Prophylactic Therapy

Although prophylactic therapy has dramatically reduced the incidence of bleeding in SRES, a reduction in mortality due to bleeding has not been demonstrated. The inhibition of gastric acid secretion with H2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) is the method used most extensively. The rationale for this approach stems from in vitro studies where an increase of intragas-tric pH to 3.5 to 4.0 is associated with decreased conversion of pepsinogen to pepsin and reduced proteolytic activity in the stomach. Moreover, when intragastric pH approaches 7.0, pepsinogen is irreversibly denatured and clotting factors become operable, enabling activation of the coagulation cascade. Finally, platelet aggregation, which occurs only at a pH > 5.9, also contributes to successful hemostasis and prevention of bleeding due to SRES. Although it has been postulated that optimal prophylaxis would require maintenance of intragastric pH at 7.0 or higher, most studies have demonstrated that an intragastric pH > 3.5 to 4.0 is associated with a reduction of gastroduodenal hemorrhage (Wolfe and Sachs, 2000).

Other approaches used to prevent GI bleeding due to SRES include the neutralization of gastric acid with antacids, the use of mucosal protective agents such as sucralfate or prostaglandins, and nonpharmacologic measures, such as the administration of enteral nutrition.

Antacids

Antacids effectively neutralize intraluminal gastric acid and inhibit pepsin activity by increasing gastric pH. Antacids significantly reduce the frequency of overt and clinically significant GI bleeding from SRES by 15 to 20%. The goal of acid neutralization therapy is to increase the intragastric pH to a 4 to inhibit the conversion of pepsinogen to active pepsin and thereby reduce proteolytic activity.

The administration of antacids in the ICU requires close monitoring of intragastric pH and individual titration to maintain the pH > 4. Gastric residual should also be assessed to avoid the possibility of distention and subsequent tracheopulmonary aspiration. Antacids may also impair the systemic absorption of drugs, including antibiotics. Other shortcomings of antacids include the increased incidence of diarrhea caused by the high magnesium con centration found in many antacid preparations, the need for frequent administration (every 1 to 2 hours) usually via nasogastric tube, increased nursing time, and elevated cost. Aluminum-based antacids may cause hypophosphatemia, constipation, and metabolic alkalosis, as well as potentially toxic plasma aluminum levels in patients with renal insufficiency. Because antacids are cumbersome to administer and the dose required to maintain intragastric pH near 4.0 is significant, these agents are no longer the drug of choice for SERS prophylaxis.

Histamine H2RAs

H2RAs inhibit acid secretion by competitively binding to histamine type 2 receptors located on the basolateral membrane of the gastric parietal cell. Numerous placebo- controlled trials have established the efficacy of H2RAs in preventing overt and clinically significant SRES hemorrhage. A meta-analysis of 16 studies, including 2,133 patients, showed no significant difference in efficacy between antacids and H2RAs in the prevention of clinically significant SRES hemorrhage. Moreover, both regimens were shown to be superior to placebo and were tolerated equally well (Shuman et al, 1987). A more recent meta-analysis suggested that H2RAs may be more effective than antacids in SRES (Tryba and Cook, 1997).

Only cimetidine (Tagamet) administered as a continuous intravenous (IV) infusion has Food and Drug Administration (FDA) approved labeling for the prevention of bleeding in critically ill patients. Other H2RAs given in equipotent doses appear to provide equivalent prophylactic efficacy. Cimetidine is typically administered intravenously by continuous infusion at doses of 37.5 to 100 mg/h, while ranitidine (Zantac) is dosed at 6.25 to 12.5 mg/h and famotidine (Pepcid) at 1.7 to 2.1 mg/h; all can be administered with or without a loading dose. Although no randomized controlled trials of adequate sample size have compared dosing regimens (intermittent versus continuous IV infusion) or routes (oral versus IV) using clinically significant bleeding as study endpoint, continuous H2RA infusion appears to provide more stable acid suppression than intermittent therapy ( Baghaie, 1995). Continuous infusion administration of H2RAs for more than 48 hours has been associated with tolerance and intragastric pH variability, likely due in part to enhanced gastrin-induced histamine production and competition with H2RAs at the H2 receptor (Baghaie, 1995). A randomized controlled study of 1,200 patients requiring mechanical ventilation compared IV ranitidine with sucral-fate in the prevention of upper GI bleeding. The rate of clinically significant bleeding in the ranitidine group was 1.7% compared with 3.8% for the sucralfate group; the difference was statistically significant (p = .02) (Cook et al, 1998).

Although H2RAs are considered to be very safe agents, they do possess both class specific and individual side effect profiles. The most prominent class specific effect is

CNS toxicity, which appears to be idiosyncratic rather than dose-related and occurs more frequently in elderly patients and usually within the first 2 weeks of therapy. Dose adjustments are necessary in individuals with impaired renal function. In addition, cimetidine and ranitidine, unlike famotidine and nizatidine, inhibit the clearance of drugs by the cytochrome P450 system and thereby interfere with the clearance of a wide variety of drugs.

Because of their efficacy, excellent safety profile, and ease of administration, H2RAs are generally preferred over antacids and PPIs in the prevention of SRES-related GI hemorrhage.

PPIs

PPIs are substituted benzimidazoles that work by irreversibly blocking hydrogen/potassium-ATPase (H+/K+-ATPase), the enzyme mediating the final common pathway involved in the secretion of acid. The following PPIs are currently available: (1) omeprazole (Prilosec), (2) lansoprazole (Prevacid), (3) rabeprazole (Aciphex), (4) pantoprazole (Protonix), and (5) esomeprazole (Nexium). All PPIs are available as oral agents, and pantoprazole (Protonix) as an IV preparation. PPIs are prodrugs, which are normally activated after systemic absorption in the highly acidic milieu of the secretory canaliculus of activated parietal cells. Activation occurs principally after a meal, and because patients at risk for the development of SRES are generally fasting, these drugs would be significantly less effective unless administered in a manner that maintains a plasma level exceeding that generally achieved by oral dosing (ie, IV) (Wolfe and Sachs, 2000).

Despite a prolonged biological half-life, the plasma halflife of PPIs is short (1 to 2 hours) and, if administered intermittently, several doses would be required to achieve adequate inhibition of H+/K+-ATPase. Tolerance to PPIs has not been reported.

The use of PPIs in SRES prophylaxis is controversial. Although a few small studies have suggested a beneficial effect, no large randomized trials have been performed to date to evaluate the benefit of these agents in the prophylaxis of SRES-associated GI bleeding. Difficulties in the oral administration of omeprazole and lansoprazole to mechanically ventilated ICU patients have not been resolved despite the recent development of suspensions that are somewhat effective in keeping gastric pH > 4. Two studies in mechanically ventilated ICU patients suggested that a simplified omeprazole suspension might not only prevent clinically significant SRES-related hemorrhage, but is also safe and cost effective (Phillips et al, 1996; Lasky et al, 1998). However, the studies were small, open label, and nonrandomized. Omeprazole and lansoprazole are acid labile prodrugs that have been formulated as granules with an enteric coating designed to dissolve at pH 5.5. Thus, with the bicarbonate suspension the protective enteric coating is dissolved.

Although the drug is purportedly protected from the acidic environment in the gastric lumen by the bicarbonate, many other factors may influence acid exposure, including the amount of bicarbonate, as well as the pH and volume of the solution used to flush the suspension through a nasogastric tube. It is thus possible that the PPI released from the granules undergoes acid-catalyzed conversion to the reactive species, a thiophilic sulfenamide, with inactivation of the drug before arrival at its intended target site (Wolfe et al, 2001).

Although IV pantoprazole (Protonix) is currently approved by the FDA only for patients with gastroesophageal reflux disease (GERD) who are unable to receive oral PPIs, this agent has shown to be beneficial in the prevention of recurrent hemorrhage due to ulcers, and is quite likely to be useful for other indications, including SRES prophylaxis. Studies comparing the ability of IV administrations of H2RAs and PPIs to raise and maintain intragastric pH suggest that, although both can raise the pH to > 4, PPIs are much more likely to maintain this pH. Unlike H2RAs, PPIs can elevate and maintain the intragastric pH at > 6, and unlike H2RAs, tolerance does not develop with IV preparations. Preliminary findings from clinical trials conducted within an ICU setting have shown that intermittent administration of IV panto-prazole is as effective in raising intragastric pH on the first day as a continuous infusion of an H2RA. These data suggest that intermittent or continuous infusion with an IV PPI may be an alternative to high dose continuous infusions of an H2RA. If continuous IV infusion is used, the recommended dose of pantoprazole is an 80 mg loading dose, followed by an infusion of 8 mg/h (Wolfe and Sachs, 2000).

Mucosal Protective Agents Sucralfate

Sucralfate is a basic nonabsorbable aluminum salt of sucrose octasulfate. Despite weak antacid properties, the protective effect of sucralfate is not mediated by acid suppression or neutralization, but by a mucosal protective effect on the gastric mucosa. The mucosal protection afforded by sucralfate is mediated by several mechanisms, including formation of a protective barrier, stimulation of gastric mucosal blood flow, prostaglandin-mediated increase in mucus and bicarbonate secretion, and by the stimulation of a variety of growth factors that have been implicated in ulcer healing.

Despite this theoretical benefit, the role of sucralfate in the prophylaxis of clinically significant SRES hemorrhage is controversial. Although some studies suggest that sucralfate is an effective prophylactic agent with a benign side effect profile that possibly includes a lower incidence of nosocomial pneumonia, in many of the studies reviewed, sucralfate was not statistically superior to the control group in preventing SRES hemorrhage. In a large study by Cook and colleagues (1998), including 1,200 mechanically ventilated patients, sucralfate was inferior to ranitidine in the prevention of upper GI bleed ing, and there was no significant differences in the rates of ventilator-associated pneumonia between the two agents (Cook et al, 1998). Sucralfate (Carafate) is available as tablets or as liquid slurry that is administered 1 g orally or by naso-gastric tube every 4 to 6 hours. Although usually well tolerated, constipation occurs in 2 to 4% of patients receiving sucralfate, and aluminum toxicity has occurred in patients with chronic renal failure.

Despite some theoretical advantages of sucralfate, including its ease of use, lack of need for monitoring, lack of need for supplemental antacid therapy, and cost effectiveness, this agent cannot be recommended as the drug of choice in SRES because of discordant study results.

Prostaglandin Analogues Despite the promise demonstrated in earlier trials, synthetic prostaglandin derivatives, such as misoprostol (Cytotec) have not been shown to be effective in the prophylaxis of SRES. Synthetic prostaglandin analogues exert a cytoprotective effect at low doses and have been demonstrated to protect the gastric mucosa from a variety of agents. Given the relatively high cost and major side effects associated with their use, it is unlikely that any large scale randomized clinical trial will be performed to investigate the role of prostaglandin analogues in SRES hemorrhage; therefore, the use of these agents in the prophylaxis of SERS cannot be recommended.

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

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