Liver transplantation for children – the red cross children's hospital experience

Pediatr Transplantation 2004: 8: 136–144 Liver transplantation for children – the RedCross Children’s Hospital experience Millar AJW, Spearman W, McCulloch M, Goddard E, Raad J, Rode H, Kahn D, Cywes S. Liver transplantation for children – the Red Cross Children’s Hospital experience.
Pediatr Transplantation 2004: 8: 136–144. Ó 2004 Blackwell Munksgaard Department of Paediatric Surgery, Paediatrics,Medicine and Surgery, Red Cross Children's Hospital, Abstract: Liver transplantation for infants and children has been Institute of Child Health and Medical Research available in South Africa at a single centre, the only established service Council Liver Research Centre, University of Cape in Sub-Saharan Africa, for more than a decade. Current concerns have shifted from an initial target of early post-transplant survival to qualityof life in the long-term. Materials and methods: Since 1985, 225 infantsand children have been assessed, with 146 accepted for transplantation.
Sixty-nine have had 71 orthotopic liver transplants (OLTx). Biliaryatresia was the most frequent diagnosis (54%) followed by acute liverfailure (ALF) (15%). Waiting list mortality has remained high (23%),particularly for the ALF group (50%). Forty-three were reduced sizetransplants with donor: recipient weight ratios ranging from 2:1 to 11:1.
Twenty-seven were <10kg. Results: Fifty (74%) survive 1 month–12 years post-transplant. Actuarial survival after 1996 since HBV coreantibody positive donor livers were refused and prophylactic IVganciclovir used has been >82%. Early post-OLTx mortality was low(5%), one primary non-function, one IVC thrombosis, one PV throm-bosis, but late morbidity and mortality (20%) was mainly due to viralinfection: de novo hepatitis B (five patients, three deaths), EBV-relatedpost-transplantation lymphoproliferative disease (PTLPD) (eightpatients, six deaths) and CMV disease (11 patients, five deaths).
Tuberculosis prophylaxis, required in six cases, resulted in majormorbidity in two and mortality in one. Poor compliance played a sig-nificant role in seven deaths. Hypertension requiring medication along Key words: liver transplantation – children – South with some compromise of renal function has been present in all but two Africa – tuberculosis – hepatitis B – Epstein–Barr patients. However, all those of school-going age (25) attend school virus – cytomegalovirus – human immunodeficiency normally and remain in good health and only three of the survivors have abnormal liver function tests. Conclusions: Successful liver trans-plantation is possible in a developing country with limited resources.
A.J.W. Millar, Red Cross Children's Hospital, Scarcity of virus-free donors (HBV and HIV) leading to waiting list University of Cape Town, Rondebosch 7700, CapeTown, mortality and infrequent re-transplantation along with long-term consequences of immunosuppression (infection, lymphoma and renal toxicity) remain problems. Intense education of the caregiver and close follow-up, particularly of those living at long distances haspartly addressed the compliance problem.
Accepted for publication 30 September 2003 During the early and mid-1980s several SouthAfrican children with end stage liver disease weresent abroad to the USA and UK at great Abbreviations: AZA, azathioprine; CMV, cytomegalovirus; expense, the money in most cases being raised CyA, cyclosporin A; EBV, Epstein–Barr virus; HBV, by public appeal. It was during this time that hepatitis B virus; HIV, human immunodeficiency virus; preparations were made to develop liver trans- INH, isoniazid; IVC, inferior vena cava; OLTx, orthotopic plantation for children at the Red Cross Chil- liver transplants; PCR, polymerase chain reaction; PTLPD,post-transplantation dren’s Hospital, Cape Town. The first children portal vein thrombosis; TB, tuberculosis.
were accepted on to a transplant waiting list as psychosocial factors (parental substance abuse, psychiatric problems), rarely socio-economic factors and parental decision, but most importantly poor compliance with pre- operative therapy. Compliance was most difficult to predictin children with acute hepatic failure as time from presen- tation to transplant was so much shorter. Indications for early transplant were evidence of poor synthetic liver func- tion including prolonged prothrombin time, low serumalbumin and cholesterol, presence of ascites, bleeding from oesophageal varices not controlled by sclerotherapy and failing nutritional status (3, 7, 8). Those with acute hepatic failure who developed encephalopathy, hypoglycaemia, aprothrombin time of greater than 100 s, and factor five level less than 20% were considered for transplant, as almost alldie without transplantation. There were few medical contra- Fig.1. Geographical origin of all patients, referred for indications, however children with disseminated TB, severe consideration for liver transplant since 1985.
cardiac, renal or pulmonary disease, marked neurologicalimpairment, chronic Hep B infection and HIV infectedpatients were not accepted. All patients accepted underwent early as mid-1985. Since then 225 children have intensive medical and nutritional resuscitation to treat been referred for assessment (Fig. 1). The first complications of liver disease, portal hypertension and transplant took place on 6 December 1987 on a nutritional deprivation (3, 10). Immunization status was 6-yr-old girl with end stage liver disease and reviewed and supplemented with Hepatitis A and B, Hinfluenza and pneumococcal vaccine in most cases. The cirrhosis from alpha I anti-trypsin deficiency.
decision as to which waiting list patient to transplant was The patient survived the operation but died from taken at the time a donor presented. In principle, the sickest complications in January 1988. A successful patient was transplanted first with a blood group compat- adult programme was commenced during that ible donor but also taken into account was the best possible year at Groote Schuur Hospital and when this use of the donor organ. This resulted in some patients had become established, the paediatric pro- remaining on the waiting list until their medical conditionhad deteriorated to the extent that they were considered too gramme was restarted in November 1991 (1).
sick to withstand the transplant operation. Of the 146 Liver disease has been generally underestima- children accepted, 33 have died prior to transplant (23%).
ted as a cause of death in children in South These included 17 with biliary atresia and nine with acute Africa as elsewhere. This is probably because hepatic failure. Most of the biliary atresia deaths occurred in many liver conditions in children have led to the early years of our programme, current waiting list rapid deterioration and death in the past (2).
At the time of writing, of the 32 children accepted and However, it has taken at least a decade of hard awaiting transplant only 14 are considered urgent cases. The work to publicize amongst medical colleagues the others have established liver disease but 18 are in good fact that in most cases the only chance of a cure is health at present and would not be transplanted until liver transplantation and that this service was deterioration of growth velocity or complications became available locally (3). Also, that, liver transplan- evident. Six patients have had transplants abroad, three in tation should be considered as an option for USA and three in the UK, four of whom survive, 5 monthsto 17 yr after transplant.
chronic liver disease before the condition of endstage liver disease is realized; thus allowing time for a thorough assessment of the child and thefamily, for full and frank discussions of treat- The surgical techniques used for donor retrieval and ment options and assessment of the family’s recipient liver removal and engraftment have been previ-ously described in detail (1, 4, 5). Because of donor recipient capacity to sustain long-term compliance after height and weight mismatch, reduced sized livers have been transplantation, which is so crucial to the success used since 1992 (Fig. 2) (11). With all reduced size livers and in patients with biliary atresia, choledochojejunostomy hasbeen used for biliary drainage without stents or T-tubes. In most cases of reduced size grafts, the hepatic venous outflowwas anastomosed to the preserved recipient inferior vena Since 1985, 225 children have been referred to our unit for cava with a large, flush, triangular anastomosis to avoid assessment for transplantation. Initially they predominantly venous outflow obstruction (Fig. 2) (12). To overcome the came from the Western Cape Province and were few but disparity in size of the often small and hypoplastic recipient numbers have increased over the last 6 yr, on average 16 portal vein, the right and left bifurcation of the recipient referrals a year, with a greater proportion coming from vein was preserved and opened to make a trumpet-shaped elsewhere in South Africa (Fig. 1). In addition, several orifice to anastomose to the larger donor portal vein or else families have migrated from other provinces so that they the anastomosis was done at the confluence of the splenic could be managed before and after transplantation in close and superior mesenteric veins (13). The arterial anastomoses proximity to our centre. Of these 225 patients, 146 were were in most cases from the recipient common hepatic accepted for transplant. Reasons for refusal included artery to the base of the donor coeliac trunk. The various Right and middle hepatic veins opened. Left sutured or ligated.
IVC incised inferiorly and donor hepatic vein sutured onto this opened at bifurcationand sutured to donor Connective tissue sheath and bloodvessels supplying the hepatic ducts leftundisturbed to preserve blood supply Fig.2. The surgical technique of a left lateral segment reduced size liver transplant.
types of interposed grafts described in other series were not instead of AZA in three patients because of persistent used in any of our cases. Crucial to the success of the rejection with conventional therapy and rapamycin has been operative procedure was good anaesthetic support (14, 15).
used in two patients with chronic rejection and high EB viruslevels. In the last 2 yr anti-CD25 antibodies have been used weight < 20kg, daclizumab 1 mg/kg/dose) both as a two dose regimen (20). Later conversion from cyclosporin totacrolimus was prompted in a few cases because of cosmetic CyA (5 mg/kg) was given immediately prior to the operation side effects of gingival hyperplasia and hirsutism.
and was continued in the post-operative period initiallyintravenously but since 1997 as an oral dose using cyclosp-orin emulsion (Neoral) (Novartis), given as a three times a day dosage aiming for a trough level of around 350ng/mLinitially and currently a 2 h peak level of >1000 ng/mL (17– Fungal prophylaxis was given prior to transplant as 19). Dosage was adjusted frequently in the post-operative mycostatin orally and after transplant, amphotericin B period as particularly in small children, absorption was er- lozenges were added and continued over a period of several ratic with diarrhoea and rejection and low CyA levels being a months. Infants in poor condition with prolonged pre- recognized association. AZA (1–2 mg/kg) and methyl- prednisolone (10mg/kg) were given at the time of reper- amphotericin for 2–3 wk. From 2–3 wk after transplant for fusion of the graft. The methylprednisolone doses were at least the first year, trimethoprim/sulphamethoxazole was reduced over the first week to 1 mg/kg for the first month given at a dose of 6 mg/kg a day in two divided doses 3 days and then further reduced to a level of 0.2 mg/kg as main- a week for prevention of pneumocystis carinii infection. As tenance. This was later reduced in some patients to alternate oral therapy has been found to be less effective, intravenous day therapy or even withdrawn. The AZA dose 0.5–1 mg/kg gancyclovir 5 mg/kg per dose 12 hourly was given as viral was monitored keeping the leukocyte count above 4000/mm prophylaxis against CMV and EBV infection, initially for (2) and was continued for at least 6 months. Tacrolimus was 2 wk but currently this is continued for up to 3 months in used as rescue therapy if an acute rejection did not respond high risk patients not previously exposed to EBV in an to three or four daily pulses of methylprednisolone attempt to prevent post-transplantation lymphoproliferative 10mg/kg/dose and recently with compatible but not disease (PTLPD). (25) Either hyperimmune CMV globulin identical blood types. Mycophenolate mofetil was used or immunoglobulin in the form of Polygam (Natal Blood Transfusion Service) was given to assist viral prophylaxis.
Leucocyte filtered blood products were used since 1995 toreduce CMV viral load. Prophylactic antibiotics were given with induction of anaesthesia and continued for 3–5 days.
Since 1991, 71 transplants have been carried out These were changed according to cultures taken of blood,secretions, sputum and urine. Anti-TB prophylaxis was on 68 patients of whom 46 were black and 22 given only if the reason for transplant was a reaction to anti- white (Fig. 3). Thirty-three were female and 25 TB drugs, where evidence of TB was found prior to surgery male. The mean weight was 18 kg with a range of or if close family contact was recorded. Ofloxacin, 4–53 kg. Twenty-five were less than 10kg in rifampicin and ethambutol or ethionamide was used in weight (37%). The mean age was 5.3 yr with a addition to INH but very careful monitoring of liver func-tion tests was required because of both drug induced hepatic range of 6 months to 14 yr. Patient diagnoses toxicity and decrease in levels of cyclosporin or tacrolimus and survival are listed in Table 1. There were due to enzyme p450induction with increased drug meta- three retransplants, one for acute fulminant rejection and two for chronic rejection. Themean anaesthetic time was 10h with a range of 7–16 and the mean volume of blood transfused Post-operative management was according to protocol (3, was 2.5 blood volumes with a range of 0.5–5.7.
28). Patients were usually weaned off the ventilator within Blood group crossmatch was identical in 53, the first 48 h. Liver ultrasound with a colour flow doppler compatible in 15 and blood group B to O in was performed frequently to confirm vascular patency and three. The mean donor liver ischaemic time was absence of biliary dilatation. Liver biopsies were performed 8 h with a range of 5–16 h. Reduced size liver if indicated by increasing serum liver enzyme activity or transplants were performed on 42 occasions, bilirubin levels by means of the Menghini technique [Hep-afix needle (Braun) diameter 1.4 mm] unless biliary dilata- which included the left lateral segment in 23, the tion was observed on ultrasonography. Biopsies were left lobe in 15 and the right lobe in four. Donor routinely assayed for viral and bacterial activity.
recipient weight ratios averaged 3.4:1 with a Diagnosis of rejection was made on the basis of clinical, range of 2:1 to 11:1. Three patients received a biochemical and histologic criteria (29). The grade of whole liver and a kidney graft for primary rejection was according to established histologic criteriabeing graded from 0to 4. Rejection was treated with four hyperoxaluria in two, and polycystic disease in doses of methylprednisolone 10mg/kg, the first three on one. We have performed one living related successive days and then the fourth dose on the fifth day after commencing treatment. If rejection persisted, the All patients survived the operative procedure.
immunosuppressive protocol was changed to tacrolimus at a Currently, of the 68 patients transplanted, 50 starting dose of 0.3 mg/kg per day in two divided doses to survive (74%), 2 months to 12 yr post-trans- obtain a trough level of 10–15 ng/mL initially.
Hypertension, which was present in all of our patients was plant. Forty-seven of these are in excellent health managed initially with nifedipine as required in conjunction (Fig. 4). Three have persistent liver dysfunction with diuretic agents and subsequently enalapril or amlodi- pine in the appropriate dosage (30). Aspirin 3 mg/kg was convalescing after recent transplant. The causes given on alternate days as prophylaxis against hepatic and timing of deaths are listed in Table 2 and can arterial thrombosis along with sucralfate initially and lat- be divided into those occurring early after terly omeprazole for gastric mucosal protection (31).
Nutrition and vitamin supplementation was commenced transplant which were predominantly related to usually within 72 h of surgery and was supplemented by the operative procedure itself and those occur- nasogastric feeding or parenteral nutrition in the early phase ring later on, which were predominantly due to if there was delay in restoration of bowel function. Mag- the consequences of immunosuppression or of nesium and phosphate deficiency required replacement immunosuppressive failure but in one case of Table 1. Primary diagnosis of recipients from 1991 to 2003. Sixty-eight patients Table 2. Current status of transplant patients 1991–2003, n ¼ 68 requiring 71 transplants with 50 surviving (74%) PTLPDs (n ¼ 6)Chronic rejection (n ¼ 2) bleeding oesophageal varices, the consequence ofa PVT which occurred shortly after transplant.
sion and subsequent uncontrollable bleeding varices 6 months post-transplant. Two other bile Fortunately these have been relatively few. Hep- leaks occurred. The first patient developed a bile atic artery thrombosis occurred on one proven leak on the 8th day post-surgery which was occasion and one suspected. The first patient successfully repaired and another reduced size developed a bile leak 1 month post-transplant, liver transplant had bile stained ascites, which which was successfully treated with revision resolved spontaneously. Two patients developed IVC thrombosis, the first, 6 months post-trans- child, an infant of under 10kg in weight, devel- plant probably secondary to chronic rejection and oped fulminant hepatic failure 3 wk post-trans- enlargement of the donor graft with distortion of plant and no cause was identified. The hepatic the IVC anastomosis. The second developed an artery was seen to be pulsating on ultrasound.
IVC thrombosis in the immediate post-operative Post-mortem examination was refused. Histology period shortly after an acute rejection episode, of a needle biopsy showed a massive fallout of which had resulted in significant graft swelling.
liver cells, which was in keeping with either an Both patients were treated with thrombolytic ischaemic, toxic or viral injury. PVT occurred on therapy, the first successfully but the second three occasions, two of which were repaired developed significant bleeding from the cut edge successfully and the third led to portal hyperten- of the reduced size graft and sepsis and died Fig.4. Pediatric liver transplan-tation: cumulative proportion surviving (Kaplan–Meier), Nov1991–1995 vs 1996–2003. The 1996 – Aug 2003 (n = 47)
divided into those receivingtransplants before 1996 and after. Current expected 5 yrsurvival is >80%.
Nov 1991 – 1995 (n = 22)
shortly after. At post-mortem, however, there was which was described as polyclonal in four, no visible thrombus in the vena cava. Post- monoclonal in two and T-cell lymphoma in two.
operative gastrointestinal bleeding occurred in Management strategies included adenotonsil- three patients. One ceased spontaneously, an- lectomy, reduction of immunosuppression and in other required laparotomy and was found to be two complete withdrawal (24, 25). Three received bleeding from the Roux-en-Y anastomotic site chemotherapy and these three died within 10wk and the third bled uncontrollably from a large of diagnosis. Three died despite significant ulcer in the lower oesophagus secondary to pretransplant sclerosant injection for control of patients have made a complete recovery although one required retransplant for chronic rejectionafter total immunosuppression withdrawal. Thusoverall there was a 14% incidence of PTLPD with a 75% mortality. Currently, pre-emptive Most could be discharged from the intensive care intravenous gancyclovir therapy given for at least unit within the first week after transplantation 3 months to high risk children and PCR viral although in practice this was delayed because monitoring only available in the last year, has so logistical problems of a full surgical ward.
far been effective management (23, 25).
Bacterial infection in the post-transplant period Hepatitis B de novo infection has occurred in was frequent but had surprisingly little morbidity five children and resulted in three deaths.
and only one suspected mortality. The only Although not proven, these almost certainly systemic fungal infection was the first transplant were acquired from the donor liver as prior to in 1987 who died of a ruptured mycotic (Can- 1996 donor livers were not tested for HBV core dida) aneurysm at the hepatic arterial anastomo- antibody and since excluding HBV core antibody sis. Minor skin infections have been frequent and positive donors, we have not seen a case (35). Of have been treated with local anti-fungal agents these five patients, three developed HBV hepati- and fluconazole. Viral infections, however, have tis post-transplant and have died of severe been a problem with major morbidity and late progressive chronic active hepatitis. The other mortality (25, 30, 32–34). CMV is endemic in our two survivors have responded very well to anti- population and 90% of donors carried the virus viral therapy using initially famciclovir and (34). CMV disease occurred in 11 patients (13 currently, lamivudine with reduction of HBV transplants) and CMV infection in a further 12.
Five of 11 patients with CMV disease died. The below recordable levels (32, 36, 37). One patient site of the CMV disease was the lung in four, however escaped initial control and being poorly liver in seven and pancreas and gastrointestinal compliant, developed DNA levels in excess of tract in one each. Initially the diagnosis was made using serology and cultures but from 1995, All children have received some form of anti- the CMV PP65 antigen test became available.
hypertensive therapy in the post-transplant per- Particularly at risk were patients with poor iod. As a degree of renal impairment is almost clinical status prior to transplantation and those inevitable with patients suffering from severe who required steroid pulses for more than one chronic liver disease and with the additional rejection episode. EBV infection has also resulted burden of use of the nephrotoxic calcineurin in significant morbidity and mortality. Ten chil- inhibitors, cyclosporin and tacrolimus for immu- dren developed EBV infection and eight subse- nosuppression, most children continue to require quent PTLPD. All were transplanted for biliary at least one anti-hypertensive agent (30). When atresia following a failed Kasai procedure. The the doses of steroids were reduced and cyclosp- development of PTLPD in five patients followed orin and tacrolimus levels were allowed to settle a typical acute membranous tonsilitis with asso- to the lower therapeutic range, less anti-hyper- ciated cervical lymphadenopathy. Mean time to development of PTLPD in these children was All surviving children of school-going age (25) 9.2 months, with a range of 3–30months post- attend school normally and participate in normal transplant. Three of the eight children were EBV sporting and recreational activities. Three chil- nuclear antigen positive at the time of transplant dren transplanted for biliary atresia, have learn- and all were positive at the time of diagnosis of ing difficulties and attention deficit disorder and require special schooling but are physically fully included four tonsillar, one intestinal, two gas- rehabilitated (38). All eight children transplanted trointestinal tract and one central nervous system for fulminant hepatic failure made a complete involvement. Histology confirmed the diagnosis, neurologic recovery after transplant.
The overall cumulative 5 yr survival is around recent years. The premorbid clinical state had 60% but the projected survival since 1996 when significant detrimental impact on the subsequent aggressive anti-viral prophylaxis was started outcome following surgery (3, 7, 8, 41). The along with exclusion of HBV c AB +ve donors increasing evidence that patients with cholestatic and a more pro-active follow-up programme is liver disease early on in life have nutritional deficiencies which render them at risk for neuro-developmental impairment was confirmed being present in four of our longer-term survivors (38,42). There is thus a need for earlier referral and Careful planning, extensive preparation of per- transplantation in these children. We have made sonnel and a broad base of skills along with it an absolute requirement that any patient excellent team work between adult and paediatric referred would need caring health professionals health professionals allowed for the development to take on the responsibility of looking after that of a successful paediatric transplant programme patient on return to his/her home following (3–5). Further improvements in surgical tech- successful transplantation. Current methods of nique, anaesthetic skills, medical care and immu- improved management and long-term follow-up projected 5 yr survival to greater than 80% and much longer survival in good health is clearly Endemic viral and bacterial infections partic- possible and should become the norm in the ularly CMV, EBV and TB have had a significant future. These results are equivalent to other negative impact on our programme (32–34, 36, reported series (39, 40). However, liver trans- 43). Specifically the strategies of anti-viral pro- plantation remains an extremely demanding tection have required extended hospital stay and surgical procedure with many potential early are clearly expensive, but fortunately seem to be and late complications (41, 42). Most of the effective in preventing CMV disease and the serious complications occurred in the first few consequences of EB virus infection or reactiva- months after operation and many of these could have been avoided with meticulous attention to Hepatitis B acquired after liver transplant is a technical detail and intensive prophylactic meas- tragic occurrence and in our experience is not a ures. The regrettable need for immunosuppres- benign disease. Evidence that most were acquired sive therapy with all its consequences along with from HBV core antibody positive donors is immunosuppressive failure still remain major overwhelming. One published series quotes a stumbling blocks to an uneventful post-operative greater than 80% conversion rate (35). In two of course. After the first few months post-transplant our five patients anti-viral therapy has been complications usually resulted from immunosup- effective in reducing viral DNA levels but eAg pressive therapy whether this was infection, remains positive in both (37). Since 1996, when usually viral, or from the toxic effects of the we introduced HBV core Ab screening for liver drugs themselves (30). All three children receiv- transplants we have not seen a further case.
ing liver and kidney grafts have done well. One TB with its very high endemic incidence in the older child (10yr) with hyperoxaluria continues South African population (150–200 per 100 000) to receive overnight hydration via button gas- is a constant hazard to any immunosuppressed trostomy. The one child transplanted for mult- child. Careful screening of the child and family isectoral hepatoblastoma had portal vein tumour pretransplant is necessary. Prophylaxis or full treatment can be successfully carried out but apparent complete surgical clearance developed hepatotoxicity and markedly reduced cyclosporin multiple hepatic metastases 3 months post-trans- levels which may require up to five times increase plant. Her tumour showed evidence of vascular in dosage are potential dangers and should be invasion on histology and did not respond well to cisplatinum and adriamycin chemotherapy. At The costs of our transplant programme are the time of writing, she has an enlarging liver and difficult to quantify but detailed costing of some of no further anti-tumour therapy is contemplated.
our patients has indicated that an uncomplicated Patients have been referred from all over South transplant costs in the region of 20 000 US$ for the Africa and clearly this dislocation from family, first 3 months and thereafter approximately 500– friends and workplace has had major emotional 1000 US$ per month for the first year. The costs of and financial implications. Initially referrals fre- immunosuppression medication are significant quently occurred when the child was in very poor but decrease, as smaller doses are required.
condition, however this has been less frequent in Complications after transplantation and retrans- receiving liver transplants is likely to increase.
plantation become very expensive thus we have There will thus be an increasing need for a wider attempted to transplant those children who would involvement of local medical and surgical teams likely benefit most from the procedure. This has and perhaps the development of other transplant meant in some instances that patients on the centres in South Africa to cater for this demand.
waiting list in a poor medical condition have been As with any new development, knowledge and overlooked in favour of those in better health but experience improves, costs decline, application still with irreversible liver disease. Also retrans- increases and success is ensured (51).
plantation has rarely been an option because ofdonor scarcity. Compliance with regard to medi- cation and follow-up is an absolute requirementfor success. This is easier to predict pretransplant The support and enthusiasm of our anaesthetic and medicalcolleagues and nursing personnel is greatly appreciated.
in those with chronic liver disease than those who They have been an integral part of the transplant manage- present with fulminant hepatic failure. Poor socio- ment team from the commencement of the programme.
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NOTE: Pages in each section start with #1. Therefore, the pages go section 1 page 1, section 1 page 2, etc. Section 1 PROTOCOL ACKNOWLEDGMENT AND AUTHORIZATION Standing Medical Orders and Treatment Protocols . 1.2 Section 2 ADVANCED CARDIAC LIFE SUPPORT GUIDELINES Asystole . 2.2 Bradycardia (Heart rate < 60 beats per minute). 2.4 Tachycardia (heart rate > 100 beats per minute

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