American Journal of Health-System Pharmacy

Devlin, John, W.

doi: 10.1093/ajhp/62.10_Supplement_2.S2pmid: 15905597

Clinically important stress-related mucosal bleeding affects up to 4% of critically ill patients, with a mortality rate that approaches 50%.1,2 Acid suppression has become the cornerstone of therapy for patients at risk for stress-related mucosal bleeding. Treatment usually involves a histamine H2-receptor antagonist (H2RA) or a proton pump inhibitor (PPI), with a target intra-gastric pH of 4 or higher.1,3,4 Nearly two thirds of respondents to a recent survey of critical care physicians reported using H2RAs as first-line pro-phylactic therapy for stress-related ulcers.3 Another one in four respondents used PPIs as first-line therapy for this purpose. Sucralfate and antacids were preferred by 12% and 1% of respondents, respectively. The use of PPIs appears to be increasing, despite a relative lack of published data supporting use of these drugs for acid suppression in patients at risk for stress-related mucosal bleeding. Peptic ulcer bleeding is responsible for about half of cases of acute upper GI bleeding and is a frequent reason for admission to the intensive care unit (ICU).5,6 Variceal bleeding, another possible cause of upper GI bleeding, is beyond the scope of this supplement because of its unique etiology and treatment. Peptic ulcer bleeding accounts for approximately 150,000 hospitalizations annually in the United States.5 Bleeding recurs after endoscopic therapy (i.e., the use of electric or heat cauterization, localized injection of epinephrine, or both during endoscopy to provide hemostasis) in many patients. The mortality rate from peptic ulcer bleeding is as high as 11%.7 Mortality has not declined in recent years, despite improvements in care, for a number of reasons including the ever-increasing average age of patients who frequently have more co-morbid conditions.5,6 Acid-suppression therapy in patients with peptic ulcer bleeding requires a higher target intragastric pH (6 or higher) than that used for patients at risk for stress-related mucosal bleeding, and thus PPIs are first-line therapy.1,8 Although H2RAs are often used for stress-related ulcer prophylaxis, these drugs are not typically used in patients with peptic ulcer bleeding because they are less potent in suppressing acid secretion than PPIs and the target intragastric pH is higher.1 The use of intravenous (i.v.) PPIs has almost completely replaced the use of i.v. H2RAs in some hospitals, although programs to restrict the prescribing of i.v. PPIs have been established in many institutions. In most cases, the use of i.v. PPIs is for indications other than those that are approved by the Food and Drug Administration (pantoprazole is approved for the treatment of gastroesophageal reflux disease associated with erosive esophagitis and pathological hypersecretion associated with Zollinger-Ellison Syndrome, and lansoprazole is approved for the treatment of erosive esophagitis).9,10 In a 2002 survey, of i.v. PPI therapy use to prevent the recurrence of peptic ulcer bleeding in patients in acute care hospitals in Michigan, 24% of respondents reported never using i.v. PPI therapy and only 13% reported using it either frequently or all the time.11 The most commonly used i.v. dosage of pantoprazole (the only i.v. PPI available at the time the survey was conducted) varied widely, with 26% of respondents using high-dose i.v. continuous infusion therapy (80 mg as a bolus infusion followed by a continuous infusion of 8 mg/ hr), another 25% using 40 mg every 12 hours, and another 24% using 40 mg every 24 hours. The optimal dosing of pantoprazole and other PPIs in critically ill patients is the subject of ongoing controversy. There is evidence in the literature of inappropriate use of i.v. PPI therapy in patients at risk for stress-related ulcers and patients with peptic ulcer bleeding. The potential exists for both the overuse and underuse of i.v. PPI therapy to occur. Substantial costs are associated with each scenario in the ICU. Chan and colleagues found that only 57 (46%) of 124 patients with peptic ulcers who received i.v. PPI therapy were at high risk for recurrent bleeding.12 The rate of recurrent bleeding was only 16% in the 44 high-risk patients who received an appropriate dosage of the i.v. PPI (and endoscopic therapy). However, the rate of recurrent bleeding was considerably higher (46%) in the 13 high-risk patients who received an inappropriate dosage (and endoscopic therapy). In a separate series of 854 patients who received i.v. PPI therapy for known or suspected upper GI bleeding, a peptic ulcer disease-related lesion with a high risk of recurrence of bleeding was found during endoscopy in only 120 (14%) patients.13 A wide variety of dosage forms and routes of administration are available for PPI therapy, affording many options for treating patients in the ICU. New dosage forms continue to be developed (a parenteral form of esomeprazole is expected to become available this year). Criteria to guide the use of these various dosage forms remain to be developed. Several controversies and unresolved questions surround the use of acid-suppression therapy in critically ill patients, and these issues are the focus of this supplement. The first article in this supplement provides a review of the pharmacologic principles of acid suppression and a description of commercially available and extemporaneously compounded PPIs. In the second article, Martindale discusses the risk factors for and pathophysiology and clinical presentation of stress-related mucosal bleeding in critically ill patients. Therapeutic strategies for preventing bleeding also are outlined. In the third article, Olsen explores prognostic factors that predict outcomes in patients with peptic ulcer bleeding and therapeutic strategies for preventing the recurrence of bleeding. Finally, the rationale for limiting the PPI products included in an institutional formulary, factors to consider when making formulary decisions about PPI products, the results and limitations of cost-effectiveness analyses of PPI therapy in critically ill patients, and the role of clinical practice guidelines in improving PPI use in the intensive care setting are addressed and discussed in the fourth article. Based on the proceedings of a symposium held December 6, 2004, during the 39th ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from TAP Pharmaceutical Products Inc. Dr. Devlin received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Devlin reports that he has received research support from AstraZeneca and TAP Pharmaceutical Products Inc. and serves on the speakers bureau for AstraZeneca and TAP Pharmaceutical Products Inc. References 1 Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically ill patient: rationale for the therapeutic benefits of acid suppression. Crit Care Med . 2002 ; 30 (6 suppl): S351 –5. Crossref Search ADS PubMed 2 Cook DJ, Fuller HD, Guyatt GH et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med . 1994 ; 330 : 377 –81. Crossref Search ADS PubMed 3 Daley RJ, Rebuck JA, Welage LS et al. Prevention of stress ulceration: current trends in critical care. Crit Care Med . 2004 ; 32 : 2008 –13. Crossref Search ADS PubMed 4 Martin LF, Booth FV, Karlstadt RG et al. Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage without promoting pneumonia. Crit Care Med . 1993 ; 21 : 19 –30. Crossref Search ADS PubMed 5 Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med . 1994 ; 331 : 717 –27. Crossref Search ADS PubMed 6 Kupfer Y, Cappell MS, Tessler S. Acute gastrointestinal bleeding in the intensive care unit. The intensivist’s perspective. Gastroenterol Clin North Am . 2000 ; 29 : 275 –307. Crossref Search ADS PubMed 7 Rockall TA, Logan RF, Devlin HB et al. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ . 1995 ; 311 : 222 –6. Crossref Search ADS PubMed 8 Lin HJ, Lo WC, Lee FY et al. A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med . 1998 ; 158 : 54 –8. Crossref Search ADS PubMed 9 Protonix I.V. package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; December 2004 . 10 Prevacid I.V. package insert. Lake Forest, IL: TAP Pharmaceuticals Inc.; May 2004 . 11 Nguyen C, Barletta J, Devlin JW. Use of acid suppression agents following acute, nonvariceal, upper gastrointestinal bleeding. Hosp Pharm . 2004 ; 39 : 970 –5. Crossref Search ADS 12 Chan EP, Goebig M, Demers RF et al. Intravenous pantoprazole to prevent re-bleeding after endoscopic hemostasis of bleeding ulcers: initial U.S. experience. Gastroenterology . 2003 ; 124 : A626 . Abstract. 13 Enns R, Andrews CN, Fishman M et al. Description of prescribing practices in patients with upper gastrointestinal bleeding receiving intravenous proton pump inhibitors: a multicentre evaluation. Can J Gastroenterol . 2004 ; 18 : 567 –71. Crossref Search ADS PubMed Author notes Based on the proceedings of a symposium held December 6, 2004, during the 39th ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from TAP Pharmaceutical Products Inc. Dr. Devlin received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Devlin reports that he has received research support from AstraZeneca and TAP Pharmaceutical Products Inc. and serves on the speakers bureau for AstraZeneca and TAP Pharmaceutical Products Inc. Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

Martindale, Robert, G.

doi: 10.1093/ajhp/62.10_Supplement_2.S11pmid: 15905595

Abstract Purpose. The purpose of this review is to describe the clinical presentation and pathophysiology of stress-related mucosal bleeding and review the strategies to prevent bleeding. Summary. The mortality rate associated with clinically significant stress-related mucosal bleeding is high. Respiratory failure requiring mechanical ventilation for more than 48 hours and coagulopathy are two strong, independent risk factors for bleeding. Splanchnic hypoperfusion is the underlying etiology of stress-related mucosal injury and bleeding. Mucosal damage typically manifests as multiple superficial lesions without perforation, and bleeding often originates in superficial capillaries after the patient is admitted to the intensive care unit. Providing adequate visceral perfusion is vital to preventing bleeding. Gastrointestinal function should be taken into consideration before using enteral nutrition, and enteral nutrition should not be the sole stress ulcer prophylactic therapy. Acid-suppression therapy should be used to raise the intragastric pH above 3.5 because it reduces the incidence of stress-related mucosal bleeding. Proton pump inhibitors are at least as effective, and may be more effective than histamine H2-receptor antagonists in achieving this pH goal and preventing bleeding. Conclusion. The key to reducing mortality from stress-related bleeding in critically ill patients is to prevent mucosal damage. Providing adequate visceral perfusion and acid-suppression therapy can reduce the risk of stress-related mucosal damage and bleeding. Critical illness, Gastrointestinal drugs, Gastrointestinal hemorrhage, Mortality, Nutrition, Tolerance Stress-related mucosal disease (SRMD) (i.e., damage, ulceration, and bleeding) causes considerable morbidity and mortality in critically ill patients. The mortality rate from stress-related mucosal bleeding is nearly 50%.1 Stress-related mucosal damage is common in patients in the intensive care setting. Most patients (74–100%) have endoscopic evidence of mucosal damage within one or two days after admission to the intensive care unit (ICU).2 This damage is of little consequence because healing occurs rapidly. Clinically-evident bleeding—the presence of material with the appearance of coffee grounds in the nasogastric (NG) aspirate, guaiac-positive NG aspirate or stool, hematemesis, melena, or hematochezia—occurs in 5–25% of critically ill patients.1,2 Clinically-important bleeding affects 3–6% of patients, and it is more serious than clinically-evident bleeding because it involves hemodynamic instability or the need for blood transfusion.3,–5 Clinically-important bleeding is defined as overt bleeding and a spontaneous decrease in systolic blood pressure of more than 20 mmHg within 24 hours after gastrointestinal (GI) bleeding, an orthostatic increase in heart rate of 20 beats/minute and a decrease in systolic blood pressure of 10 mmHg when the patient assumes an upright position, a decrease in hemoglobin concentration of at least 2 g/dL and transfusion of two units of packed red blood cells within 24 hours after bleeding, or failure of the hemoglobin concentration to increase after transfusion by at least the number of transfused units minus 2 g/dL.1 In a prospective multicenter cohort study of 2252 patients admitted to ICUs, the mortality rate was significantly higher in patients with stress-related mucosal bleeding (49%) than in patients without such bleeding (9%).1 Two strong, independent risk factors for bleeding were identified in this cohort: (1) respiratory failure requiring mechanical ventilation for more than 48 hours and (2) coagulopathy. The odds ratios of clinically important GI bleeding in patients with these risk factors were 15.6 and 4.3, respectively. Other risk factors for stress-related mucosal bleeding are listed in Table 11. In a study of stress-related mucosal injury, a prospective analysis of 103 patients in an ICU for an average of 3.8 consecutive days found that the intramural pH and number of risk factors were significant predictors of massive bleeding from stress ulceration.6 The risk of bleeding decreased as the intramural pH increased from 6 to 8 and as the number of risk factors decreased from four to none. Case study SD is a 38-year-old morbidly obese woman with a history of several previous episodes of cholecystitis, chronic gastroesophageal reflux disease (GERD), and osteoarthritis of the knees. She intermittently takes nonprescription histamine H2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) to manage her GERD. SD takes acetaminophen for her knee pain, avoiding nonsteroidal antiinflammatory drugs (NSAIDs) on the advice of her physician. SD presents to the hospital emergency department with acute abdominal pain, nausea, and vomiting and is subsequently admitted with cholecystitis and choledocolithiasis diagnosed by abdominal ultrasound. She undergoes endoscopic retrograde cholangiopancreatography (ERCP), but problems arise during the procedure when the pancreas is inadvertently cannulated instead of the common bile duct. Within hours of the ERCP, SD develops signs of worsening pancreatitis and hypovolemia (with a systolic and diastolic blood pressure of 100 mmHg and 74 mmHg, respectively, and a heart rate of 120 beats/min). SD is admitted to the ICU, where volume resuscitation (i.e., intravenous [i.v.] fluids) is provided and her blood pressure returns to normal (systolic and diastolic blood pressures of 135 mmHg and 85 mmHg, respectively). SD’s pancreatic enzyme levels gradually decrease toward normal over the next several days. Her hematocrit is slightly lower than normal (33%), but this was felt to be secondary to the volume resuscitation and multiple blood draws. Her heart rate remains somewhat elevated (110 beats/min). On day five of SD’s hospitalization, material with the appearance of coffee grounds is aspirated from her NG tube. SD’s hematocrit has decreased to 27%, her heart rate is increased (120 beats/min), and her systolic and diastolic blood pressures are low (110 mmHg and 84 mmHg, respectively). SD had been receiving subcutaneous heparin twice daily and intermittent pneumatic compression to prevent deep vein thrombosis during her hospitalization. The heparin is discontinued once evidence of upper gastrointestinal (GI) bleeding is discovered. On day seven of hospitalization, SD develops hematemesis, and esophagogastroduodenoscopy (EGD) reveals a diffuse superficial hemorrhagic area in the fundus (i.e., upper portion) of the stomach. SD’s signs and symptoms are more consistent with stress-related mucosal damage than peptic ulcer disease because of the clinical presentation, EGD results, and lack of NSAID use in the patient history. Stress-related mucosal damage typically manifests as multiple superficial lesions in the proximal stomach (i.e., the fundus or cardia) during endoscopy.7,8 Bleeding most commonly originates in superficial capillaries. Lesions can progress to form deep ulcers if the pathophysiology is not corrected. However, perforation is extremely rare. As in SD’s case, admission to the ICU typically precedes stress-related mucosal bleeding. Splanchnic hypoperfusion is the underlying etiology of stress-induced ulcer formation and bleeding. If the pathophysiology is not corrected, the prognosis is poor for many patients with this condition. Patients rarely die of the bleeding but usually die of some other etiology, most commonly multiple organ failure. Lesions associated with SRMD are usually multiple and superficial and are not amenable to therapeutic endoscopy (i.e., electric or heat cauterization, localized injection of epinephrine, or both performed during endoscopy to provide hemostasis). As opposed to the SRMD, peptic ulcers usually are deep and solitary or few in number. Bleeding typically involves a single blood vessel.7,8 These ulcers typically develop in the antrum, pyloric channel, and duodenum. Perforation is not uncommon. Peptic ulcer bleeding as opposed to SRMD typically precedes admission to the ICU. The etiology of peptic ulcers is most commonly associated with Helicobacter pylori infection or the use of NSAIDs.9 The mortality rate in patients presenting with major bleeds remains relatively low at about 7–10%.10,11 Pathophysiology The splanchnic hypoperfusion that causes stress-related mucosal damage in critically ill patients is multifactorial and results from sympathetic nervous system activation, increased catecholamine release and vasoconstriction, hypovolemia, decreased cardiac output, and the release of proinflammatory cytokines (Figure 11).2,12 These stress-related effects are part of the “fight-or-flight” phenomenon that ordinarily serves a protective function by shifting blood away from the GI tract and skin to locations where it is needed to cope with stress (e.g., the brain, muscle tissues). However, when prolonged, these effects can be maladaptive in critically ill patients. Splanchnic hypoperfusion reduces GI mucosal blood flow, oxygen delivery to the mucosa, mucus production, and bicarbonate secretion which are effects that ordinarily protect the mucosa from the damaging effects of acid and pepsin. These changes increase the permeability of the mucosal barrier and allow acid back diffusion into the mucosa. Slowed mucosal blood flow impairs the healing process when mucosal damage occurs. Splanchnic hypoperfusion also decreases GI motility, which delays the removal of acidic, bilious material and other irritants from the stomach, prolonging the time during which the material is in contact with the GI mucosa.2 Reperfusion injury due to hyperemia and an enhanced inflammatory response when blood flow is restored after prolonged periods of hypo-perfusion contributes to GI epithelial cell damage.2 The diminished bicarbonate secretion and acid-neutralizing capacity associated with splanchnic hypoperfusion result in increased activation of pepsin, a proteolytic enzyme that can damage unprotected GI epithelial cells. At pH below 4, pepsin also can degrade the newly formed clots on vessels that have recently bled. Most patients with stress-related mucosal bleeding die of multiple organ system failure or sepsis, not the bleeding itself.13 Bleeding is a marker for the severity of illness. In general, once GI bleeding develops in a critically ill patient, interventions are ineffective. Therefore, the key to reducing mortality from stress-related bleeding in critically ill patients is to have an aggressive management strategy for prophylaxis. Prophylaxis Maintaining adequate visceral perfusion through aggressive volume resuscitation and hemodynamic support is the key to preventing SRMD. Further therapeutic options for preventing SRMD include the use of enteral nutrition, sucralfate, H2RAs, and PPIs. Antacids are no longer considered a viable therapeutic option because of labor intensive frequent dosing and potential side effects. Acid-suppression therapy (e.g., an H2RA or PPI) should be used to achieve and maintain an intragastric pH of greater than 3.5. There is support for this concept and a reported reduced incidence of stress-related bleeding compared with lower pH values.14 Enteral nutrition. Providing early enteral nutrition in critically ill patients is associated with stimulation of gut-associated lymphoid tissue (i.e., improved immunity), fewer infections, increased visceral blood flow, maintenance of the mucosal barrier, attenuation of the hyper-metabolic response, and improved glycemic control compared with parenteral nutrition.15 However, enteral feeding is only well tolerated in ICU patients that have been adequately resuscitated restoring visceral perfusion. The benefits of enteral nutrition depend on metabolic demands, the efficiency of nutrient utilization, and the ease of nutrient delivery. The results of retrospective studies of the impact of enteral nutrition on stress-related mucosal disease are conflicting. Analysis of retrospective data over the course of one year from 43 mechanically-ventilated patients in an ICU revealed evidence of stress-related mucosal bleeding in 14 (70%) of 20 patients receiving antacids, 7 (78%) of 9 patients receiving the H2RA cimetidine (300 mg i.v. every 6 hours), and none (0%) of 14 patients receiving a standard enteral nutrition formula.16 A retrospective analysis of data from a four-year period involving 526 seriously burned patients in an ICU found a lower incidence of bleeding (3%) in the 273 patients who received enteral nutrition than in the 253 patients who received cimetidine (400 mg i.v. every 4–6 hours) with or without antacids (8%).17 However, in a retrospective review of 298 ICU charts, enteral nutrition was associated with a significantly higher incidence of GI bleeding (56%) than i.v. cimetidine 1–1.2 g/24 hours (15%), antacids (5%), or cimetidine plus antacids (25%).18 The results of prospective studies are often confounded by poor study design and small sample sizes.19 Therefore, until further well-controlled studies have been performed, enteral nutrition should not be used alone for the prevention of stress-related ulcers in critically ill patients. Enteral nutrition should be used in combination with acid-suppression therapy (i.e., an H2RA or PPI). It does appear that once the patient is over the severe nature of the metabolic insult and is able to tolerate enteral feeding, acid suppression therapy can be stopped with enteral nutrition supplying adequate coverage. Intolerance to enteral nutrition is common in the ICU and ranges from 15–50%.2 Possible mechanisms for intolerance include splanchnic hypoperfusion and altered GI motility. Hypomotility is multifactorial and can result from electrolyte abnormalities, excessive sympathetic input, and inflammatory changes in the bowel wall.20 GI function (i.e., the presence of GI hypomotility) should be taken into consideration before attempting enteral nutrition in critically ill patients; when done judiciously and with caution it can be very beneficial and successful but can be disasterous when attempted in patients with severe dysmotility. The optimal timing and site for delivery of enteral nutrition remain to be determined. Whether jejunal feeding protects the stomach from stress-related mucosal damage is suggested yet not well studied. The duration of prophylactic acid-suppression therapy needed in patients who tolerate enteral nutrition also is uncertain. Additional research is required to resolve these therapeutic dilemmas. Sucralfate. In the past, some clinicians used sucralfate instead of acid-suppression therapy in critically ill patients at risk for stress-related mucosal disease because of theoretical concerns about gram-negative bacterial overgrowth when the pH of the stomach contents was increased.21 Aspiration of gastric contents is common in critically ill patients, especially those with NG tubes. In theory, bacterial overgrowth and aspiration of gastric contents could lead to nosocomial pneumonia. Sucralfate is a gastroprotective agent that appears to improve mucosal barrier function (see Welage article in this supplement) without affecting acid secretion or the intragastric pH. Conflicting results were reported from small studies comparing the incidence of nosocomial pneumonia in critically ill patients treated with sucralfate or H2RAs. 14,21,–25 Concerns about nosocomial pneumonia from acid-suppression therapy were put to rest by a larger, more recent, randomized, double-blinded, placebo-controlled trial involving 1200 patients who required mechanical ventilation and were at risk for stress-related mucosal bleeding.5 No significant difference was found in the incidence of nosocomial pneumonia between patients treated with the H2RA ranitidine 50 mg i.v. every 8 hours (19%) and patients treated with sucralfate 1 g as an oral suspension by NG tube every 6 hours (16%).5 The incidence of clinically-important upper GI bleeding was significantly lower with ranitidine (1.7%) than with sucralfate (3.8%). H2RAs. Cimetidine remains the only H2RA that is approved by the Food and Drug Administration (FDA) for the prevention of upper GI bleeding in critically ill patients.26 The regimen approved by FDA is a 50-mg/hr continuous i.v. infusion. In a randomized, double-blind, placebo-controlled study of 131 critically ill patients, the incidence of stress-related upper GI bleeding was significantly lower with cimetidine 50–100 mg/hr by continuous i.v. infusion (14%) than with placebo (33%).14 Intravenous H2RAs most commonly used in clinical practice are administered as intermittent bolus infusions instead of continuously. The impact of these two methods for i.v. cimetidine administration on intragastric pH was compared in a randomized, crossover study of 23 critically ill patients.27 An intragastric pH greater than the target value of 4 was maintained more consistently in a larger number of patients by a 300-mg i.v. bolus infusion followed by a continuous i.v. infusion of 37.5–50 mg/hr than by intermittent 300-mg i.v. bolus infusions every 4–8 hours. In a typical patient, the pH was maintained at around 6 over the course of a 12-hour period after the start of the continuous infusion. When a typical patient was crossed over to receive the intermittent bolus infusions, a similar peak intragastric pH was achieved, but the pH dropped below the target level of 4 within 4–5 hours after a dose. Thus, continuous i.v. infusion of cimetidine is more effective for maintaining the target intragastric pH needed to prevent stress-related mucosal bleeding than intermittent bolus infusions. A meta-analysis of 10 randomized, placebo-controlled trials of stress-related ulcer prophylaxis found that H2RAs substantially reduce the risk of clinically-important bleeding.28 The risk of bleeding was reduced by 56% by H2RA therapy. PPIs. In a small randomized study of 108 patients who were at risk for SRMD, the efficacy of the PPI omeprazole (50 mg i.v. every 12 hours) in preventing overt GI bleeding was compared with that of sucralfate (1 g orally every 6 hours) and i.v. ranitidine (150 mg/day).29 The incidence of overt bleeding was 0% with omeprazole, 9.3% with sucralfate, and 10.5% with ranitidine. The differences between treatments were not significant. The efficacy of omeprazole (40 mg/day by NG tube) for preventing stress-related mucosal bleeding was compared with that of ranitidine (150 mg/day by continuous i.v. infusion) in a randomized study of 67 patients at high risk for stress-related ulcers.30 The incidence of clinically-important bleeding was significantly lower with omeprazole (6%) than with ranitidine (31%). The percentage of patients with an intragastric pH value of 4 or less (i.e., inadequate pH control) was significantly lower in the omeprazole group (12%) than in the ranitidine group (28%). The incidence of nosocomial pneumonia also was significantly lower in the omeprazole group (3%) than in the ranitidine group (14%). However, one should be cautioned that the number of risk factors per patient was significantly lower in the omeprazole group (1.9) than in the ranitidine group (2.7), and this difference may have affected the outcomes. In two small, open-label trials, no clinically-important bleeding occurred in mechanically-ventilated patients at risk for stress ulcers who were given extemporaneously compounded simplified omeprazole suspensions (two 40-mg loading doses 6–8 hours apart on day one, followed by 20 mg/day).31,32 The lack of a control group is a shortcoming of these studies. In a recent randomized study, an immediate-release formulation of omeprazole powder with bicarbonate for oral suspension (40 mg/day) was compared with continuous i.v. infusion of cimetidine (a 300-mg bolus infusion, followed by 50 mg/hr) in 359 patients who were at risk for stress-related ulcers.33 The incidence of any GI bleeding was significantly lower with omeprazole (19%) than with cimetidine (32%). The incidence of clinically important GI bleeding (a more clinically relevant outcome than any GI bleeding) was slightly lower but not significantly different with omeprazole (3.9%) than with cimetidine (5.5%). There was no significant difference between the two treatments in the rate of failure of intragastric pH control (pH ≤4 on two successive measures taken at least one hour apart) or the incidence of nosocomial pneumonia (7.9% and 6.1%, respectively). A comparison of mean intragastric pH on day one and day two of treatment with i.v. cimetidine (300 mg by bolus infusion, followed by 50 mg/hr) and various dosages of i.v. pantoprazole (40 mg once or twice daily and 80 mg two or three times daily) revealed that tolerance associated with cimetidine (i.e., a reduction in acid-suppressive effect, resulting in a decrease in intragastric pH over time) is not a problem with pantoprazole.34 The intragastric pH on day two was significantly higher in patients receiving pantoprazole 80 mg two or three times daily than in patients receiving cimetidine or other dosages of pantoprazole. There were no significant differences among treatment groups in the incidence of clinically important bleeding. The effects of perioperative administration of single i.v. doses of pantoprazole before elective major surgery were evaluated in a randomized, single-blind pilot study.35 Pantoprazole 40 mg or 80 mg was administered one hour before surgery in 26 patients. Study endpoints included the volume of gastric secretions as well as the intragastric pH because of the risk of aspiration of gastric contents and nosocomial pneumonia in surgical patients. Both pantoprazole doses were effective in reducing gastric volume and gastric acid output as early as one hour after administration, and the effect was maintained for up to 12 hours after the dose. These results suggest that perioperative i.v. PPI therapy might be beneficial in preoperative high-risk surgical patients to lower pH and gastric volume.36 Future research The optimal strategy for preventing SRMD remains unclear despite literally hundreds of reports evaluating the options. Clearly, prevention is the best strategy and primary prevention revolves around aggressive resuscitation and maintaining adequate visceral perfusion. Several unresolved questions remain. For example, how should patients who were on PPIs as outpatients be managed when admitted to the hospital and ICU? How should differences in PPI metabolism due to genetic polymorphisms be assessed? (See Welage article in this supplement for additional information about genetic polymorphism). The influence of PPIs and other stress ulcer prophylactic therapies on colonic flora (especially Clostridium difficile) also requires further investigation.37 Exciting new avenues for research in critically ill patients include the influence of PPIs on the endogenously-produced trefoil peptides that protect GI epithelial surfaces.38 Preliminary in vitro data suggest that delivery of the amino acid glutamine to the gastric mucosa might attenuate proinflammatory cytokine expression and increase heat shock protein, which protects cells from stress.39 Arginine, an amino acid that serves as a substrate for nitric oxide synthase yielding nitric oxide, is a potent vasodilator. These and other techniques to enhance mucosal protection and visceral perfusion are areas fertile for research. Discussion Significant stress-related mucosal bleeding in the ICU population is associated with a high mortality rate. Establishing adequate visceral perfusion is the key to preventing stress-related mucosal disease in critically ill patients. Enteral nutrition provides benefits to patients once adequate volume resuscitation has been provided, but GI function should be taken into consideration before using enteral nutrition and it should not be used as the sole stress ulcer prophylactic therapy. Acid-suppression therapy to achieve and maintain an intragastric pH above 3.5 reduces the risk of stress-related bleeding. Recent large series reports support the concept that nosocomial pneumonia is not a valid concern in patients receiving acid-suppressive therapy. Conclusion PPIs are at least as effective as H2RAs—and limited data suggest that PPIs may be more effective—in achieving the target intragastric pH and preventing stress-related mucosal bleeding, without a risk for tolerance. Table 1. Risk Factors for Stress-Related Mucosal Bleeding1,3,a,b aGI = gastrointestinal. bRespiratory failure requiring mechanical ventilation and coagulopathy are two strong, independent risk factors for bleeding. Respiratory failure requiring mechanical ventilation for more than 48 hrb Coagulopathyb Acute renal failure Acute hepatic failure Sepsis syndrome Hypotension Severe head trauma History of GI bleeding Thermal injury involving more than 35% of the body surface area Major surgery (lasting more than 4 hours) aGI = gastrointestinal. bRespiratory failure requiring mechanical ventilation and coagulopathy are two strong, independent risk factors for bleeding. Respiratory failure requiring mechanical ventilation for more than 48 hrb Coagulopathyb Acute renal failure Acute hepatic failure Sepsis syndrome Hypotension Severe head trauma History of GI bleeding Thermal injury involving more than 35% of the body surface area Major surgery (lasting more than 4 hours) Table 1. Risk Factors for Stress-Related Mucosal Bleeding1,3,a,b aGI = gastrointestinal. bRespiratory failure requiring mechanical ventilation and coagulopathy are two strong, independent risk factors for bleeding. Respiratory failure requiring mechanical ventilation for more than 48 hrb Coagulopathyb Acute renal failure Acute hepatic failure Sepsis syndrome Hypotension Severe head trauma History of GI bleeding Thermal injury involving more than 35% of the body surface area Major surgery (lasting more than 4 hours) aGI = gastrointestinal. bRespiratory failure requiring mechanical ventilation and coagulopathy are two strong, independent risk factors for bleeding. Respiratory failure requiring mechanical ventilation for more than 48 hrb Coagulopathyb Acute renal failure Acute hepatic failure Sepsis syndrome Hypotension Severe head trauma History of GI bleeding Thermal injury involving more than 35% of the body surface area Major surgery (lasting more than 4 hours) Figure 1. Open in new tabDownload slide Pathophysiology of Stress Ulcers. Adapted with permission.2,12 Figure 1. Open in new tabDownload slide Pathophysiology of Stress Ulcers. Adapted with permission.2,12 Based on the proceedings of a symposium held December 6, 2004, during the 39th ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from TAP Pharmaceutical Products Inc. Dr. Martindale received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Martindale reports that he has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 Cook DJ, Fuller HD, Guyatt GH et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med . 1994 ; 330 : 377 –81. Crossref Search ADS PubMed 2 Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving mechanical ventilation. Chest . 2001 ; 119 : 1222 –41. Crossref Search ADS PubMed 3 ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. Am J Health-Syst Pharm . 1999 ; 56 : 347 –79. Crossref Search ADS PubMed 4 Cook D, Heyland D, Griffith L et al. Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. Crit Care Med . 1999 ; 27 : 2812 –7. Crossref Search ADS PubMed 5 Cook D, Guyatt G, Marshall J et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med . 1998 ; 338 : 791 –7. Crossref Search ADS PubMed 6 Fiddian-Green RG, McGough E, Pittenger G et al. Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterology . 1983 ; 85 : 613 –20. PubMed 7 Howden CW. Use of proton-pump inhibitors in complicated ulcer disease and upper gastrointestinal tract bleeding. Am J Health-Syst Pharm . 1999 ; 56 (suppl 4): S5 –11. 8 Goldin GF, Peura DA. Stress-related mucosal damage. What to do or not to do. Gastrointest Endosc Clin N Am . 1996 ; 6 : 505 –26. Crossref Search ADS PubMed 9 Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology . 2000 ; 118 (2 suppl 1): S9 –31. Crossref Search ADS PubMed 10 Daneshmend TK, Hawkey CJ, Langman MJ et al. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ . 1992 ; 304 : 143 –7. Crossref Search ADS PubMed 11 Silverstein FE, Gilbert DA, Tedesco FJ et al. The national ASGE survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. Gastrointest Endosc . 1981 ; 27 : 80 –93. Crossref Search ADS PubMed 12 Silen W. The prevention and management of stress ulcers. Hosp Pract . 1980 ; 15 : 93 –100. 13 Lewis JD, Shin EJ, Metz DC. Characterization of gastrointestinal bleeding in severely ill hospitalized patients. Crit Care Med . 2000 ; 28 : 46 –50. Crossref Search ADS PubMed 14 Martin LF, Booth FV, Karlstadt RG et al. Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage without promoting pneumonia. Crit Care Med . 1993 ; 21 : 19 –30. Crossref Search ADS PubMed 15 Schmidt H, Martindale R. The gastrointestinal tract in critical illness. Curr Opin Clin Nutr Metab Care . 2001 ; 4 : 547 –51. Crossref Search ADS PubMed 16 Pingleton SK, Hadzima SK. Enteral alimentation and gastrointestinal bleeding in mechanically ventilated patients. Crit Care Med . 1983 ; 11 : 13 –6. Crossref Search ADS PubMed 17 Raff T, Germann G, Hartmann B. The value of early enteral nutrition in the prophylaxis of stress ulceration in the severely burned patient. Burns . 1997 ; 23 : 313 –8. Crossref Search ADS PubMed 18 Gurman G, Samri M, Sarov B et al. The rate of gastrointestinal bleeding in a general ICU population: a retrospective study. Intensive Care Med . 1990 ; 16 : 44 –9. Crossref Search ADS PubMed 19 MacLaren R, Jarvis CL, Fish DN. Use of enteral nutrition for stress ulcer prophylaxis. Ann Pharmacother . 2001 ; 35 : 1614 –23. Crossref Search ADS PubMed 20 Kalff JC, Turler A, Schwarz NT et al. Intra-abdominal activation of a local inflammatory response within the human muscularis externa during laparotomy. Ann Surg . 2003 ; 237 : 301 –15. PubMed 21 Prod’hom G, Leuenberger P, Koerfer J et al. Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer. A randomized controlled trial. Ann Intern Med . 1994 ; 120 : 653 –62. Crossref Search ADS PubMed 22 Eddleston JM, Vohra A, Scott P et al. A comparison of the frequency of stress ulceration and secondary pneumonia in sucralfate- or ranitidine-treated intensive care unit patients. Crit Care Med . 1991 ; 19 : 1491 –6. Crossref Search ADS PubMed 23 Driks MR, Craven DE, Celli BR et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. The role of gastric colonization. N Engl J Med . 1987 ; 317 : 1376 –82. Crossref Search ADS PubMed 24 Simms HH, DeMaria E, McDonald L et al. Role of gastric colonization in the development of pneumonia in critically ill trauma patients: results of a prospective randomized trial. J Trauma . 1991 ; 31 : 531 –6. Crossref Search ADS PubMed 25 Ryan P, Dawson J, Teres D et al. Nosocomial pneumonia during stress ulcer prophylaxis with cimetidine and sucralfate. Arch Surg . 1993 ; 128 : 1353 –7. Crossref Search ADS PubMed 26 Tagamet package insert. Research Triangle Park, NC: GlaxoSmithKline; June 2002 . 27 Ostro MJ, Russell JA, Soldin SJ et al. Control of gastric pH with cimetidine: boluses versus primed infusions. Gastroenterology . 1985 ; 89 : 532 –7. Crossref Search ADS PubMed 28 Cook DJ, Reeve BK, Guyatt GH et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA . 1996 ; 275 : 308 –14. Crossref Search ADS PubMed 29 Azevedo JR, Soares MG, Silva C et al. Prevention of stress ulcer bleeding in high risk patients: comparison of three drugs. Crit Care Med. 1999 ; 27 : A145 . Abstract 411. 30 Levy MJ, Seelig CB, Robinson NJ et al. Comparison of omeprazole and ranitidine for stress ulcer prophylaxis. Dig Dis Sci . 1997 ; 42 : 1255 –9. Crossref Search ADS PubMed 31 Lasky MR, Metzler MH, Phillips JO. A prospective study of omeprazole suspension to prevent clinically significant gastrointestinal bleeding from stress ulcers in mechanically ventilated trauma patients. J Trauma . 1998 ; 44 : 527 –33. Crossref Search ADS PubMed 32 Phillips JO, Metzler MH, Palmieri MT et al. A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med . 1996 ; 24 : 1793 –800. Crossref Search ADS PubMed 33 Conrad SA, Gabrielli A, Margolis B et al. Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients. Crit Care Med . 2005 ; 33 : 1 –6. PubMed 34 Somberg L, Karlstadt R, Blatcher D et al. Intermittent intravenous pantoprazole (P) maintains control of gastric pH in intensive care unit patients. Am J Gastroenterol. 2002 ; 97 : S47 . Abstract. 35 Pisegna JR, Martindale RG. Acid suppression in the perioperative period. J Clin Gastroenterol . 2005 ; 39 : 10 –6. PubMed 36 Pisegna JR, Oh D, Karlstadt R et al. Perioperative use of i.v. pantoprazole (IVP) effectively controls gastric volume and acid output in NPO patients in the perioperative period: analysis of results from the perioperative IVP pilot study. Crit Care Med. 2003 ; 31 : A84 . Abstract 308. Crossref Search ADS 37 Dial S, Alrasadi K, Manoukian C et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ . 2004 ; 171 : 33 –8. Crossref Search ADS PubMed 38 Choo D, Khwaja K, Nori K et al. In vivo characterization of the molecular-genetic changes in gastric mucosa during the development of acute gastritis and stress ulceration. J Trauma . 2002 ; 52 : 720 –5. PubMed 39 Wischmeyer PE, Riehm J, Singleton KD et al. Glutamine attenuates tumor necrosis factor-alpha release and enhances heat shock protein 72 in human peripheral blood mononuclear cells. Nutrition . 2003 ; 19 : 1 –6. Crossref Search ADS PubMed Author notes Based on the proceedings of a symposium held December 6, 2004, during the 39th ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from TAP Pharmaceutical Products Inc. Dr. Martindale received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Martindale reports that he has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

Olsen, Keith, M.

doi: 10.1093/ajhp/62.10_Supplement_2.S18pmid: 15905596

Abstract Purpose. Prognostic factors in patients with peptic ulcer bleeding and therapeutic strategies for preventing the recurrence of bleeding are described. Summary. The risk of complications and death in a patient with acute upper gastrointestinal bleeding can be predicted based on certain clinical factors, the most important being the endoscopic findings. Proton pump inhibitors (PPIs) are the drugs of choice for patients with peptic ulcer bleeding because the drugs are more effective than histamine H2-receptor antagonists for maintaining the target intragastric pH (6 or higher) and preventing the recurrence of peptic ulcer bleeding, although an impact on mortality has not been demonstrated. High-dose intravenous PPI therapy should be used for patients at high risk of rebleeding (based on endoscopic findings). Oral PPI therapy may be used for low-risk patients. Underlying causes of ulcers should also be addressed and treated as necessary. Conclusion. Acid-suppression therapy using PPIs is effective for reducing the risk for recurrence of peptic ulcer bleeding. Dosage, Drug administration routes, Gastrointestinal drugs, Gastrointestinal hemorrhage, Mortality, Ulcers Gastrointestinal (GI) hemorrhage is a common cause of hospitalization in the United States, accounting for at least 300,000 hospitalizations each year.1 The mortality rate from acute upper GI bleeding is 7–10%. Despite advances in medical and surgical care, the mortality from acute upper GI bleeding has not changed over the past several decades. The single most common cause of GI bleeding is peptic ulcers; about half of cases of GI hemorrhage are attributed to peptic ulcers.2 GI hemorrhage spontaneously stops in most patients; however, up to 20% or more may continue to bleed or re-bleed, which places the patient at an increased risk of mortality and surgical intervention. Thus, the primary goal in initial management is identifying these high-risk patients for aggressive pharmacologic and endoscopic intervention.3 Case study CK is a 64-year-old man who presents to the emergency department complaining of “coffee-grounds” emesis three times over the past six hours. His blood pressure is low (systolic and diastolic pressures of 98 mmHg and 56 mmHg, respectively), his heart rate is high (112 beats/min), and his respiratory rate is elevated (22 breaths/min). Laboratory testing reveals a low hemoglobin (8.7 g/dL), hematocrit (25.2%), and red blood cell count (2.3 × 1012 cells/L). CK’s past medical history includes an episode of upper GI bleeding two years ago and hypertension and coronary artery disease, which were diagnosed 10 years ago. His prescription medications include extended-release diltiazem 180 mg once daily and atorvastatin 10 mg once daily. On questioning, CK admits to taking nonprescription ibuprofen 400 mg as often as four times daily for joint aches. The initial management of CK and other patients with acute upper GI bleeding includes fluid resuscitation (intravenous [i.v.] fluids and blood products) and supportive measures to correct hemodynamic instability, a common contributor to mortality.2,3 Therapeutic endoscopy (i.e., use of electric or heat cauterization, localized injection of epinephrine, or both to provide hemostasis) usually is performed in patients with acute upper GI bleeding, and it can be performed in the emergency department. The case of CK illustrates the dilemma that clinicians often face when deciding how to further manage patients with acute upper GI bleeding. Acid-suppression therapy plays an important role in these patients because bleeding tends to recur in the presence of gastric acid and pepsin, which prevent clot formation and promote clot dissolution. Fibrinolysins in the arterial blood supply also contribute to clot dissolution. Acid-suppression therapy with a target in-tragastric pH of 6 or higher inactivates pepsin; promotes proper platelet aggregation, clot formation, and coagulation; and prevents recurrence of ulcer bleeding.4,–6 The majority (99.9%) of acid is neutralized at this pH. Determining how aggressively to initiate acid-suppression therapy in CK and other patients with acute upper GI bleeding requires assessment of the patient and his or her risk for recurrent bleeding (Figure 11). The risk of complications and death in a patient with acute upper GI bleeding can be predicted by assessing the patient for the prognostic factors listed in Table 11. The presence of one or more prognostic factors (i.e., a high risk for complications and death) is usually cause for admission to the intensive care unit (ICU). CK is admitted to the ICU because of his advanced age and low systolic blood pressure. The ideal medical approach would be to perform endoscopy as soon as possible, preferably in the emergency room to assess ulcer stigmata and to assign the most appropriate treatment regimen. Admission to the ICU is typically dependent upon the age of the patient (>60 years), cardiovascular stability (e.g., hypotension, tachycardia), active bleeding, comorbid conditions, low systolic blood pressure, blood transfusion (>6 units), shock, ongoing bleeding, prolonged prothrombin time, and erratic mental status. Patients with no prognostic factors are at low risk for complications and death, and they often can be managed conservatively in a medical ward or even in the emergency department. Endoscopy is required to detect major stigmata (i.e., visible evidence) of recent hemorrhage, and most patients with acute upper GI bleeding undergo therapeutic or diagnostic endoscopy. Table 22 lists the prevalence of various possible endoscopic findings and subsequent outcomes in patients with bleeding peptic ulcers. Patients who have ulcers with a clean base or flat spot are less likely to benefit from aggressive (i.e., high-dose i.v.) acid-suppression therapy than patients with a nonbleeding, visible vessel or active arterial bleeding because their risk for recurrent bleeding, need for surgical intervention, and mortality are lower.2 In these low-risk patients, treatment should be designed to heal the ulcer and address the underlying cause (i.e., eradicate Helicobacter pylori, discontinue nonsteroidal antiinflammatory drug [NSAID] use if possible, or both). Treatment should include oral (not i.v.) acid-suppression therapy.3 All patients, regardless of risk, should be assessed with respect to NSAID use and H. pylori infection. If it is determined that the patient uses NSAIDs or has H. pylori infection, counseling or treatment should occur before discharge. The management of ulcers with adherent clots is controversial because the risk of recurrent bleeding, need for surgical intervention, and mortality are intermediate. Some clinicians consider vigorous washing and oral acid-suppression therapy sufficient if the clot remains stable after washing. However, most clinicians prefer to use therapeutic endoscopy and aggressive acid-suppression therapy for up to 72 hours in these patients. When CK undergoes endoscopy, active arterial bleeding is detected and heat cauterization is used to stop the bleeding. Because CK had active arterial bleeding, he is at high risk for recurrent bleeding and should receive aggressive acid-suppression therapy beginning promptly. Whether acid-suppression therapy should be initiated earlier in patients like CK (i.e., at the time of initial presentation at the emergency department before endoscopy is performed) is unclear. However, if a significant delay is expected before endoscopy can be performed and the patient has any risk factors, aggressive acid-suppression therapy should be initiated. As soon as visual observation and findings confirm the patient to be at low risk, therapy can be eased. Upon discharge from the ICU, CK should be advised to discontinue his use of ibuprofen because of the contributory role of NSAIDs in peptic ulcer disease.3 Therapeutic dilemmas Clinicians who treat patients with acute upper GI bleeding often are faced with several dilemmas, including whether to use therapeutic endoscopy with or without acid-suppression therapy, histamine H2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) for acid suppression, a high or low dosage, the oral or i.v. route of administration, and continuous or intermittent i.v. infusion. Drawing conclusions from clinical trial reports in the literature is complicated by inconsistencies in the definition of what constitutes recurrent bleeding and the heterogeneity of study subjects (e.g., the exclusion of high-risk patients from some studies). Study outcomes may reflect the geographic location of the study, racial and ethnic differences between study subjects, and genetic polymorphism in the rate of drug metabolism (see Welage article in this supplement). An impact of acid-suppression therapy on mortality has been difficult to demonstrate, even by meta-analysis, because of the inadequate power of the studies.7,11,12 The importance of endoscopic therapy (i.e., therapeutic endoscopy) in preventing recurrence of bleeding was affirmed in a study of 156 patients with upper GI bleeding and nonbleeding, visible vessels or adherent clots.13 In this single-blind study with blinded evaluation of study endpoints, patients were randomized to undergo therapeutic endoscopy in combination with the PPI omeprazole (80 mg as a bolus i.v. infusion, followed by 8 mg/hr by continuous i.v. infusion for 72 hours) or sham endoscopic therapy plus the same omeprazole regimen (i.e., omeprazole alone). The incidence of recurrent bleeding and transfusion requirements were significantly lower in the group treated with a combination of therapeutic endoscopy and omeprazole than in the group receiving omeprazole alone. Recurrence of ulcer bleeding before discharge occurred in none (0%) of 78 patients who received combination therapy and 7 (9%) of 78 patients who received omeprazole alone, a difference that is significant. Therefore, the use of a PPI alone is not recommended for patients with acute upper GI bleeding who are at high risk for recurrent bleeding. H2RAs Data from studies of the efficacy of i.v. H2RAs for preventing recurrence of peptic ulcer bleeding are conflicting.12,13 A meta-analysis revealed that a trend toward reduction in bleeding recurrence by 10% has been reported.12 However, <20% of all patients rebleed or continue to bleed and 10% of this population represents a very small group that would potentially derive benefit from H2RAs. Several randomized, placebo-controlled studies of the efficacy of H2RAs for preventing recurrence of ulcer bleeding found no significant difference between active treatment and placebo.14,–16 The efficacy of H2RAs might depend on the location of the ulcer (i.e., the stomach or duodenum). A second meta-analysis of studies in patients with duodenal ulcer bleeding found no benefit from H2RA therapy in preventing bleeding recurrence, surgery, or death.13 Small but significant reductions in the recurrence of bleeding, need for surgery, and death by 7.2%, 6.7% and 3.2%, respectively, were provided by H2RA therapy in patients with bleeding gastric ulcers.12 Possible explanations for the marginal efficacy of H2RAs in patients with peptic ulcer bleeding include the drugs’ limited acid-suppressive potency (i.e., poor intragastric pH control), the development of tolerance to the drugs (a gradual reduction in acid-suppressive effect due to up regulation of histamine H2 receptors over time), and the mechanism of action; only one of the three pathways for proton pump activation and acid secretion is inhibited by H2RAs. (See Welage article in this supplement.) PPIs Clinical trials have been conducted to compare the efficacy of PPIs with that of H2RAs for preventing ulcer bleeding recurrence. In one study, 100 patients with active bleeding or nonbleeding visible vessels underwent therapeutic endoscopy and were randomized to receive i.v. omeprazole (a 40-mg bolus, followed by 6.7 mg/hr for three days) or i.v. cimetidine (a 300-mg bolus, followed by 50 mg/hr for three days).17 The frequency of recurrent bleeding was significantly lower in the omeprazole group (6%) than in the cimetidine group (22%). Continuous intragastric pH monitoring over a 24-hour period revealed consistent pH control in both groups, but the pH was around 6 in the omeprazole group and around 5 in the cimetidine group. A significant variance of the pH was observed in the cimetidine group. The mean duration of intra-gastric pH higher than the target of 6 (i.e., the adequacy of pH control) was significantly longer in the omeprazole group than in the cimetidine group (84% versus 54% of the 24-hour monitoring period). Differences between the treatment groups in the technique used for therapeutic endoscopy might have affected the study outcomes. The study was conducted in Asia, which may limit the ability to extrapolate the results to non-Asian patient populations (e.g., genetic polymorphism). The antisecretory effects of i.v. omeprazole (80 mg as a bolus infusion, followed by a 2- to 12-mg/hr continuous infusion) and i.v. ranitidine (50 mg as a bolus infusion, followed by a 4- to 24-mg/hr continuous infusion) were compared over a 72-hour period in 20 healthy volunteers.18 Dosing of both drugs was titrated to maintain an intragastric pH above 4. The median percentage of time with the pH higher than 4 with omeprazole was 93% on day one and 96% on day three; corresponding values in the ranitidine group were 67% on day one and 43% on day three. This reduction in pH over time in the ranitidine group reflects the rapid development of tolerance. There was no evidence of tolerance to omeprazole. A meta-analysis was conducted of 11 randomized controlled trials in which the rate of recurrence of peptic ulcer bleeding was compared with H2RAs and with PPIs.19 The results of this meta-analysis favored PPIs. Administration route and schedule Oral PPIs. Data from studies of the efficacy of oral omeprazole therapy in preventing recurrent peptic ulcer bleeding have been analyzed to answer questions about the optimal route of administration of the drug. Oral omeprazole (40 mg every 12 hours for 5 days) was evaluated in a randomized, double-blind, placebo-controlled trial in 220 patients with peptic ulcers, including 26 patients with arterial spurting; 35 patients with nonbleeding, visible vessels; 34 patients with active oozing; and 125 patients with adherent clots.20 Omeprazole significantly reduced the incidence of recurrent bleeding compared with placebo in patients with nonbleeding, visible vessels and patients whose ulcers had adherent clots. In patients with arterial spurting or active oozing (i.e., patients at a higher risk for recurrent bleeding than those with nonbleeding, visible vessels or adherent clots), there was a lower incidence of recurrent bleeding with omeprazole than with placebo, but the difference was not significant. The study was conducted in Asia and therapeutic endoscopy was not used initially, factors that limit extrapolation of the results to the United States where therapeutic endoscopy has become the standard of care in patients with acute upper GI bleeding. Nevertheless, the results suggest that oral PPI therapy may provide some benefit in patients with bleeding peptic ulcers. These results were confirmed by a recent meta-analysis showing that the reduction of rebleeding rates by PPIs is independent of the route of administration.7 In a separate randomized, double-blind, placebo-controlled study of 149 patients with bleeding peptic ulcers who underwent therapeutic endoscopy, omeprazole (20 mg) or placebo was administered by nasogastric tube every 6 hours for 5 days.21 Endoscopic findings in the 149 patients included 57 (38%) non-bleeding, visible vessels; 80 (54%) ulcers with active oozing; and 12 (8%) ulcers with a spurting artery (i.e., patients were at high risk for recurrence of bleeding). The incidence of recurrent bleeding was significantly lower in the omeprazole group (17%) than in the placebo group (33%). Transfusion requirements also were significantly lower with omeprazole than with placebo. Parenteral PPIs. In a landmark randomized, double-blind, placebo-controlled study, 240 patients with actively bleeding ulcers or nonbleeding, visible vessels were randomized to receive i.v. omeprazole (80 mg as a bolus infusion, followed by 8 mg/hr) or placebo for 72 hours after therapeutic endoscopy (epinephrine injections and thermocoagulation).22 Patients whose ulcers had clean bases or flat spots (i.e., at low risk for recurrent bleeding) were excluded from the study. All patients in both treatment groups subsequently received omeprazole 20 mg/day orally for eight weeks. A significantly lower incidence of recurrent bleeding after 30 days was found in the omeprazole group (7%) than in the placebo group (23%). Most episodes of recurrent bleeding occurred during the first three days after therapeutic endoscopy; nevertheless, a significant difference between treatment groups in the incidence of recurrent bleeding (4% with omeprazole and 20% with placebo) was evident within three days after therapeutic endoscopy. The need for surgical intervention and the 30-day mortality rate were lower with omeprazole than placebo, although the differences were not significant. The findings of this landmark study form the basis for the current standard of care in patients with peptic ulcer bleeding who are at high risk for recurrent bleeding. The importance of these findings was confirmed by a consensus conference that recommended following this regimen in managing patients with non-variceal upper gastrointestinal bleeding.3 A meta-analysis of randomized, controlled trials comparing i.v. PPIs with H2RAs or placebo found a reduction in the recurrence of peptic ulcer bleeding with i.v. PPI therapy.7 However, i.v. PPI therapy had no impact on mortality. The reduction in risk of recurrent peptic ulcer bleeding with continuous i.v. omeprazole therapy for 72 hours is well documented in placebo-controlled trials.22,–24 The omeprazole dosage used in these studies (80 mg as a bolus followed by 8 mg/hr) is relatively large. Several clinical trials have explored the use of intermittent i.v. omeprazole therapy in patients with acute upper GI bleeding. The daily dosages used in these studies were aggressive, although they were lower than those administered by continuous infusion in other studies. In a large placebo-controlled trial, an 80-mg i.v. bolus of omeprazole was followed by three 40-mg i.v. doses every 8 hours and then 40 mg orally every 12 hours.25 In other smaller studies, omeprazole 80 mg as an i.v. bolus followed by 40 mg i.v. every 8 or 12 hours was compared with ranitidine 50 mg i.v. every 4 or 6 hours.26,–28 Intermittent i.v. infusion of omeprazole was not significantly more effective than placebo or ranitidine in reducing the risk of recurrent bleeding in these studies. Therefore, continuous i.v. omeprazole therapy is preferred over intermittent i.v. omeprazole therapy. Other i.v. PPIs Whether data derived from i.v. omeprazole studies can be extrapolated to other i.v. PPIs (i.e., pantoprazole, lansoprazole and esomeprazole [pending FDA approval]) remains to be determined. In theory, pharmacokinetic, pharmacodynamic, and safety differences between the drugs might be a consideration. However, the safety profiles of the PPIs are similar, and the clinical relevance of the pharmacokinetic and pharmacodynamic differences among them is unknown (see Welage article in this supplement).29 The effects of i.v. pantoprazole (an 80-mg bolus injection followed by 6 mg/hr or 8 mg/hr for 72 hr) on intragastric pH were explored over a 24- to 48-hour period in two pilot studies of a total of 40 patients with acute bleeding peptic ulcers who had undergone therapeutic endoscopy.30 A high intragastric pH (above or near 6) was achieved with both dosages, although pH control was more consistent over the 24- to 48-hour study period with the larger of the two dosages. In a study of 1244 patients with high-risk bleeding ulcers, including actively bleeding ulcers and nonbleeding, visible vessels, the incidence of bleeding recurrence after therapeutic endoscopy was not significantly different with i.v. pantoprazole (80 mg bolus followed by 8 mg/hr) and i.v. ranitidine (50 mg bolus followed by 13.3 mg/hr).31 However, in a subgroup analysis of 98 ulcers with arterial spurting, the incidence of bleeding recurrence was significantly lower with pantoprazole (11%) than with ranitidine (35%). In 441 patients with gastric ulcers (the type of bleeding peptic ulcers that are known to benefit from H2RA therapy), the bleeding recurrence rate was lower with pantoprazole (5%) than with ranitidine (11%), although the difference was not significant. These findings suggest that high-dose i.v. pantoprazole may be more effective than H2RAs in preventing recurrence of ulcer bleeding in certain high-risk patients. A single-center study evaluated lower doses of i.v. pantoprazole versus i.v. ranitidine for the prevention of rebleeding after endoscopic hemostasis of bleeding peptic ulcers. After hemostasis was achieved, 102 patients were randomized to receive i.v. pantoprazole (initial 40 mg bolus followed by 40 mg every 12 hours for 3 days, followed by 40 mg orally daily) or ranitidine (initial 50 mg bolus dose followed by 50 mg every 8 hours for 3 days, then 150 mg orally every 12 hours). Bleeding occurred in 2 patients (4%) in the pantoprazole arm compared with 8 (16%) in the ranitidine arm (p = 0.04). There was no statistical significance between the groups with regard to surgery, transfusion requirements, hospital stay, or mortality.32 Patient management In patients like CK who are at high risk for recurrent peptic ulcer bleeding because an adherent clot; non-bleeding, visible vessel; or active bleeding is detected during endoscopy, high-dose i.v. PPI therapy (a bolus followed by continuous infusion) should be initiated promptly and continued for up to 72 hours.3 H2RAs should not be used because they are ineffective for maintaining a sufficiently high intragastric pH to prevent recurrent bleeding and because of the rapid development of tolerance. PPIs are the drugs of choice because they are more effective than H2RAs for maintaining the target intragastric pH and preventing the recurrence of peptic ulcer bleeding, although an impact on mortality has not been demonstrated. Tolerance does not develop to the acid-suppressive effect of PPIs. Experience to date with oral PPIs in patients at high risk for recurrent peptic ulcer bleeding is inconclusive. Therefore, therapy should be administered i.v. (preferably continuously) instead of orally in high-risk patients. If endoscopy reveals a low risk of bleeding recurrence (i.e., an ulcer with a clean base or a flat spot), PPI therapy may be given orally instead of i.v.3 An eight-week course is generally used to heal the ulcer. The underlying cause of the ulcer (Helicobacter pylori infection or NSAID use) also should be addressed to prevent ulcer recurrence. Patients at a low risk for recurrent ulcer bleeding may be discharged once their condition is stabilized; inpatient treatment may not be necessary. Most of the available data from clinical trials of PPIs in patients with bleeding peptic ulcers are for omeprazole, but the data that recently became available support the use of high-dose i.v. pantoprazole.30,31 The consistent intragastric pH control and efficacy in preventing the recurrence of peptic ulcer bleeding that have been demonstrated with pantoprazole probably also will be demonstrated in the future for i.v. lansoprazole and esomeprazole. Conclusion Peptic ulcers are the most common cause of upper GI bleeding and they are associated with substantial morbidity and mortality. PPIs are the drugs of choice for patients with peptic ulcer bleeding because they are more effective than H2RAs for maintaining the target intragastric pH and preventing bleeding recurrence, although an impact on mortality has not been demonstrated. The preferred route of administration is high-dose i.v. therapy, although oral therapy may be appropriate in low-risk patients without major ulcer stigmata. Table 1. Prognostic Factors in Patients with Acute Upper GI Bleeding 8,–10,a,b aGI = gastrointestinal. bThe presence of one or more of these factors predicts the development of complications and death in patients with acute non-variceal upper GI bleeding and warrants admission to the intensive care unit. Age >60 yr Transfusion requirement of >6 units of blood Shock Comorbidity hepatic, renal, or pulmonary disease cancer congestive heart failure Major stigmata of recent hemorrhage Ongoing bleeding Low systolic blood pressure Elevated prothrombin time Erratic mental status aGI = gastrointestinal. bThe presence of one or more of these factors predicts the development of complications and death in patients with acute non-variceal upper GI bleeding and warrants admission to the intensive care unit. Age >60 yr Transfusion requirement of >6 units of blood Shock Comorbidity hepatic, renal, or pulmonary disease cancer congestive heart failure Major stigmata of recent hemorrhage Ongoing bleeding Low systolic blood pressure Elevated prothrombin time Erratic mental status Table 1. Prognostic Factors in Patients with Acute Upper GI Bleeding 8,–10,a,b aGI = gastrointestinal. bThe presence of one or more of these factors predicts the development of complications and death in patients with acute non-variceal upper GI bleeding and warrants admission to the intensive care unit. Age >60 yr Transfusion requirement of >6 units of blood Shock Comorbidity hepatic, renal, or pulmonary disease cancer congestive heart failure Major stigmata of recent hemorrhage Ongoing bleeding Low systolic blood pressure Elevated prothrombin time Erratic mental status aGI = gastrointestinal. bThe presence of one or more of these factors predicts the development of complications and death in patients with acute non-variceal upper GI bleeding and warrants admission to the intensive care unit. Age >60 yr Transfusion requirement of >6 units of blood Shock Comorbidity hepatic, renal, or pulmonary disease cancer congestive heart failure Major stigmata of recent hemorrhage Ongoing bleeding Low systolic blood pressure Elevated prothrombin time Erratic mental status Table 2. Endoscopic Findings in Patients with Bleeding Peptic Ulcers: Prevalence and Outcomes2 Parameters Clean Base Flat Spot Adherent Clot Nonbleeding Visible Vessel Active Arterial Bleeding Prevalence (%) 42 20 17 17 18 Risk of recurrent bleeding (%) 5 10 22 43 55 Need for surgical intervention (%) 0.5 6 10 34 35 Mortality (%) 2 3 7 11 11 Parameters Clean Base Flat Spot Adherent Clot Nonbleeding Visible Vessel Active Arterial Bleeding Prevalence (%) 42 20 17 17 18 Risk of recurrent bleeding (%) 5 10 22 43 55 Need for surgical intervention (%) 0.5 6 10 34 35 Mortality (%) 2 3 7 11 11 Table 2. Endoscopic Findings in Patients with Bleeding Peptic Ulcers: Prevalence and Outcomes2 Parameters Clean Base Flat Spot Adherent Clot Nonbleeding Visible Vessel Active Arterial Bleeding Prevalence (%) 42 20 17 17 18 Risk of recurrent bleeding (%) 5 10 22 43 55 Need for surgical intervention (%) 0.5 6 10 34 35 Mortality (%) 2 3 7 11 11 Parameters Clean Base Flat Spot Adherent Clot Nonbleeding Visible Vessel Active Arterial Bleeding Prevalence (%) 42 20 17 17 18 Risk of recurrent bleeding (%) 5 10 22 43 55 Need for surgical intervention (%) 0.5 6 10 34 35 Mortality (%) 2 3 7 11 11 Figure 1. Open in new tabDownload slide Management of Acute Upper GI Bleeding in Patients with Peptic Ulcer Disease. Adapted with permission.2,7 H2RA = histamine-2 receptor antagonist, PPI = proton pump inhibitor, NSAID = non-steroidal antiinflammatory drug, D/C = discontinue. Figure 1. Open in new tabDownload slide Management of Acute Upper GI Bleeding in Patients with Peptic Ulcer Disease. Adapted with permission.2,7 H2RA = histamine-2 receptor antagonist, PPI = proton pump inhibitor, NSAID = non-steroidal antiinflammatory drug, D/C = discontinue. Based on the proceedings of a symposium held December 6, 2004, during the 39th ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from TAP Pharmaceutical Products Inc. Dr. Olsen received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Olsen reports that he has received research support from Merck and is a consultant and speaker for Wyeth, TAP Pharmaceutical Products Inc., AstraZeneca, Abbott, and Bristol-Myers Squibb. References 1 Kupfer Y, Cappell MS, Tessler S. Acute gastrointestinal bleeding in the intensive care unit. The intensivist’s perspective. Gastroenterol Clin North Am . 2000 ; 29 : 275 –307. Crossref Search ADS PubMed 2 Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med . 1994 ; 331 : 717 –27. Crossref Search ADS PubMed 3 Barkun A, Bardou M, Marshall JK; Non-variceal Upper GI Bleeding Consensus Conference Group. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med . 2003 ; 139 : 843 –57. Crossref Search ADS PubMed 4 Vorder Bruegge WF, Peura DA. Stress-related mucosal damage: review of drug therapy. J Clin Gastroenterol . 1990 ; 12 (suppl 2): S35 –40. Crossref Search ADS PubMed 5 Li Y, Sha W, Nie Y et al. Effect of intragastric pH on control of peptic ulcer bleeding. J Gastroenterol Hepatol . 2000 ; 15 : 148 –54. Crossref Search ADS PubMed 6 Yacyshyn BR, Thomson AB. Critical review of acid suppression in nonvariceal, acute, upper gastrointestinal bleeding. Dig Dis . 2000 ; 18 : 117 –28. Crossref Search ADS PubMed 7 Leontiadis GI, McIntyre L, Sharma VK et al. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev . 2004 ; (3): CD002094 . 8 Rockall TA, Logan RF, Devlin HB et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut . 1996 ; 38 : 316 –21. Crossref Search ADS PubMed 9 Kollef MH, O’Brien JD, Zuckerman GR et al. BLEED: a classification tool to predict outcomes in patients with acute upper and lower gastrointestinal hemorrhage. Crit Care Med . 1997 ; 25 : 1125 –32. Crossref Search ADS PubMed 10 Silverstein FE, Gilbert DA, Tedesco FJ et al. The national ASGE survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. Gastrointest Endosc . 1981 ; 27 : 80 –93. Crossref Search ADS PubMed 11 Levine JE, Leontiadis GI, Sharma VK et al. Meta-analysis: the efficacy of intravenous H2-receptor antagonists in bleeding peptic ulcer. Aliment Pharmacol Ther . 2002 ; 16 : 1137 –42. Crossref Search ADS PubMed 12 Collins R, Langman M. Treatment with histamine H2 antagonists in acute upper gastrointestinal hemorrhage. Implications of randomized trials. N Engl J Med . 1985 ; 313 : 660 –6. Crossref Search ADS PubMed 13 Sung JJ, Chan FK, Lau JY et al. The effect of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots: a randomized comparison. Ann Intern Med . 2003 ; 139 : 237 –43. Crossref Search ADS PubMed 14 Zuckerman G, Welch R, Douglas A et al. Controlled trial of medical therapy for active upper gastrointestinal bleeding and prevention of rebleeding. Am J Med . 1984 ; 76 : 361 –6. Crossref Search ADS PubMed 15 Birnie GG, Quigley EM, Allan G et al. A double-blind randomized trial of cimetidine in acute upper gastrointestinal bleeding. Scand J Gastroenterol . 1984 ; 19 : 885 –8. Crossref Search ADS PubMed 16 Walt RP, Cottrell J, Mann SG et al. Continuous intravenous famotidine for haemorrhage from peptic ulcer. Lancet . 1992 ; 340 : 1058 –62. Crossref Search ADS PubMed 17 Lin HJ, Lo WC, Lee FY et al. A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med . 1998 ; 158 : 54 –8. Crossref Search ADS PubMed 18 Merki HS, Wilder-Smith CH. Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing? Gastroenterology . 1994 ; 106 : 60 –4. Crossref Search ADS PubMed 19 Gisbert JP, Gonzalez L, Calvet X et al. Proton pump inhibitors versus H2-antagonists: a meta-analysis of their efficacy in treating bleeding peptic ulcer. Aliment Pharmacol Ther . 2001 ; 15 : 917 –26. Crossref Search ADS PubMed 20 Khuroo MS, Yattoo GN, Javid G et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med . 1997 ; 336 : 1054 –8. Crossref Search ADS PubMed 21 Kaviani MJ, Hashemi MR, Kazemifar AR et al. Effect of oral omeprazole in reducing re-bleeding in bleeding peptic ulcers: a prospective, double-blind, randomized, clinical trial. Aliment Pharmacol Ther . 2003 ; 17 : 211 –6. Crossref Search ADS PubMed 22 Lau JY, Sung JJ, Lee KK et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med . 2000 ; 343 : 310 –6. Crossref Search ADS PubMed 23 Hasselgren G, Lind T, Lundell L et al. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicenter study. Scand J Gastroenterol . 1997 ; 32 : 328 –33. Crossref Search ADS PubMed 24 Schaffalitzky de Muckadell OB, Havelund T, Harling H et al. Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomized double-blind placebo-controlled multi-centre study. Scand J Gastroenterol . 1997 ; 32 : 320 –7. Crossref Search ADS PubMed 25 Daneshmend TK, Hawkey CJ, Langman MJ et al. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ . 1992 ; 304 : 143 –7. Crossref Search ADS PubMed 26 Orti E, Canelles P, Quiles F et al. Does the antisecretory agent used affect the evolution of upper digestive hemorrhage? Rev Esp Enferm Dig . 1995 ; 87 : 427 –30. PubMed 27 Lanas A, Artal A, Blas JM et al. Effect of parenteral omeprazole and ranitidine on gastric pH and the outcome of bleeding peptic ulcer. J Clin Gastroenterol . 1995 ; 21 : 103 –6. Crossref Search ADS PubMed 28 Villanueva C, Balanzo J, Torras X et al. Omeprazole versus ranitidine as adjunct therapy to endoscopic injection in actively bleeding ulcers: a prospective and randomized study. Endoscopy . 1995 ; 27 : 308 –12. Crossref Search ADS PubMed 29 Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J Am Pharm Assoc (Wash) . 2000 ; 40 : 52 –62. Crossref Search ADS PubMed 30 van Rensburg CJ, Hartmann M, Thorpe A et al. Intragastric pH during continuous infusion with pantoprazole in patients with bleeding peptic ulcer. Am J Gastroenterol . 2003 ; 98 : 2635 –41. Crossref Search ADS PubMed 31 Barkun A, Racz I, van Rensburg et al. Prevention of peptic ulcer rebleeding using continous infusion of pantoprazole vs. ranitidine: a multicenter, multinational, randomized, double-blind, parallel-group comparision. Gastroenterology . 2004 ; 126 : A78 . Abstract. 32 Hsu Pi, Lo GH, Lo CC et al. Intravenous pantoprazole versus ranitidine for prevention of rebleeding after endoscopic hemostasis of bleeding peptic ulcers. World J Gastroenterol . 2004 ; 10 : 3666 –9. Crossref Search ADS PubMed Author notes Based on the proceedings of a symposium held December 6, 2004, during the 39th ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from TAP Pharmaceutical Products Inc. Dr. Olsen received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Olsen reports that he has received research support from Merck and is a consultant and speaker for Wyeth, TAP Pharmaceutical Products Inc., AstraZeneca, Abbott, and Bristol-Myers Squibb. Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

doi: 10.1093/ajhp/62.10_Supplement_2.S31pmid: N/A

Learning objectives After studying these articles, the reader should be able to Explain the role of acid-suppression therapy in preventing stress-related mucosal disease and the recurrence of peptic ulcer bleeding. Compare and contrast the mechanisms of action, pharmacodynamics, pharmacokinetics, advantages, and disadvantages of histamine H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) in critically ill patients, including commercially available and extemporaneously compounded H2RA and PPI products. Describe risk factors, pathophysiology and clinical presentation of stress-related mucosal disease (i.e., damage, ulceration, and bleeding). Summarize contemporary strategies for the prevention of stress-related mucosal bleeding in critically ill patients. Explain the use of acid-suppression therapy for treatment of non-variceal upper gastrointestinal bleeding. Explain formulary considerations when using proton pump inhibitors for acid suppression in the intensive care unit. Self-assessment questions For each question there is only one best answer. The intragastric pH goal for preventing the recurrence of peptic ulcer bleeding is 4 or higher. 5 or higher. 6 or higher. 8 or higher. When comparing H2RAs and PPIs in terms of mechanism of action and pharmacodynamics, which of the following statements is most correct? H2RAs inhibit the proton pump reversibly; PPIs inhibit it irreversibly. H2RAs inhibit only histamine; PPIs inhibit gastrin, acetylcholine, and histamine. H2RAs are more potent and raise the intragastric pH to higher levels than PPIs. H2RAs can cause rebound acid hypersecretion when discontinued; PPIs do not. Which of the following phenomena explains the 3–4-day lag after starting therapy, before the maximum acid-suppressant effect of PPIs is observed? Up regulation of receptors. Inhibition of only active proton pumps. Rebound acid hypersecretion. Irreversible binding to proton pumps. The half-lives of PPIs are of little clinical relevance because All PPIs have a long half-life. All PPIs inhibit their own metabolism. The pKa determines duration of action. Binding to the proton pump determines duration of action. Which of the following phenomena associated with H2RAs is not associated with PPIs? Tolerance. Drug interactions due to an increase in intragastric pH. Genetic polymorphism in metabolism. Auto inhibition of metabolism. Which of the following PPIs is available as an orally disintegrating tablet that can be placed on the tongue or dissolved in water for administration through a nasogastric tube? Omeprazole. Lansoprazole. Pantoprazole. Rabeprazole. Which of the following characteristics typically is associated with stress-related mucosal ulcers? Involvement of a single blood vessel. Perforation. Bleeding from superficial capillaries. Bleeding prior to ICU admission. Which of the following is a strong, independent risk factor for stress-related mucosal bleeding? Age > 60 years. Coagulopathy. Sepsis syndrome. High systolic blood pressure. Which of the following effects of splanchnic hypoperfusion contributes to stress-related mucosal damage? Increased bicarbonate secretion. Increased gastric acid secretion. Reduced GI mucosal blood flow. Reduced GI mucosal permeability. Providing which of the following interventions is most important for preventing stress-related mucosal bleeding in a critically ill patient? Adequate visceral perfusion. Enteral nutrition. Prophylactic acid-suppression therapy. Gastroprotection using sucral-fate or antacids. Which of the following statements about therapeutic strategies for the prevention of stress-related mucosal disease in critically ill patients is most correct? Sucralfate is preferred over H2RAs and PPIs because it reduces the risk of nosocomial pneumonia. Enteral nutrition is preferred over H2RAs and PPIs because it reduces the risk of infection. Acid-suppression therapy is indicated, and H2RAs are preferred over PPIs because PPIs are not approved by FDA for this indication. Acid-suppression therapy is indicated, and there is evidence that PPIs are at least as effective as H2RAs for prophylaxis. Which of the following might best explain how critically ill patients become intolerant to enteral nutrition? Stimulation of gut-associated lymphoid tissue. GI hypomotility. Attenuation of the hypermetabolic response. Hemodynamic instability. Which one of the following prognostic factors is most associated with the development of complications and death in patients with acute upper GI bleeding? Age > 60 years. Coagulopathy. Sepsis syndrome. High systolic blood pressure. Which of the following endoscopic findings places a patient with peptic ulcer bleeding at the greatest risk for bleeding recurrence? Clean base. Flat spot. Adherent clot. Active arterial bleeding. Which of the following therapies is preferred to prevent recurrence of peptic ulcer bleeding in a patient with a nonbleeding, visible vessel? High-dose i.v. PPI therapy given as a bolus infusion followed by a continuous infusion. High-dose i.v. PPI therapy given by intermittent infusion. High-dose i.v. H2RA therapy given as a bolus infusion followed by a continuous infusion. An oral PPI given for at least 8 weeks. Which of the following PPI oral suspension products is most palatable (i.e., contains a flavoring)? Immediate-release omeprazole suspension. Simplified omeprazole suspension. Simplified lansoprazole suspension. Esomeprazole suspension in water. Which of the following PPI oral suspension products has the highest relative bioavailability compared with intact delayed-release PPI capsules or tablets? Simplified omeprazole suspension. Simplified lansoprazole suspension. Lansoprazole orally disintegrating tablet in water. Pantoprazole bicarbonate suspension. For which of the following therapies and indications has cost-effectiveness been demonstrated in decision analyses? Oral PPI therapy for preventing stress-related mucosal bleeding. Intravenous PPI therapy for preventing stress-related mucosal bleeding. Oral PPI therapy for preventing the recurrence of peptic ulcer bleeding. Intravenous PPI therapy for preventing the recurrence of peptic ulcer bleeding. Which of the following is the most important limitation of the cost-effectiveness analyses of PPI therapy conducted to date? Failure to use data from randomized controlled studies. Failure to consider the i.v. route of administration. Reliance on data from healthy volunteers. Reliance solely on data from randomized controlled studies. AJHP continuing education AJHP CE process The continuing-education (CE) test for this supplement can only be taken online through ASHP’s CE Testing Center. If you score 70% or better on the test, you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your own transcript through the online CE service. To view the list of available AJHP CE articles, go to www.ashp.org/ce-selfstudy/ajhp-ce.cfm. Supplement: Treatment options and formulary considerations in the management of acid suppression in critically ill patients ACPE #: 204-000-05-004-H01 CE credit: 3.0 hours Expiration date: May 15, 2008 Instructions ASHP members may go directly to www.ashp.org/ce/, select “Enter CE Testing Center,” type in ASHP ID and password, and then select the supplement for which CE credit is desired. AJHP CE is free to members. Nonmember pharmacists, nurses, nurse practitioners, and physicians should proceed to the CE Testing Center (http://www.ashp.org/ce/registration.cfm). Click on “Create your new ASHP Customer ID (8 digits) number to access selected ‘free’ CE test for ASHP Publications on the ASHP CE Testing Center.” Once you have created your login and password, retype http://www.ashp.org/ce/registration.cfm into your Web browser window. Enter your login and password. A list of CE exams will appear. Please scroll down to the supplement and select the test that is specific for your clinical specialty (e.g., pharmacist, nurse, nurse practitioner, and physician). Follow the prompts. Questions? Call ASHP Customer Service at 866-279-0681 (toll free) or 011-734-556-4536 (international callers). Physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of North Shore-Long Island Jewish Health System and ASHP Advantage. North Shore-Long Island Jewish Health System is accredited by the Accreditation Council for Continuing Medical Education to sponsor Continuing Medical Education for physicians. North Shore-Long Island Jewish Health System designates this Continuing Medical Education activity for a maximum of two category 1 credits towards the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Nurses. This Educational Design Activity has been presented by North Shore-Long Island Jewish Health System which has been approved as a provider of continuing education by the New York State Nurses Association, an accredited approver by the American Nurses’ Credentialing Center’s Commission on Accreditation. It has been assigned approval code 5PVK98-PRV-059 for 2.4 contact hours. Nurse practitioners. This program has been approved for 3.0 contact hours of continuing education by the American Academy of Nurse Practitioners. Program ID 0503125. The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

Devlin, John, W.

doi: 10.1093/ajhp/62.10_Supplement_2.S24pmid: 15905598

Abstract Purpose. The rationale for limiting the proton pump inhibitor (PPI) products included in an institutional formulary, factors to consider when making formulary decisions about PPI products, the results and limitations of cost-effectiveness analyses of PPI therapy in critically ill patients, the role of clinical practice guidelines in improving PPI use in the intensive care setting, and how these guidelines can be developed are discussed. Summary. Therapeutic interchange may make it possible to limit the number of PPI products included in the formulary and reduce costs without compromising the efficacy or safety of drug therapy. The results of studies comparing the pharmacokinetics, pharmacodynamics, and efficacy of different PPI dosage forms and routes of administration; practical considerations; safety; and costs are among the factors to consider when making formulary decisions. Some of the newer oral PPI products offer advantages over older ones in improved palatability and ease of preparation, storage, and administration. The cost-effectiveness of intravenous (i.v.) PPIs for preventing the recurrence of peptic ulcer bleeding has been demonstrated, but the cost-effectiveness of oral therapy for this indication and both oral and i.v. therapy for preventing stress-related mucosal bleeding has not been well established. Conclusion. Intravenous PPIs are cost-effective for patients at risk for the recurrence of peptic ulcer bleeding. The introduction of new oral PPI products that can be administered as a suspension has expanded the therapeutic options for critically ill patients. The use of clinical practice guidelines can optimize the use of PPIs in the intensive care setting. Costs, Critical illness, Decision-making, Dosage forms, Drug administration, Drug administration routes, Economics, Formularies, Gastrointestinal drugs, Gastrointestinal hemorrhage, Hospitals, Pharmacodynamics, Pharmacokinetics, Protocols, Stability, Storage, Substitution, Taste, Toxicity, Ulcers Proton pump inhibitors (PPIs) are widely used as acid-suppressive therapy for patients in the intensive care setting to prevent stress-related mucosal disease (SRMD) (i.e., mucosal damage, ulceration, and bleeding) or the recurrence of peptic ulcer bleeding (see the articles by Martindale and Olsen in this supplement). PPIs are available in a wide variety of dosage forms, including delayed-release tablets, delayed-release capsules containing enteric-coated granules or pellets, delayed-release oral suspension (packets of enteric-coated granules), immediate-release oral suspension (packets of powder with sodium bicarbonate), delayed-release orally disintegrating tablets, and injections (see the article by Welage in this supplement). Pharmacists who serve on an institution’s pharmacy and therapeutics committee may be called on to decide which PPI formulations to include on the formulary. It may be possible to limit the number of products on the formulary through therapeutic interchange and thus potentially decrease overall PPI drug acquisition costs. Therapeutic interchange is defined as the authorized exchange of chemically different alternatives having similar therapeutic or pharmacologic effects in accordance with previously established and approved written guidelines or protocols under the auspices of a formulary system.1,2 The therapeutic effects and adverse reaction profile of these alternatives are similar when therapeutically equivalent dosages are used. The primary rationale for therapeutic interchange is to reduce drug acquisition costs without compromising the efficacy or safety of drug therapy. A variety of factors must be taken into consideration when making decisions about which PPI products to include in the formulary. These factors include the results of studies comparing the pharmacokinetics, pharmacodynamics, and efficacy of different dosage forms and routes of administration; practical considerations (e.g., product preparation, administration, and storage requirements); safety; and costs. The PPIs have a favorable safety profile, and the type and frequency of adverse effects are similar among the individual PPIs.3 The use of PPIs in critically ill patients has not been extensively studied and most formulations are not approved by the Food and Drug Administration (i.e., use is “off label”). Most critically ill patients cannot swallow solid oral dosage forms, and many patients have nasogastric (NG) or feeding tubes. Initial PPI therapy often (but not necessarily) is parenteral, but the need to maintain continuity of care when making the transition from parenteral therapy to oral or enteral therapy is a consideration in formulary decisions. The bioequivalence of PPI oral liquid and solid oral dosage forms is another factor to consider. Many studies comparing the bioavailability of PPI oral liquid and solid oral dosage forms were conducted in healthy volunteers. The results of these studies are not readily extrapolated to critically ill patients, who typically have gastrointestinal (GI) abnormalities that can affect drug absorption (see Welage and Martindale articles in this supplement). Parenteral products Two parenteral PPI products (lansoprazole and pantoprazole) currently are available and a third injectable product (esomeprazole) is expected to become available this year. The storage, preparation, and administration requirements for the two currently available products (Table 11) are similar. Parenteral PPIs generally are unstable compounds that can interact with other drugs if administered in the same intravenous (i.v.) tubing, resulting in precipitation. Therefore, it usually is necessary to establish a separate i.v. line for administration of the PPI or flush the tubing with a compatible diluent before and after PPI administration. The i.v. form of lansoprazole is approved by the Food and Drug Administration (FDA) for the short-term treatment of all grades of erosive esophagitis.5 A 30-mg dose is given once daily. The i.v. form of pantoprazole is approved by FDA for the short-term treatment of gastroesophageal reflux disease (GERD) associated with a history of erosive esophagitis (40 mg once daily) and the treatment of pathological hyper-secretion associated with Zollinger-Ellison Syndrome (80 mg every 8 or 12 hours).4 The pharmacodynamics of i.v. and oral lansoprazole were compared in a placebo-controlled study of 87 patients with erosive esophagitis.6 Patients received oral lansoprazole (capsules) for seven days and then were randomized to receive i.v. lansoprazole or an i.v. placebo. The same lansoprazole dosage (30 mg/day) was used by the i.v. and oral routes of administration. The gastric acid output values on day eight after oral lansoprazole therapy and on day fifteen after i.v. lansoprazole therapy were equivalent and significantly lower than those on day fifteen after i.v. placebo therapy. Similar findings were reported from a randomized, placebo-controlled study comparing the gastric acid output after oral and i.v. pantoprazole therapy (20 mg/day and 40 mg/day) in 65 patients with GERD.7 Gastric acid output was comparable with the oral and i.v. routes of administration. A rapid onset of the acid-suppressive effect of i.v. pantoprazole (within one hour after drug administration) was observed in patients with Zollinger-Ellison Syndrome.8 A dose–response relationship has been found between the i.v. pantoprazole dosage and the median percentage of time in a 24-hour period that the intragastric pH was maintained above the target pH value.9 Larger i.v. pantoprazole dosages (e.g., 80 mg as a bolus infusion, followed by 8 mg/hr; 40 mg/hr for two hours followed by 8 mg/hr) were more effective in maintaining a high intragastric pH than lower i.v. dosages (e.g., 40 mg as a bolus infusion followed by 4 mg/hr; intermittent administration of 40 mg every 8 hours). This relationship was consistent for target pH values ranging from less than 3 to 6, including the target pH values needed to prevent stress-related mucosal disease (3.5–4.5) and recurrence of peptic ulcer bleeding (6).10 The median time that the intragastric pH was maintained above 4, 5, and 6 was 99%, 94%, and 84%, respectively, in patients receiving pantoprazole 80 mg followed by 8 mg/hr.9 The results of small studies of i.v. omeprazole in patients at risk for recurrence of peptic ulcer bleeding suggest that a large dosage (80 mg followed by 8 mg/hr) is needed to maintain the high target intragastric pH (6).11,12 Pharmacodynamic data are not yet available for i.v. lansoprazole or esomeprazole administered as a bolus infusion followed by a continuous infusion. Studies have compared the efficacy of i.v. omeprazole with that of placebo or histamine H2-receptor antagonists (H2RAs) for preventing the recurrence of peptic ulcer bleeding and found omeprazole to be superior (see Olsen article in this supplement).13 However, i.v. omeprazole has not been compared with placebo or H2RAs for stress-related ulcer prophylaxis. Studies comparing the efficacy of i.v. pantoprazole with that of H2RAs for preventing recurrence of peptic ulcer bleeding or stress-related ulcers have been conducted (the therapies were judged comparable in efficacy).14,15 However, no controlled studies evaluating the efficacy of i.v. lansoprazole or esomeprazole for either indication have been conducted. Rabeprazole is not available in a parenteral formulation. Studies directly comparing one i.v. PPI with another i.v. PPI in critically ill patients are not likely to be performed because an extremely large sample size would be required to provide sufficient power to detect a true difference in efficacy between treatments if one does exist. A recent meta-analysis of 21 randomized controlled trials of PPI treatment (oral or i.v.) compared with either placebo or H2RAs in patients with acute peptic ulcer bleeding found that both i.v. and oral PPI therapy significantly reduce the risk of recurrent bleeding, although they have no impact on mortality.16 Oral products The results of studies comparing the pharmacokinetics and pharmacodynamics of various oral PPI products can be useful in determining which products to include in a formulary. Pharmacokinetic studies using 15-mg and 30-mg strengths of lansoprazole delayed-release capsules (which contain enteric-coated granules) and delayed-release orally disintegrating tablets in healthy volunteers found that the two dosage forms are bioequivalent.17,18 The orally disintegrating tablets were placed on the tongue without water and allowed to disintegrate, after which time (usually less than one minute) the particles were swallowed in saliva. Absorption does not occur across the oral mucosa. Alternatively, the orally disintegrating lansoprazole tablets may be placed in an oral syringe into which water is subsequently drawn. Dispersion of the tablet in water occurs quickly and the medication is then promptly administered orally or into an NG tube.19 In a randomized, crossover study of 40 healthy adults, the pharmacokinetics of a single, 15-mg lansoprazole orally disintegrating tablet were compared using the two administration techniques: (1) placing the tablet directly on the tongue without water and (2) dispersing the tablet in 4 mL of water in a syringe and administering it orally.20 Three days elapsed between doses. The peak plasma concentration, time to peak plasma concentration, and area under the plasma concentration–time curve (AUC) over a 12-hour period after drug administration were similar, and the two techniques for administering drug were judged bioequivalent. The bioavailability of esomeprazole was compared when two methods for administering the drug orally were used in a randomized, open-label, crossover pharmacokinetic study of 47 healthy subjects.21 Capsules containing 40 mg as enteric-coated pellets were either taken intact or they were opened and the contents were mixed with 50 mL of water to form a suspension for administration by NG tube. The drug was given by one method for 5 days with a 7- to 14-day washout period before crossing over to the other administration method for the second 5 days of treatment. The AUC was compared on both day one and day five of treatment because esomeprazole is known to inhibit its own metabolism, resulting in an increase in esomeprazole AUC and bioavailability over a period as short as several days.22 The peak plasma concentration and AUC on day one and day five were comparable with the two administration techniques, demonstrating that administration of the capsule contents in water by NG tube instead of as intact capsules did not compromise the bioavailability of the drug. Oral suspensions of PPIs have been compounded extemporaneously from delayed-release capsules and tablets. With the exception of the orally disintegrating lansoprazole tablets, the bioavailability of these oral suspensions is less than that of the intact solid oral dosage form (Table 22). Immediate-release omeprazole packets of powder with sodium bicarbonate for mixing with water and oral administration via the oral or NG route recently became available commercially (Zegerid, Santarus, Inc.). The relative bioavailability of this product compared with omeprazole delayed-release capsules and tablets is unknown. Ease of product preparation and storage, palatability (i.e., the presence of a flavoring agent), and ease of administration through NG and feeding tubes also are considerations in choosing among PPI oral liquid dosage forms. In terms of ease of preparation and storage, the suspension made from the oral lansoprazole disintegrating tablets is likely easier and more efficient to manufacture than the other PPI suspension products. Particle size and tube bore size may affect drug delivery through feeding tubes.28,–30 The smaller particle size of the lansoprazole oral disintegrating tablet as well as the lack of precipitation observed when it is mixed in water suggests that it would be preferential to other PPI suspensions for use in patients with smaller caliber feeding tubes (e.g., size 8 French NG tube). Only two of the PPI suspensions are flavored (immediate-release omeprazole suspension and lansoprazole oral disintegrating tablets suspension). These products would be preferable if the PPI suspension is to be administered orally (e.g., pediatrics). Numerous clinical studies of the efficacy of extemporaneously compounded PPI oral suspensions (i.e., simplified omeprazole or lansoprazole suspension or pantoprazole bicarbonate suspension) for preventing SRMD and recurrence of peptic ulcer bleeding have been conducted in critically ill patients with favorable results.16,31,–34 A study of the recently introduced immediate-release omeprazole packets of powder with sodium bicarbonate was conducted in patients at risk for SRMD, but additional research is needed in this patient population and in patients at risk for recurrence of peptic ulcer bleeding.35 No studies of esomeprazole suspension in water or lansoprazole orally disintegrating tablets have been conducted in critically ill patients. Previous experience with oral PPI products and the patient mix at an institution (e.g., pediatric patients, critical care patients) may influence PPI formulary decisions. Although limited data are available for the use of some PPIs in critically ill patients, data are available for use of the drugs in other acid-related disease states (e.g., GERD, atypical GERD) in a broader patient population. Costs Cost can be an important consideration in determining which PPI products to include in a formulary once efficacy and safety concerns have been addressed. Dollar figures used for the acquisition cost of a particular product should reflect contractual agreements and any rebates and discounts. Cost comparisons should not be limited simply to the drug acquisition cost. Product preparation and administration costs (i.e., pharmacy and nursing time, the cost of supplies) also should be taken into consideration. The potential costs associated with inappropriate drug use may be a factor because they often can be substantial. These costs may be associated with inadequate use (e.g., the cost of managing avoidable bleeding) as well as with excessive use when the drug is not indicated (e.g., drug acquisition costs, the costs of managing adverse effects).36 Cost-effectiveness research addressing the use of PPIs for preventing stress-related mucosal disease is lacking. Several decision analyses based on the results of randomized controlled trials found the use of i.v. PPIs in preventing recurrent peptic ulcer bleeding to be cost-effective under specific circumstances (e.g., for patients at high risk for recurrent bleeding).37,–42 Cost savings were associated with avoidance of recurrent bleeding episodes and reductions in hospital length of stay.38 These pharmacoeconomic analyses raise many concerns and leave questions unanswered, which affects their usefulness for formulary decision making.43 Limitations of the analyses include a reliance solely on data from randomized controlled studies instead of “real life” experience outside the rigorous conditions of a clinical study. Several decision analyses were conducted in Asia or Canada from the perspective of a third-party payer, and the results are not readily extrapolated to the United States.39,40 In one study, comparisons were drawn with the use of second-look endoscopy, a procedure rarely used in the United States.41 Most analyses did not take into consideration the use of oral PPI therapy. Clinical practice guidelines Decisions about which drug products to include in a formulary often are made in conjunction with the development of clinical practice guidelines governing use of the drugs. Clinical practice guidelines are an important tool in efforts to eliminate inappropriate drug use.44 Clinical practice guidelines for the use of PPIs in critically ill patients have the potential to improve drug use and patient outcomes in the intensive care setting. Clinical practice guidelines should be evidence-based, using the best clinical literature available (i.e., randomized controlled trials with sound research methodology in appropriate patient populations). Institution-specific factors (e.g., patient mix, local clinical practices) should be taken into consideration in developing guidelines. A consensus of prescribers and approval by the appropriate institutional authority (usually the executive committee, the pharmacy and therapeutics committee, or both) should be sought. Obtaining the “buy in” of influential members of the physician staff (i.e., opinion leaders among the medical and surgical staff) in developing guidelines can improve the likelihood that the guidelines will be accepted and followed by others. Providing education about the guidelines for the nursing, pharmacy, and house staff is a key component of successful guideline implementation. The clinical and economic impact of and compliance with the guidelines should be assessed after implementation. This assessment is particularly important if the guidelines restrict prescribing because it can ensure that the restrictions do not compromise patient outcomes. Subsequent revision of the guidelines should be considered if appropriate. The paucity of clinical experience with PPIs for prevention of SRMD and recurrence of peptic ulcer bleeding in critically ill patients makes the development of evidence-based clinical practice guidelines for this patient population a challenge. Nevertheless, such guidelines have been developed and implemented in some institutions. At one facility, a targeted educational program was provided for medical house staff on the appropriate use of medications for stress-related ulcer prophylaxis in patients in the medical and surgical intensive care units.36 The educational program significantly reduced the duration of inappropriate drug use (compared with the period before the intervention) without increasing the risk of bleeding. In another institution, the implementation of stress ulcer prophylaxis guidelines for trauma patients significantly reduced the prescribing of prophylactic therapy from 70% of patients to 26% of patients without affecting the incidence of major GI bleeding or blood transfusion requirements.45 One (0.6%) of 150 patients experienced major GI bleeding before guideline implementation and none of 150 patients had a major GI bleeding episode after implementation. The indications for prophylactic drug therapy and duration of prophylaxis should be incorporated into clinical practice guidelines because of the potential waste associated with providing prophylaxis when it is not appropriate. Stress ulcer prophylaxis should be provided only for patients who are at high risk for stress-related ulcers.46 Guidelines also should address the dosage form and route of administration of PPIs, the primary variable being an assessment of patients’ ability to absorb PPI therapy. Prophylaxis is recommended for all patients with bleeding peptic ulcers, but the route of administration depends on the degree of risk for recurrent bleeding (i.v. for a high risk and oral for a low risk).47,48 Evaluation of the continued need for prophylaxis when the patient is extubated or discharged from the intensive care unit should be a component of clinical practice guidelines for both stress ulcer prophylaxis and preventing recurrent peptic ulcer bleeding.46 Discussion Studies comparing the efficacy of various dosage forms and routes of administration of PPIs in critically ill patients at risk for stress ulcers or recurrence of peptic ulcer bleeding are limited. The results of these studies, practical issues, and costs are among the factors taken into consideration in choosing which PPIs to include in a formulary. The storage, preparation, and administration requirements of parenteral PPI dosage forms are similar. Some of the newer PPI oral formulations offer advantages over older ones in improved palatability and ease of preparation, storage, and administration. Intravenous PPIs are cost-effective for preventing recurrent peptic ulcer bleeding. Conclusion The cost-effectiveness of i.v. PPIs for stress ulcer prophylaxis and oral PPI therapy for stress ulcers and recurrent peptic ulcer bleeding remains to be determined. The use of clinical practice guidelines can optimize the use of PPIs in the intensive care setting. Table 1. Parenteral Proton Pump Inhibitor Storage, Preparation, and Administration Requirements4,5,a,b Characteristic Lansoprazole Pantoprazole aD5W = 5% dextrose injection, USP; i.v. = intravenous; LR = lactated Ringer’s injection, USP; NS = 0.9% sodium chloride injection, USP; SW = sterile water for injection, USP. bRoom temperature is approximately 25 °C (77 °F), with excursions to 15 °C–30 °C or 59 °F–86 °F permitted for vials of unreconstituted drug. Dosage form, packaging supplied by manufacturer, and storage requirements Lyophilized powder in 30-mg vials stored at room temperature, protected from light Freeze-dried powder in 40-mg vials stored at room temperature, protected from light Diluent type, volume for reconstitution, and stability 5 mL SW for 1 hr at room temperature 10 mL NS (4 mg/mL) for 2 hr at room temperature Admixture preparation Dilute further in 50 mL NS, LR, or D5W Use 100 mL NS, LR, or D5W for 40-mg or 80-mg dose, resulting in 0.4 mg/mL or 0.8 mg/mL Admixture stability 24 hr in NS or LR and 12 hr in D5W at room temperature 22 hr at room temperature Duration of i.v. infusion 30 min 2 min for 4 mg/mL or 15 min for 0.4 and 0.8 mg/mL Requirement for in-line filter Yes No Type of i.v. line and flushing required Dedicated i.v. line not required, but flushing of tubing with NS, LR, or D5W before and after drug administration required Dedicated i.v. line or administration through a Y-site required Characteristic Lansoprazole Pantoprazole aD5W = 5% dextrose injection, USP; i.v. = intravenous; LR = lactated Ringer’s injection, USP; NS = 0.9% sodium chloride injection, USP; SW = sterile water for injection, USP. bRoom temperature is approximately 25 °C (77 °F), with excursions to 15 °C–30 °C or 59 °F–86 °F permitted for vials of unreconstituted drug. Dosage form, packaging supplied by manufacturer, and storage requirements Lyophilized powder in 30-mg vials stored at room temperature, protected from light Freeze-dried powder in 40-mg vials stored at room temperature, protected from light Diluent type, volume for reconstitution, and stability 5 mL SW for 1 hr at room temperature 10 mL NS (4 mg/mL) for 2 hr at room temperature Admixture preparation Dilute further in 50 mL NS, LR, or D5W Use 100 mL NS, LR, or D5W for 40-mg or 80-mg dose, resulting in 0.4 mg/mL or 0.8 mg/mL Admixture stability 24 hr in NS or LR and 12 hr in D5W at room temperature 22 hr at room temperature Duration of i.v. infusion 30 min 2 min for 4 mg/mL or 15 min for 0.4 and 0.8 mg/mL Requirement for in-line filter Yes No Type of i.v. line and flushing required Dedicated i.v. line not required, but flushing of tubing with NS, LR, or D5W before and after drug administration required Dedicated i.v. line or administration through a Y-site required Table 1. Parenteral Proton Pump Inhibitor Storage, Preparation, and Administration Requirements4,5,a,b Characteristic Lansoprazole Pantoprazole aD5W = 5% dextrose injection, USP; i.v. = intravenous; LR = lactated Ringer’s injection, USP; NS = 0.9% sodium chloride injection, USP; SW = sterile water for injection, USP. bRoom temperature is approximately 25 °C (77 °F), with excursions to 15 °C–30 °C or 59 °F–86 °F permitted for vials of unreconstituted drug. Dosage form, packaging supplied by manufacturer, and storage requirements Lyophilized powder in 30-mg vials stored at room temperature, protected from light Freeze-dried powder in 40-mg vials stored at room temperature, protected from light Diluent type, volume for reconstitution, and stability 5 mL SW for 1 hr at room temperature 10 mL NS (4 mg/mL) for 2 hr at room temperature Admixture preparation Dilute further in 50 mL NS, LR, or D5W Use 100 mL NS, LR, or D5W for 40-mg or 80-mg dose, resulting in 0.4 mg/mL or 0.8 mg/mL Admixture stability 24 hr in NS or LR and 12 hr in D5W at room temperature 22 hr at room temperature Duration of i.v. infusion 30 min 2 min for 4 mg/mL or 15 min for 0.4 and 0.8 mg/mL Requirement for in-line filter Yes No Type of i.v. line and flushing required Dedicated i.v. line not required, but flushing of tubing with NS, LR, or D5W before and after drug administration required Dedicated i.v. line or administration through a Y-site required Characteristic Lansoprazole Pantoprazole aD5W = 5% dextrose injection, USP; i.v. = intravenous; LR = lactated Ringer’s injection, USP; NS = 0.9% sodium chloride injection, USP; SW = sterile water for injection, USP. bRoom temperature is approximately 25 °C (77 °F), with excursions to 15 °C–30 °C or 59 °F–86 °F permitted for vials of unreconstituted drug. Dosage form, packaging supplied by manufacturer, and storage requirements Lyophilized powder in 30-mg vials stored at room temperature, protected from light Freeze-dried powder in 40-mg vials stored at room temperature, protected from light Diluent type, volume for reconstitution, and stability 5 mL SW for 1 hr at room temperature 10 mL NS (4 mg/mL) for 2 hr at room temperature Admixture preparation Dilute further in 50 mL NS, LR, or D5W Use 100 mL NS, LR, or D5W for 40-mg or 80-mg dose, resulting in 0.4 mg/mL or 0.8 mg/mL Admixture stability 24 hr in NS or LR and 12 hr in D5W at room temperature 22 hr at room temperature Duration of i.v. infusion 30 min 2 min for 4 mg/mL or 15 min for 0.4 and 0.8 mg/mL Requirement for in-line filter Yes No Type of i.v. line and flushing required Dedicated i.v. line not required, but flushing of tubing with NS, LR, or D5W before and after drug administration required Dedicated i.v. line or administration through a Y-site required Table 2. Relative Bioavailability of Proton Pump Inhibitor Oral Suspensions Compared with Intact Delayed-Release Capsules or Tablets17,18,20,21,23,–27 Oral Suspension Bioavailability of Intact Tablet or Capsule Formulation (%) Relative Bioavailability of Oral Suspension Compared with Intact Tablets or Capsules (%) aSimplified omeprazole suspension prepared from the contents of omeprazole delayed-release capsules (Prilosec, AstraZeneca LP) in sodium bicarbonate. bSimplified lansoprazole suspension prepared from the contents of lansoprazole delayed-release capsules (Prevacid, TAP Pharmaceutical Products Inc.) in sodium bicarbonate. cPrepared by dissolving delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) in water. dComparison is of (1) delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) dispersed in water and administered orally with (2) delayed-release capsules containing enteric-coated granules (Prevacid, TAP Pharmaceutical Products Inc.) taken orally. ePantoprazole bicarbonate suspension prepared from crushed pantoprazole delayed-release tablets (Protonix, Wyeth Pharmaceuticals Inc.) in sodium bicarbonate. fPrepared from the contents of esomeprazole delayed-release capsules (Nexium, AstraZeneca LP) in water. Simplified omeprazole suspensiona 30–65 49–81 Simplified lansoprazole suspensionb 80 68–85 Lansoprazole orally disintegrating tablet in waterc 80 100d Pantoprazole bicarbonate suspensione 77 75 Esomeprazole suspension in waterf 64 88 Oral Suspension Bioavailability of Intact Tablet or Capsule Formulation (%) Relative Bioavailability of Oral Suspension Compared with Intact Tablets or Capsules (%) aSimplified omeprazole suspension prepared from the contents of omeprazole delayed-release capsules (Prilosec, AstraZeneca LP) in sodium bicarbonate. bSimplified lansoprazole suspension prepared from the contents of lansoprazole delayed-release capsules (Prevacid, TAP Pharmaceutical Products Inc.) in sodium bicarbonate. cPrepared by dissolving delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) in water. dComparison is of (1) delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) dispersed in water and administered orally with (2) delayed-release capsules containing enteric-coated granules (Prevacid, TAP Pharmaceutical Products Inc.) taken orally. ePantoprazole bicarbonate suspension prepared from crushed pantoprazole delayed-release tablets (Protonix, Wyeth Pharmaceuticals Inc.) in sodium bicarbonate. fPrepared from the contents of esomeprazole delayed-release capsules (Nexium, AstraZeneca LP) in water. Simplified omeprazole suspensiona 30–65 49–81 Simplified lansoprazole suspensionb 80 68–85 Lansoprazole orally disintegrating tablet in waterc 80 100d Pantoprazole bicarbonate suspensione 77 75 Esomeprazole suspension in waterf 64 88 Table 2. Relative Bioavailability of Proton Pump Inhibitor Oral Suspensions Compared with Intact Delayed-Release Capsules or Tablets17,18,20,21,23,–27 Oral Suspension Bioavailability of Intact Tablet or Capsule Formulation (%) Relative Bioavailability of Oral Suspension Compared with Intact Tablets or Capsules (%) aSimplified omeprazole suspension prepared from the contents of omeprazole delayed-release capsules (Prilosec, AstraZeneca LP) in sodium bicarbonate. bSimplified lansoprazole suspension prepared from the contents of lansoprazole delayed-release capsules (Prevacid, TAP Pharmaceutical Products Inc.) in sodium bicarbonate. cPrepared by dissolving delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) in water. dComparison is of (1) delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) dispersed in water and administered orally with (2) delayed-release capsules containing enteric-coated granules (Prevacid, TAP Pharmaceutical Products Inc.) taken orally. ePantoprazole bicarbonate suspension prepared from crushed pantoprazole delayed-release tablets (Protonix, Wyeth Pharmaceuticals Inc.) in sodium bicarbonate. fPrepared from the contents of esomeprazole delayed-release capsules (Nexium, AstraZeneca LP) in water. Simplified omeprazole suspensiona 30–65 49–81 Simplified lansoprazole suspensionb 80 68–85 Lansoprazole orally disintegrating tablet in waterc 80 100d Pantoprazole bicarbonate suspensione 77 75 Esomeprazole suspension in waterf 64 88 Oral Suspension Bioavailability of Intact Tablet or Capsule Formulation (%) Relative Bioavailability of Oral Suspension Compared with Intact Tablets or Capsules (%) aSimplified omeprazole suspension prepared from the contents of omeprazole delayed-release capsules (Prilosec, AstraZeneca LP) in sodium bicarbonate. bSimplified lansoprazole suspension prepared from the contents of lansoprazole delayed-release capsules (Prevacid, TAP Pharmaceutical Products Inc.) in sodium bicarbonate. cPrepared by dissolving delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) in water. dComparison is of (1) delayed-release orally disintegrating lansoprazole tablets (Prevacid SoluTab, TAP Pharmaceutical Products Inc.) dispersed in water and administered orally with (2) delayed-release capsules containing enteric-coated granules (Prevacid, TAP Pharmaceutical Products Inc.) taken orally. ePantoprazole bicarbonate suspension prepared from crushed pantoprazole delayed-release tablets (Protonix, Wyeth Pharmaceuticals Inc.) in sodium bicarbonate. fPrepared from the contents of esomeprazole delayed-release capsules (Nexium, AstraZeneca LP) in water. 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American Society of Health-System Pharmacists, Inc. All rights reserved.

Welage, Lynda, S.

doi: 10.1093/ajhp/62.10_Supplement_2.S4pmid: 15905600

Abstract Purpose. The physiology of acid secretion, rationale and goals for acid suppression in critically ill patients, and mechanism of action, pharmacokinetics, pharmacodynamics, and safety of histamine H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are discussed. Summary. Acid-suppressant therapy may be used in critically ill patients to prevent stress-related mucosal disease or the recurrence of peptic ulcer bleeding. The intragastric pH goal is 3.5–4.5 and 6 or higher, respectively. H2RAs block only one of three pathways in acid secretion and provide less potent acid suppression than PPIs, which block the final common pathway in acid secretion. In addition, tolerance that occurs with H2RAs does not occur with PPIs. All PPIs work in a similar manner, but differences exist in the pharmacokinetic profiles and binding to the proton pump; the clinical relevance of these differences remains debated. The safety profiles of H2RAs and PPIs are similar; however, the H2RA dose, but not the PPI dose, must be adjusted for patients with renal dysfunction. The risk of drug interactions mediated by cytochrome P-450 enzymes is lower with PPIs than with cimetidine, an H2RA. Several new PPI dosage forms have been introduced, facilitating drug administration in the critical care setting. Conclusion. Both H2RAs and PPIs are safe agents to use for providing acid suppression in critically ill patients, but PPIs offer several potential advantages over H2RAs. Cimetidine, Critical illness, Dosage, Dosage forms, Drug interactions, Gastrointestinal drugs, Kidney failure, Mechanism of action, Pharmacodynamics, Pharmacokinetics, Tolerance, Toxicity Gastric acid is secreted by parietal cells in the stomach in response to gastrin, histamine, or acetylcholine.1 Receptors for these substances are located in the basolateral membrane of the parietal cell. Gastrin can act directly through the gastrin receptor or, more importantly, indirectly by triggering the release of histamine from enterochromaffin-like cells. Acetylcholine is released in response to vagal nerve signals and it then stimulates receptors for the neurotransmitter. Stimulation of receptors for gastrin, histamine, or acetylcholine results in increases in intracellular calcium, cyclic adenosine monophosphate, and protein kinases, and activation of the hydrogen-potassium adenosine triphosphatase (ATPase) enzyme. This enzyme, the proton pump, actively exchanges hydrogen ions in the parietal cell for luminal potassium ions, thereby secreting hydrogen ions into the lumen. Acid-suppression therapy Gastric acid suppression plays a role in treating a variety of diseases, including gastroesophageal reflux disease, peptic ulcer disease, and hypersecretory states. The prevention of stress-related mucosal disease (i.e., damage, ulceration, and bleeding), recurrence of peptic ulcer bleeding, and aspiration pneumonitis are possible prophylactic uses for acid-suppressant therapy. The degree of acid suppression required depends on the condition being treated. An intragastric pH of 3.5–4.5 is sought in patients at risk for stress-related mucosal disease (Table 11).2 A pH greater than 3.5 is associated with a reduced incidence of stress-related bleeding.3 Pepsin is activated at a low pH and it contributes to ulcer formation by digesting the mucosal lining.4 Pepsin is inactivated at a pH of 4.5 or higher.2 A higher target pH (above 6) usually is sought to prevent the recurrence of bleeding in patients with peptic ulcers because it avoids the platelet dysfunction and clot instability observed at lower pH values.2 A high pH promotes proper platelet function and clot stability. Gastroprotective agents Gastroprotective agents, which comprise sucralfate and antacids, have no effect on acid production. Sucralfate appears to provide a physical barrier and enhance mucosal protection in part by stimulating prostaglandin release, thereby increasing bicarbonate and mucus production.5 Antacids produce dose-dependent neutralization of gastric acid within the lumen, although antacids that contain calcium can stimulate acid production. Gastroprotective agents are not widely used for acid-suppression therapy in the critical care setting because of safety concerns, practical considerations, and the lack of clinical studies in critically ill patients. Multiple daily sucralfate doses are required, and the drug can clog nasogastric (NG) tubes.5 Large frequent doses of antacids are required to maintain the goal intragastric pH, and aspiration can occur.5,6 The potential for adverse effects (e.g., constipation or diarrhea) and drug interactions due to binding also are concerns with sucralfate and antacids.5 Accumulation of cations leading to toxicity can occur in patients with renal impairment who receive sucralfate (the drug contains aluminum) or antacids. Histamine H2-receptor antagonists Histamine H2-receptor antagonists (H2RAs) competitively block histamine H2 receptors and, therefore, they interfere with only one of three pathways for proton pump activation. By contrast, proton pump inhibitors (PPIs) block hydrogen-potassium ATPase, which is the final common step in acid secretion. H2RAs cause a substantial reduction in acid secretion, but they do not completely inhibit acid production.1 Multiple dosage forms are available, which facilitate use in the intensive care setting. Cimetidine, ranitidine, and famotidine products are available for both oral and parenteral use. Nizatidine is available in dosage forms only for oral use; therefore, it is used less often than other H2RAs in the intensive care setting. The only H2RA approved by the Food and Drug Administration (FDA) for the prevention of upper gastrointestinal (GI) bleeding in critically ill patients (i.e., prevention of stress-related mucosal bleeding) is cimetidine (50 mg/hr by continuous intravenous [i.v.] infusion).7 However, the H2RAs are more commonly given by intermittent i.v. infusion than by continuous i.v. infusion. Thus, most use of H2RAs in the intensive care setting is “off-label.” Tolerance to the acid-suppressant effect of H2RAs and rebound acid hypersecretion can develop.8 In a randomized, double-blind, crossover study of 34 healthy volunteers, a decrease in the median intragastric pH was observed between day one and day three of ranitidine therapy (a 50-mg i.v. bolus injection, followed by 0.25 mg/kg/hr by continuous i.v. infusion).9 This loss of effect has been attributed to “up” regulation of histamine H2 receptors over time. Increasing the dosage does not overcome the problem. When the healthy volunteers crossed over to treatment with the PPI omeprazole (an 80-mg i.v. bolus injection, followed by 8 mg/hr by continuous i.v. infusion), no change in median intragastric pH was observed between day one and day three of treatment, reflecting a lack of tolerance. All H2RAs have short half-lives, so multiple daily doses are needed.10,–12 All agents are eliminated by the kidneys; therefore, dosage adjustment is required for patients with renal dysfunction. H2RAs generally are safe agents, although mental status changes (e.g., confusion) and thrombocytopenia can pose problems in the intensive care setting.13,14 Thrombocytopenia associated with H2RA usage is extremely rare, but can be of concern in patients who recently experienced bleeding or are at risk for bleeding.13 Short-term adverse effects from H2RAs include headache and mild, transient diarrhea.15 Drug interactions resulting from inhibition of hepatic cytochrome P-450 drug-metabolizing enzymes by H2RAs (primarily cimetidine and, to a lesser extent, ranitidine) can lead to toxicity.5,10 Cimetidine inhibits cytochrome P-450 1A2, 2C19, 3A4, 2E1, and other isoenzymes involved in the metabolism of theophylline, phenytoin, diazepam, caffeine, and other drugs.16 Other interactions resulting from an increase in intragastric pH and leading to alterations in drug absorption can occur with any H2RA. The absorption of agents that require an acidic environment (e.g., weak bases, such as ketoconazole, cefpodoxime, enoxacin, and indinavir) may be reduced by acid-suppressant therapy, resulting in therapeutic failure.16,17 In contrast, acid suppression may increase the absorption of some compounds (e.g., digoxin, nifedipine, aspirin) by decreasing the degradation of agents that ordinarily are degraded in an acidic environment or increasing the dissolution of weak acids.16 Clinical experience with H2RAs is extensive, even in the critical care setting. This experience and the ease of use and relative safety of H2RAs must be weighed against the disadvantages associated with their use. Disadvantages include the incomplete suppression of acid production, the risk of tolerance and rebound acid hypersecretion, the need for dosage adjustment in patients with renal dysfunction, and the potential for drug interactions (primarily with cimetidine). PPIs There are five PPIs, two of which (pantoprazole and lansoprazole) are available in the United States in parenteral and oral dosage forms. The other three PPIs (omeprazole, esomeprazole, and rabeprazole) are available in oral dosage forms only. A parenteral form of esomeprazole is expected to become available this year. All PPIs are administered as the inactive prodrug, regardless of the route of administration. The pro-drug remains inactive during absorption and distribution. It enters the parietal cell through the basolateral membrane and is activated in the acidic secretory canalicular space. In the presence of acid, the prodrug is protonated and undergoes a conformational change into the sulfenamide, which is the active moiety. This active moiety binds covalently to cysteine residues on the proton pump, thereby inactivating the pump (i.e., inactivating the enzyme).17,–20 All five PPIs have the same mechanism of action. However, there are differences among them in the binding sites on the cysteine residues of the proton pumps.18 Binding to cysteine residues 813 or 822 within the hydrogen-potassium ATPase enzyme is key for inhibition of acid secretion. All of the currently available PPIs bind to cysteine residue 813. Pantoprazole also binds to cysteine residue 822. These differences in binding have been postulated to lead to differences in duration of action among the PPIs.21,22 The pKa value (i.e., the pH at which half of the drug is protonated) varies from one PPI to another. Rabeprazole has the highest pKa, pantoprazole has the lowest pKa, and the pKa values of the other three PPIs fall in between. Differences in pKa value affect the rate of drug accumulation in parietal cells, although the concentrations of all PPIs in the parietal cell are 1000 times higher than those in serum.23 The pKa value also influences acid stability and rate of activation of the PPIs. At high pH values (e.g., pH = 5), pantoprazole is activated much more slowly than rabeprazole.18,23 However, at low pH values (e.g., pH = 1.2), such as those encountered within the acidic environment of the secretory canaliculus of the parietal cell, all of the PPIs are rapidly activated. Although an agent with a higher pKa value may theoretically lead to more of the active sulfenamide moiety being formed in tissues outside of the parietal cell resulting in toxicity, the sulfenamide moiety has an extremely short half-life. To date, the potential impact of differences in pKa values remains mainly theoretical. Proton pump inhibitors inactivate only active proton pumps; the drugs have no effect on resting pumps. Meals are the primary stimulus for acid secretion, but only about 70–80% of proton pumps are activated after a meal.24 Therefore, only about 70–80% of proton pumps can be inhibited after a PPI dose. Subsequently, a percentage of the 20–30% of pumps that were not inhibited with the first dose of the PPI as well as newly regenerated pumps will become activated and then can be inhibited by subsequent PPI doses. The percentage of proton pumps that are inhibited becomes progressively greater over the first several days of PPI therapy until a steady state for acid secretion is reached after 3–4 days. The percentage of time in a 24-hour period with the intragastric pH higher than 4 increases progressively during this three-day period until acid secretion reaches a steady state.24 These pharmacodynamic observations explain the 3–4-day lag before the maximum acid-suppressant effect of PPIs is observed. The observations also provide the rationale for administering PPIs 30 minutes before breakfast to maximize both proton pump activation and inhibition. In addition, these principles provide a rationale for administering multiple PPI doses on day one of therapy (i.e., loading dose by giving two doses approximately six hours apart), as is often done when using PPIs for the prevention of stress-related mucosal bleeding.25 Although based on these concepts, some may question whether PPIs will be effective in patients who are not eating (i.e., NPO patients) as acid is continually being secreted throughout the day even in absence of food (i.e., basal acid secretion). Approximately 45% of acid production is stimulated independent of the presence of food in the stomach or intestines.26 The results of an open-label pilot study of i.v. pantoprazole over two days in critically ill patients who were not eating suggest that gastric acid secretion was adequate and the pH in the secretory canaliculi was low enough for PPI activation.27 Moreover, the proteins in blood serve as a stimulus for acid secretion in patients with blood in the gastric lumen (i.e., patients with upper GI bleeding).28 PPIs effectively inhibit active proton pumps regardless of stimulus (i.e., basal, cephalic, food) and thus reduce acid secretion in fed and NPO patients. Pharmacokinetics. The pharmacokinetic characteristics of orally administered PPIs formulated as conventional delayed-release tablets or capsules are shown in Table 22. The bioavailability of omeprazole and esomeprazole increases during the first five days of oral therapy as a result of a decrease in first-pass metabolism due in part to inhibition by the drug of its own metabolism.17,37,–40 The pharmacokinetics of a single 40-mg i.v. dose of esomeprazole were compared with the pharmacokinetics of the same single i.v. dose after five days of oral esomeprazole therapy (40 mg/day) in healthy volunteers.40 There was a marked decrease in clearance of the drug and slight increases in peak plasma concentration and half-life after the i.v. dose on day six compared with day one. These findings are consistent with autoinhibition of metabolism (i.e., inhibition by the drug of its own metabolism). The bioavailability of the other three PPIs does not change over time. The area under the plasma concentration–time curve (i.e., total body exposure to the drug) reflects bioavailability and other factors.41 For an individual agent, the degree of acid suppression is related to the area under the plasma concentration–time curve.42,43 However, the clinical relevance of differences among PPIs in bioavailability and plasma concentrations is unknown. All PPIs have a relatively short half-life, but the half-life of PPIs has little clinical relevance because binding to the proton pump determines the duration of action. All PPIs are metabolized to some extent by cytochrome P-450 2C19 and 3A4.17 Cytochrome P-450 2C19 exhibits genetic polymorphism. Approximately 2.5% of white Americans, 2% of African Americans, 3.5% of white Europeans, 12.6% of Koreans, and 18–22% of Japanese have the poor-metabolizer phenotype or genotype for this isoenzyme.44,–47 Poor metabolizers metabolize PPIs slowly, resulting in higher area under the plasma concentration–time curves and longer half-lives and greater intragastric pH values than homozygous or heterozygous extensive metabolizers.47 The half-lives of PPIs are around 1 hour in extensive metabolizers and 2–10 hours in poor metabolizers.48 However, toxicity is not a concern in poor metabolizers because the drugs have a wide margin of safety. All PPIs are marketed as racemic mixtures of S- and R-enantiomers except for esomeprazole, which is the S-enantiomer of omeprazole. The PPIs exhibit stereoselective metabolism in that the two enantiomers are metabolized at different rates (i.e., metabolism is stereoselective). The impact of stereoselective metabolism is readily apparent if one compares omeprazole to esomeprazole. When omeprazole, a racemic mixture, is given the R-enantiomer is rapidly cleared by the liver; however, the S-enantiomer is cleared more slowly. When esomeprazole is given, which contains only S-enantiomer, it will be cleared slowly by the liver. The net effect is that the area under the curve will be approximately 20–60% higher for esomeprazole compared with omeprazole even when identical dosages are administered.49 Safety. Proton pump inhibitors are well tolerated. The short-term adverse effects from PPIs are similar to those associated with H2RAs. However, the mental status changes and thrombocytopenia associated with H2RAs have not been reported with PPIs.10,17 Dosage adjustment is not required for PPIs in patients with renal dysfunction. As with H2RAs, there is a potential for drug interactions with PPIs because of the increase in intragastric pH, which can affect the absorption of other drugs.17 Proton pump inhibitors are less likely to interact with other drugs by inhibiting cytochrome P-450 enzymes than is cimetidine or other H2RAs. Omeprazole and esomeprazole selectively inhibit the 2C19 isoenzyme, reducing the metabolism of diazepam, phenytoin, and the R-isomer of warfarin. Lansoprazole slightly induces the 1A2 isoenzyme and increases the metabolism of theophylline.17 Rabeprazole and pantoprazole have not been shown to interact with the cytochrome P-450 system. Clinical use. Omeprazole immediate release (Zegerid, Santarus, Inc.) was recently approved by the FDA for the prevention of stress-related mucosal bleeding; however, none of the PPIs are approved by the FDA for the prevention of recurrent peptic ulcer bleeding.50 Clinical experience with PPIs in the intensive care unit (ICU) is less extensive than that with H2RAs because the latter have been available for a longer period of time. Nevertheless, the greater acid-suppressive potency of PPIs is well established; these drugs provide more consistent intragastric pH control than H2RAs.17 Dosing of PPIs is simpler because there is no need to adjust the dosage for patients with renal dysfunction. There is no risk of tolerance to PPIs, but rebound acid hypersecretion can occur.8,51 In the past, administering PPIs to critically ill patients who are unable to swallow solid oral dosage forms presented a challenge because the drugs were formulated only for oral use and only as delayed-release tablets or capsules containing enteric-coated delayed-release granules or pellets. In order to utilize these agents in critically ill patients who are unable to swallow the intact capsule or tablet, several extemporaneous formulations emerged over the years. Omeprazole, lansoprazole, and esomeprazole capsules containing enteric-coated granules or pellets may be opened and the contents may be sprinkled in slightly acidic fruit juice (e.g., apple, orange), applesauce, or yogurt. However, this process must be done immediately before administration, and some patients may be unable to swallow soft food and liquids. Various liquid formulations with a limited shelf-life for administration by nasogastric (NG), gastric, or duodenal tube have been compounded extemporaneously from sodium bicarbonate solution and omeprazole or lansoprazole granules (referred to as simplified omeprazole suspension and simplified lansoprazole suspension, respectively) or crushed pantoprazole tablets (pantoprazole bicarbonate solution).52,53 PPIs are unstable in the acidic environment of the stomach, so the two general approaches that have been utilized over the years are designed to keep the enteric coating intact (i.e., place the pellets in an acidic beverage) or formulate the PPI in a bicarbonate solution. Both formulations are designed to protect the drug from acid degradation if administered intragastrically. Bicarbonate delivery entails dissolution of the enteric coating on drug pellets or granules in sodium bicarbonate solution. In theory, the PPI is protected from degradation in the acidic stomach environment by the bicarbonate solution. However, the amount of bicarbonate used can be of potential concern in some patients because using too much bicarbonate can affect acid–base balance and using too little bicarbonate can allow drug degradation. By contrast, acidic delivery involves placing the enteric-coated granules or pellets in an acidic beverage, such as juice. In theory, the enteric coating on the granules and pellets remains intact until the drug reaches the alkaline environment of the duodenum, where drug absorption occurs. However, the stickiness of juice mixtures and adherence of the drug to the oral syringe and tubing can pose problems. The delivery site and amount and type of flush solution (e.g., water, sodium bicarbonate) are considerations with both approaches to enteral PPI delivery. Several new oral PPI dosage forms have become available in recent years, expanding the therapeutic options for critically ill patients (Table 33). These new products include lansoprazole delayed-release orally disintegrating tablets (for dissolving directly on the tongue, with or without water, or dissolution in water in an oral syringe for administration by mouth or NG tube) and delayed-release oral suspension (packets of enteric-coated granules for mixing with water and oral administration).35 Omeprazole immediate-release oral suspension (packets of powder with sodium bicarbonate for mixing with water and administration orally or via a nasogastric tube) also is now available.50 Healthy volunteer studies indicate that esomeprazole pellets may also be given in water and administered through a nasogastric tube.54 In addition, parenteral formulations of pantoprazole and lansoprazole are available in the United States.55,56 The optimal PPI route of administration—oral, enteral via an NG or duodenal tube, or i.v.—and dosage form depend on several factors, including gastrointestinal (GI) function. Critically ill patients often have GI abnormalities that can affect drug absorption. These abnormalities include delayed gastric emptying, impaired GI motility, mucosal ischemia, and increased intestinal permeability.57,–59 Considerations in the use of the enteral route of administration include GI function, access site (e.g., stomach, duodenum), tubing material, vehicle for drug delivery (e.g., risk of interaction between the tubing material and vehicle), drug particle size, and tube size (i.e., lumen diameter and risk for clogging). Taking these factors into consideration, one can develop strategies to optimize the appropriate method of PPI delivery in critically ill patients. Conclusion PPIs block the final common step in acid secretion and provide morec potent acid suppression than H2RAs, with a similar adverse effect profile, no risk for tolerance, and a lower risk for drug interactions mediated by cytochrome P-450 enzymes. The clinical relevance of differences among PPIs in bioavailability, plasma concentration, and binding to proton pumps is unknown. The ease of administration of PPIs in the critical care setting has improved since the introduction of new dosage forms. Table 1. Rationale for Acid Suppression in Preventing Stress-Related Mucosal Disease and Recurrence of Peptic Ulcer Bleeding2,a Intragastric pH Physiologic Activity aBased on in vitro and animal studies. ≥3.5 Decreased incidence of stress-induced bleeding >4.0 Target pH - Prevention of stress related mucosal bleeding ≥4.5 Pepsin inactivation 5.0 99.9% acid neutralization 5.1–7.0 Alterations in coagulation and platelet aggregation >6 Target pH - Prevention of peptic ulcer recurrence ≥7.0 Potential decrease in incidence of rebleeding ≥8.0 Pepsin destruction Intragastric pH Physiologic Activity aBased on in vitro and animal studies. ≥3.5 Decreased incidence of stress-induced bleeding >4.0 Target pH - Prevention of stress related mucosal bleeding ≥4.5 Pepsin inactivation 5.0 99.9% acid neutralization 5.1–7.0 Alterations in coagulation and platelet aggregation >6 Target pH - Prevention of peptic ulcer recurrence ≥7.0 Potential decrease in incidence of rebleeding ≥8.0 Pepsin destruction Table 1. Rationale for Acid Suppression in Preventing Stress-Related Mucosal Disease and Recurrence of Peptic Ulcer Bleeding2,a Intragastric pH Physiologic Activity aBased on in vitro and animal studies. ≥3.5 Decreased incidence of stress-induced bleeding >4.0 Target pH - Prevention of stress related mucosal bleeding ≥4.5 Pepsin inactivation 5.0 99.9% acid neutralization 5.1–7.0 Alterations in coagulation and platelet aggregation >6 Target pH - Prevention of peptic ulcer recurrence ≥7.0 Potential decrease in incidence of rebleeding ≥8.0 Pepsin destruction Intragastric pH Physiologic Activity aBased on in vitro and animal studies. ≥3.5 Decreased incidence of stress-induced bleeding >4.0 Target pH - Prevention of stress related mucosal bleeding ≥4.5 Pepsin inactivation 5.0 99.9% acid neutralization 5.1–7.0 Alterations in coagulation and platelet aggregation >6 Target pH - Prevention of peptic ulcer recurrence ≥7.0 Potential decrease in incidence of rebleeding ≥8.0 Pepsin destruction Table 2. Pharmacokinetic Profile of Orally Administered Proton Pump Inhibitors17,29,–38,a,b Parameter Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole a AUC = area under the plasma concentration–time curve; Cmax = peak plasma concentration; Tmax = time to peak plasma concentration. bThe data presented in this table are from pharmacokinetic studies of intact delayed-release tablets or capsules swallowed whole. Bioavailability (%)     day 1 30 64 80 52 77     day 5 65 89 . . . . . . . . . AUC (μmol/L • hr)     day 1(range) 1.1–2.0 4.32–7.3 5.0–5.2 2.1–2.2 9.93–15.9     day 5 2.23 11.21 . . . . . . . . . Half-life (hr) 0.5–1.0 1.2 1.3–1.7 1.0–2.0 1.0–1.9 Tmax (hr) 0.5–3.5 1.5 1.7 2.0–5.0 1.1–3.1 Effect of food on absorption No effect on bioavailability of 20-mg enteric-coated tablet ↓AUC after 40- mg dose ↓AUC and Cmax after 30-mg dose ↑Tmax after 20-mg dose ↑Tmax after 40-mg dose Parameter Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole a AUC = area under the plasma concentration–time curve; Cmax = peak plasma concentration; Tmax = time to peak plasma concentration. bThe data presented in this table are from pharmacokinetic studies of intact delayed-release tablets or capsules swallowed whole. Bioavailability (%)     day 1 30 64 80 52 77     day 5 65 89 . . . . . . . . . AUC (μmol/L • hr)     day 1(range) 1.1–2.0 4.32–7.3 5.0–5.2 2.1–2.2 9.93–15.9     day 5 2.23 11.21 . . . . . . . . . Half-life (hr) 0.5–1.0 1.2 1.3–1.7 1.0–2.0 1.0–1.9 Tmax (hr) 0.5–3.5 1.5 1.7 2.0–5.0 1.1–3.1 Effect of food on absorption No effect on bioavailability of 20-mg enteric-coated tablet ↓AUC after 40- mg dose ↓AUC and Cmax after 30-mg dose ↑Tmax after 20-mg dose ↑Tmax after 40-mg dose Table 2. Pharmacokinetic Profile of Orally Administered Proton Pump Inhibitors17,29,–38,a,b Parameter Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole a AUC = area under the plasma concentration–time curve; Cmax = peak plasma concentration; Tmax = time to peak plasma concentration. bThe data presented in this table are from pharmacokinetic studies of intact delayed-release tablets or capsules swallowed whole. Bioavailability (%)     day 1 30 64 80 52 77     day 5 65 89 . . . . . . . . . AUC (μmol/L • hr)     day 1(range) 1.1–2.0 4.32–7.3 5.0–5.2 2.1–2.2 9.93–15.9     day 5 2.23 11.21 . . . . . . . . . Half-life (hr) 0.5–1.0 1.2 1.3–1.7 1.0–2.0 1.0–1.9 Tmax (hr) 0.5–3.5 1.5 1.7 2.0–5.0 1.1–3.1 Effect of food on absorption No effect on bioavailability of 20-mg enteric-coated tablet ↓AUC after 40- mg dose ↓AUC and Cmax after 30-mg dose ↑Tmax after 20-mg dose ↑Tmax after 40-mg dose Parameter Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole a AUC = area under the plasma concentration–time curve; Cmax = peak plasma concentration; Tmax = time to peak plasma concentration. bThe data presented in this table are from pharmacokinetic studies of intact delayed-release tablets or capsules swallowed whole. Bioavailability (%)     day 1 30 64 80 52 77     day 5 65 89 . . . . . . . . . AUC (μmol/L • hr)     day 1(range) 1.1–2.0 4.32–7.3 5.0–5.2 2.1–2.2 9.93–15.9     day 5 2.23 11.21 . . . . . . . . . Half-life (hr) 0.5–1.0 1.2 1.3–1.7 1.0–2.0 1.0–1.9 Tmax (hr) 0.5–3.5 1.5 1.7 2.0–5.0 1.1–3.1 Effect of food on absorption No effect on bioavailability of 20-mg enteric-coated tablet ↓AUC after 40- mg dose ↓AUC and Cmax after 30-mg dose ↑Tmax after 20-mg dose ↑Tmax after 40-mg dose Table 3. Commercially Available and Extemporaneously Compounded Proton Pump Inhibitor Products33,–36,38,50,52,–56,a Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole aICU = intensive care unit; NG = nasogastric. bData in ICU patients not available. cPackets of enteric-coated granules (for mixing with water and administration by mouth; not for administration by enteral feeding tubes; data in ICU patients not available). dPackets of powder with sodium bicarbonate (for mixing with water and oral or NG administration). eSimplified omeprazole suspension. fSimplified lansoprazole suspension. gPantoprazole bicarbonate suspension. Commercially-available products Parenteral form Pending FDA approval X X Delayed-release (enteric-coated) tablets X X Delayed-release (enteric-coated pellets or granules) capsules X X X Delayed-release orally disintegrating tablets Xb Delayed-release oral suspension Xc Immediate-release oral suspension Xd Extemporaneously compounded liquid formulations Pellets or granules (i.e., contents of capsules) in water Not recommended Xb Not recommended Pellets or granules (i.e., contents of capsules) in slightly acidic juice X X X Suspension or solution in sodium bicarbonate Xe Xf Xb,g Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole aICU = intensive care unit; NG = nasogastric. bData in ICU patients not available. cPackets of enteric-coated granules (for mixing with water and administration by mouth; not for administration by enteral feeding tubes; data in ICU patients not available). dPackets of powder with sodium bicarbonate (for mixing with water and oral or NG administration). eSimplified omeprazole suspension. fSimplified lansoprazole suspension. gPantoprazole bicarbonate suspension. Commercially-available products Parenteral form Pending FDA approval X X Delayed-release (enteric-coated) tablets X X Delayed-release (enteric-coated pellets or granules) capsules X X X Delayed-release orally disintegrating tablets Xb Delayed-release oral suspension Xc Immediate-release oral suspension Xd Extemporaneously compounded liquid formulations Pellets or granules (i.e., contents of capsules) in water Not recommended Xb Not recommended Pellets or granules (i.e., contents of capsules) in slightly acidic juice X X X Suspension or solution in sodium bicarbonate Xe Xf Xb,g Table 3. Commercially Available and Extemporaneously Compounded Proton Pump Inhibitor Products33,–36,38,50,52,–56,a Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole aICU = intensive care unit; NG = nasogastric. bData in ICU patients not available. cPackets of enteric-coated granules (for mixing with water and administration by mouth; not for administration by enteral feeding tubes; data in ICU patients not available). dPackets of powder with sodium bicarbonate (for mixing with water and oral or NG administration). eSimplified omeprazole suspension. fSimplified lansoprazole suspension. gPantoprazole bicarbonate suspension. Commercially-available products Parenteral form Pending FDA approval X X Delayed-release (enteric-coated) tablets X X Delayed-release (enteric-coated pellets or granules) capsules X X X Delayed-release orally disintegrating tablets Xb Delayed-release oral suspension Xc Immediate-release oral suspension Xd Extemporaneously compounded liquid formulations Pellets or granules (i.e., contents of capsules) in water Not recommended Xb Not recommended Pellets or granules (i.e., contents of capsules) in slightly acidic juice X X X Suspension or solution in sodium bicarbonate Xe Xf Xb,g Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole aICU = intensive care unit; NG = nasogastric. bData in ICU patients not available. cPackets of enteric-coated granules (for mixing with water and administration by mouth; not for administration by enteral feeding tubes; data in ICU patients not available). dPackets of powder with sodium bicarbonate (for mixing with water and oral or NG administration). eSimplified omeprazole suspension. fSimplified lansoprazole suspension. gPantoprazole bicarbonate suspension. Commercially-available products Parenteral form Pending FDA approval X X Delayed-release (enteric-coated) tablets X X Delayed-release (enteric-coated pellets or granules) capsules X X X Delayed-release orally disintegrating tablets Xb Delayed-release oral suspension Xc Immediate-release oral suspension Xd Extemporaneously compounded liquid formulations Pellets or granules (i.e., contents of capsules) in water Not recommended Xb Not recommended Pellets or granules (i.e., contents of capsules) in slightly acidic juice X X X Suspension or solution in sodium bicarbonate Xe Xf Xb,g Based on the proceedings of a symposium held December 6, 2004, during the 39th ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from TAP Pharmaceutical Products Inc. Dr. Welage received an honorarium for her participation in the symposium and for the preparation of this article. 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Dr. Welage received an honorarium for her participation in the symposium and for the preparation of this article. Dr. Welage discloses that she has received research support from AstraZeneca and GlaxoSmithKline and serves on the speakers bureau and as a consultant for AstraZeneca, Wyeth, and TAP Pharmaceutical Products Inc. Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.