Robyn G. Karlstadt

Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage without promoting pneumonia

ObjectivesTo determine whether a continuous iv infusion of cimetidine, a histamine-2 (H2) receptor antagonist, is needed to prevent upper gastrointestinal (GI) hemorrhage when compared with placebo and if that usage is associated with an increased risk of nosocomial pneumonia. Due to the importance of this latter issue, data were collected to examine the occurrence rate of nosocomial pneumonia under the conditions of this study. DesignA multicenter, double-blind, placebocontrolled study. InterventionsPatients were randomized to receive cimetidine (n = 65) as an iv infusion of 50 to 100 mg/hr or placebo (n = 66). SettingIntensive care units in 20 institutions. PatientsCritically ill patients (n = 131), all of whom had at least one acute stress condition that previously had been associated with the development of upper GI hemorrhage. Measurements and Main ResultsSamples of gastric fluid from nasogastric aspirates were collected every 2 hrs for measurement of pH and were examined for the presence of blood. Upper GI hemorrhage was defined as bright red blood or persistent (continuing for >8 hrs) “coffee ground material” in the nasogastric aspirate. Baseline chest radiographs were performed and sputum specimens were collected from all patients, and those patients without clear signs of pneumonia (positive chest radiograph, positive cough, fever) at baseline were followed prospec-tively for the development of pneumonia while receiving the study medication.Cimetidine-infused patients experienced significantly (p = .009) less upper GI hemorrhage than placebo-infused patients: nine (14%) of 65 cimetidine vs. 22 (33%) of 66 placebo patients. Cimetidine patients demonstrated significantly (p = .0001) higher mean intragastric pH (5.7 vs. 3.9), and had intragastric pH values at >4.0 for a significantly (p = .0001) higher mean percentage of time (82% vs. 41%) than placebo patients. Differences in pH variables were not found between patients who had upper GI hemorrhage and those patients who did not, although there was no patient in the cimetidine group who bled with a pH < 3.5 compared with 11 such patients in the placebo group. Also, the upper GI hemorrhage rate in patients with one risk factor (23%) was similar to that rate in patients with two or more risk factors (25%). Of the 56 cimetidine-infused patients and 61 placebo-infused patients who did not have pneumonia at baseline, no cimeti-dine-infused patient developed pneumonia while four (7%) placebo-infused patients developed pneumonia. ConclusionsThe continuous iv infusion of cimetidine was highly effective in controlling

Intermittent intravenous pantoprazole and continuous cimetidine infusion: effect on gastric pH control in critically ill patients at risk of developing stress-related mucosal disease.

BACKGROUND This study aimed to assess intermittent intravenous (IV) pantoprazole for control of gastric acid and the possible prevention of upper gastrointestinal (UGI) bleeding in intensive care units (ICU) patients. METHODS This was a multicenter, randomized, open-label, dose-ranging pilot study of IV pantoprazole (40 mg q24 hour; 40 mg q12 hour; 80 mg q24 hour; 80 mg q12 hour; 80 mg q8 hour) or continuously infused cimetidine (300 mg bolus; 50 mg/h) in patients at risk for UGI bleeding. The primary endpoint was percent time gastric pH >/=4.0. UGI bleeding and pneumonia were measured as secondary endpoints. RESULTS Two hundred two ICU patients were randomized. Gastric pH was well controlled by all treatments. Gastric pH control improved from day 1 to day 2 in all pantoprazole groups, whereas there was decreased pH control in the cimetidine group. There were no cases of protocol defined UGI bleeding in any treatment group. Adverse event frequency and pneumonia incidence were similar between pantoprazole and cimetidine treated patients. CONCLUSIONS This pilot study indicates that intermittent IV pantoprazole effectively controls gastric pH and may protect against UGI bleeding in high risk ICU patients without the development of tolerance.

Comparison of Cimetidine and Placebo for the Prophylaxis of Upper Gastrointestinal Bleeding Due to Stress-related Gastric Mucosal Damage in the Intensive Care Unit

A multicenter, randomized, double-blind, placebo- controlled study was conducted with 87 patients in in tensive care units to study the effectiveness of constant infusions of cimetidine (50 mg/hr) in the prophylaxis of stress-related mucosal bleeding. Fifty-four patients re ceived cimetidine and 33 received placebo. The groups were comparable by age, sex, and severity of illness. One (2%) of the 54 patients receiving cimetidine had upper gastrointestinal hemorrhage and 7 (21%) of the 33 patients receiving placebo had upper gastrointestinal hemorrhage (p = 0.002). The risk of bleeding for every 100 patient days in intensive care units was reduced by 94% in the patients receiving cimetidine. Constant infu sion cimetidine was well tolerated. Only one patient (cimetidine) developed pneumonia during the study, but it was not considered to be related to drug therapy. No patients experienced adverse drug interactions. Two patients (4%) experienced reversible side effects from treatment. Cimetidine, administered as a continuous in travenous 50-mg/hour infusion, is safe and significantly more effective than placebo for preventing upper gas trointestinal bleeding in critically ill patients.

Maintenance therapy of duodenal ulcer with H2‐receptor antagonists—a meta‐analysis

A theoretical basis for similar recurrence rates among H2‐receptor antagonists exists based on recent concepts of ulcer recurrence, ulcer healing and suppression of nocturnal gastric acidity. In order to compare H2‐receptor antagonists in the maintenance therapy of duodenal ulcer, a meta‐analysis was carried out using 29 studies in the literature that met strict criteria. When the results of the placebo‐controlled studies were expressed as odds ratios, a technique used to minimize differences in protocol design and patient populations among studies, cimetidine, ranitidine, famotidine and nizatidine were all found to be superior to placebo to approximately the same extent. Odds ratios (and 95% confidence limits) for the recurrences in the pooled studies were cimetidine 0.22 (0.18–0.28), ranitidine 0.23 (0.18–0.30), famotidine 0.28–0.31 and nizatidine 0.36. These reflected similar 1‐year recurrence rates of 24.9% (n= 530) for 400 mg cimetidine nocte, 22.4 (n= 508) for 150 mg ranitidine nocte, 28.0% (n= 371) for 20 mg or 40 mg famotidine nocte, and 21.8% (n= 261) for 150 mg nizatidine nocte. In studies to compare cimetidine and ranitidine directly, the odds ratio (and 95% confidence limits) was 0.64 (0.48–0.86). However, for two studies done by a single protocol, the odds ratio of 0.51 (0.35–0.75) tended todiffer from the odds ratio of 0.85 (0.54‐1.33) for six other studies (P = 0.09). These reflected recurrence rates for cimetidine and ranitidine of 28.3% and 16.8% (two studies) and 23.3% and 20.6% (six studies) respectively.

Famotidine increases plasma alcohol concentration in healthy subjects

The effect of famotidine on plasma alcohol concentration was studied in 24 healthy male subjects who demonstrated high apparent ethanol first‐pass metabolism after oral (p.o.) and intravenous (i.v.) ethanol administration (i.e. AUCpo S 40% of AUCiv, where AUC is area under the plasma ethanol concentration‐time curve). Six of the original 30 subjects screened (20%) did not demonstrate high first‐pass metabolism and were excluded. In a randomized open crossover study, oral ethanol pharmacokinetics were assessed after breakfast in the morning following a 3‐day regimen of famotidine, 40 mg/day, and following a no‐drug control period. Famotidine increased the area under the plasma ethanol concentration‐time curve (AUC0‐t) by 29% (7.1 vs 5.5 mg.h/dL, P= 0.006) and maximal plasma concentration (Cmax) by 23% (9.2 vs 7.5 mg/dL, P= 0.013). The changes in ethanol AUC0‐t and Cmax may have been associated with changes in gastric emptying, as they were inversely correlated with changes in the time at which maximal plasma concentration was attained. There was considerable intra‐individual variation in ethanol AUC and Cmax. As a result, regression to the mean is a potentially confounding problem in ethanol pharmacokinetic studies when subjects are selected on the basis of having low AUCpo, and properly controlled randomized studies of substantial size are required to detect modest drug effects. Small effects on ethanol pharmacokinetics have now been demonstrated with all four of the major H2‐receptor antagonists, but these effects are seen only under specific experimental conditions and appear to be unimportant clinically.

Comparison between continuous and intermittent infusion regimens of cimetidine in ulcer patients

The relative effectiveness of intermittent infusions and primed continuous infusions of cimetidine in the maintenance of intragastric pH ≥ 4.0 was evaluated in a double‐blind crossover trial in 26 patients who had active or healed gastroduodenal ulcers. During the intermittent phase, each patient received 300 mg cimetidine intravenously every 6 hours. During the continuous infusion phase, each patient was given a continuous infusion of 37.5 mg cimetidine per hour, preceded by a priming dose of 300 mg cimetidine that was given for 15 minutes. Intragastric pH was monitored continuously. During the last 12 hours of the study, the continuous infusion regimen provided 20% more time in which the pH was less than 4.0 with 25% less medication than did the intermittent infusion regimen.

Acute treatment of benign gastric ulcer with once-daily bedtime dosing of cimetidine compared with placebo

This multicentre, double‐blind study evaluated the efficacy of cimetidine 800 mg nocte compared to placebo for ulcer healing and pain relief in patients with endoscopically confirmed, benign gastric ulcers treated for up to 8 weeks. Cimetidine accelerated ulcer healing throughout the study. More cimetidine‐treated patients (35 of 82, 43%) than placebotreated patients (26 of 79, 33%) had healed ulcers after 4 weeks of therapy. Similarly, after 6 and 8 weeks of treatment, cimetidine continued to have superior healing rates, 76% (59 of 78, P= 0.02) and 91% (69 of 76, P= 0.02) heal rates for cimitidine recipients compared with 58% (42 of 73) and 74% (52 of 70) for placebo. For every week of the study except the second, a greater proportion of cimetidine‐treated patients were free of daytime and night‐time pain than placebo‐treated patients; the differences were statistically significant for night‐time pain. Adverse reaction profiles were similar for the cimetidine and placebo groups. In conclusion, cimetidine 800 mg nocte was comparably safe and significantly more effective than placebo in accelerating healing and relieving pain in the treatment of acute, benign gastric ulcer.