One hundred thirty-seven patients with fulminant hepatic failure were entered into two controlled trials of charcoal hemoperfusion carried out concurrently. In trial A, 75 patients with grade 3 encephalopathy were randomized to receive 5 or 10 h of hemoperfusion daily. Overall survival rates for the two groups were similar (51.3% vs. 50.0%) as was the frequency of major complications including cerebral edema and renal failure. In trial B, in which 62 patients with established grade 4 encephalopathy on admission were randomized to a no-perfusion group or to have 10 h of hemoperfusion daily, overall survival rates for the two groups were again similar (39.3% and 34.5%, respectively). There was in both trials a significant relationship between survival and etiology quite independent of the use or duration of hemoperfusion. Thus, percentage survival for the acetaminophen-overdose cases was 52.9%, for hepatitis A 66.7%, for hepatitis B 38.9%, for presumed non-A, non-B hepatitis 20%, and for halothane or drug reaction 12.5%. Within the etiologic subgroups survival was also influenced by the three major complications that developed, being inversely related to their frequency and combination, except in the non-A, non-B hepatitis and halothane or drug reaction subgroups, which had a high mortality throughout. In the latter cases particularly, orthotopic liver transplantation merits early consideration and in the group with better "intrinsic" survival (acetaminophen, hepatitis A and B) intensive management of complications (rather than charcoal hemoperfusion) would appear to be of major importance.

The efficacy of 5-aminosalicylic acid enemas in maintaining remission in left-sided ulcerative colitis was studied. Twenty-five patients in remission for at least 2 mo were randomized to receive either 1-g 5-aminosalicylic acid or placebo enemas daily and were followed up for 1 yr. Eleven of 13 patients randomized to placebo relapsed after a mean of 16 wk. Nine of 12 patients randomized to 5-aminosalicylic acid remained in remission for 1 yr, 2 others in remission withdrew by request, and 1 relapsed at 10 wk. The difference between relapse rate on 1-g 5-aminosalicylic acid versus placebo was significant (p less than 0.005). Seven patients entered the blinded trial a second time. Three of 4 patients randomized to 5-aminosalicylic acid remained in remission and 1 relapsed. Three randomized to placebo relapsed at a mean of 14 wk. One-gram 5-aminosalicylic acid enemas are safe and effective in maintaining remission in patients with left-sided ulcerative colitis.

Growth failure often complicates Crohn's disease in pediatric patients and is principally due to inadequate caloric intake. To assess whether intermittent courses of an elemental diet could reestablish growth, 8 children (aged 9.8-14.2 yr) with Crohn's disease and growth failure entered into a prospective trial. Each patient was studied during an observation year on standard therapy, then for an experimental year during which they received enteral elemental diet 1 out of 4 mo. An age- and disease-matched control group of 4 patients was treated by conventional medical therapy during both years. Elemental diet therapy was administered nocturnally, at home, by continuous nasogastric infusion and increased the daily caloric intake by 25% (p less than 0.01). Anthropometric measurements demonstrated significant height and weight gains in the elemental diet group vs. controls (p less than 0.01). Crohn's disease activity index and prednisone intake decreased significantly in patients receiving elemental diet therapy when compared with themselves and with controls on conventional medical therapy (p less than 0.05). In contrast, the rate of pubertal development was similar in both groups irrespective of the treatment modality. This study demonstrates that chronic intermittent elemental diet effectively reverses growth arrest, while decreasing prednisone requirements and Crohn's disease activity index in pediatric Crohn's disease patients prior to puberty.

Patients who have lost such a large portion of their small bowel that they permanently require total parenteral nutrition for survival would greatly benefit by receiving a small-intestinal transplant. Over the past two decades, many experimental studies have delineated the specific problems surrounding small-bowel transplantation and provided strategies for their control. Control of rejection, the most difficult problem, may be achieved with a combination of cyclosporine, azathioprine, prednisone, antithymocyte globulin, and monoclonal antibodies. The threat of graft-versus-host disease originating from the allogeneic lymphatic tissues in the allograft is abolished by in vitro x-irradiation of the cold, nonperfused graft with 1000 rads. Monitoring of the intestinal allograft is possible with the combination of a function test (maltose absorption, glucose absorption, or any other function test) and repeated graft biopsy. Effective short-term preservation of small-bowel segments for up to 18 h is possible by intravascular flushing with a balanced electrolyte solution containing 3% fructose and by subsequent hypothermic storage. Clinical small-bowel transplantation is certainly not an imminent therapeutic tool. However, clinical trials in highly selected patients could be envisioned on the basis of our present understanding of small-bowel transplantation and of transplantation biology in general, and in view of the clinical successes achieved with duodenal grafts transplanted in conjunction with pancreatic grafts.

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.

A randomized controlled trial of hepatic arterial embolization was conducted in 63 consecutive patients who had unresectable but still embolizable hepatocellular carcinoma. Patients were randomized into three groups. Patients in group 1 received multiple hepatic arterial embolizations; patients in group 2 were given hepatic arterial embolization once, followed by monthly chemotherapy with high doses of 5-fluorouracil; and patients in group 3 received only monthly chemotherapy with high doses of 5-fluorouracil. Complete response was achieved in only 1 patient who received multiple hepatic arterial embolizations. Partial responses were observed in 13 patients (61.9%) in group 1, 10 patients (47.6%) in group 2, and 2 patients (9.5%) in group 3. The survival rates of patients in group 1 at the end of the ninth, 12th, 15th, 18th, and 21st months were 53.2%, 42.2%, 42.2%, 42.2%, and 42.2%, respectively, which were not significantly different from those of patients in group 2 but were better than the survival rates of patients in group 3. The results suggest that hepatic arterial embolization is an effective palliative treatment that prolongs survival of patients with unresectable hepatocellular carcinoma.

To determine the clinical importance of Campylobacter pyloridis infection, its association with gastric inflammation, and the response to drug therapy, patients with a duodenal or gastric ulcer (n = 63), patients with nonulcer dyspepsia (n = 240), and asymptomatic volunteers (n = 34) were studied. In a prospective longitudinal study, the type, intensity, and distribution of inflammation in antral biopsy specimens were correlated with the presence of C. pyloridis. Campylobacter pyloridis was cultured from antral biopsy specimens in 98% of the ulcer patients, 70% of the nonulcer dyspepsia patients, and 20% of the asymptomatic volunteers. The dependency of chronic active gastritis on the presence of C. pyloridis was shown by an association of gastritis with positive culture and healing of gastritis with negative culture after various therapeutic regimens. Spontaneous disappearance of C. pyloridis never occurred. Colloidal bismuth subcitrate, amoxicillin, and the combination of colloidal bismuth subcitrate and amoxicillin were effective therapies in eradicating C. pyloridis. Recolonization with the same bacterial subtype and recurrence of gastritis frequently occurred within 1 mo after initial eradication. In this study we demonstrate ultimate normalization of gastric mucosa after successful eradication of C. pyloridis. Especially complete normalization of gastric mucosa after amoxicillin monotherapy provides additional strong evidence for a true cause-effect relationship between C. pyloridis colonization and gastritis.

Hepatic and systemic hemodynamics were measured in 19 cirrhotic patients with variceal bleeding enrolled in a controlled trial of propranolol for the prevention of rebleeding. The patients were studied on three separate occasions. The first study was performed before randomization within 24 h of the bleeding episode, once hemodynamic stabilization had been achieved. The second study was performed after 10 days of treatment, and the third after 6 mo without rebleeding. Propranolol dosage was titrated according to blood levels. Wedged and free hepatic venous pressures and the hepatic venous pressure gradient were recorded. Hepatic blood flow and cardiac output were also measured. Before treatment, the groups of patients treated with propranolol (n = 11) or placebo (n = 8) were comparable according to clinical, biochemical, and hemodynamic parameters. After 10 days, hepatic venous pressure gradient decreased similarly in the two groups (-20% in the propranolol group, -25% in the placebo group). Cardiac output fell only in the propranolol group (-40%). Hepatic blood flow remained unchanged in either group. After 6 mo, hepatic venous pressure gradient remained lower than the values from the first (within 24 h of bleeding) study in both the propranolol group (n = 5) and the placebo group (n = 6). Our results suggest that portal pressure increases shortly after hemorrhage with a return to baseline values 10 days later, and that propranolol does not further magnify these changes. Spontaneous changes in hepatic hemodynamics after variceal hemorrhage must be taken into account when evaluating the effect of pharmacologic agents on portal pressure.

The results of a prospective randomized controlled trial of elective endoscopic intravariceal sclerotherapy carried out over a 36-mo period in comparison with elective percutaneous transhepatic obliteration of varices (PTO) are presented. Sixty-six patients with nonalcoholic cirrhosis were randomized after they had stabilized, usually between 7 and 14 days after variceal bleeding had stopped following medical treatment (balloon tamponade and vasopressin infusion). Thirty-three patients were assigned to the sclerotherapy group and the other 33 patients were assigned to the PTO group. The mean follow-up period was similar in both groups. There was no significant difference in demographic, clinical, and laboratory data between the two groups. Six patients (18%) in the sclerotherapy group and 21 (64%) in the PTO group had at least one episode of gastrointestinal bleeding during the follow-up period (p less than 0.005). Three patients in the sclerotherapy group and 1 patient in the PTO group bled from lesions other than varices; therefore the incidence of variceal bleeding was 9% in the former and 61% in the latter (p less than 0.005). The cumulative variceal bleeding rate was significantly lower in the sclerotherapy group than the PTO group (p less than 0.05). Five patients in the sclerotherapy group died during the follow-up period but none died of recurrent variceal bleeding. Nineteen patients in the PTO group died and 10 of them died of bleeding from varices. The cumulative survival rate was significantly better in the sclerotherapy group (p less than 0.05). These results indicate that elective endoscopic intravariceal sclerotherapy is superior to elective PTO in the prevention of recurrent variceal hemorrhage and mortality in nonalcoholic cirrhosis.

Sixty-six outpatients with active ulcerative colitis who were intolerant of sulfasalazine were treated in a double-blind randomized trial. They received placebo or olsalazine sodium in daily doses of 0.75, 1.5, or 3 g. Overall, 35% of patients receiving olsalazine improved clinically, compared to 16% of patients receiving placebo. When the colitis activity at study entry was compared with that observed at the completion of the study period, statistically significant or nearly significant improvement was demonstrated within the combined olsalazine group (p = 0.01) and within patient groups receiving olsalazine at daily doses of 1.5 g (p = 0.04) and 3 g (p = 0.055). A dose-response relationship was suggested because 16%, 29%, 27%, and 50% of patients improved in the placebo and 0.75-, 1.5-, and 3-g olsalazine groups, respectively, (p = 0.04). A similar pattern of improvement was seen when sigmoidoscopic criteria were used, although a dose-response relationship was not demonstrated. There were no differences between the treatment and placebo groups for any of the adverse effects or laboratory variables reported at baseline or during the trial period. Four patients were withdrawn because of adverse reactions: 2 developed a skin rash while receiving olsalazine and 2 had diarrhea, one while on olsalazine and the other while on placebo. The data suggest that olsalazine is effective for the treatment of ulcerative colitis and is well tolerated among patients intolerant to sulfasalazine.

In this review, we compared the outcome of 25 studies of experimentally induced pancreatitis in animals with 13 studies of human acute pancreatitis in which the same therapeutic agents were used (aprotinin, glucagon, 5-fluorouracil, somatostatin, peritoneal lavage). Whereas 81% of the animal studies had a positive outcome (improvement in survival), only 7.7% of the human studies showed a positive outcome on survival. Most animal studies suffered from a protocol in which treatment was not significantly delayed after induction of acute pancreatitis. Of the 12 human studies that showed no effect of treatment on survival, none had sufficient statistical power (1 - beta error) for the investigators to have confidence in the negative outcomes. This was due to the fact that the studies had too few patients or that the event rates in the untreated populations were too low. Only five of the human studies reported the complication rates of acute pancreatitis in patients who did not die of their disease. Treatment (by any agent) did not improve the complication rate in these studies, but only one of the five reports had sufficient statistical power for the investigators to have confidence in these negative results. Large multicenter studies with sufficient numbers of patients with severe pancreatitis (high mortality and complication rates) are needed to evaluate new therapies in this disease.

In a prospective controlled study, 68 patients undergoing maintenance sclerotherapy were randomized to have intravariceal sclerotherapy based on either manometric assessment (n = 35) or visual assessment (controls, n = 33) of varix patency. For manometric assessment, a perfused variceal needle punctured each variceal column and, if low pressures fluctuating with respiration were obtained, the varix was injected. Control patients had patent varices injected based on visual assessment alone. During a mean follow-up of 13 mo (range 4-16 mo), 1 manometrically assessed patient bled once (0.002 bleeds/patient month) and 7 visually assessed patients bled 14 times from varices (0.03 bleeds/patient-month) (p less than 0.05). Two and nine episodes of ulceration occurred in manometric and visually assessed patients, respectively, (p less than 0.05). Varices were obliterated (i.e., disappeared) in 11 patients undergoing manometric assessment and in 2 patients undergoing visual assessment (p less than 0.01). Comparing results of visual and manometric assessment within "manometric" patients showed a consistent 25% error rate in diagnosing patency or thrombosis by visual assessment. Manometric assessment of varices during maintenance sclerotherapy reduces rebleeding and ulceration to very low levels.

The combination of laser with endoluminal 192-iridium radiation for the palliation of malignancies of the oesophagus and the cardia has been introduced to overcome the short-lived effect of laser treatment alone. Concluding from early experience, this method seems to prolong the effect of laser treatment alone, with a low risk of complications. However the initial optimistic results, claiming a permanent relief of dysphagia in 80% of the patients, cannot be reproduced under prospective conditions. The combination of laser and 192-iridium radiation with other palliative methods, such as external radiation and/or chemotherapy is feasible and remains to be studied in a comparative way.

Isosorbide dinitrate, a long-acting organic nitrate, has been shown to decrease portal pressure in the experimental animal and humans. We conducted a double-blind randomized hemodynamic evaluation of the effects of placebo and 10 mg and 20 mg isosorbide dinitrate in stable individuals with alcoholic cirrhosis. Baseline values for all three groups were similar. Isosorbide dinitrate resulted in a peak reduction of the hepatic venous gradient of 24.7% +/- 3.0%, with significantly decreased values 4 h after the administration of the 20-mg dose. A reduction of arterial pressure and cardiac index (peak decrease of 25.7% +/- 1.5%) was well tolerated by 13 of 15 patients. Changes in mean arterial pressure were not predictive of modifications in the hepatic vein wedge pressure. There was no relation between the area under the plasma isosorbide dinitrate concentration curve and hemodynamic changes. Levels of isosorbide-5-mononitrate, a vasoactive metabolite, were detectable for an 8-h period. Isosorbide dinitrate significantly reduced portal pressure in stable cirrhotics, in association with systemic hemodynamic changes. Thus, titration of isosorbide dinitrate is required to maximize hemodynamic benefits in individual patients. As the decrease in portal pressure is more predictable than the effect of previously tested pharmacologic agents, isosorbide dinitrate should be evaluated for its efficacy in the management of portal hypertension.

The effects of cisapride on gastric emptying, esophageal emptying, and gastrointestinal symptoms were evaluated in 8 patients with progressive systemic sclerosis who had delayed gastric emptying of the solid or liquid component of a meal, or both. A double-isotope technique was used to measure gastric emptying, and esophageal emptying was measured as the time for a bolus of the solid meal to enter the stomach. Gastrointestinal symptoms were assessed by a questionnaire. On 2 days each patient received cisapride (10 mg) or placebo intravenously, 5 min before an esophageal and gastric emptying test. After these 2 days each subject took cisapride (10 mg q.i.d., p.o.) for 1 mo. Cisapride improved solid and liquid gastric emptying (p less than 0.001), but had no significant effect on esophageal emptying (p less than 0.1). Upper gastrointestinal symptoms were reduced after cisapride (p less than 0.001), and no side effects were reported. These results indicate that gastroparesis is a treatable cause of morbidity in progressive systemic sclerosis.

To investigate whether paracentesis could be an alternative therapy for ascites, 117 cirrhotics with tense ascites were randomly allocated into two groups. Fifty-eight patients (group 1) were treated with paracentesis (4-6 L/day until disappearance of ascites) and intravenous albumin infusion (40 g after each tap). Fifty-nine patients (group 2) were treated with spironolactone (200-400 mg/day) plus furosemide (40-240 mg/day). Patients from group 2 not responding to diuretics were treated with a LeVeen shunt. After disappearance of ascites, patients from both groups were discharged from hospital and were instructed to take diuretics. Patients developing tense ascites during follow-up were readmitted to hospital and treated according to their initial schedule. Paracentesis was effective in eliminating the ascites in 56 patients from group 1 (96.5%) and did not induce significant changes in renal and hepatic function, plasma volume, cardiac index, peripheral resistance, plasma renin activity, plasma norepinephrine and antidiuretic hormone concentration, and urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1 alpha. Diuretics were effective in eliminating the ascites in 43 patients from group 2 (72.8%) (p less than 0.05). Ten patients in group 1 and 36 in group 2 developed complications during their first hospital stay (p less than 0.001). This difference was due to the significantly higher incidence of hepatic encephalopathy, renal impairment, and electrolyte disturbances occurring in patients treated with diuretics. The duration of hospital stay was 11.7 +/- 1.5 days for patients from group 1 and 31 +/- 2.8 days for patients from group 2 (p less than 0.001). The two groups did not differ significantly with respect to the probability of requiring readmission to hospital during follow-up, reasons for readmission, survival probability after entry into the study, and causes of death. These results indicate that paracentesis associated with intravenous albumin infusion is a fast, effective, and safe therapy for ascites in patients with cirrhosis.

Placebo-controlled trials are not available to assess the efficacy of smooth muscle relaxants in the treatment of painful esophageal motility disorders. Therefore, we compared the effects of oral nifedipine (10-30 mg t.i.d.) and placebo in 20 patients (mean age 50 yr) with chronic noncardiac chest pain and the nutcracker esophagus in a 14-week double-blind crossover study. Compared to placebo, nifedipine significantly decreased distal esophageal contraction amplitude (mean +/- SEM, 198 +/- 11 mmHg to 123 +/- 9 mmHg; p less than 0.005), as well as duration and lower esophageal sphincter pressure. Nifedipine, however, was no better than placebo in the relief of daily chest pain frequency, severity, or index (frequency X severity) as assessed by patient diaries. Despite these disappointing results, long-term follow-up (mean, 16.6 mo) suggests these patients do improve. Mean daily chest pain index significantly (p less than 0.005) decreased from 10.3 +/- 2.0 at the beginning of the study to 3.2 +/- 0.8 at follow-up. Prescription drug use and physician visits for chest pain also significantly decreased. Distal esophageal contraction pressures significantly fell during the long-term follow-up but there was poor correlation with chest pain improvement. This study suggests that identification of the esophagus as the cause of chest pain coupled with supportive intervention may be more effective than drug therapy in improving these patients' chest pain.