Sixteen recipients of neonatal liver grafts were compared with 114 contemporaneous pediatric recipients of grafts from older donors. Graft and patient survival were worse in the neonatal group although the differences were not statistically significant. Patients with neonatal livers who had no technical complications required a longer time postoperatively to correct jaundice and a prolonged prothrombin time. These functional differences were limited to the 1st postoperative month and the end result was the same as with liver transplantation from older donors. © 1992 Springer-Verlag

Bismuth H

Brolsch CE

Buchanan GR

Hamil PVV

Kalayoglu M

Maisels MJ

Starzl TE

Urbach AH

Zitelli BJ

English

PubMed

Itsuo Yokoyama

Andreas G. Tzakis

Oscar Imventarza

Satoru Todo

Adrian Casavilla

Antonio Leggio

Thomas E. Starzl

MUCC (Crossref)

Pediatric liver transplantation from neonatal donors

Crossref

Yokoyama, I

Tzakis, AG

Imventarza, O

Todo, S

Casavilla, A

Leggio, A

Starzl, TE

Name not available

D-Scholarship@Pitt

Transplant I nt ( 1l)l)2 1 :'i: 20:'\-208 TRANSPLANTI International !I ~ Springer-Verlag 1992 Pediatric liver transplantation from neonatal donors Itsuo Yokoyama. Andreas G. Tzakis. Oscar Imventarza. Satoru Todo. Adrian Casavilla. Antonio Leggio. and Thomas E. Starzl Department of Surgery, University Health Center of Pittsburgh, University of Pittsburgh. 3601 Fifth Avenue. Pittsburgh, PA 15213. USA Received July 10, 1991/Received after revision November 5, 1991/ Accepted December 31, 1991 Abstract. Sixteen recipients of neonatal liver grafts were compared with 114 contemporaneous pediatric recipients of grafts from older donors. Graft and patient survival were worse in the neonatal group although the differences were not statistically significant. Patients with neonatal livers who had no technical complications required a longer time postoperatively to correct jaundice and a pro-longed prothrombin time. These functional differences were limited to the 1st postoperative month and the end result was the same as with liver transplantation from older donors. Key words: Liver transplantation. neonatal liver - Neo-natal liver. in liver transplantation The available liver donor pool has been expanded with the use of grafts from older donors [13.19]. In liver trans- I plantation in infants and small children. the number of candidates far exceeds organ availability, resulting in sig-nificant mortality of patients on waiting lists [4, 23]. Possible options include the use of reduced-size or split liver grafts [1. 2. 7, 8. 12] and the use of livers from neo-natal donors. Results of our experience with the use of neonatal livers for transplantation in very small pediatric recipients is herein reported. A minimum of 14 months follow-up is provided. Patients and methods' The charts of all patients who underwent primary liver transplanta· tion at the Children s Hospital of Pittsburgh under cyclosporine-ste-roid therapy and had liver grafts preserved with University of Wis-consin solution [7J were reviewed. These transplants took place between October 1l)87. when University of Wisconsin solution be-(arne a\ailahle to us for clinical use. and September 1lF~9K when FK SOb was introduced as the primary immunosuppressive agent 1201. Follow-up is provided to December 31. 19YO. and consequently ranged from 1.+ to .19 months (median 25 months). ()ne hundrt:d and thirty patients were studied: their pnmary liver dlsc:ast: is shown In Table I. The recipient age ranged from I to 20.+ months (mean 51.1 ± .+.9 months 1 and the male/female ratio was 7/0. ( ITrt'sl'olll/1'IIC(, II): T. E. Starzl .. Two groups were identified depending on the age of the donor: group A were recipients of neonatal (age 28 days or less) donor grafts (n = 16) and group B recipients of grafts from older donors (n = 114). In case of retransplantation. the age of only the primary donor was considered. Donor age. body weight. prothrombin time. serum total bilirubin and alanine aminotransferase (ALT) were recorded. These labora-tory data were missing for 10 donors in group B. An accounting of the donors and recipients in group A is given in Table 2. Anoxic injury due to birth asphyxia was the most common cause of donor death (75 % ). Thirteen donors (81 % ) were less than 2 weeks old and all weighed less than 5 kg. All but two recipients were less than 1 year old and all weighed less than 10 kg. Biliary atre-sia was the underlying disease in 11 patients. Nine of them (82 % ) had had previous failed portoenterostomies. A summary of the donor and recipient demographic data in group B is shown in Table 3. The surgical techniques employed for graft recovery and trans-plantation have been reported previously [14. 16. 18]. Organ preser-vation period (cold ischemic time) ranged from 6.7 h to 17.9 h (9.4 ± 1.4 h) in group A and from 5.1 h to 29.1 h (8.5 ± 0.5 h) in group B. No statistical differences were noted between the two groups. Heparin (50 IV/kg subcutaneously twice a day), aspirin (20 mg forbodyweight < 8 kg,40 mgfor8-15 kg,orSO mgfor > 15 kg. orally. once a day) and Persantine (dipyridamole. 6.25 mg for body weight < 12 kg or 12.5 mg for ~ 12 kg, orally, twice a day) were administered, unless bleeding occurred, when the prothrombin time was less than 20 s throughout the hospitalization. All ofthe patients in group A re-ceived parenteral hyperalimentation including vitamin K immedi-ately postoperatively until they tolerated oral feeding well. Doppler ultrasonography was performed routinely within 24 h postoperatively and was repeated when a complication was sus-pected. Absence of arterial pulsations on two consecutive ultra-Table L Indications for liver transplantations (n = 130) Diagnosis Biliary atresia or other type of biliary cirrhosis Cirrhosis secondary to metabolic disorders Chronic hepatitis Postnecrotic cirrhosis Tumors Budd-Chiari syndrome Total No. of patients S5 15 13 l) o LlO '. ~MS Table 2. Donor and recipient patient characteristics in group A (neonatal donors). ICH.lntracerehral hemorrhage: SIDS. sudden infant death ~yndrome: BA. biliary atresia: ATD. aI-antitrypsin deficiency: NH. neonatal hepatitis: AS. Alagille's syndrome: PNC. post necrotic cirrhosis Donor Recipient Patient Age Body weight Cause of Age no. (davs) (kg) death (months) 1'\ 3.7 Anoxia 7 ~ ~o 2.3 Anoxia 6 .' 12 3.2 ICH 9 ~ ~U ~Kl Anoxia 5 5 X 3.3 SIDS 7 0 3 2.7 Anoxia 2 7 ., 2.7 Anoxia 13 .. B 5 2.6 ICH 7 9 3 3.7 ICH 9 10 16 3.2 Anoxia 2 11 6 4.5 Anoxia 12 12 2 3.2 Anoxia 11 13 6 3.3 Anoxia 19 14 12 3.2 Anoxia 5 15 3 3.3 Anoxia 5 16 4 3.4 Anoxia 9 Mean 5.6 3.3 B.O SEM 1.B 0.1 1.1 a Previous portoenterostomy b Received third graft Table 3. Summary of donor and recipient demographic data in group B (nonneonatal donors) Donor Age (years) Body weight (kg) Recipient Age (years) Body weight (kg) Sex (male:female) Mean±SEM 4.9±0.4 14.0± 1.1 4.B±0.4 IB.O±O.1 62:52 (32 days to 42 years) (2.7...{jB.2 kg) (1 month to 17 years) (4.l-S4.3 kg) • sound examinations established the diagnosis of arterial thrombosis. In some patien ts, this diagnosis was made by arteriography or during surgical exploration. Body weight of.the patients in group A was recorded preopera-tively and followed for the duration ofthe study. Control values were obtained from the National Center for Health Statistics percentiles [5]. The patients in each group who survived and had a technically uncomplicated postoperative course were identified (group Al and group Bl,respectively). Ten patients in group Bl were excluded due to incompleteness of data. Body weight, prothrombin time, serum total bilirubin and ALTpreoperatively and postoperatively at days 1 through 7 and.days 14 and 30 were recorded. The prothrombin time values were not in all cases available for postoperative days 14 and 30. In these cases. the mean of the immediately preceding and the following available values were entered. All data are presented as mean ± the standard error of the mean (i + SEM); differences in the mean were tested using Student's t test or X2 for comparison procedure. Actuarial survival rates were calcu-lated by the method of Kaplan-Meier. A Pvalue ofless than 0.05 was considered to be statistically significant. Results Out of all the 130 patients. 35 died (27 % ), 6 in group A and 29 in group B. The primary causes of death in these 35 patients are shown in Table 4. Body weight Sex Liver disease Retrans- Outcome (kg) plantation 5.0 M BA No Alive R.I M BA No Dead 7.3 M Am Yes" Alive 5.7 M BA' Yes Dead 5.9 F BA' Yes Dead 2.7 M NH No Dead 7.4 F BA' No Alive 5.5 F BA" No Dead 5.4 F BAa Yes Dead 5.B M Tyrosinemia No Alive 6.3 M BA' Yes Alive 6.3 M BA' No Alive 7.5 M AS No Alive 3.6 F PNC No Alive 6.5 F BA" No Alive 6.7 M BAa No Alive 6.0 0.3 Table 4. Postoperative complications and deaths in 130 patients. HATX, hepatic artery thrombosis; PVTX, portal vein thrombosis Complications No of patients (deaths) Group A GroupB (n= 16) ,(n=114) Vascular HATX' 5 (2) 10 (4) PVTX I (1) 2 (0) Portal vein rupture 0(0) 1 (1) Vena caval occlusion 0(0) 1 (1) Biliary' 0(0) 11 (0) Others Perioperative deathb 1 (1) 6 (6) Graft nonfunction 1 (1) 6 (3) Bacterial sepsis 0(0) 5 (5) Viral infection 1 (1) 4 (4) Rejection 0(0) 3 (1) Malignancy 0(0) 3 (3) Pulmonary hypertension 0(0) 1 (1) Total 9 (6) 53 (29) , The incidences are significantly different between the two groups (P<0.05) b Complications including intra-operative death or brain death Actuarial survival rates at 1,2, and 3 years postopera-tively were 68%, 68%, and 51 % respectively in group A and 76 %, 74 % and 74 % in group B (Fig. 1, top). Actua-riall-, 2-, and 3-year graft survival rates were 56 %,56 %, and 38 % respectively in group A and 70 %, 68 %, and 67 % in group B (Fig. 1. bottom). None of the differences in patient or graft survival achieved statistical significance (P = 0.37 and 0.19, respectively). o 6 12 18 24 a Month 1MM~--------------------------------~ 80 ; l60 ~ a: 40 20 f 01, 0 b . , '. , , , '-----------.-._----------------_.-6 12 18 24 30 36 Month Fig.I. a Cumulative patient survival rates in group A (n = 16: donor age S 2R days) and group B (n = 114: donor age> 28 days). The dif· ference was not statistically significant (P = 0.37). b Cumulative graft survival rates in group A and group B. The difference was not statistically significant (P = 0.19).-Group A, --- group B Five patients (31 %) in group A underwent retrans-plantation. due in three patients to hepatic artery throm-bosis, in one to primary nonfunction, and in one to he-patitis (Table 2). Two of them were alive at the end of follow-up, including one patient who had a third graft. Nineteen (16%) patients in group B underwent retrans-, plantation, due in ten patients to hepatic artery throm-bosis, in six patients to primary nonfunction, and in three patients to rejection. Of them nine were alive at the end of follow-up. Three patients received a third graft: all three died. Perioperative complications are presented in Table 4. Hepatic artery thrombosis was the most common in group A and its incidence was significantly higher than in group B (31 %, n =5 vs 9%, n= 10, P=O.027). Of the 15 patients who developed hepatic artery thrombosis nine survived. three in group A, of them one without retrans-plantation. and six in group B, of them two without re-transplantation. Three patients developed portal vein thrombosis: one in group A and two in group B. The patient in group A died as a result of this complication. Both patients in group B were alive. one after successful thrombectomy and one other after distal splenorenal shunt. One patient in group B developed portal vein rup-ture due to infection. Biliary complications not associated with hepatic artery thrombosis were more common in group B. but the difference was not significant (p = 0.4). The biochemical profile of the donors in the two groups was similar (mean ALT: 64.2 ± 22.2 vs 79.3±2.1, mean prothrombin time 10.5 ± 0.9 vs 12.8 ± 0.4. respectively) except for the total bilirubin which was 1.7 + 0.5 (0.4-ORIr-----------------------------------~ * * * s ~ Rr_----~~~------------------~~--~ ., ........ -._ .......................................... __ .. a ot---~--~--~--~--~ __ ~ __ ~ __ ~ __ u ~K-----------------------------------~ ~r-------;---------------------------~ i ~ ~r---~===---~----------------------~ ~ ~ ~r-q---------~~~------------------~ -E o E 1Rr-------~~~--~~~~~~~==~==~ (5 ........ ~ 1Mr-----------------------------------~ b Ru---~--~--~~--~ __ ~ __ ~ __ ~ __ _u ~r---------------------------------~ ~r_--------------------------------__4 ~ r ~~r_--------------------------------__4 ............. 1 ...... . c ~ [~h~··_· ':'::: y=~!==D!i .. ':":' =·:!::···.: .= .... t = .. = .. ::!.... ~K~ ..; .. ~ ... ~ ..; .. ;K--~ ... ;.. ;; ..;; ..jJ.f 2 3 4 5 6 7 14 30 Postoperative days 207 Fig.2. a Serum total bilirubin, * P < 0.05. b Prothrombin time. * P < 0.05, ** P < 0.01. c ALT (alanine aminotransferase) in groups Al and BI (patients without complications).-o-Group AI, n = 7: --group B1.n =51 15 oL-------------------------------10 20 30 40 50 Age (months) Fig. 3. Body weight changes in eight patients in group A who sur· vived with their primary grafts during the observation period. Dotted line denotes 50th percentile body weight from the study of the National Center for Health Statistics Percentiles [51 208 8.4)mg/dl in groupA and 0.7±0.1 (O.l-6.7)mg/dl in group B (P < 0.05). Perioperative biochemical values were compared be-tween groups Al (1/ = 7) and B I (n = 51. Fig. 2). Serum total bilirubin levels in days 1 through 14 and prothrombin time for days 1 through 4 were significantly higher in group AI. Serum ALTlevels were not significantly different. Eight of the patients in group A were alive with their primary grafts. The body weight at the time of transplan-tation was below the 5th percentile in six of them. at the 5th-10th percentile in one, and at the 25th-50th percentile in the eight patient. All patients gained weight during the observation period. While three patients remained at the 5th percentile, all others upgraded (Fig.3). Discussion There are two features of neonatal liver transplantation requiring special consideration: technical difficulties due to the small size of the grafts [4], and functional perfor-mance, because neonatal livers are thought to be imma-ture [3,9, 11]. The increased incidence of hepatic artery thrombosis in the patients with neonatal transplants can be seen as a reflection of the technical difficulties encountered [10, 17, 21]. Interestingly, other complications related to the venous or biliary reconstructions did not occur with a greater frequency in the neonatal group. The possible role of immaturity of the graft and delayed function may also be related to hepatic artery thrombosis because of de-creased or absent protein C synthesis by the newly trans-planted liver [6]. Of the liver function tests referred to here, the pro-thrombin time is representative of the synthetic function of the liver and the total bilirubin of its ability to clear metabolic waste products. It appears that neonatal liver grafts gain normal synthetic function within 4-5 qays after transplantation. Older donor grafts normally function im-mediately after transplantation. The ability to clear bili-rubin is even more slowly regained: total bilirubin did not return to normal for 1 month, as compared to 1 week in grafts from older donors. Interestingly, after this slow re-covery, which appears to be characteristic of the neonatal donor livers, the ultimate result is indistinguishable from that of livers from older donors. • Growth of the patients.with liver grafts from neonatal donors appears to be similar to that observed previously in pediatric liv~r transplant recipients [15, 22]. In conclusion. if successful. neonatal liver transplanta-tion can have equally good results as transplantation with livers from older donors. Acknowledgements. Supported by research grants from the Vet-erans Administration and project grant no. DK 29961 from the National Institutes of Health, Bethesda, Md., USA. References 1. Bismuth H. Houssin D (1984) Reduced-sized orthotopic liver graft in hepatic transplantation in children. Surgery 95: 367-370 2. Brolsch CEo Emond Jc, Thistlethwaite JR Whitington PF, Zucker AR, Baker AL, Aran PF, Rouch DA, Lichtor JL (1988) Liver transplantation. including the concept of reduced-size liver transplants in children. Ann Surg 208: 410 .... 420 3. Buchanan GR E1!FT~F Neonatal coagulation: normal phvsiology and pathophvsiology. Clin Haematol7: il5-I09 4. EsqUivel CO. Koneru B. Karrer F. Todo S. Iwatsuki S. Gordon RD. Makowka N. Marsh WJ. Starzl TE (1987) Liver transplanta-tion before one year of age. J Pediatr 1\0: 545 .... 548 5. Hamil PVv. DrizdTA.Johnson CL Reed RB. Roche AF. Moore WM (1979) Physical growth: National Center for Health Statis-tics Percentiles. Am J Clin N ulr 32: 007 .... 02!) 6. Harper PL Edgar PF. Luddinglon RJ, Seaman MJ. Carrel RW. Salt AT. Barnes N. Rolles K. Caine RY (19&;) Protein C defi-ciency and portal thrombosis in liver transplantation. Lancet II: 924-927 7. Kalayoglu M, Sollinger HW, Stratta RJ. D'Alessandro AM. Hoffmann RM. Pirsch JD, Belzer Fa (1988) Extended preserva-tion of the liver for clinical transplantation. Lancet I: 017--619 8. Kalayoglu M. D'Alessandro AM. Sollinger HW. Hoffman RM. Pirsch JD. Belzer FO (1990) Experience with reduced-size liver transplantation. Surg Gynecol Obstet 171: 139-147 9. Maisels MJ (1972) Bilirubin - on understanding and intluencing its metabolism in the newborn infant. Pediatr Clin North Am 19: 447-501 10. Mazzaferro V, Esquivel CO, Makowka L, et aJ (1989) Hepatic artery thrombosis after pediatric liver transplantation: medical or surgical event? Transplantation 47: 971 .... 977 11. Oski FA (ed) (1981) Neonatology. Lippincott. Philadelphia. pp545-582 12.0tte JB, Ville de Goyet J de, Sokal E, Alberti D. Moulin D. Hemptinne B de. Veyckemans F. Van Obbergh L Carlier M. Clapuyt PH. Claus D, Jamart J (1990) Size reduction of the donor liver is a safe way to alleviate the shortage of size-matched organs in pediatric liver transplantation. Ann Surg 211: 146-157 13. Report of the medical consultants on the diagnosis of death to the president's commission for the study of ethical problems in medicine and biomedical and behavioral research (1981) Guidelines for the determination of death. JAMA 246: 2184-2186 14. Shaw BW. Martin OJ, Marquez JM, Kang YG. Bugbee AC, Iwatsuki I, Griffith BP, Hardesty RL, Bahnson HT, Starzl TE (1984) Venous bypass in clinical liver transplantation. Ann Surg 200:524-534 15. Spolidoro JPN, Berquist WE, Pehlivanoglu E. Saluski I. Vargas J. Ament ME (1988) Growth acceleration in children after ortho-topic liver transplantation. J Pediatr 112: 41-44 16. Starzl TE (ed) (1969) Experience in hepatic transplantation. Saunders. Philadelphia. pp 1-545 17. Starzl TE. Iwatsuki S, Van Thiel DH, Gartner JC Zitelli B. Malatack JJ, Schade RR. Shaw BW Jr, Hakala TR. RosenthallT. Porter KA (1982) Evolution ofliver transplantation. Hepatology 2:614--636 18. Starzl TE, Iwatsuki S, Esquivel CO, Todo S, Kam I, Lynch S, Gordon RD (1985) Refinements in surgical technique of liver transplantation. Semin Liver Dis 5: 349-356 19. Teperman L Podesta L. Mieles L. Stanl TE (1989) The success-ful use of older donors for liver transplantation. lAMA 262: 2838 20. Todo S. Fung JJ. Starzl TE, Tzakis A. Demctris AJ. Kormos R. Jain A. Ales;iani M. Takaya S, Shapiro R (1990) Liver. kidney and thoracic organ transplantation under FK 506. Ann Surg 212: 295-307 21. Tzakis AG, Gordon RD. Shaw BW, Iwatsuki S, Starzl TE (1985) Clinical presentation of hepatic artery thrombosis after liver transplantation in the cyclosporine era. Transplantation 40: 667--671 22. Urbach AH. Gartner JC Jr. Malatack JJ. Zitelli BJ. Iwatsuki S. Shaw BW, Starzl TE (1987) Linear growth following pediatric liver transplantation. Am J Dis Child 141: 547-549 23. Zitelli BJ. Malatack JJ. Gartner Je, Urbach AH, Williams L Miller Jw, Kirkpatrick B (1987) Evaluation of the pediatric patient for liver transplantation. ~ediatrics 78: 559-565 ~~;-"D:~~D I!~- ... : " :KK!;ID~ .- .. D~D:"- DI<KI<_~~; .. :-- •• ~1~-¥DK~-~·-"~"""D-D ~"D-K-D ~ - .. : --

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Pediatric liver transplantation from neonatal donors

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