Mark Feldman, M.D. Selected Summaries Editor Dallas Veterans Administration Medical Service (111) Dallas, Texas 75216

Medical Center

STAFF James L. Achord, Jackson, Miss. Eugene B. Chang, Chicago, Ill. Kiertisin Dharmsathaphorn, San Diego, Calif.

Charles 0. Elson, Birmingham, Ala. Hans Fromm, Washington, DC. Raymond S. Koff, Framingham, Mass.


Robert C. Kurtz, New York, N.Y. M. Peter Lance, Buffalo, N.Y.

Caroline A. Riely, Memphis, Tenn. Mitchell L. Schubert, M.D., Richmond, Virginia

Arthur M..Magun, New York, N.Y. Peter F. Malet, Philadelphia, Pa. Thomas A. Miller, Houston, Tex. Walter L. Peterson, Dallas, Tex. Joel E. Richter, Birmingham, Ala.

Konrad Schulze-Delrieu, Iowa City, Iowa Joseph Sweeting, New York, N.Y. Dwain L. Thiele, Dallas, Tex. Richard C. Thirlby, Seattle, Wash.

REVOLUTIONARY LIFESAVING THERAPY FOR ACUTE HEPATIC FAILURE, OR YET ANOTHER FALSE HOPE? Sinclair SB, Greig PD, Blendis LM, et al. (Liver Disease Program, Toronto, Ontario, Canada). Biochemical and clinical response of fulminant viral hepatitis to administration of prostaglandin E. A preliminary report. J Clin Invest 1989;84: 1063-1069. This report details the results of an unblinded, uncontrolled trial of prostaglandin E (PGE) therapy in 17 consecutive patients presenting with either fulminant hepatic failure [FHF; i.e., hepatic encephalopathy (HE) from 2 wk of initial jaundice] or subfulminant hepatic failure (SFHF; HE within z wk-3 mo of initial jaundice] attributed to acute hepatitis A (HAV, n = 31, acute hepatitis B (HBV, n = S] or acute non-A, non-B (NANB) viral hepatitis fn = 8). These diagnoses were confirmed by standard serologic criteria and pretherapy liver biopsies that displayed histologic patterns typical of acute viral hepatitis with massive or submassive necrosis. In addition to monitoring standard measures of liver function, coagulation and serum hepatic enzyme levels, patients were assessed by electroencephalography and use of the Trail test. At presentation, 8 patients were judged to have stage I HE, 4 had stage II HE, 4 had stage III HE, and only 1 patient presented with stage IV HE. However, following the 24- 48-h evaluation interval between ppesentation and initiation of PGE therapy, 14 of 17 patients manifested stage III or IV HE. PGE treatment consisted of intravenous PGE, infused initially at 0.2 rg . kg . h , then increased by 0.1 pg . kg . h to a maximum of 0.6 pg - kg . h. Dosage was adjusted to clinical response and the presence of adverse effects, and infusion was continued for up to-28 days or until improvement in HE and liver function tests was noted, at which time the infusion rate was tapered. In no patient did complications lead to discontinuation of therapy, but headaches, abdominal cramps, fever, diarrhea, swelling and paresthesias of the face and extremities, when they occurred, were attributed to the PG therapy. Twelve of 17 patients (71%) appeared to respond with recovery from HE, improvement of liver functions, and normalization of liver histology. Upon tapering of the PGE, infusion, the HAV or

HBV B responders continued to progressively improve. However, all 5 responders with NANB hepatitis suffered 1 or more biochemical relapses documented largely by rises in hepatic transaminase levels. In 2 patients, such relapses were associated with HE recurrence. Reinstitution of PGE, infusions were associated with declines in transaminase levels and with addition of oral PGE,, PGE, was tapered without subsequent relapse. Five nonresponder patients (3 with NANB and 2 with HBV) showed improvements in aspartate transaminases and coagulation times but not in serum bilirubin levels or HE. All were posted for liver transplantation. Three died of cerebral edema before transplantation. Two received liver transplants but 1 died. The nonresponders were those who initially presented with stage III or IV HE, whereas all responders initially presented with stage I or II HE. The authors contrast their 45% survival rate in patients with stage IV HE at onset of therapy and 71% overall survival rate with lower survival rates noted in previous reports. They conclude that these findings suggest efficacy of PGE for FHF induced by viral hepatitis and report that a controlled randomized trial is now underway. Comment. FHF or SFHF are dreaded complications of viral or drug-induced hepatitis. Since historical survival rates in either syndrome have been notoriously poor, any therapy associated with an overall survival rate of 71% clearly warrants consideration. However, it should be noted that this is not-the first therapy for FHF that has been reported to have impressive efficacy when a series of treated patients has been compared with historical controls. Ducci et al. [Gastroenterology 1952;21:357; Gastroenterology 1962;42:258265) ushered in the era of corticosteroid therapy in the 1950s with reports of unprecedented survival of FHF patients treated with these agents. Thus, they had noted a 0 of 16 (0%) survival rate in patients treated between 1940 and 1950 without benefit of steroids, whereas 9 of 23 (39%) corticosteroid-treated patients hospitalized between 1951 and 1961 were reported to make complete recoveries. This led to extensive use of this therapy worldwide. However, in 1 small controlled trial performed in the early 1970s. 7 of 11 (63%) of placebo-treated patients survived, whereas all 4 steroid-treated patients died (Am J Gastroent 1974;62:130-133). Finally, after more than 2 decades of use in FHF, larger randomized trials indicated that steroid therapy has either no efficacy or even potentially adverse effects in this syndrome [Gut 1979;20:620-6231.In 1966, Trey et al. [N Engl J Med 1966;275:497] reported the dramatic recovery

April 1990

from coma in 7 of 7, and long-term survival in 5 of 7 (71%) FHF patients treated with exchange transfusions. By 1970. nearly 100 recipients of this therapy had been reported in the literature. However, again the first randomized, controlled trial found no evidence for efficacy [Lancet 1973;1:3-81. In the late 1960s and early 197Os, a host of other therapies including hyperbaric oxygen, “coenzyme” infusion, and crosscirculation with human or animal volunteers were touted as affording a 60%-80% survival rate in FHF [Liver and Drugs, 1972, Academic Press, London/New York, pp. 213-2281. However, as additional experience with these therapies was accumulated, and after at least 1 crosscirculation volunteer died of a fatal complication [Ann Gastroenterol Hepatol1971;7:25521. lesser efficacy rates were seen and enthusiasm waned. Yet, again in 1974, enthusiastic reports were made of reversal of coma in FHF patients treated with charcoal hemoperfusion. Ten of 22 patients (45%) were noted to fully recover from stage IV coma following this treatment whereas only 10% of historical controls presenting to the same institution with stage III or IV coma had survived [Lancet 1974;1:1301-1307) When charcoal hemoperfusion was initiated during stage III HE, even better survival rates (65%) were reported [Lancet 1982;2:681-6831. As previously chronicled in this journal, well over 500 patients were treated with this therapy before publication in 1988 of the first report of controlled trials that again demonstrated no efficacy [Gastroenterology 1988;94:1186-11921. Why have physicians been so frequently misled? Certainly a major problem in evaluating outcome from therapeutic trials in FHF has been the heterogeneity of diseases involved and the historical trend towards improved survival rates that may relate to improved supportive therapies provided in modern intensive care units [Gastroenterology 1988;94:1186-11921. The stage of HE at presentation or at accession to a therapeutic trial as well as the underlying cause of FHF may have profound effects on survival rates. Furthermore, in the earlier phases of enthusiasm over new therapies, positive reports of therapeutic efficacy tend to far outnumber reports of therapeutic failure [Liver and Drugs, 1972, Academic Press, London/San Diego, Calif., pp. 213-2281. Thus, as eloquently stated in a previous editorial published in this journal [Gastroenterology 1988;94:1228-12301.and as acknowledged by the authors of the current report in a single sentence at the end of their manuscript, controlled, randomized trials are absolutely essential in evaluating therapy in this clinical syndrome. If one accepts this principal, what then can be learned from uncontrolled studies such as this? Certainly one would hope to gain some impression regarding potential for efficacy, the nature of complications, and doses of drugs that seem to be associated with either of these outcomes. The design of the present study entailed use of doses of PGE, that were to be increased in a systematic manner until apparent efficacy or adverse effects [or a set maximum dose] were reached. Yet doses of drugs at which these endpoints were reached were not explicitly stated at any point in the manuscript. Similarly, no information was given regarding blood or urine levels of PGE, or PGE, metabolites that were achieved in these patients. For the ample reasons that have been stated above, comparison of the survival of PGE-treated patients detailed in the present study with that of historical controls cannot provide firm evidence of efficacy. In this regard it should be specifically noted that this therapy only “worked” in the subset of parients presenting in stage I or II HE-a patient subgroup that is sparsely represented in most FHF trials. Although the majority of such patients progressed to stage III-IV HE, it is possible that supportive therapy initiated between time of admission and initiation of PGE, treatment rather than PGE, per se was responsible for the good therapeutic outcome. Also, among the initial 6 NANB and 2 HBV patients reported in abstract form in 1987 [Hepatology 1987;7: 110418 of 8 survived, yet in the presumably cumulative group of 8 NANB and 6 HBV patients detailed in this manuscript, only 9 of 14 recovered. One therefore wonders whether the historical pattern of decreasing efficacy rates for new FHF therapies has not already



been observed. However, the survival rate in the present trial can hardly be said to be worse than previous results. Furthermore, the waxing and waning course of liver function tests and encephalopathy in response to withdrawal and reinstitution of PGE, therapy in selected NANB hepatitis patients is indeed impressive evidence that the course of this disease is modulated by this therapy. Thus, cautious enthusiasm can be registered for the potential utility of

PGE therapy in FHF. Such enthusiasm is based not only on the present results but also on a series of animal studies that suggest that PG analogs afford cytoprotective effects from viral hepatitis or toxin-induced hepatic injury [reviewed by Sinclair et al). However, it is sincerely hoped that any physicians planning to adopt this agent for use in FHF will begin by “randomizing the first patient” [Med Clin North America 1975;50:1035-10381. Otherwise we seem destined towards 1 of 2 equally unfortunate outcomes: either yet another era of therapeutic misadventure will be entered in which hundreds of patients will be submitted to ineffective and potentially dangerous therapy: or equal numbers of patients will be denied use of a life-saving therapy because their physicians remain unconvinced of its efficacy. D. L. THIELE. M.D.



Pitt HA, Kaufman SL, Coleman J, et al. [Departments of Surgery and Radiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland). Benign postoperative biliary strictures: Operate or dilate? Annals of Surgery 1989;210:417425. Several recent reports have suggested that nonoperative balloon dilatation of benign postoperative biliary strictures may be an acceptable alternative to surgical management (Radiology 1985;156:625-629; Am J Surg 1985;149:73-77; Radiology 1986;160:17-22; Radiology 1987;163:625-628; Radiology 1987;163:629-634). This contention is based on the fact that with such dilatation, success rates with follow-up periods of 2-3 yr are similar [i.e., 70%-85%) to those reported when such strictures are surgically managed and followed for as long as 5-10 yr. Unfortunately, appropriate comparison of results of these 2 approaches to stricture management has been difficult because of differing definitions among the various published series with respect to what constitutes success, as well as differing techniques with regard to dilatation of the stricture itself, and the length of follow-up. Thus, the results of balloon dilatation and surgery at one institution over the same period of time, utilizing similar management techniques and the same definition of a successful outcome, were analyzed. The patient population comprised 42 patients who were treated for benign postoperative biliary strictures at The Johns Hopkins Hospital from 1979-1987. The overwhelming majority of these patients had previously undergone surgery for gallstone disease. Of these patients, 25 underwent surgical repair with Roux-Y choledocho- or hepaticojejunostomy with postoperative transhepatic stenting for a mean of 13.8 f 1.3 mo. Initially, 20 patients had balloon dilatation, a mean of 3.9 times, and were also stented transhepatically for a mean of 13.3 + 2 mo. Three patients in this latter group subsequently required surgery for definitive management of their strictures.

Revolutionary lifesaving therapy for acute hepatic failure, or yet another false hope?

GASTROENTEROLOGY SELECTED 1990;98:1089-1093 SUMMARIES Mark Feldman, M.D. Selected Summaries Editor Dallas Veterans Administration Medical Service...
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