Authors: Aaron Woofter, MD; Richard Goodgame, MD Series Editor: Richard Goodgame, MD

Disclosures

August 22, 2006

Therapeutic Intervention

Drug

The only US Food and Drug Administration (FDA) approved intravenous medication for stress-related bleeding is cimetidine, and the most commonly recommended intravenous medication is a histamine-2 receptor antagonist (H2RA).[19] A survey of 500 intensivists was performed to assess current practice regarding prophylaxis of stress-related bleeding.[11] Of the 500 respondents, 64% used H2RAs by intermittent infusion, 23% primarily used PPIs, and 12% used sucralfate. The trend toward abandoning sucralfate and using oral and intravenous PPIs seems irreversible.

Intravenous PPIs have not been studied using clinically significant bleeding as an endpoint. Omeprazole immediate-release suspension is the only PPI drug or formulation with US FDA approval for stress-related mucosal bleeding prophylaxis. But PPIs are becoming preferred over H2RAs because they provide more potent acid suppression, maintain gastric pH ≥ 4 for prolonged periods, have a favorable adverse effect profile, have multiple administration routes, are not associated with tolerance, and are less likely to cause drug interactions mediated by cytochrome P450 enzymes.[28]

Both enteral and intravenous PPIs are potent acid suppressive agents in the ICU setting.[29] They are effective in preventing stress-related mucosal disease.[30,31,32] Direct comparison with ranitidine in stress-ulcer prophylaxis showed omeprazole was superior -- but the groups were not of equal risk.[33] Studies suggesting increased efficacy and decreased cost with PPI use are nonrandomized and observational.[34] Recent reviews support the rationale for using PPIs in this setting, but urge that more studies be performed.[35,36] These studies will probably not be conducted because of the low rate of bleeding and the large numbers of subjects required to show a difference between ranitidine and PPI therapy.

A recent 2-part article by Devlin and colleagues[28,37] addressed the efficacy, dose, and administration route permutations that have been brought about by the availability of multiple intravenous, oral, and other PPI formulations. They also identified the numerous unanswered questions regarding the use of PPIs for prophylaxis: What is the role for intravenous PPIs relative to intravenous H2RAs? What is the appropriate intravenous PPI dose for this indication? What is the role for newer enteral PPI formulations, such as the lansoprazole oral disintegrating tablet in water, vs the sodium bicarbonate-based suspensions? When should intravenous vs enteral therapy be employed? What is the role of intravenous-to-oral switch therapy?

Route

Oral. Recently, the number of commercially available PPI formulations has greatly expanded to include several oral formulations that may be administered enterally to patients unable to swallow a tablet or capsule (eg, immediate-release omeprazole with sodium bicarbonate packaged powder for suspension; lansoprazole tablet that can be dissolved in water; esomeprazole pellets administered in water).[28] Perhaps the best study of oral PPIs for the prevention of upper gastrointestinal bleeding in critically ill patients was published in 2005.[38] In this placebo-controlled study, 359 mechanically ventilated patients were randomized to receive either omeprazole immediate-release suspension 40 mg twice on day 1 (6-8 hours apart) through a nasogastric tube followed by 40 mg daily thereafter, or intravenous cimetidine 300-mg bolus and then 50 mg/hour thereafter. Gastric aspirates were frequently sampled for blood and pH monitoring. Clinically significant bleeding occurred in 3.9% of the omeprazole-treated patients and in 5.5% of the cimetidine-treated patients. When the more liberally defined outcome of any gastrointestinal bleeding was compared between groups, fewer omeprazole-treated patients experienced any bleeding (19.1% vs 32.0% with cimetidine; P < .005). The incidence of nosocomial pneumonia was similar between groups (7.9% vs 6.1%, respectively; P > .05). Significantly more cimetidine-treated (58%) than omeprazole-treated (18%) patients had inadequate pH control (P < .001). On the basis of these data, the US FDA recently approved immediate-release omeprazole 40 mg for the prevention of stress-related mucosal bleeding. Clearly, patients who are likely to absorb a medication should receive it orally or enterally if possible.

Intravenous. Enteral medication administration is not possible in many ICU patients with bleeding, obstruction, ileus, or mesenteric ischemia (vasopressors). One study evaluated intravenous PPIs compared with H2RAs for stress ulcer prophylaxis.[39] In this study, 210 mechanically ventilated patients were randomized to receive either cimetidine (300-mg bolus, then 50 mg/hour) or 1 of 4 pantoprazole intravenous dosing regimens: 40 mg daily, 40 mg every 12 hours, 80 mg once daily, 80 mg every 12 hours, and 80 mg every 8 hours. Clinically significant gastrointestinal bleeding did not occur in any of the patients.

Dose

All of the dosing permutations for oral and parenteral PPIs are provided in the reviews by Devlin and colleagues reviews.[28,37] The strategy of administering 2 doses of PPI 6 hours apart on the first day has been used to try to inactivate more proton pumps at the beginning of therapy because with daily dosing, several days are required to obtain maximal effect.[30,38]

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