surgery

Stress ulcer prophylaxis in the ICU patients

INTRODUCTION —

• Stress ulcerations are mucosal erosions that generally occur in the fundus and body of the stomach, but sometimes develop in the antrum, duodenum, or distal esophagus.
• They tend to be shallow and cause oozing of blood from superficial capillary beds, but deeper lesions can erode into the submucosa, causing massive hemorrhage and/or perforation.

The risk of stress ulceration depends upon the severity and type of a patient’s underlying illness.

• Studies of various intensive care unit populations have estimated the risk of stress ulceration complicated by clinically significant bleeding at 1.5 to 15 percent.
• Stress ulcerations are the most common cause of gastrointestinal (GI) bleeding in intensive care unit (ICU) patients, and the presence of GI bleeding due to these lesions is associated with a five-fold increase in mortality compared to ICU patients without bleeding.

Considerable effort and expense are devoted to the prevention of stress ulcerations in pati
ents in the ICU because the consequences of GI bleeding can be severe.

• However, continued use of stress ulcer prophylaxis in hospitalized patients who have been discharged from the ICU is generally unwarranted and alarmingly common.

PATHOPHYSIOLOGY —

• Erosions begin to develop in the proximal regions of the stomach within hours of major trauma or serious illness.
• In one study, endoscopy performed within 72 hours of a major burn or cranial trauma revealed evidence of acute mucosal disease in 75 to 100 percent of patients.
• Up to 50 percent of these early mucosal lesions have endoscopic evidence of recent or ongoing bleeding,
  • but only a small percentage of these patients experience hemodynamic compromise due to acute blood loss.

Stress ulcerations that evolve after the first several days of hospitalization tend to be deeper and occur more distally within the GI tract.

• As an example, one study of 67 patients with GI bleeding which occurred a mean of 14 days after admission found that duodenal ulceration was the most common source of bleeding.
• It is uncertain if early and late ulcerations have the same pathophysiology, but both types are thought to result from derangements in the balance between gastric acid production and mucosal protective mechanisms.

One or more of the following processes may be involved:

Hypersecretion of acid —

• Hypersecretion of acid due to excessive gastrin stimulation of parietal cells is seen primarily in patients with head trauma.
• Acid secretion tends to be normal or subnormal in most other patients, in whom stress ulceration results from a breakdown of mechanisms normally protecting the gastric mucosa from the effects of acid.

Defects in gastric glycoprotein mucus —

• The stomach normally is protected by a glycoprotein mucous layer, which both forms a physical barrier to hydrogen ion diffusion and traps bicarbonate, allowing neutralization of gastric acid in the area adjacent to the stomach wall.
• In critically ill patients, increased concentrations of refluxed bile salts or the presence of uremic toxins can denude the glycoprotein mucous barrier and permit gastric injury.

Ischemia —

• Shock, sepsis, and trauma can lead to impaired perfusion of the gut.
• Experimental models of shock suggest a relationship between gastric mucosal ischemia and diminished secretion of protective mucus and bicarbonate.

H pylori —

• The influence of infection with H. pylori on the development of stress ulcers in the intensive care unit has not been well studied.
• One multicenter case-control study identified 29 patients with acute upper GI bleeding following admission to an intensive care unit, and found that these patients were more likely than nonbleeding ICU patients to have evidence of H. pylori infection (36 versus 16 percent).
• In a separate report, a statistically nonsignificant trend toward an increased risk of macroscopic gastrointestinal bleeding was observed among 67 H. pylori positive patients compared to 33 H. pylori negative controls.
• Furthermore, nurses in the intensive care unit were more likely to be infected with H. pylori than age-matched controls (40 versus 19 percent), suggesting the possibility of nosocomial transmission.

RISK FACTORS —

A prospective multicenter cohort study of 2252 ICU patients identified two major risk factors for clinically significant bleeding due to stress ulcers:

1. mechanical ventilation for more than 48 hours (odds ratio 15.6); and
2. coagulopathy (odds ratio 4.3).

• The risk of clinically important bleeding in patients without either of these risk factors was only 0.1 percent.

A number of smaller studies have reported additional risk factors for stress ulcerations, including :

• Shock
• Sepsis
• Hepatic failure
• Renal failure
• Multiple trauma
• Burns over 35 percent of total body surface area
• Organ transplant recipients
• Head or spinal trauma
• Prior history of peptic ulcer disease or upper GI bleeding

PROPHYLACTIC AGENTS — A variety of medications may be used to reduce the incidence of stress ulceration, including antacids, H2 blockers, sucralfate, proton pump inhibitors, and prostaglandin analogs.

Antacids —

• The action of antacids are to decrease gastric acidity by direct neutralization of stomach acid.
• Antacids are generally considered effective in the prevention of stress ulceration because numerous studies have shown roughly equivalent outcomes with these agents and H2 blockers.
• However, one meta-analysis found only a nonsignificant trend toward efficacy with antacids compared to placebo.

Drug costs are low, but these agents require administration of 30 to 60 mL orally or via nasogastric tube every one to two hours.

• The increase in nursing costs necessary for such administration negates some of the potential cost savings.
• Side effects of antacids can include hypermagnesemia, hypophosphatemia, constipation, diarrhea, nasogastric tube obstruction, and an increased risk of nosocomial pneumonia.

H2 blockers —

• H2 blockers raise gastric pH by decreasing the stimulatory effects of histamine on parietal cell acid secretion.
• Their effectiveness in preventing stress ulceration has been documented in most (but not all) trials.
• One meta-analysis, for example, reported a significantly lower risk of clinically significant GI hemorrhage with cimetidine versus placebo (3 versus 15 percent).

Administration of H2 blockers by continuous infusion provides better control of gastric pH than bolus infusion, but is not more effective in preventing clinically significant bleeding.

• H2 blockers are also effective if given orally or via nasogastric tube.

• H2 blockers are generally well tolerated, but occasionally the drugs may produce interstitial nephritis, confusion, or thrombocytopenia.
• Furthermore, the pharmacokinetics of drugs such as theophyline and warfarin may be significantly affected by cimetidine but not other H2 blockers.
• The costs of H2 blockers can be substantial, and dosing via continuous infusion may increase the number of intravenous catheters required by the patient.

Sucralfate —

• Sucralfate is a complex polyaluminum hydroxide salt of sucrose sulfate which exerts its effects via coating and protection of the gastric mucosa rather than through neutralization or inhibition of gastric acid.
• Sucralfate becomes highly polar at acid pH and binds preferentially to the granulation tissue of exposed ulcer beds, protecting them from further damage from acid, bile salts, or pepsin.

• The most rigorous randomized trial to date studied 1200 mechanically ventilated patients and found a significantly higher risk of clinically important GI bleeding with sucralfate versus H2 blocker (ranitidine) (3.8 versus 1.7 percent).
• This trial was important because of its large sample size, the fact that care givers, research personnel, and analysts were blinded to treatment assignments, its high rates of compliance, and the fact that clinical bleeding and pneumonia were strictly defined.
• One meta-analysis described similar findings, but reported a reduced mortality rate with sucralfate versus antacids and H2 blockers, possibly due to the less frequent development of nosocomial pneumonia (see below).
• Other, less rigorous trials have been done and in general reported that sucralfate and H2 blockers have similar efficacy.

Sucralpate is generally well tolerated.

• Elevations of plasma aluminum concentration have not been observed in intubated patients receiving 6 grams/day of sucralfate for 14 days, even in the presence of renal impairment.
• Costs may differ substantially between institutions, but the use of sucralfate generally is less expensive than the use of parenteral H2 blockers.

Proton pump inhibitors —

• Proton pump inhibitors, such as, omeprazole and others, contain a reactive sulfhydryl group that forms a disulfide bond with a cysteine residue on the H-K-ATPase pump, thereby inactivating the enzyme.
• Data regarding the efficacy and potential adverse effects of these drugs in the prevention of stress ulceration are less extensive than the sucrafate, H2 blockers, and antacids.
• Short-term use of proton pump inhibitors is rarely associated with significant side effects.
• Hypotheses regarding an increased incidence of nosocomial pneumonia due to elevations in gastric pH have not been adequately tested.

The ability of omeprazole oral suspension to decrease stress-induced GI bleeding was assessed in two prospective, open-label trials of mechanically ventilated with at least one additional risk factor for stress-related mucosal damage.

• In the first study, 75 patients received two doses of omeprazole oral suspension 40 mg six to eight hours apart, followed by 20 mg/day delivered via nasogastric tube.
  • There were no episodes of bleeding and no evidence of toxicity.
  • Similar results were noted in a subsequent study of 60 patients treated with omeprazole administered using the dosing regimen described above.

The relative efficacy of intravenous omeprazole, intravenous H2 blocker, and sucralfate in preventing bleeding associated with stress ulcers was evaluated in a prospective, randomized, three-arm trial published in abstract form.

• Omeprazole (40 mg every 12 hours) and ranitidine (150 mg/day) were administered intravenously; sucralfate 1 g every six hours was administered by nasogastric tube.
• The frequency of upper gastrointestinal bleeding was similar in patients treated with ranitidine and sucralfate (10.5 percent and 9.3 percent, respectively).

One study randomized 67 high-risk patients to prophylaxis with either intravenous H2 blocker or oral omeprazole.

• A significantly larger proportion of patients in the ranitidine group developed clinically important bleeding (31 versus 6 percent); however the ranitidine group had more risk factors for GI bleeding despite randomization, potentially confounding the results of the study.
• A subsequent larger trial compared oral omeprazole and intravenous the cimetidine in 359 ICU patients, and noted similar rates of GI bleeding in both groups (4.5 versus 6.8 percent, respectively;) .
• It has been suggested that oral PPI therapy may be more cost-effective than intravenous cimetidine for the prevention of stress ulcer-related gastrointestinal bleeding.

Prostaglandin analogs —

• Prostaglandin analogs such as the mesoprostol have both antisecretory and cytoprotective effects.
• The latter may result from capillary bed vasodilation, which protects against local ischemia.
• Several small trials and animal experiments suggest that misoprostol may be as effective as H2 blockers or antacids, in preventing stress ulceration, but the paucity of data and the propensity to cause diarrhea limit its clinical use in this setting.

Nutrition —

• Several studies have reported that enteral nutrition may reduce the risk of bleeding due to stress ulcerations.
• As an example, one study of 526 seriously burned patients compared treatment with antacids and cimetidine, versus enteral nutrition in the absence of prophylactic medications.
• The rate of overt GI hemorrhage was significantly lower in the group that received enteral nutrition as the sole form of GI prophylaxis (3.3 versus 8.3 percent).

A separate study analyzed data from 1077 critically ill Canadian patients who required mechanical ventilation for more than 48 hours.

• Patients who received enteral nutrition were significantly less likely to develop an upper gastrointestinal hemorrhage (risk ratio 0.30; 95% CI 0.13-0.67).
• However, treatment was not randomized, so it is possible that patients with a lower intrinsic risk of bleeding were better able to tolerate enteral feeding.

The effect of enteral nutrition is not mediated by an increase in gastric pH.

• Nutrition may prevent exhaustion of gastric epithelial energy stores and thereby prevent necrosis and ulcer formation; this mechanism may explain the protective effect against stress ulceration that has been reported with total parenteral nutrition (TPN).

NOSOCOMIAL PNEUMONIA —

• The major concern about prophylactic therapy for stress ulceration has been the potential increased risk of nosocomial pneumonia.
• Agents that raise gastric pH may promote the growth of bacteria in the stomach, particularly gram-negative bacilli that originate in the duodenum.
• Esophageal reflux and aspiration of gastric contents along the endotracheal tube may lead to endobronchial colonization and to pneumonia.

A number of studies have documented an increased frequency of nosocomial pneumonia in patients treated with H2 blockers or antacids as compared with the sucralfate.

• As an example, one study randomized 258 intubated patients to treatment with one of the following regimens: ranitidine at a rate of 6.25 mg/hour,; antacid 20 mL of antacid via nasogastric tube every two hours; or 1 gram of sucralfate via nasogastric tube every four hours.
• Nosocomial pneumonia occurring four or more days after intubation was significantly less frequent in patients receiving sucralfate (five versus 16 percent with antacids and 21 percent with ranitidine).
• No significant differences in macroscopic gastric bleeding were noted among the three treatment groups.

• A subsequent study of 1200 mechanically ventilated patients randomized to prophylaxis with either 1 gram every 6 hours of sucralfate or 50 mg every 8 hours of intravenous H2 blocker found only a nonsignificant trend toward a lower incidence of ventilator-associated pneumonia among sucralfate-treated patients.

SUMMARY

• Stress ulcers are mucosal erosions which primarily occur in the stomach, but can also be found in the distal esophagus or duodenum. They can develop within hours of a trauma or the onset of a critical illness. Critically ill patients who bleed from these lesions have a five-fold increase in mortality compared with patients who do not bleed.

• Stress ulcers are believed to be caused by an imbalance between gastric acid production and mucosal protection mechanisms. Mucosal ischemia may be an important cause in patients with underlying shock, sepsis, and trauma.

• Definite risk factors for the development of stress ulcers include mechanical ventilation for more than 48 hours and coagulopathy.
  • In addition, possible risk factors include shock, sepsis, hepatic and renal failure, multiple trauma, burns (>35 percent total body surface area), organ transplantation, head and/or spinal trauma, and a prior history of upper GI bleeding or peptic ulcer disease.

• Pharmacologic agents available for stress ulcer prophylaxis include H2-antagonists, antacids, sucralfate, prostaglandin analogs, and proton pump inhibitors (PPIs).
  • It is widely suggested that oral PPIs are for patients who are able to receive enteral medications, rather than intravenous H2 blockers, because they are superior at maintaining gastric pH >4, are not limited by tolerance, and may be more cost-effective.
  • In contrast, intravenous H2 blockers in for patients who cannot receive enteral medications, rather than intravenous PPIs.
  • This is based on the opinion that the far greater cost of intravenous PPIs outweighs the nominally greater efficacy that may exist.

• Stress ulcer prophylaxis should be discontinued after discharge from the ICU.

• The role of enteral nutrition in stress ulcer prophylaxis is uncertain.
  • Early enteral nutrition contributes to stress ulcer prophylaxis;
  • however, it alone cannot be recommended as sole stress ulcer prophylaxis in high risk patients.

• Whether acid suppression therapy confers an increased risk of nosocomial pneumonia is uncertain due to conflicting published data.

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