32
REVIEW ARTICLE
Liver transplantation for acute hepatic failure?
In the absence of definitive medical treatment for fulminant hepatic failure, liver transplantation may be appropriate in selected patients. However, uniform and easily applicable criteria for diagnosis of severity and analysis of results are needed to prevent unnecessary transplantation and to ensure that patients who may benefit are appropriately treated. Previous regimens for treatment of fulminant hepatic failure were often advocated, on the basis of data from historical controls, for several years until controlled trials failed to show any benefit. To obtain reliable information more rapidly than achieved before, a controlled trial between specialist liver transplant units is needed to establish the role of emergency hepatic transplantation in patients with fulminant hepatic failure. Lancet 1990; 335: 32-35. severe
Introduction Fulminant hepatic failure, as defined by Trey and Davidson,l is the development of encephalopathy within 8 weeks of the onset of hepatic symptoms, in the absence of underlying chronic liver disease. Fulminant hepatic failure is commonly divided into four grades (I-IV), and the prognosis of patients with grade ill or grade IV disease remains poor: even in specialist units, mortality exceeds 50% and in some series approaches 90%. Several largely independent factors influence survival, including age, the cause of liver disease, the depth and duration of encephalopathy in relation to onset of symptoms, and the prevention of complications.6 O’Grady et aF recently emphasised the importance of the underlying cause of liver failure: despite similar intensive medical support, and independently of use or duration of charcoal haemoperfusion, survival was more likely in patients who had taken a paracetamol overdose (53%) or who had hepatitis A infection (67%) than in patients with hepatitis B infection (39%), presumed non-A, non-B hepatitis (20%), or other drug-induced reactions (12%).
Medical treatment of fulminant failure
hepatic
Patients with fulminant hepatic failure are often young and previously healthy: if they survive, their livers may well
completely to normal. But how can survival be improved? Over the years many intensive treatments have been used, including corticosteroids, exchange transfusion, extracorporeal pig-liver perfusion, plasmapheresis, haemodialysis, heparin, and charcoal haemoperfusion. All these treatments have had a logical basis and had some early claims to success but, with further experience, enthusiasm has generally been replaced by pessimism.8 Corticosteroids, for example, were first used for fulminant hepatic failure with "encouraging results" in 1952,9 but the first controlled observations were not published until 1974. Four return
randomised controlled trials have since found no benefit from corticosteroid treatment’0-13 and there was even a suggestion, when results of three studies were combined, that such treatment might be harmful.13 Exchange transfusion was first described for the treatment of fulminant hepatic failure in 1966:14 5 of 7 patients survived, and both those who died briefly regained consciousness. For several years, exchange transfusion was widely accepted as beneficial but, in 1973, the first randomised controlled observations failed to show any benefit;15 before long the procedure was abandoned. Again, when haemodialysis with a polyacrylonitrile membrane was introduced, the initial, uncontrolled observations appeared to show some benefit (8 of 24 survived; 33%) over conservative management alone.16 However, this form of treatment did not gain wide acceptance (Opolon et all found only 9 of 41 [22%] survived), and was abandoned without formal assessment-as were the use of pig-liver perfusion, plasmapheresis, and heparin. After a case report by Chang in 1972,18 there was optimism that charcoal haemoperfusion might be beneficial in the treatment of patients with fulminant hepatic failure. Early uncontrolled studies showed favourable results when compared with historical controls: in one early report by Gazzard et al/9 10 of 22 such patients (45%) survived after treatment with charcoal haemoperfusion. Gimson and colleagues2o described 29 survivors from 76 patients (38%) ADDRESSES. Department of Gastroenterology, John Radcliffe Hospital, Oxford (R W. Chapman, MD); ICRF Cancer Epidemiology Unit (D. Forman, PhD) and ICRF/MRC Clinical Trial Service Unit (R. Peto, FRS), Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, UK; and Gastroenterology Unit, Austin Hospital, Heidelberg, Victoria, Australia (Prof R Smallwood, MD). Correspondence to Dr R. W. Chapman, Department of Gastroenterology, John Radcliffe Hospital, Oxford OX3 9DU, UK.
33
with fulminant hepatic failure. Compared with historical controls, the results seemed at first to be so encouraging that it was deemed unethical to withold charcoal haemoperfusion from such patients in the course of randomly controlled clinical trials.20 The procedure did not, however, gain widespread acceptance: some 16 years (and 500 treated patients) after the first report, the results of the first controlled trials were published.7 In the first part of the study, 75 patients with grade III encephalopathy were randomised to receive either 5 hours or 10 hours of charcoal haemoperfusion daily: overall survival rates were similar (51 % vs 50%), as was the frequency of major complications. Subsequently, 62 patients with grade iv encephalopathy on admission were randomised to receive no perfusion or 10 hours of haemoperfusion daily: overall survival rates were again similar (39% vs 34%, respectively). These differences were not significant and were much less striking than had been expected from non-randomised comparisons. Over the past 15 years, the progressively improved survival of patients with fulminant hepatic failure may be due largely or wholly to advances in conventional intensive care.
Early results of liver transplantation As enthusiasm for charcoal haemoperfusion diminished, the success of liver transplantation for chronic end-stage liver failure21 encouraged liver transplant units to consider its use in acute liver failure. Unlike charcoal haemoperfusion, liver transplantation has been taken up with great enthusiasm by many units in Europe, the United States, and Australia.8,22 Successful orthotopic liver transplantation for acute hepatic failure requires an established liver transplant unit and careful patient selection but, in some technical aspects, the operation may be less difficult in patients with acute rather than chronic liver disease because there are no large collateral veins associated with longstanding portal hypertension. The severe coagulopathy that invariably occurs in patients with fulminant hepatic failure can usually be controlled by fresh frozen plasma and platelet infusions. Early published results of liver transplantation in fulminant hepatic failure ,23-27 are shown in the table. At first sight, the results again appear favourable compared with historical controls: in studies since 1973,7,16,17,19,20 104 of 267 patients (39%) survived on medical treatment. The mean survival in transplanted patients is just over 50%, while that in the few patients who satisfied criteria for transplantation, but were not operated upon, is about one-third (see table). However, in the absence of controlled data there is considerable potential for bias in favour of transplantation. First, patients have to be fit enough to reach a transplant unit, and the patients at highest risk may not be referred for transplantation by the admitting hospital. Secondly, the mean age of such transplant recipients is low; patients over 60 were excluded from one study, and younger patients are more likely to be referred for transplant on emotional grounds. Thirdly, some high-risk patients will have been considered unfit for surgery by the transplant team. The cumulative effects of these biases may be substantial: in Vickers and colleagues’ series,26 for example, patients with unreactive pupils, absent brainstem reflexes, or absent cerebral electrical activity on electroencephalography for at least 48 h were regarded as having irreversible neurological damage and excluded from transplantation. Bismuth et al24 reported a 74% survival rate, but 12 of their 17 patients had grade I or grade IIhepatic coma: by contrast, survival of 18 of 19 conservatively treated patients with grade I or grade II
encephalopathy has been reported.26 Thus far, the closest approach to a controlled trial was reported by Vickers and co-workers.26 26 patients with fulminant hepatic failure were thought to merit transplantation: 9 of 16 (56%) who received a transplant survived, compared with 4 of 10 patients (40%) for whom a donor liver did not become available. This comparison is not large, is not statistically significant, and does not constitute unequivocal evidence that transplantation is beneficial. Need for a controlled trial There is general agreement that patients with fulminant hepatic failure in grade IV coma who have unreactive dilated pupils, absent brain-stem reflexes, and absent cerebral electrical activity on electroencephalography for 48 h will not respond to any treatment.26 For patients with less profound neurological dysfunction, however, the prognosis is more variable and poor prognosis is not necessarily equivalent to a need for transplantation. Bernuau et al28 described two indicators of imminent death in patients admitted with fulminant hepatic failure: rapid deterioration of the neurological status of patients from grade I to grade III coma, and a coagulation factor V concentration below 20% of the normal value; the presence of both features is associated with a mortality of 95%.28 O’Grady et al29 used multivariate analysis on over 600 patients with fulminant hepatic failure to identify features associated with a poor survival, which were: age above 40 or below 11years; delay between the onset of jaundice and onset of encephalopathy (the longer the delay, the worse the prognosis); serum
above 300 mmol/l; and an uncorrected prothrombin time of greater than 100 (in patients who have taken a paracetamol overdose, an arterial pH below 7-2 is also closely associated with a poor prognosis). A score can be derived which, in their patients, closely predicts the risk of death. However, neither set of prognostic indicators has been assessed in other units and standard assessments of the severity of fulminant hepatic failure will be required for accurate comparisons to be made between units. Is a controlled trial of transplantation versus medical treatment of severe fulminant hepatic failure really necessary? Liver transplantation is expensive, timeconsuming, and labour-intensive, and patients, usually young, who survive transplantation require life-long immunosuppression-with its associated clinical care, expense, and complications. Without transplantation, fulminant liver failure may be completely reversible and those who recover spontaneously can expect a normal life. We therefore believe that it is essential to seek clear evidence that transplantation improves outcome and, if possible, to determine which patients are most likely to benefit. In the light of the experience gained from charcoal haemoperfusion, Berk and Goldberg3O have recently
bilirubin
NON-RANDOMISED COMPARISONS OF SURVIVAL AFTER LIVER TRANSPLANTATION FOR FULMINANT HEPATIC FAILURE
’Includes patients in grade 1/11 coma; tincludes subacute liver failure Results shown as survivors/total %. NA=not available.
34
restated the drawbacks of non-randomised or historical controls in the assessment of a new treatment. They quote an editorial written 10 years before the evaluation of charcoal haemoperfusion with controlled trials,31 in which Berk stated "It should be emphasized that nonnon-randomized controls simply will not contemporaneous, do. Differences in patient material or in subtle aspects of supportive care may greatly influence the outcome". This statement has particular relevance to assessment of treatment of fulminant hepatic failure because, over the last 15 years, advances in the treatment of cerebral oedema, renal failure, and other haematological and cardiovascular complications of hepatic failure have greatly improved survival. Chalmers32 has also stressed the need for controlled studies in surgery, even when anecdotal evidence appears to be strong. He cites the example of the use of portocaval shunt surgery for the control of portal hypertension, which was not tested systematically until thousands of patients had been surgically treated over about 20 years. Many clinicians were fooled by comparison with historical controls, and an accurate analysis of the technique emerged only after the use of randomised trials which failed to show a benefit in patients treated by portocaval shunt surgery. The arguments used against a randomised controlled trial
in patients with fulminant hepatic failure have some similarities to those recently advanced to "justify" the failure to conduct reliable clinical trials in patients with AIDS. Most patients with fulminant hepatic failure are young and previously fit, most patients in grade III and IV coma will die despite intensive medical therapy, and published survival figures after transplantation are encouraging. However, in patients with fulminant hepatic failure, from previous experience, such arguments are relevant only if the improvement in survival is real (which it may not be), and sufficient to outweigh those patients (over a third) who would have recovered completely but received a transplant and thereby became permanently dependent on
immunosuppressants. The "uncertainty
principle" design
in ethical
study
Random assignment of a patient to a non-transplant group when the clinician strongly believes that transplantation would improve the prognosis would be ethically
unacceptable. Similarly, to perform a transplant on a patient in whom such treatment is strongly believed to be inappropriate would be equally wrong. Participation in any randomised clinical trial is appropriate for a particular patient if-and only if-for that patient the clinician responsible is substantially uncertain about the likely benefit or appropriateness of intervention. The crucial question, therefore, is whether a valid trial of transplantation can be organised within the limits of clinical uncertainty in patients with fulminant hepatic failure. All clinicians involved in the treatment of fulminant hepatic failure would be able to identify patients for whom they are reasonably certain that transplantation would be contraindicated--either because the coma is relatively mild and medical recovery seems highly likely, or because coma is extremely severe and the prognosis hopeless. Many clinicians, especially those in liver transplant units, may also be able to identify patients for whom they are reasonably certain that transplantation is indicated. There may be some clinicians who will confidently assign virtually all their patients to one or other group and treat them accordingly. Many clinicians,
may have an intermediate group of patients for whom they are substantially uncertain as to the possible benefits of transplantation. It should be possible to organise a randomised trial of transplantation for these patients in the intermediate group, even though participating centres will almost certainly use very different criteria to define their areas of uncertainty. Indeed, clinicians within one centre may have different opinions and change their views over the years as new evidence accumulates. The laxity of the entry criteria for such a study need not introduce any bias; indeed, only if the patients entered into such a study are heterogeneous will a trial be able to identify those for whom greatest benefit is achieved. However, standard assessments of severity and outcome would be essential. The central question to be addressed by such a trial is whether entry to an acute liver transplantation programme improves the prognosis in distinct groups of patients with severe fulminant hepatic failure. In general, therapeutic trials compare the effects of adopting different treatment policies (to be implemented wherever possible), rather than direct comparison of treatments. 33 The primary comparison would, therefore, be of active recruitment into a transplantation programme, with surgery as soon as a suitable donor is found (unless overriding reasons not to operate were thought to have developed), against a conservative treatment policy (unless an overriding reason for transplantation was thought to have developed). Patients would remain in the policy group to which they are originally randomised even if, in the transplant group, no donor organ becomes available. The initial comparison would be between transplantation policies33 and not between patients with and without transplanted livers; subsequent comparisons may add supplementary information later. Each centre would have to be able to offer intensive medical support to patients in both arms of the trial. A strict mortality follow-up for all randomised patients would be necessary, but could be done indefinitely through national mortality records, without inconvenience to patients or doctors. All centres would have to be part of a network that could guarantee donor organs for a large proportion of the patients assigned to the transplant group, but this would surely be advantageous for all parties. How many patients would be required to obtain a clear result? If survival in non-transplanted patients is about 40%, then a trial in which 300 patients are randomised would have a 95 % chance of detecting a 20 % improvement (to 60% survival) at p=0-05, and an 80% chance of detecting such an improvement at p = 0 001. A 15% improvement (to 55% survival), similar to the smallest degree of improvement that is claimed by some centres, could likewise be detected with 550 patients. The numbers involved, although large, might be feasible in the context of an international collaborative study of the benefit of entry into a transplantation programme. Larger numbers would, however, be necessary to determine which patients with fulminant hepatic failure are most likely to benefit.
however,
REFERENCES 1.
Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F, eds. Progress in liver disease, vol III. New York: Grune & Stratton, 1970: 282-90. 2. Tygstrup N, Ranek L. Fulminant hepatic failure. Clin Gastroenterol 1981; 10: 151-208.
O’Grady J, Ede RJ, et al. Late onset fulminant hepatic failure; serological and histological features. Hepatology 1986; 6:
3. Gimson AES, 288-94.
35
SM, Ludwig J, Baldus WP. Fulminant hepatitis; Mayo clinic experience with 34 cases. Mayo Clin Proc 1985; 60: 289-92. 5. Christensen E, Bremmelgaard A, Bahnsen M, Andreasen PB, Tigstrap N. Prediction of fatality in fulminant hepatic failure. Scand J Gastroenterol 1984; 19: 90-96. 6. Tygstrup N, Rannak L. Assessment of prognosis in fulminant hepatic failure. Semin Liver Dis 1986; 6: 129-37. 7. O’Grady JG, Gimson AES, O’Brien CJ, et al. Controlled trials of charcoal haemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988; 94: 1186-92. 8. Editorial. Transplantation for acute liver failure. Lancet 1987; ii: 1248-49. 9. Ducci H, Katz R. Cortisone, ACTH and antibiotics in fulminant hepatitis. Gastroenterology 1952; 21: 357-74. 10. Ware AJ, Jones RE, Shorey JW, Combes B. A controlled trial of steroid therapy in massive hepatic necrosis. Am J Gastroenterol 1974; 62: 4. Rakela J, Lange
130-33. 11. Redeker AG, Schwartzer IL, Yamahiro HS. Randomisation of corticosteroid therapy in fulminant hepatitis. N Engl J Med 1976; 294: 728-29. 12. Gregory PB, Knauer CM, Kempson RL, Miller R. Steroid therapy in severe viral hepatitis. N Engl J Med 1976; 294: 681-87. 13. European association for the study of the liver. Randomized trial of steroid therapy in acute liver failure. Gut 1979; 20: 620-23.
14. Berger RL, Liversage RM, Chalmers TC, Graham JH, McGoldrick DM, Stohlman F. Exchange transfusion in treatment of fulminating hepatitis. N Engl J Med 1966; 274: 497-501. 15. Redeker AG, Yamahiro HS. Controlled trial of exchange-transfusion therapy in fulminant hepatitis. Lancet 1973; i: 3-6. 16. Silk DBA, Hanid MA, Trewby PN, et al. Treatment of fulminant hepatic failure by polyacrylonitrile-membrane haemodialysis. Lancet 1977; ii:
20. Gimson
AES, Braude S, Mellon PJ, Canalese J, Williams R. Earlier charcoal haemoperfusion in fulminant hepatic failure. Lancet 1982; ii: 681-83. 21. Bismuth H, Caistang D, Ericzon BG, et al. Hepatic transplantation in Europe. Lancet 1987; ii: 674-76. 22. Powell LW. Liver transplantation: an update for physicians. Aust NZ J Med 1989; 19: 369-77. 23. Ringe B, Pichlmayr R, Lauchart W, Muller R. Indications and results of liver transplantation in acute hepatic failure. Transplant Proc 1986; 18 (suppl 3): 86-88. 24. Bismuth H, Samule D, Gugenheim J, et al. Emergency liver transplantation for fulminant hepatitis. Ann Intern Med 1987; 107: 337-41. 25. Peleman RR, Gavaler JS, van Thiel DH, et al. Orthotopic liver transplantation for acute and sub-acute hepatic failure in adults. Hepatology 1987; 7: 484-89. 26. Vickers C, Neuberger J, Buckels J, McMaster P, Elias E. Transplantation of the liver in adults and children with fulminant hepatic failure. J Hepatol 1988; 7: 143-50. 27. Emond JC, Aran PP, Whitington P, Broelsch CE, Baker AL. Liver transplantation in the management of fulminant hepatic failure. Gastroenterology 1989; 96: 1583-88. 28. Bernuau J, Goudeau A, Poynard T, et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986; 6: 648-51. 29. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439-45. 30. Berk PD, Goldberg JD. Charcoal haemoperfusion. Gastroenterology 1988; 94: 1228-30. 31. Berk PD. Artificial liver: a baby delivered prematurely. Gastroenterology
1-3.
1978; 74: 789-90.
17. Opolon DP, Nusinovici V, Grainger A, Darnis F. Treatment of encephalopathy during fulminant hepatic failure during haemodialysis with high permeability membrane. Gut 1978; 19: 783-93. 18. Chang TMS. Haemoperfusion over a microencapsulated absorbant in a patient with hepatic coma. Lancet 1973; ii: 1371-72. 19. Gazzard BG, Portmann B, Weston MJ, et al. Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Lancet 1974; i: 1301-07.
32. Chalmers TC. Randomized clinical trials in surgery. In: Vargo RL, Delaney JP, eds. Controversies in surgery. Philadelphia: Saunders, 1976: 3-11. 33. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised trials requiring prolonged observation of each patient. Part 1: design. Br J Cancer 1976; 34: 585-612.
VIEWPOINT Medical
One of the
litigation and the quality of care
concerns voiced by doctors about the inexorable increase in medical litigation is seemingly whether quality of health care will be affected. The suggestion is that litigation leads to defensive medicine (both the avoidance and the reduction of risk taking), discourages quality assurance, and reduces the availabilty of health care. If these outcomes are true, litigation is a major obstacle to high quality care. Are such claims justified and is there any evidence to support them?
principal
The evidence Studies in the US over the past 30 years in which groups of clinicians were asked to report on changes in their own practice provide the main evidence,l-6 but interpretation of the results is difficult. In all but one survey, no more than 35% of doctors responded (the exception being 65%’’). Additionally, there will have been recall bias because of the retrospective design of the studies, which required doctors
to
report how their clinical behaviour had altered over many
Moreover, the respondents were also asked to assess the contribution that fear of medical litigation had made to such changes. In view of such methodological difficulties, such surveys can only identify possible adverse effects of litigation rather than provide reliable measures of the impact of such effects. The latter can be partly achieved by the use of a quasi-experimental design that exploits differences in medical litigation rates between similar populations; only one such study (which compared California, a high litigation area, with North Carolina, where there have been relatively few malpractice claims) has adopted this approach.2 The results, based on a 54% response, did not support the notion that litigation was encouraging poor quality care. However years.
ADDRESS: Health Services Research Unit, Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK (N. Black, MD).
REVIEW ARTICLE
Liver transplantation for acute hepatic failure?
In the absence of definitive medical treatment for fulminant hepatic failure, liver transplantation may be appropriate in selected patients. However, uniform and easily applicable criteria for diagnosis of severity and analysis of results are needed to prevent unnecessary transplantation and to ensure that patients who may benefit are appropriately treated. Previous regimens for treatment of fulminant hepatic failure were often advocated, on the basis of data from historical controls, for several years until controlled trials failed to show any benefit. To obtain reliable information more rapidly than achieved before, a controlled trial between specialist liver transplant units is needed to establish the role of emergency hepatic transplantation in patients with fulminant hepatic failure. Lancet 1990; 335: 32-35. severe
Introduction Fulminant hepatic failure, as defined by Trey and Davidson,l is the development of encephalopathy within 8 weeks of the onset of hepatic symptoms, in the absence of underlying chronic liver disease. Fulminant hepatic failure is commonly divided into four grades (I-IV), and the prognosis of patients with grade ill or grade IV disease remains poor: even in specialist units, mortality exceeds 50% and in some series approaches 90%. Several largely independent factors influence survival, including age, the cause of liver disease, the depth and duration of encephalopathy in relation to onset of symptoms, and the prevention of complications.6 O’Grady et aF recently emphasised the importance of the underlying cause of liver failure: despite similar intensive medical support, and independently of use or duration of charcoal haemoperfusion, survival was more likely in patients who had taken a paracetamol overdose (53%) or who had hepatitis A infection (67%) than in patients with hepatitis B infection (39%), presumed non-A, non-B hepatitis (20%), or other drug-induced reactions (12%).
Medical treatment of fulminant failure
hepatic
Patients with fulminant hepatic failure are often young and previously healthy: if they survive, their livers may well
completely to normal. But how can survival be improved? Over the years many intensive treatments have been used, including corticosteroids, exchange transfusion, extracorporeal pig-liver perfusion, plasmapheresis, haemodialysis, heparin, and charcoal haemoperfusion. All these treatments have had a logical basis and had some early claims to success but, with further experience, enthusiasm has generally been replaced by pessimism.8 Corticosteroids, for example, were first used for fulminant hepatic failure with "encouraging results" in 1952,9 but the first controlled observations were not published until 1974. Four return
randomised controlled trials have since found no benefit from corticosteroid treatment’0-13 and there was even a suggestion, when results of three studies were combined, that such treatment might be harmful.13 Exchange transfusion was first described for the treatment of fulminant hepatic failure in 1966:14 5 of 7 patients survived, and both those who died briefly regained consciousness. For several years, exchange transfusion was widely accepted as beneficial but, in 1973, the first randomised controlled observations failed to show any benefit;15 before long the procedure was abandoned. Again, when haemodialysis with a polyacrylonitrile membrane was introduced, the initial, uncontrolled observations appeared to show some benefit (8 of 24 survived; 33%) over conservative management alone.16 However, this form of treatment did not gain wide acceptance (Opolon et all found only 9 of 41 [22%] survived), and was abandoned without formal assessment-as were the use of pig-liver perfusion, plasmapheresis, and heparin. After a case report by Chang in 1972,18 there was optimism that charcoal haemoperfusion might be beneficial in the treatment of patients with fulminant hepatic failure. Early uncontrolled studies showed favourable results when compared with historical controls: in one early report by Gazzard et al/9 10 of 22 such patients (45%) survived after treatment with charcoal haemoperfusion. Gimson and colleagues2o described 29 survivors from 76 patients (38%) ADDRESSES. Department of Gastroenterology, John Radcliffe Hospital, Oxford (R W. Chapman, MD); ICRF Cancer Epidemiology Unit (D. Forman, PhD) and ICRF/MRC Clinical Trial Service Unit (R. Peto, FRS), Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, UK; and Gastroenterology Unit, Austin Hospital, Heidelberg, Victoria, Australia (Prof R Smallwood, MD). Correspondence to Dr R. W. Chapman, Department of Gastroenterology, John Radcliffe Hospital, Oxford OX3 9DU, UK.
33
with fulminant hepatic failure. Compared with historical controls, the results seemed at first to be so encouraging that it was deemed unethical to withold charcoal haemoperfusion from such patients in the course of randomly controlled clinical trials.20 The procedure did not, however, gain widespread acceptance: some 16 years (and 500 treated patients) after the first report, the results of the first controlled trials were published.7 In the first part of the study, 75 patients with grade III encephalopathy were randomised to receive either 5 hours or 10 hours of charcoal haemoperfusion daily: overall survival rates were similar (51 % vs 50%), as was the frequency of major complications. Subsequently, 62 patients with grade iv encephalopathy on admission were randomised to receive no perfusion or 10 hours of haemoperfusion daily: overall survival rates were again similar (39% vs 34%, respectively). These differences were not significant and were much less striking than had been expected from non-randomised comparisons. Over the past 15 years, the progressively improved survival of patients with fulminant hepatic failure may be due largely or wholly to advances in conventional intensive care.
Early results of liver transplantation As enthusiasm for charcoal haemoperfusion diminished, the success of liver transplantation for chronic end-stage liver failure21 encouraged liver transplant units to consider its use in acute liver failure. Unlike charcoal haemoperfusion, liver transplantation has been taken up with great enthusiasm by many units in Europe, the United States, and Australia.8,22 Successful orthotopic liver transplantation for acute hepatic failure requires an established liver transplant unit and careful patient selection but, in some technical aspects, the operation may be less difficult in patients with acute rather than chronic liver disease because there are no large collateral veins associated with longstanding portal hypertension. The severe coagulopathy that invariably occurs in patients with fulminant hepatic failure can usually be controlled by fresh frozen plasma and platelet infusions. Early published results of liver transplantation in fulminant hepatic failure ,23-27 are shown in the table. At first sight, the results again appear favourable compared with historical controls: in studies since 1973,7,16,17,19,20 104 of 267 patients (39%) survived on medical treatment. The mean survival in transplanted patients is just over 50%, while that in the few patients who satisfied criteria for transplantation, but were not operated upon, is about one-third (see table). However, in the absence of controlled data there is considerable potential for bias in favour of transplantation. First, patients have to be fit enough to reach a transplant unit, and the patients at highest risk may not be referred for transplantation by the admitting hospital. Secondly, the mean age of such transplant recipients is low; patients over 60 were excluded from one study, and younger patients are more likely to be referred for transplant on emotional grounds. Thirdly, some high-risk patients will have been considered unfit for surgery by the transplant team. The cumulative effects of these biases may be substantial: in Vickers and colleagues’ series,26 for example, patients with unreactive pupils, absent brainstem reflexes, or absent cerebral electrical activity on electroencephalography for at least 48 h were regarded as having irreversible neurological damage and excluded from transplantation. Bismuth et al24 reported a 74% survival rate, but 12 of their 17 patients had grade I or grade IIhepatic coma: by contrast, survival of 18 of 19 conservatively treated patients with grade I or grade II
encephalopathy has been reported.26 Thus far, the closest approach to a controlled trial was reported by Vickers and co-workers.26 26 patients with fulminant hepatic failure were thought to merit transplantation: 9 of 16 (56%) who received a transplant survived, compared with 4 of 10 patients (40%) for whom a donor liver did not become available. This comparison is not large, is not statistically significant, and does not constitute unequivocal evidence that transplantation is beneficial. Need for a controlled trial There is general agreement that patients with fulminant hepatic failure in grade IV coma who have unreactive dilated pupils, absent brain-stem reflexes, and absent cerebral electrical activity on electroencephalography for 48 h will not respond to any treatment.26 For patients with less profound neurological dysfunction, however, the prognosis is more variable and poor prognosis is not necessarily equivalent to a need for transplantation. Bernuau et al28 described two indicators of imminent death in patients admitted with fulminant hepatic failure: rapid deterioration of the neurological status of patients from grade I to grade III coma, and a coagulation factor V concentration below 20% of the normal value; the presence of both features is associated with a mortality of 95%.28 O’Grady et al29 used multivariate analysis on over 600 patients with fulminant hepatic failure to identify features associated with a poor survival, which were: age above 40 or below 11years; delay between the onset of jaundice and onset of encephalopathy (the longer the delay, the worse the prognosis); serum
above 300 mmol/l; and an uncorrected prothrombin time of greater than 100 (in patients who have taken a paracetamol overdose, an arterial pH below 7-2 is also closely associated with a poor prognosis). A score can be derived which, in their patients, closely predicts the risk of death. However, neither set of prognostic indicators has been assessed in other units and standard assessments of the severity of fulminant hepatic failure will be required for accurate comparisons to be made between units. Is a controlled trial of transplantation versus medical treatment of severe fulminant hepatic failure really necessary? Liver transplantation is expensive, timeconsuming, and labour-intensive, and patients, usually young, who survive transplantation require life-long immunosuppression-with its associated clinical care, expense, and complications. Without transplantation, fulminant liver failure may be completely reversible and those who recover spontaneously can expect a normal life. We therefore believe that it is essential to seek clear evidence that transplantation improves outcome and, if possible, to determine which patients are most likely to benefit. In the light of the experience gained from charcoal haemoperfusion, Berk and Goldberg3O have recently
bilirubin
NON-RANDOMISED COMPARISONS OF SURVIVAL AFTER LIVER TRANSPLANTATION FOR FULMINANT HEPATIC FAILURE
’Includes patients in grade 1/11 coma; tincludes subacute liver failure Results shown as survivors/total %. NA=not available.
34
restated the drawbacks of non-randomised or historical controls in the assessment of a new treatment. They quote an editorial written 10 years before the evaluation of charcoal haemoperfusion with controlled trials,31 in which Berk stated "It should be emphasized that nonnon-randomized controls simply will not contemporaneous, do. Differences in patient material or in subtle aspects of supportive care may greatly influence the outcome". This statement has particular relevance to assessment of treatment of fulminant hepatic failure because, over the last 15 years, advances in the treatment of cerebral oedema, renal failure, and other haematological and cardiovascular complications of hepatic failure have greatly improved survival. Chalmers32 has also stressed the need for controlled studies in surgery, even when anecdotal evidence appears to be strong. He cites the example of the use of portocaval shunt surgery for the control of portal hypertension, which was not tested systematically until thousands of patients had been surgically treated over about 20 years. Many clinicians were fooled by comparison with historical controls, and an accurate analysis of the technique emerged only after the use of randomised trials which failed to show a benefit in patients treated by portocaval shunt surgery. The arguments used against a randomised controlled trial
in patients with fulminant hepatic failure have some similarities to those recently advanced to "justify" the failure to conduct reliable clinical trials in patients with AIDS. Most patients with fulminant hepatic failure are young and previously fit, most patients in grade III and IV coma will die despite intensive medical therapy, and published survival figures after transplantation are encouraging. However, in patients with fulminant hepatic failure, from previous experience, such arguments are relevant only if the improvement in survival is real (which it may not be), and sufficient to outweigh those patients (over a third) who would have recovered completely but received a transplant and thereby became permanently dependent on
immunosuppressants. The "uncertainty
principle" design
in ethical
study
Random assignment of a patient to a non-transplant group when the clinician strongly believes that transplantation would improve the prognosis would be ethically
unacceptable. Similarly, to perform a transplant on a patient in whom such treatment is strongly believed to be inappropriate would be equally wrong. Participation in any randomised clinical trial is appropriate for a particular patient if-and only if-for that patient the clinician responsible is substantially uncertain about the likely benefit or appropriateness of intervention. The crucial question, therefore, is whether a valid trial of transplantation can be organised within the limits of clinical uncertainty in patients with fulminant hepatic failure. All clinicians involved in the treatment of fulminant hepatic failure would be able to identify patients for whom they are reasonably certain that transplantation would be contraindicated--either because the coma is relatively mild and medical recovery seems highly likely, or because coma is extremely severe and the prognosis hopeless. Many clinicians, especially those in liver transplant units, may also be able to identify patients for whom they are reasonably certain that transplantation is indicated. There may be some clinicians who will confidently assign virtually all their patients to one or other group and treat them accordingly. Many clinicians,
may have an intermediate group of patients for whom they are substantially uncertain as to the possible benefits of transplantation. It should be possible to organise a randomised trial of transplantation for these patients in the intermediate group, even though participating centres will almost certainly use very different criteria to define their areas of uncertainty. Indeed, clinicians within one centre may have different opinions and change their views over the years as new evidence accumulates. The laxity of the entry criteria for such a study need not introduce any bias; indeed, only if the patients entered into such a study are heterogeneous will a trial be able to identify those for whom greatest benefit is achieved. However, standard assessments of severity and outcome would be essential. The central question to be addressed by such a trial is whether entry to an acute liver transplantation programme improves the prognosis in distinct groups of patients with severe fulminant hepatic failure. In general, therapeutic trials compare the effects of adopting different treatment policies (to be implemented wherever possible), rather than direct comparison of treatments. 33 The primary comparison would, therefore, be of active recruitment into a transplantation programme, with surgery as soon as a suitable donor is found (unless overriding reasons not to operate were thought to have developed), against a conservative treatment policy (unless an overriding reason for transplantation was thought to have developed). Patients would remain in the policy group to which they are originally randomised even if, in the transplant group, no donor organ becomes available. The initial comparison would be between transplantation policies33 and not between patients with and without transplanted livers; subsequent comparisons may add supplementary information later. Each centre would have to be able to offer intensive medical support to patients in both arms of the trial. A strict mortality follow-up for all randomised patients would be necessary, but could be done indefinitely through national mortality records, without inconvenience to patients or doctors. All centres would have to be part of a network that could guarantee donor organs for a large proportion of the patients assigned to the transplant group, but this would surely be advantageous for all parties. How many patients would be required to obtain a clear result? If survival in non-transplanted patients is about 40%, then a trial in which 300 patients are randomised would have a 95 % chance of detecting a 20 % improvement (to 60% survival) at p=0-05, and an 80% chance of detecting such an improvement at p = 0 001. A 15% improvement (to 55% survival), similar to the smallest degree of improvement that is claimed by some centres, could likewise be detected with 550 patients. The numbers involved, although large, might be feasible in the context of an international collaborative study of the benefit of entry into a transplantation programme. Larger numbers would, however, be necessary to determine which patients with fulminant hepatic failure are most likely to benefit.
however,
REFERENCES 1.
Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F, eds. Progress in liver disease, vol III. New York: Grune & Stratton, 1970: 282-90. 2. Tygstrup N, Ranek L. Fulminant hepatic failure. Clin Gastroenterol 1981; 10: 151-208.
O’Grady J, Ede RJ, et al. Late onset fulminant hepatic failure; serological and histological features. Hepatology 1986; 6:
3. Gimson AES, 288-94.
35
SM, Ludwig J, Baldus WP. Fulminant hepatitis; Mayo clinic experience with 34 cases. Mayo Clin Proc 1985; 60: 289-92. 5. Christensen E, Bremmelgaard A, Bahnsen M, Andreasen PB, Tigstrap N. Prediction of fatality in fulminant hepatic failure. Scand J Gastroenterol 1984; 19: 90-96. 6. Tygstrup N, Rannak L. Assessment of prognosis in fulminant hepatic failure. Semin Liver Dis 1986; 6: 129-37. 7. O’Grady JG, Gimson AES, O’Brien CJ, et al. Controlled trials of charcoal haemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988; 94: 1186-92. 8. Editorial. Transplantation for acute liver failure. Lancet 1987; ii: 1248-49. 9. Ducci H, Katz R. Cortisone, ACTH and antibiotics in fulminant hepatitis. Gastroenterology 1952; 21: 357-74. 10. Ware AJ, Jones RE, Shorey JW, Combes B. A controlled trial of steroid therapy in massive hepatic necrosis. Am J Gastroenterol 1974; 62: 4. Rakela J, Lange
130-33. 11. Redeker AG, Schwartzer IL, Yamahiro HS. Randomisation of corticosteroid therapy in fulminant hepatitis. N Engl J Med 1976; 294: 728-29. 12. Gregory PB, Knauer CM, Kempson RL, Miller R. Steroid therapy in severe viral hepatitis. N Engl J Med 1976; 294: 681-87. 13. European association for the study of the liver. Randomized trial of steroid therapy in acute liver failure. Gut 1979; 20: 620-23.
14. Berger RL, Liversage RM, Chalmers TC, Graham JH, McGoldrick DM, Stohlman F. Exchange transfusion in treatment of fulminating hepatitis. N Engl J Med 1966; 274: 497-501. 15. Redeker AG, Yamahiro HS. Controlled trial of exchange-transfusion therapy in fulminant hepatitis. Lancet 1973; i: 3-6. 16. Silk DBA, Hanid MA, Trewby PN, et al. Treatment of fulminant hepatic failure by polyacrylonitrile-membrane haemodialysis. Lancet 1977; ii:
20. Gimson
AES, Braude S, Mellon PJ, Canalese J, Williams R. Earlier charcoal haemoperfusion in fulminant hepatic failure. Lancet 1982; ii: 681-83. 21. Bismuth H, Caistang D, Ericzon BG, et al. Hepatic transplantation in Europe. Lancet 1987; ii: 674-76. 22. Powell LW. Liver transplantation: an update for physicians. Aust NZ J Med 1989; 19: 369-77. 23. Ringe B, Pichlmayr R, Lauchart W, Muller R. Indications and results of liver transplantation in acute hepatic failure. Transplant Proc 1986; 18 (suppl 3): 86-88. 24. Bismuth H, Samule D, Gugenheim J, et al. Emergency liver transplantation for fulminant hepatitis. Ann Intern Med 1987; 107: 337-41. 25. Peleman RR, Gavaler JS, van Thiel DH, et al. Orthotopic liver transplantation for acute and sub-acute hepatic failure in adults. Hepatology 1987; 7: 484-89. 26. Vickers C, Neuberger J, Buckels J, McMaster P, Elias E. Transplantation of the liver in adults and children with fulminant hepatic failure. J Hepatol 1988; 7: 143-50. 27. Emond JC, Aran PP, Whitington P, Broelsch CE, Baker AL. Liver transplantation in the management of fulminant hepatic failure. Gastroenterology 1989; 96: 1583-88. 28. Bernuau J, Goudeau A, Poynard T, et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986; 6: 648-51. 29. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439-45. 30. Berk PD, Goldberg JD. Charcoal haemoperfusion. Gastroenterology 1988; 94: 1228-30. 31. Berk PD. Artificial liver: a baby delivered prematurely. Gastroenterology
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17. Opolon DP, Nusinovici V, Grainger A, Darnis F. Treatment of encephalopathy during fulminant hepatic failure during haemodialysis with high permeability membrane. Gut 1978; 19: 783-93. 18. Chang TMS. Haemoperfusion over a microencapsulated absorbant in a patient with hepatic coma. Lancet 1973; ii: 1371-72. 19. Gazzard BG, Portmann B, Weston MJ, et al. Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Lancet 1974; i: 1301-07.
32. Chalmers TC. Randomized clinical trials in surgery. In: Vargo RL, Delaney JP, eds. Controversies in surgery. Philadelphia: Saunders, 1976: 3-11. 33. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised trials requiring prolonged observation of each patient. Part 1: design. Br J Cancer 1976; 34: 585-612.
VIEWPOINT Medical
One of the
litigation and the quality of care
concerns voiced by doctors about the inexorable increase in medical litigation is seemingly whether quality of health care will be affected. The suggestion is that litigation leads to defensive medicine (both the avoidance and the reduction of risk taking), discourages quality assurance, and reduces the availabilty of health care. If these outcomes are true, litigation is a major obstacle to high quality care. Are such claims justified and is there any evidence to support them?
principal
The evidence Studies in the US over the past 30 years in which groups of clinicians were asked to report on changes in their own practice provide the main evidence,l-6 but interpretation of the results is difficult. In all but one survey, no more than 35% of doctors responded (the exception being 65%’’). Additionally, there will have been recall bias because of the retrospective design of the studies, which required doctors
to
report how their clinical behaviour had altered over many
Moreover, the respondents were also asked to assess the contribution that fear of medical litigation had made to such changes. In view of such methodological difficulties, such surveys can only identify possible adverse effects of litigation rather than provide reliable measures of the impact of such effects. The latter can be partly achieved by the use of a quasi-experimental design that exploits differences in medical litigation rates between similar populations; only one such study (which compared California, a high litigation area, with North Carolina, where there have been relatively few malpractice claims) has adopted this approach.2 The results, based on a 54% response, did not support the notion that litigation was encouraging poor quality care. However years.
ADDRESS: Health Services Research Unit, Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK (N. Black, MD).
