J. Lacey Smith

Variceal Hemorrhage:A Critical Evaluation of Survival Analysis

Treatment of variceal hemorrhage is one of the most controversial subjects in medicine. The resurgence of old therapies (endoscopic sclerotherapy) and the introduction of new modalities (obliterative angiotherapy) has exacerbated the controversy. No widely accepted controlled therapeutic trial is available. The problem related to survival analysis has been studied in the light of the available information concerning the natural history of variceal bleeding. It is believed that controlled trials can be designed which will prove the efficacy, or lack of it, for any proposed treatment; however, valid conclusions based on previous studies are limited, largely because of the many confounding variables. Time, as a variable factor both for randomization and therapeutic intervention, has been largely ignored, yet, we believe it is the major variable in this setting. For the population of variceal bleeders, risk of rebleeding or death rapidly diminishes over the first few days after a bleed, and early survival may be the best marker for later survival. Neither presentation nor treatment seems to alter this fundamental behavior. Variceal hemorrhage may serve as a prototype for problems of survival analysis of diseases with early high mortality.

Gastric adaptation occurs with aspirin administration in man

Endoscopy has become a standard method to evaluate drug-induced damage to the gastroduodenal mucosa; however, studies defining the time course, extent, and duration of the injury in man are unavailable. We report a systematic endoscopic evaluation of the effect of aspirin administration on the gastric mucosa in normal volunteers. Aspirin (2.6 g/day) or placebo was administered for 1 or 7 days. Gastroscopy was performed after 1, 2, 4, and 8 days, and every other day thereafter until the lesions resolved. Submocosal hemorrhages and/or focal erosions were present within 24 hr in all subjects. With continuous aspirin administration, injury was maximal within 3 days and then lessened, ie, damage present after 7 days of aspirin was significantly less than after 1 day of therapy. The time to resolution of the damage was also longer following 1 day than after 7 days of aspirin (median 8 days for 1 day of aspirin vs median 3 days for 7 days of aspirin). Thus, gastric mucosal adaptation occurred and was associated both with less damage and with an accelerated healing process. Acute administration of aspirin produced well-defined areas of submucosal hemorrhages within 2 hr of administration; additional doses increased the area of involvement but not necessarily the severity of involvement.

Dyspepsia in NSAID users: The size of the problem

Gastroduodenal intolerance is one of the major factors limiting the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatic diseases. We previously demonstrated that dyspepsia was not a marker for ulcer in NSAID users. We have now evaluated dyspeptic symptoms in 245 arthritic patients (receiving 13 different NSAIDs) from the practices of two rheumatologists. Fifty-seven patients (23%) gave a history of previous peptic ulcers. Heartburn, indigestion, or sour stomach at least once within the past year was present in 62.5%; 36.7% had experienced these symptoms within the previous 2 months and 28.6% within the previous week. Only 39 patients (15.9%) had experienced dyspepsia more than once daily within the previous month, and 8 (3.3%) had dyspepsia >5 times/day. Thirtyfour of the 39 patients with daily dyspepsia claimed to obtain relief with cimetidine or antacids (34 patients) or food (2 patients), whereas 3 had not discovered anything that provided relief. Women smokers were more likely than nonsmokers to experience dyspepsia (p < 0.001). Neither men smokers nor those with a history of previous ulcer were more likely to have dyspepsia than nonsmokers or those without a history of ulcer (p > 0.5). We were not able to find a statistical association between any NSAID, or combination of NSAIDs, and the frequency of dyspepsia.

A multicenter, double-blind, randomized, placebo-controlled comparison of nocturnal and twice-a-day famotidine in the treatment of active duodenal ulcer disease

The efficacy and safety of famotidine, a potent new long-acting H2-receptor antagonist, was compared with placebo in a multicenter, double-blind, randomized, placebo-controlled study in the United States. A total of 384 patients with endoscopically proven acute duodenal ulcer disease were enrolled. Patients received either famotidine or a placebo. The patients receiving famotidine were treated with one of three dose regimens, 40 mg h.s., 40 mg b.i.d., or 20 mg b.i.d. Patients were reassessed by endoscopy at 2, 4, and 8 wk if ulcer healing had not occurred sooner. A diary was kept to record the duration and intensity of the day and night pain and the amount of Gelusil antacid (Parke-Davis, Morris Plains, N.J.) ingested. Three hundred sixty-three patients met the evaluation criteria. The results revealed a 4-wk healing rate of 70%, 75%, 67%, and 31% for the famotidine 40 mg h.s., 40 mg b.i.d., 20 mg b.i.d., and placebo groups, respectively. The 8-wk healing rates for the same respective groups were 83%, 82%, 82%, 45%. Ulcer pain and antacid consumption occurred less often in the famotidine groups. The clinical and laboratory safety profile of the famotidine groups was similar to that of the placebo group. Famotidine appears to be an effective and safe once-a-day therapy for the treatment of acute duodenal ulcer disease. The recommended dosage is 40 mg h.s.

Effects of aspirin and an aspirin-acetaminophen combination on the gastric mucosa in normal subjects

Abstract Coadministration or preadministration of acetaminophen with aspirin affords partial protection against aspirin-induced gastric mucosal injury in animals. Recently, it was reported that preadministration of acetaminophen in humans yielded similar protection. That study used pylorus occlusion, intravenous atropine, and exogenous acid, and thus may not have mimicked the usual clinical situation. We studied a clinical regimen, in 7 normal volunteers. We coadministered acetaminophen (1.95 or 2.6 g/ day) and aspirin (in a 1:1 ratio) and used gastroscopy to evaluate if there was gastric mucosal protection. Aspirin alone was used as a positive control. We found the expected significant increase in mucosal damage associated with increasing aspirin dose (p

Intragastric accumulation of Evan's blue as a method for assessing aspirin-induced acute gastric mucosal injury in humans

Aspirin administration results in gastric mucosal damage. Although the pathogene sis of these lesions remains unclear, in animals it appears that increased vascular permeability precedes development of grossly visible lesions. We examined the effect of aspirin administration on gastric vascular permeability in eight healthy subjects. We used gastric accumulation of Evans blue dye (which is bound to albumin) as a marker of vascular integrity and assessed gastric accumulation of Evans blue, blood, and DNA during serial 10-min washes. Both bleeding and Evans blue in the gastric washings increased with time after administration of aspirin in an acid solution (P <0.01).Evans blue increased from a median value of 8 μg/10min to 24.5 μg/10min period after 60 min of aspirin administration. By 20 min after aspirin administration, the accumulation of Evans blue in the gastric wash was significantly greater than the initial aspirin period (P <0.05).Blood loss increased from 147 to 650 μgHgb/10-min period. The increase in bleeding rate did not become significant until 40 min after the first aspirin dose. Our study showed that aspirin-induced gastric mucosal damage can be detected by assessing accumulation of Evans blue in the gastric contents after aspirin administration. Studies in which various doses of aspirin or other agents are administered will be required to confirm whether the increased vascular permeability actually precedes bleeding in man. Measurement of Evans blue dye in the gastric contents appears to provide a qualitative (and possibly quantitative) and sensitive early index of gastric mucosal injury.

Gastroscopic localization of a microencapsulated KCI preparation in the human stomach

A slow release polymer-coated preparation of potassium chloride granules (Micro-K Extencaps) was initially thought not to be associated with gastric mucosal damage. Recent studies have shown that acute gastric ulcers occur with approximately the same frequency as in patients taking wax matrix KCl formulations. The development of acute gastric ulcers was not consistent with the proposed dispersion characteristics of the microencapsulated KCl preparation. The authors therefore endoscopically evaluated the dispersion characteristics of microencapsulated KCl in a double-blind, placebo-controlled study. Subjects received four capsules of Micro-K or matching placebo and endoscopy was performed 30, 60, or 120 min after each drug ingestion. The material was identified with the Olympus HM (high magnification) endoscope and then quantitatively aspirated using the 3.5-mm biopsy channel of the Pentax 34JA endoscope. Microencapsulated KCl particles dispersed poorly and were found adhering to the mucosa and to one another, as a semisolid mass, most frequently in the gastric antrum. In contrast, the placebo (ethyl cellulose) was widely dispersed throughout the stomach. The authors concluded that gastric emptying must be considered in three phases: liquids, solids, and solids which adhere to the mucosa. No unique dispersion characteristics of Micro-K Extencaps were identified, and adherence of the KCl to the gastric mucosa may explain its ability to cause occasional acute gastric ulceration.

Ranitidine and Hepatotoxicity

Excerpt To the editor: Two articles in the August issue reported liver injury possibly associated with the use of ranitidine. Lima (1) reported a well-documented case of ranitidine hepatitis, prove...