHARMACEUTIQUES Laval Médical Vot.41- Fév.1970 l\u2019hémostase du champ opératoire et présente des avantages particuliers sur les tourniquets traditionnels.Il sauve du temps et du travail et élimine la préparation et le nettoyage préalable à l\u2019intervention chirurgicale.Il est facile à appliquer et peut être utilisé de façon régulière ou en état d'urgence.Le tourniquet Redi-Cuff est fabriqué de matériau entièrement antistatique.Il est mis en place par des liens de plastique transparent et ses tubulures s\u2019adaptent facilement aux sources de pression manuelle ou automatique.I] permet l\u2019utilisation d\u2019un adapteur du type Luer pour le joindre à des tourniquets de type Kidde ou Zimmer.Le tourniquet Redi-Cuff est disponible en trois dimensions.Le modèle 754-A pour les extrémités inférieures, 61 x 4 pouces, fonctionne à une pression recommandée de 250 mm Hg; le modèle 754-B pour les extrémités supérieures, 39 x 3 pouces, fonctionne à une pression recommandée de 125 mm et le modèle 754-C, modèle pédiatrique, 30 x 2 pouces, à une pression recommandée de 125 mm Hg.am ser ih At \u201ca lue hg br Aten ad Hing a hr \u201chi Hig M ç Hus ta Tien dial | Fo Ae Qs alti: ie i [Ire ri be par heli all I fo\u2019 jes Tour ol HD sal fre LB pour pete ee pes À Laval Médical Vol.41- Fév.1970 L'accord semble unanime: la douleur est habituellement accompagnée de tension nerveuse.La tension se manifeste sur le terrain préparé par la douleur.Douleur et tension, Le Fiorinal-C combat ces deux aspects des phénomènes douloureux, non seulement en soulageant la douleur physique, mais en calmant la tension nerveuse qui intensifie la douleur.Le Fiorinal-C est un analgésique- sédatif puissant qui assure le soulagement que vous recherchez chez vos malades.Par sa dualité d'action il soulage la douleur et calme la tension.FIORINAL-C A (Contenant % de grain de codéine) HORINALG 5 (Contenant % grain de codéine) COMPOSITION : Chaque capsule renferme 50 mg de Sandoptal (itobarbital).200 mg d'acide acétylsalicylique, 130 mg de phénacétine, 40 mg de caféine, 16 mg (' de grain) de phosphate de codéine ou 32 mg (% grain) de phosphate de codéine.POSOLOGIE 1 ou 2 capsules dès les premiers signes de la douleur, suivies d\u2019une capsule toutes les 3 à 4 heures en cas de besoin.PRÉSENTATION: Fiorinal-C % (capsules bleu clair etbleu foncé) \u2014 flacons de 25, de 100 et de 1000 capsules.Fiorinal-C % (capsules bleu et blanc) \u2014 flacons de 25, de 100, de 500 et de 1000 capsules.EFFETS SECONDAIRES: Occasionnellement étourdissements et somnolence.Renseignements completssurdemande.SANDOZ DORVAL, QUÉBEC (26) ISOULAGE CLR] 39 LA TENSION Activité concentrée dans les infections urinaires.Etant excrétée en majeure partie par voie rénale, au moyen de la filtration glomérulaire, la GARAMYCIN injectable permet d'atteindre rapidement des concentrations urinaires élevées: elle est donc particulièrement efficace pour le traitement des infections aiguës et chroniques des voies urinaires, telles que la pyélonéphrite, la cystite, l'urétrite et la prostatite.!.2- Le champ d'action bactéricide de la GARAMYCIN contre les germes Gram-négatif est exceptionnel et il est plus étendu que celui de tout autre antibiotique connu pour usage clinique.34.5.La GARAMYCIN permet une action bactéricide contre les germes Gram-positif et Gram-négatif, et elle détruit rapidement un grand nombre de bactéries diverses.Son efficacité s'étend notamment aux germes rebelles à Gram-négatif: Proteus, Pseudomonas, E.coli, Aerobacter-Klebsiella, Salmonella et Shigella.3.4.5.Son action contre les bactéries Gram-positif, telles que des souches de staphylocoques résistant à tous les autres antibiotiques, fait de la GARAMYCIN un médicament également très utile contre certains germes Gram-positif déterminés.3.4.5.Pratiquement pas de résistance acquise. (AnD les germesagg NS L ue ; Pice que la GARAMYCIN que et détruit rapidement, Agermes pathogènes sont vraisem- bblement éliminés avant de pouvoir acquérir f résistance à cet antibiotique.Aucune ÿstance bactérienne significative ne s'est Hleloppée en usage clinique.4.6.Nibiothérapie à grande marge de sécurité \u2014 Ba posologie et les précautions recomman- 4 lès sont observées, les effets secondaires Hit rares, et ils se produisent moins fréquem- » i t qu'avec les autres antibiotiques du {fme groupe.P.fologie et mode d'emploi a fections des voies urinaires rposologie usuelle, efficace dans les infections des $S urinaires, est de 0.4 mg/kg deux ou trois fois (OUT.pendant sept à dix jours.En vue d'accroître ivité antibactérienne, il peut être utile v Caliniser les urines.Entections systémiques di it donné les particularités de la gentamicine en (if flêre d'excrétion, le traitement d'infections systé- ues demande une posologie de 0.8 mg/kg.trois | Par jour.à modifier selon les réactions du ade.Un traitement d'une durée de sept a dix Is permet généralement d'éliminer une infection prmes sensibles.nfants pon le lieu et la gravité de l'intection, la dose tidienne totale est de 1.2 - 25 mg/kg, administrée Heux ou trois doses fractionnées pendant une ode de sept a dix jours.ar =.x D.Mal/ades présentant une fonction rénale altéree Chez les malades présentant une insuffisance rénale ou soumis à une hémodialyse intermittente, la posologie doit être établie en fonction du degré d'altération rénale.Pour de plus amples renseignements, consulter 'a documentation sur le produit ou le représentant de Schering.Précautions La GARAMYCIN a provoqué une ototoxicité chez les animaux d'expérience et chez l'homme.Cette réaction qui se manifeste par une altération de la fonction vestibulaire peut être complète, peut être irréversible et peut se produire à retardement.Une altération irréversible s'est produite principalement chez des sujets souffrant d'urémie ou d'altération de la fonction rénale, et chez des malades précédemment traités à l'aide d'autres médicaments ototoxiques ou ayant été soumis à un traitement à doses plus élevées ou de plus longue durée que celui normalement recommandé.La GARAMYCIN ne doit être employée pour le nouveau-né que lorsque sa vie est en danger La GARAMYCIN n'est pas recommandée en période de grossesse.sauf lorsque la vie de la malade est en danger.Effets défavorables Une atteinte de la fonction vestibulaire a été signalée pour 2 à 5% de tous les malades traités, y compris les azotémiques.Cette proportion baisse à 1-3% pour les malades non azotémiques.J agatif.Une protéinurie transitoire et une élévation réversible du taux d'azote uréique ont été signalées dans 1-3%/ des cas.Aucune lésion rénale permanente imputable à la GARAMYCIN n'a été signalée à ce jour.Des réactions de sensibilisation, telles qu'une éruption, n'ont été observées que dans très peu de cas Toxicité Chez l'homme.le seul effet secondaire grave signalé à ce jour a été une altération de la fonction vestibulaire.Présentation Fiole à doses multiples de 2 m! contenant 40 mg/mi.La GARAMYCIN injectable est thermo-stable et n'exige pas de réfrigération.Bibliographie 1.Jackson.G.G.: The Practitioner.198:855, 1967 2.Lipton.J.H.: Antimicrobial Agents and Chemotherapy, 1966.p.172.3.Black.J.et coll.: Antimicrobia!l Agents and Chemotherapy, 1963, p.138.4.White, A.Antimicrobial Agents and Chemotherapy.1963, p.17.5.Weinstein, M.J.: Gentamicin First International Symposium, Paris, janvier 1967, pp.9-18.6.Bulger, R.J.et coll.Ann.Int.Med., 59:593-604, novembre 1963.cheng Corporation Limited, Pointe Claire 730, P.Q. Laval Médical 42 Vol.41-Fév.1970 Li il I ÙE os où we We = 10 188 NC NS NO vas 9° 100 We\u2019 ge of WW ol Be ot cP Li hy as AO wh of a* D GC \u2018 eV «© ça pe, «2 et Ne Ae ne ae et es 9 veut cs 09° WO ae We ges (3 ae os.s qos° Û ac ex® SN a2\u201d ao ot ae ges of re\u201d o® eo?\u2019 a av © a2 eP (pe o® » oN XS ov ce PN rat x Of EX oe vos xe\u201d cO 9° ae\u201d \\o ess Se x©e où es vet \\ 0° 9 9 axe Sones 0% ae o\\ A ° \\ oe es\" eV (© Ne xO 9° 108 Ne 2%\" © WC 9° G2 de os g\\ot* ot x oe de pe seu?ous a a we 2° 808° WZ ae «® \\ 9° s@ ot a Ne 2 10° ça çoo® eet » 2 on SE A oC 2 0% ES A\\ 10 _ yo © ad a pue\" Wl x\u20ac mes xoŸ de a ou \\e es 16 % ae a po bs © RS [igi bi, 10 y .cesconpioonnmus pci it tbe dat te LL dH A at Laval Médical 43 \u201c HEPAMIG QUELLES SONT LES MANIFESTATIONS CLINIQUES DE L\u2019HYPERCHOLÉRÈSE ?les douleurs et les troubles digestifs des migraineux la « crise de foie » aiguë de Paviot certaines diarrhées post-prandiales les « crises de foie » post-émotives les « embarras gastriques » après matières grasses certains troubles digestifs après intoxication alimentaire MECANISME SCHÉMATIQUE : \u2014 un stimulus \u2014 une augmentation plus ou moins brutale du flux biliaire \u2014 une hausse de pression dans les voies biliaires \u2014 une série de réflexes inhibiteurs ou stimulateurs sur la sphère digestive \u2014 une réaction colique aux sels biliaires HEPAMIG traite ces manifestations.Pourquoi ?Parce que HEPAMIG © freine l\u2019'hypercholérèse calme le spasme oddien diminue la tension biliaire ramène le calme et prévient les « crises de foie ».Essayez vous-même HEPAMIG, chef de file des drogues à action biliaire nuancée, chez vos migraineux, vos intolérants hépatiques, vos dyspeptiques biliaires.1 comprimé 2 à 3 fois par jour \u2014 6 comprimés en cas de crise.Nébulisat d\u2019aubier de tilleul physiologiquement titré .cht 250 mg LYSTER CHEMICALS LIMITEE 1760 Cote Vertu Montréal 9, Qué.DOCUMENTATION ET ECHANTILLONS DISPONIBLES.(27) de facon sûre Dans le traitement de l\u2018hypertension légère ou modérée, la sécurité est un facteur primordial.Chez la plupart des hypertendus, on constate un certain degré d'insuffisance rénale.! En diminuant le débit sanguin rénal et le taux de filtration glomérulaire, les thiazides aggravent l'insuffisance rénale.Contrairement aux thiazides, Lasix réduit la résistance vasculaire rénale et améliore ainsi le fonctionnement du rein au lieu de l\u2019altérer.: De plus Lasix rétablit l'équilibre électrolytique de façon notable et les pertes de potassium qu\u2019il entraîne sont toujours plus faibles qu'avec les thiazides.* A cause de ces avantages spécifiques, surtout précieux dans le cas de traitements prolongés, Lasix est le diurétique de choix pour traiter l'hypertension.de facon efficace Dans le traitement de l'hypertension légère ou modérée, des preuves cliniques ont démontré que Lasix est nettement aussi efficace que les thiazides.À l'encontre des thiazides, Lasix est efficace même chez les malades dont la fonction rénale est altérée.5 En présence d'hypertension grave, Lasix peut efficacement être associé à d\u2019autres hypotenseurs.Parce qu'il abaisse la tension artérielle de façon constamment efficace et sûre, Lasix est le diurétique de choix pour le traitement initial et le traitement d'entretien de l'hypertension.de facon prévisible Dans le traitement de l'hypertension légère ou modérée, Lasix a fait preuve d'une activité hypotensive prévisible et soutenue.La baisse de la tension artérielle causée par Lasix dure jusqu'à 24 heures,\u2019 assurant une maîtrise uniforme et constante de l'hypertension, même au cours de traitements prolongés.L'effet prévisible qu'il produit permet de déterminer aisément un régime posologique facile à suivre.Lasix exerce une activité sûre et constante dans le traitement à longue échéance de I'hypertension.1) Moyer, J.H., Heider, C., Pevey, K., et Ford, R.V.: Am.J.Med., 24: 164, 1958.(2) Kirkendall, W.M., et Wilson, C.B.: Med.Clin.of N.A, 52:1157, 1968.(3) Hook, J B.Blatt, A H., Brody, M.J., et Williamson, H.E.: Clin.Res, 73-424, 1965.(4) Mahabir, M et Laufer, ST.Arch.Intern.Med.24:1.1969.(5) Joynt, M.S.K., et Morrin, PAF.:CMAJ, 99:1256, 1968.(6) Atkins, L.L.Geriatrics, 27 :143, 1966, Lasix, |'hypotenseur qu'on emploie au début .et durant tout le traitement \u2014 \u2014\u2014\u2014 es a= = Li ts Laval Médical Vol.41-Fév.1970 28) Lasix soulage l'hypertension Composition: Chaque comprimé contient 40 mg de furosémide.Indications: Hypertension légère ou modérée, et avec d\u2019autres hypotenseurs dans les cas sévères.Oedème lié à l'insuffisance cardiaque, à la cirrhose du foie, à la néphrose et à la néphrite chronique, ainsi que tout autre état oedémateux, e.g.la tension prémenstruelle.Contre-indications: Arrêt complet de la fonction rénale.En présence de coma hépatique et de déplétion électrolytique, n\u2019instaurer le traitement que lorsque l'état du malade a été amélioré ou corrigé.Ne pas administrer aux enfants, faute d'expérience dans ce domaine.Hypersensibilité.Avertissements: On a rapporté que les diurétiques sulfamidés diminuaient la capacité des artères à réagir aux amines hypertensives et augmentaient l'effet de la tubocurarine.Donc, administrer avec prudence le curare ou ses dérivés pendant un traitement avec Lasix.Interrompre une semaine avant toute chirurgie élective.Précautions: L'apport en sodium ne doit pas être moins de 3 g/jour.Donner un supplément de potassium lorsque des doses élevées somt utilisées pour des périodes prolongées.Porter une attention particulière aux niveaux potassiques avec des glucosides de la digitale, des stéroïdes susceptibles de produire une déplétion potassique ou lorsqu'il y a risque de coma hépatique.Un supplément de potassium, une diminution de la dose ou l'interruption du traitement peuvent être necessaires.Ajouter un antagoniste de l'aldostérone dans la cirrhose avec ascite.Comme avec tout nouveau médicament, observer attentivement pour déceler toute dyscrasie sanguine, dommage hépatique ou autres réactions idiosyncrasiques.Grossesse : Les études de la reproduction animale n\u2019ont pas révélé d'anomalies foetales provoquées par le médicament.Cependant, Lasix a été très peu employé dans la grossesse ; comme tout nouveau médicament, l'administrer durant cette période seulement lorsque essentiel.Vérifier le glucose sanguin et urinaire car on a observé des diminutions de la tolérance aux glucides.Vérifier la calcémie car on a rapporté de rares cas de tétanie.L'administration de Lasix et de doses élevées de salicylates peut provoquer une toxicité aux salicylates à des doses inférieures.Réactions secondaires: Comme avec tout diurétique efficace, la déplétion électrolytique peut survenir, surtout avec des doses élevées et un régime hyposodé.Symptômes de déplétion électrolytique : faiblesse, étourdissements, léthargie, crampes dans les jambes, anorexie, vomissements ou confusion mentale.Vérifier les électrolytes sériques, surtout le potassium, aux doses élevées.Chez les hypertendus recevant des agents hypotenseurs, réduire la dose car Lasix augmente leur effet hypotenseur.L'hyperuricémie asymptomatique peut survenir, rarement avec goutte.Des élévations passagères de l\u2019urée sanguine sont possibles surtout durant l'insuffisance rénale.Pourront aussi survenir: dermatite, prurit, paresthésie, vision brouillée, hypotension orthostatique, nausées, vomissements, diarrhée.On a observé de l'anémie, leucopénie, et thrombocytopénie (avec purpura) et de rares cas d'agranulocytose.Pourront aussi survenir: faiblesse, lassitude, étourdissements, crampes musculaires, soif, transpiration accrue, spasme de la vessie et symptômes de pollakiurie, Surdosage: Symptômes : Déshydratation et dé- plétion électrolytique.Traitement: Discontinuer la médication et rétablir l'équilibre hydrique et électrolytique.Posologie\u2014hypertension: La dose habituelle est de 40 à 80 mg (1 à 2 comprimés) par jour.Adapter la posologie et ajuster celle des hypotenseurs concomitants.Poso- logie\u2014oedème: La dose initiale habituelle de Lasix est de 40 à 80 mg (1 à 2 comprimés).Adapter selon la réaction.Si la diurèse ne s'est pas produite après 6 heures augmenter les doses suivantes de 1 comprimé (40 mg), à toutes les 6 heures, au besoin.Ensuite, la dose efficace peut être répétée de 1 à 3 fois par jour.Ne pas dépasser 200 mg/jour.Adapter la dose d'entretien aux besoins de chaque malade.Un programme poso- logique intermittent de 2 à 4 jours consécutifs par semaine peut être utilisé.Pour des doses dépassant 120 mg/jour, on conseille des observations cliniques et biochimiques.Présentation: Comprimés (Code DLI) à 40 mg, blancs, ronds, sécables, en flacons de 50 et 500.Renseignements complets sur demande, 2 PHARMACEUTICALS 3400 0 RUE JEAN TALON MONTREAL 301 DIVISION DE HOECHST DU CANADA LIMITEE 755/710/H HReg Hoechst TM LA PENSION FEDERALE A 65 ANS Le 1° janvier 1970.1'age d admissibilité a lu pension de retraite du Régime de pensions du Canada et à la pension de la sécurité de la vieillesse sera abaissé à 65 ans.En cinq ans, l'âge de la retraite aura done été ramené de 70 à 65 ans, c'\u2019est- à-dire à sa phase terminale.On estime que la réduction d'âge augmentera d'environ 250 000 le nombre de personnes admissibles à recevoir la pension de la sécurité de la vieillesse en 1970.On pense que l'an prochain, en raison de la réduction d'âge et d'autres facteurs, 90 000 personnes environ demanderont à recevoir la pension de retraite au titre du Régime de pensions du Canada.À la fin d'octobre dernier.plus de 84 000 personnes recevaient des pensions de retraite du R.P.C.Pour recevoir une pension de retraite du Régime de pensions du Canada.une personne doit avoir contribué au régime.doit avoir un numéro d assurance sociale et doit en faire la demande.Si la personne a entre 63 et 70 ans, elle doit avoir cessé de travailler régulièrement.À l'âge de 70 aus, cependant la personne peut demander sa pension de- retraite, qu'elle continue à travailler ou non.Le ministre de Ja Santé nationale et du Bien-être social, l'honorable John Munro.engage les personnes susceptibles d\u2019être pensionnées à consulter le personnel compétent de n'importe quel bureau de district du R.P.C.au Canada.Elles recevront là de plus amples renseignements et l'aide nécessaire pour faire leur demande.(es bureaux.a-t-i1 déclaré.peuvent également fournir des renseignements sur la pension de la sécurité de la vieillesse à ceux qui ne peuvent se rendre à un bureau de la séeurité de la vieillesse.Les demandes de pension de retraite en vertu du Régime des rentes du Québec doivent être faites directement au Conseil des rentes du Québec. it i ae 3 I peu fl d\u2019antibiotiques i a pu sont aussi I utiles en milieu y hospitalier 24 i] % = & ee Fa le rai \u2018Ta 6 I {ng oy k ml SF \u2018ir \u201ctn Hy \u201ces la nie Tay | \u201cie te \u201cde So EU is, ait Dès i : Jia 5, k Ig Monte i LU tg, gy sl ly ly, Ji Ë by Se, Made N | Aen À i po % & ISITE OLR RR A SEI A Ea Laval Médical Vol.41-Fév.1970 e staphylo suspect.E.coli.JKlebsiella et autres organismes jà gram-négatif sensibles- al antrex\u2018 sulfate de kanamycine) Kantrex offre un spectre d\u2019action qui convient tout particulièrement à la pratique hospitalière.Peu d\u2019antibiotiques procurent une protection bactéricide aussi étendue contre la plupart des staph- locoques en milieu hospitalier et des espèces à gram-négatif.À l\u2019exception des Pseudomonas et Bac- téroides primaires \u201cla kanamycine est toujours le seul médicament efficace contre la majorité des organismes à gram-négatif \u201crebelles\u201d acquis dans les hôpitaux.\u201d Souvent un traitement initial de Kantrex peut être donné avant même que ne soit connu le résultat des cultures.Pour les organismes sensibles à la kanamycine, la réponse clinique se manifeste dans les 24 à 48 heures et la rémission, habituellement, dans les 5 à 7 jours.En raison du danger possible d\u2019ototoxicité: le dosage quotidien pour adultes ne doit pas excéder 1.5 Gm.même pour es patients les plus lourds.Dans les cas de déficience rénale, la posologie sera ajustée en conséquence.NFORMATION THÉRAPEUTIQUE: Consultez le dépliant pour information détaillée.Indications: Infections des voies urinaires, respiratoires et gastro-intestinales et infections de la peau, des tissus mous, du périoste et du sang causées par des bactéries sensibles.Contre-Indications : Antécédents d\u2019hypersensibilité au médicament.Si un traitement alternatif efficace est disponible, on peut considérer comme une contre-indication les ujets ayant déjà subi des troubles auditifs causés par la kanamycine ou autres agents.Mise en Garde: Une mauvaise fonction rénale peut causer es niveaux sanguins de kanamycine anormalement élevés\u2014un examen périodique du système rénal doit être pratiqué avant et au cours du traite- ent.Dans les cas d\u2019insuffisance rénale, la force et fréquence du dosage doivent être réduites.Discontinuer la kanamycine et vérifier l\u2019acuité uditive, si des symptômes de tintement d\u2019oreilles ou une augmentation de l\u2019azotémie apparaissent.Surveiller le risque d\u2019ototoxiciié chez les patients plus agés ou ceux recevant une dose totale excédant 15 grammes.Précautions: S'il survient une surinfection bactérienne ou mycosique, iscontinuer la kanamycine et instituer la thérapeutique appropriée.Des effets otoloxiques cumulatifs peuvent être notés avec d\u2019autres médicaments ototoxiques employés concurremment ou consécutivement, Des doses élevées peuvent causer une irritation au point d\u2019injection.Le Kantrex ne doit pas être mélangé physiquement avec d\u2019autres agents antimicrobiens.Effets Secondaires: Une perte d\u2019acuité auditive grave et irréversible peut se produire.Discontinuer le traitement s\u2019il y a tintement d'oreilles ou si on note une perte d\u2019acuité auditive, Des signes d\u2019irritation rénale (cylindres, hémalies et présence de protéine) peuvent se manifester.Chez les sujets dont la fonction rénale est normale, ces symptômes sont réversibles t il n\u2019est pas nécessaire d'arrêter le traitement.De rares cas d\u2019éruptions cutanées ont été notés, Afin d\u2019éviter une dépression respiratoire, il faut retarder l\u2019instillation du Kantrex dans les cas post-opératoires jusqu\u2019à ce que les effets de l\u2019anesthésie et des médications sédatives aient disparu.Posologie Ordinaire: 15 mg./Kg.de poids corporel par jour, par voie I.M.en doses divisées, préférablement aux 12 heures.La posologie quoti- fdienne moyenne pour adultes est de 1 gramme, et ne devrait pas excéder 1.5 Gm.même pour les sujets les plus lourds.Dans les cas d'insuffisance frénale, il faut réduire la posologie et prolonger les intervalles entre chaque dose.Les patients devront être bien hydratés afin de réduire le risque { d'irritation rénale.Injecter profondément dans le quart supéro-antérieur du muscle fessier.Présentation: Solution aqueuse stérile dans une fiole à | diaphragme de caoutchouc en deux concentrations\u20140.5 Gm.dans un volume de 2 ml.et 1.0 Gm.dans une volume de 3 ml.Autre Présentation\u2014Injection Pédiatrique: 75 mg.dans un volume de 2 ml.Bibliographie: 1.L.D.Thrupp, dans Discussion, Ann.New York Acad.Sc.132:796 (14 juin) 1966, p.858.Bristol Laboratories | MEMBRE BRISTOL of Canada, ( ac ee) Candiac, P.Q.Kantrex (sulfate de kanamycine) Iniection bactéricide contre les organismes à gram-négatif sensibles et les staphylocoques ÿ {*Marque déposée Bi ig K b 48 Laval Médical Vol.41-Fév.1970 Un traitement antihypertensif peut-il être efficace sans altérer en premier lieu le débit cardiaque ?Oui! Par un traitement qui réduit la tension artérielle surtout en diminuant la résistance vasculaire or a périphérique avec.| ral - (méthyldopa) .car le débit cardiaque se maintient d\u2019ordinaire.L\u2019'ALDOMET* peut constituer un traitement efficace de l'hypertension permanente de caractère modéré à grave.L'ALDOMET* est utile en particulier dans le traitement de l'hypertension ne répondant pas aux diurétiques dérivés des thiazides employés seuls.L'ALDOMET* est profitable aussi aux sujets chez qui l'hypertension est liée à une néphropathie connue ou soupçonnée.L'ALDOMET* réduit d\u2019ordinaire la tension artérielle dans toutes les positions, la nuit comme le jour.*Marque déposée y lice 186 Laval Médical Vol.41-Fév.1970 comprimés (methyldopa) COMPOSITION: Chaque comprimé renterme 250 mg de meéthyldopa.INDICATIONS: L'ALDOMET* est recommandé pour le traitement de l'hypertension artérielle permanente, de caractère modéré à grave.Il n\u2019est pas recommandé aux malades souffrant d'un phéochromocytome ni dans les cas d'hypertension bénigne ou labile répondant aux sédatifs légers ou aux diurétiques dérivés de la thiazide utilisés seuls.CONTRE-INDICATIONS: Affection hépatique en évolution; hypertension bénigne ou labile répondant à une sédation modérée ou à la seule administration de diurétiques dérivés de la thiazide; phéochromocytome; grossesse.Administrer avec prudence aux malades ayant déjà souffert d'affection du foie ou d'insuffisance hépatique.PRECAUTIONS: De rares cas d\u2019anémie hémolytique acquise se sont produits.S'il y a lieu de soupçonner de l'anémie, on doit faire la détermination du taux d'hémoglobine ou une hématocritie ou les deux à la fois.En présence d'anémie, il faut procéder à des épreuves en vue de déceler s\u2019il y a hémolyse.Il faut abandonner le médicament s'il y a évidence d'anémie hémolytique.On a obtenu une prompie rémission de l'anèmie en cessant l'administration de la méthyldopa ou en instaurant un traitement aux corticostéroïdes.Une épreuve directe de Coombs peut se révéler positive.On n'a pas déterminé le mécanisme exact de cette réaction ni sa portée.La fréquence de cette épreuve positive a varié de zéro à vingt pour cent; ce phénomène survient d'ordinaire dans les douze premiers mois du traitement.Les résultais de cette épreuve redeviennent négatifs des semaines ou des mois après l'arrêt du traitement.S'il faui recourir à une transfusion, le fait de connaître cette réaction sera utile pour évaluer l'épreuve croisée de compatibilité sanguine, car on peut être en présence d'une incompatibilité mineure.Si l'épreuve indirecte de Coombs est négative on pourra faire la transfusion de ce sang qui d\u2019auire part serait compatible.On a remarqué en de rares occasions une leucopénie réversible portant surtout sur les granulocyies et on n'a rapporté qu'un seul cas d\u2019agranulocytose.On a observé quelques rares accès fébriles, accompagnés ou non d'anomalies dans les épreuves du fonctionnement du foie.Des biopsies du foie pratiquées chez plusieurs malades, à la suite d'épreuves dont les résultats étaient anormaux, ont révélé un foyer microscopique de nécrose, phénomène compatible avec une hypersensibilité au médicamment mais donl la signification n'a pas été déterminée.On doit procéder périodiquement à une exploration fonctionnelle du foie, à des numérations leucocytaires ainsi qu'à la détermination de la formule leucocytaire, différentielle au cours des 6 à 8 premières semaines de traitement ou chaque fois que se déclare une fièvre inexpliquée.Si la fièvre survient en l'absence d'infection, cesser l'administration du médicament.Lorsque la méthyldopa est administrée avec d'autres médicaments, il peut y avoir potentialisation de son activité.Observer les précautions habituelles, comme pour toui nouveau médicament.La méthyldopa produisant une fluorescence dans l'urine, on peut rapporter des concentrations faussement élevées des catécho- lamines urinaires.Ce médicament peut donc fausser le diagnostic d'un phéochromocytome.REACTIONS DEFAVORABLES: On peut observer de la somnolence au début du traitement ou lorsqu'on accroît la posologie.La céphalée, l'asthénie ou la faiblesse sont également des symptômes passagers qu\u2019on observe au débui.On remarque aussi parfois: vertiges, étourdissements et insuffisance cérébro-vasculaire.On a rapporté une aggravation de l'angine de poitrine.Si des symptômes d\u2019hypotension orthostatique surviennent, on suggère de réduire la posologie.De la bradycardie, de l'enchifrénement, une légère sécheresse de la bouche et des symptômes gastro-intestinaux se manifestent parfois; ils peuvent en général être soulagés en diminuant la dose.L'augmentation du poids et l'œdème sont peu fréquents.Cesser le traitement si l'œdème progresse ou si des signes d'insuffisance cardiaque apparaissent.Il peut arriver que l'urine, exposée à l'air, devienne foncée par suite de la décomposition de la méthyldopa ou de ses métabolites.On a rapporté, quoique rarement, les effets suivants: nausées, vomissements, sensibilité de la langue, gonflement des seins, lactation, impuissance, éruption cutanée, arthralgie légère, myalgie, paresthésie.parkinsonisme, troubles psychiques, psychose ou dépression légère et réversible.Un ictère bénin et réversible s'est produit chez quelques malades, On a observé un cas d'élévation de l'urée sanguine (BUN).On a rapporté un seul cas de paralysie de Bell.sans pouvoir l'attribuer au médicament.On a parfois signalé de la fièvre associée au médicament, des anomalies du fonctionnement du foie, des résultats positifs de l\u2019épreuve directe de Coombs, une anémie hémolytique acquise et une leucopénie.POSOLOGIE: On commence généralement en administrant un comprimé de 250 mg, par voie buccale, trois fois par jour durant les 48 premières heures.Diminuer ou augmenter la dose quotidienne de 1 ou 2 comprimés, de préférence à intervalles d\u2019au moins deux jours, jusqu'à ce qu'on ait obtenu une réponse satisfaisante.La posologie optimale, une fois déterminée, permet, en 12 à 24 heures, une réduction douce et uniforme de la tension artérielle chez la plupart des malades.La dose globale recommandée, est de 3 gm par jour (12 comprimés).Si une dose quotidienne de 2 gm ne suffit pas pour maîtriser efficacement la tension artérielle, on recommande d'ajouter au traitement un diurétique dérivé de la thiazide.Dans les cas d\u2019insutfisance rénale, il peut être nécessaire de diminuer les doses.La syncope observée chez des malades âgés a été attribuée à l'artériosclérose cérébrale et on peut l'éviter en diminuant les doses.Chez la plupart des malades, on a commencé le traitement avec l\u2019'ALDOMET* par le retrait de tout médicament administré antérieurement, à l'exception des thiazides par exemple dont on continue l'administration.La diminution progressive de la posologie des ganglioplégiques et l'addition, également progressive.d'ALDOMET\" au traitement facilitent la période de transition.On doit limiter.au début, la dose d'ALDOMET* à 500 mg (2 comprimés) par jour, quand on substitue ce médicament à des antihypertensifs autres que les thiazides.La tolérance au médicament peut se manifester, le plus souvent après deux ou trois mois de traitement On peut y remédier en augmentant la dose ou en ajoutant au traitement un dérivé de la thiazide.PRESENTATION: (Ca 3290) Comprimés Jaunes, laqués, renfermant chacun 250 mg de méthyldopa, en flacons de 50 et de 500.DOCUMENTATION: Sur demande.MERCK SHARP & DOHME == OF CANADA LIMITED MONTREAL [acer] La recherche d'aujourd'hui au service de la thérapeutique de demain (29) 49 LA CAISSE D\u2019AIDE À LA SANTÉ ACCORDE UNE SUBVENTION À UN HÔPITAL DE TORONTO La Caisse d\u2019aide à la santé du gouvernement fédéral vient d'accorder $206 134 pour l\u2019amélioration de deux laboratoires de recherche de l\u2019hôpital St.Michael de Toronto.C\u2019est ce qu\u2019a annoneé l'honorable Donald S.Macdonald, président du Conseil privé et député de Rose- dale, au nom de l'honorable John Munro, ministre de la Santé nationale et du Bien-être social.Cette somme aidera à payer une partie du coût des installations et de l\u2019équipement nécessaires pour l\u2019enseignement dispensé aux étudiants diplômés et non diplômés.Les nouvelles installations et le nouvel équipement ont permis d\u2019agrandir l\u2019unité de recherches du département d\u2019obstétrique de l\u2019hôpital St.Michael.Ce service occupe le septième étage de l\u2019aile Sud-A.I\u2019hépital St.Michael est affilié a 1université de Toronto et les programmes d\u2019enseignement s\u2019adressent aux infirmières et aux étudiants en médecine, UN HOPITAL ONTARIEN REGOIT UNE SUBVENTION FEDERALE L\u2019Ontario Cancer Institute (hopital Princess Margaret), de Toronto, a obtenu une subvention de $456 426 pour la construction.L\u2019 honorable Donald S.Macdonald, président du Conseil privé et député de Rosedale, révèle cette approbation, au nom de l\u2019honorable John Munro, ministre de la Santé nationale et du Bien-être social.Cette subvention va aider à financer la construction et les rénovations.Une annexe de l'hôpital loge 43 autres lits pour maladies aiguës, ainsi qu\u2019une meilleure installation des consultations pour malades externes et des services de formation, et des laboratoires.Les récentes méthodes utilisées pour le dia- gnostie et pour le traitement du cancer exi- gealent de telles rénovations. 20 Laval Médical Vol.41- Fév.1970 NE LAISSEZ PAS TOMBER! Jusqu'à ce que vous ayez adopté les récipients de plastique VIAFLEX pour obtenir des techniques intraveineuses plus sûres, plus faciles et plus rapides.Les flacons ont l'habitude de tomber.Et de se briser.Ceci augmente le coût\u2014non seulement des solutés, mais aussi des médicaments dispendieux qui y ont été ajoutés.Il arrive quelquefois que des personnes se coupent avec les tessons de verre, Les récipients de plastique VIAFLEX peuvent tomber, mais ils ne peuvent se casser.Cependant, il est probable qu'ils ne tomberont pas\u2014parce qu'ils sont plus légers et plus faciles à manipuler.|| n'y a aucune bordure de métal ni couvercle à manier.Les installations et les remplacements sont plus rapides.Aussi, le mode d'emploi est plus sûr parce que le VIAFLEX représente un système complètement her- LES LABORATORIES BAXTER DU CANADA DIVISION DES LABORATOIRES TRAVENOL, INC.6405 Northam Drive, Malton, Ontario [|] EEN SE métique.Pas de prise d'air, l'air ambiant ne pénètre pas dans le contenant; aucun contaminant aérogène ne s'infiltre dans l'appareil.Le VIAFLEX constitue le premier et le seul récipient de plastique pour solutés intraveineux.Pour des techniques plus sûres, plus faciles et plus rapides, il est le premier et le seul que vous devez considérer \"Marque déposée | V \\ S ED) )) \u201c(01114 F7ÆEEEZEEEXX 0, = ma CDS $ w i > £ ee ) y = A, an À 2 2 Es > ie _ = 2 + I > re # = = # Fo w > oo.= 0) A.= = xé $; x À +28 2 nF 4 w 14 y & \u201c2 ES Lek ou or / > 3 =a ¥ $ > of Sox.> a a 3 æ 2 th S # J of x ; 45 #* Si a NS Fy Re ?a 48 \\ l * 4 A x te 3 \\ * Ÿ : a = ÿ bo a Ee Aid he % EL fo 2 4 ! RE i ki 73 LS a