(®Intravenous Pantoprazole (Protonix
by Jeffrey Bruno, Pharm.D.

Introduction:
Currently, pantoprazole sodium (Protonix®) is the only proton pump inhibitor (PPI) available in the United States for intravenous (IV) use. It is indicated for the short-term treatment of gastroesophageal reflux disease (GERD) associated with erosive esophagitis and Zollinger-Ellison Syndrome (ZES) in patients unable to take oral therapy.1 The focus of this article will be to evaluate the off-label use of continuous-infusion pantoprazole in the treatment of acute gastrointestinal (GI) bleeds secondary to peptic ulcer disease (PUD).

Acute GI Bleeds:
Acute upper GI bleeding is diagnosed in 50-150 per 100,000 individuals a year, representing the most common emergency encountered by gastroenterologists.2 This condition translates into approximately 300,000 hospitalizations per year with an annual mortality rate of 6-10% and costs surpassing $2.5 billion.3,4 Furthermore, up to 50% of all cases can be attributed to PUD.2,4,5

Risk Factors for GI Hemorrhage:
The use of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be the most common cause of PUD, generally accounting for a greater incidence of gastric versus duodenal ulcers. As a result, the risk for GI bleeding subsequently increases.6,7 Peptic ulcer disease develops in 15-30% of patients taking NSAIDs and is associated with both acute and chronic use of these agents, as well as low-dose and enteric-coated aspirin. NSAID-related PUD is especially common in the elderly, secondary to the widespread use of these medications and age-related thinning of the GI mucosa. Infection with Helicobacter pylori is also a prominent risk factor for the development of PUD, serving as the most common cause of non-NSAID-induced ulcers. Other risk factors for the development of PUD include the use of corticosteroids or oral anticoagulants (especially when taken concurrently with NSAIDs or aspirin), alcohol consumption, cigarette smoking, and psychological stress.6 Specific risk factors identified for patients in an intensive care unit (ICU) include mechanical ventilation for > 48 hours, the presence of underlying coagulopathies, and hypotension.

Patient Prognosis:
Although approximately 80% of peptic ulcer bleeds resolve spontaneously, the potential for rebleeding exists. As depicted in Table 1, patient prognosis has been found to be associated with the endoscopic appearance of the underlying lesion. Type I (actively bleeding) ulcers are associated with the greatest risk for rebleeding; however, the risk is also prominent with Type II (recent bleed) ulcers.3-5,9,10 Endoscopic treatment serves as the cornerstone of therapy for patients with a Type I or II ulcer, with hemostasis achieved in > 90% of cases. Nevertheless, even after successful endoscopic treatment, 15-20% of patients will experience rebleeding within 72 hours, thus requiring repeat endoscopy or surgical intervention.3,9
A high risk of rebleeding has also been associated with the presence of certain clinical findings. Such criteria include: age > 65 years, poor overall health status, comorbid illnesses, shock, a low initial hemoglobin level, requirement for blood transfusions, melena, and the presence of bright red blood per rectum, nasogastric tube aspirate, or vomitus.11 Acid suppressive therapy has been employed in an attempt to reduce the incidence of rebleeding and associated complications.

Optimizing pH Control:
In vitro studies have demonstrated that clot formation, clot lysis, and mucosal healing are pH-dependent processes.9,12,13 As the acidity of the environment increases, platelet disaggregation and pepsin-mediated clot lysis become more prominent. However, elevation of the gastric pH to > 6 results in irreversible inhibition of pepsin, and thus, potential clot stabilization. These findings serve as the theoretical basis for post-endoscopic use of acid suppressive therapy.

Until recently, histamine-2 receptor antagonists (H2RAs) served as the only IV option for medical management of acute GI bleeds. However, these agents have not been shown to reduce the incidence of rebleeding, need for blood transfusions, and/or surgical intervention.3 Although IV H2RAs can readily increase intragastric pH to > 4-6, such elevations are not usually maintained for
periods longer than 24 hours. It is hypothesized that tolerance occurs secondary to the ability of H2RAs to only block the effects of histamine on gastric parietal cells, thus allowing unopposed stimulation of acid production by gastrin and acetylcholine.
Unlike H2RAs, PPIs affect all three known stimulators of acid production: gastrin, acetylcholine, and histamine. Specifically, these agents irreversibly bind to the H+-K+ ATPase enzyme (proton pump) located on the surface of gastric parietal cells, thus inhibiting the secretion of H+ ions into the gastric lumen. New proton pumps must be synthesized in order for acid production to resume, a process that can take up to 48 hours.14
Numerous studies have demonstrated the ability of IV PPIs to rapidly elevate and maintain intragastric pH at levels > 6 in absence of tolerance.9,12,13,15-17 The majority of these studies have focused on the use of IV omeprazole. The greatest degree of continuous acid suppression has resulted from administration of an 80 mg IV bolus of omeprazole followed by a continuous-infusion (CI) of 8 mg/hr for 72 hours.15-17 Given the fact that IV omeprazole is not available in the United States, an identical regimen of IV pantoprazole is employed under the assumption of similar acid-suppressing effects. Brunner and colleagues evaluated the degree of acid suppression associated with four different pantoprazole dosage regimens. Similar to that observed with omeprazole, an 80 mg IV bolus of pantoprazole followed by a CI of 8 mg/hr resulted in the greatest degree of acid suppression, with a pH > 4, 5, and 6 maintained for 99%, 94%, and 84% of the day, respectively.

Acid Suppression with PPIs versus H2RAs:
The acid suppressing effects of CI omeprazole and H2RAs have been examined in comparative trials.15-17 In a study conducted by Labenz and colleagues, the median percentage of time intragastric pH was > 6 was significantly greater for patients randomized to CI omeprazole (80 mg IV bolus, followed by 8 mg/hr for 24 hours) in comparison to ranitidine (50 mg IV bolus, followed by 0.25 mg/kg/hr for 24 hours) as early as 13 hours following initiation of therapy.15 Using a similar dosage regimen, Netzer and colleagues evaluated the acid-suppressing effects of CI omeprazole and ranitidine over a 72-hour period. Overall, more sustained elevations of intragastric pH > 6 were observed in patients randomized to omeprazole, especially following the first 24 hours of therapy.17 The results of these trials reveal that CI omeprazole is able to more rapidly elevate as well as maintain intragastric pH > 6 in comparison to H2RAs.

IV PPIs for Acute GI Bleeds:
Given their theoretical potential, numerous studies have been conducted in order to evaluate the ability of PPIs to reduce the incidence of morbidity and mortality in patients diagnosed with an acute peptic ulcer-related bleed. The manner in which these agents are used in practice today can be attributed to the findings of both Lin and Lau.16,20 The primary objective of these two trials was to examine the incidence of rebleeding associated with the use of CI PPIs following endoscopic hemostasis in patients diagnosed with either a Type I or II ulcer. An overview of each trial is provided in Table 2.
Lin and colleagues enrolled patients with an actively bleeding ulcer (spurting or oozing) or a NBVV diagnosed by endoscopic evaluation within 12 hours of hospital admission. Successful hemostasis was required through use of either heater-probe thermocoagulation, utilized in the emergency room, or multi-probe electrocoagulation, utilized following admission. The incidence of rebleeding observed by study days 3 and 14, served as the primary endpoints of analysis. There were no statistically significant differences in baseline characteristics between the two treatment groups; however, more patients with an underlying active bleed were randomized to cimetidine. The majority of patients enrolled were elderly males with an underlying gastric or duodenal ulcer (median age of 65 and 66.5 years for the omeprazole and cimetidine treatment groups, respectively). As depicted in Table 2, patients treated with omeprazole experienced a statistically significant lower incidence of rebleeding by both study days 3 and 14 (0% versus 16%, respectively; p=0.003 and 4% versus 24%, respectively; p=0.004). There were no statistically significant differences between omeprazole- and cimetidine-treated patients in the volume of blood transfused after 14 days of therapy (range 0-2500 mL versus 0-5000 mL, respectively; p=0.05), length of hospital stay (median of 7 versus 6 days, respectively; p>0.5), or the incidence of all-cause mortality (0 versus 2, respectively; p>0.5). Surgical intervention for rebleeding was not required in either treatment group. Based on the reduced incidence of rebleeding observed in the omeprazole-treated patients, the authors concluded that a 40 mg IV bolus of omeprazole followed by a CI of 6.7 mg/hr should be routinely administered following endoscopic therapy in patients presenting with an actively bleeding peptic ulcer or a NBVV.
Lau and colleagues included patients who were > 16 years of age and had successfully received endoscopic therapy within 24 hours of hospital admission for either an actively bleeding peptic ulcer (spurting or oozing) or NBVV with or without the presence of an adherent clot. Epinephrine (1:10,000) in combination with heater-probe thermocoagulation was employed for endoscopic therapy. The primary endpoint of the study was the incidence of rebleeding within 30 days of endoscopic therapy. Similar to the study conducted by Lin and colleagues, the majority of enrolled patients were elderly males (mean age of 64 and 67 years for the omeprazole and placebo treatment groups, respectively), with an underlying gastric or duodenal ulcer. Baseline characteristics were similar between the two groups. A statistically significant lower incidence of rebleeding was observed in the omeprazole treatment group by study day 3 (4.2% versus 20%, respectively; p<0.001), study day 7 (5.8% versus 21.7%, respectively; p<0.001), and study day 30 (6.7% versus 22.5%, respectively; p<0.001). Statistical significance at 30-days follow-up was maintained when patients in each study group were stratified based upon the presence of an actively bleeding ulcer (4.7% versus 17.2%, respectively; p=0.04) or a NBVV (8.9% versus 27%, respectively; p=0.02). Following endoscopic therapy, patients treated with omeprazole also required fewer units of blood than patients given placebo (mean of 1.7 versus 2.4 units, respectively; p=0.03). In regards to the length of hospital stay, a greater number of patients treated with omeprazole were discharged in < 5 days (46.7% versus 31.7%, respectively; p=0.02). Shorter hospital stays were observed in omeprazole-treated patients admitted for a peptic ulcer bleed (median of 4 versus 5 days, respectively; p=0.006); however, no difference was observed in those who developed bleeds during their hospital stay. In addition, there were no statistically significant differences in the incidence of surgical intervention or all-cause mortality. Surgical intervention was employed in three patients in the omeprazole group and nine patients in the placebo group (p=0.14) secondary to profuse rebleeding (2 and 4 patients, respectively) or a second incidence of rebleeding (1 and 4 patients, respectively). One patient in the placebo group underwent surgery for heater- probe-induced peritonitis. The incidence of all-cause mortality by study day 30 observed between omeprazole- and placebo-treated patients was 4.2% and 10%, respectively (p=0.13). Recurrent bleeding was the cause of death in two placebo-treated patients. Follow-up endoscopy revealed similar rates of ulcer healing in the treatment and placebo group (84.7% and 92.8%, respectively; p=0.14). Based on these results, the authors concluded that high-dose CI omeprazole has the ability to reduce the incidence of rebleeding while minimizing the length of hospital stay, units of blood transfused, and need for endoscopic retreatment in patients presenting with an actively bleeding ulcer or NBVV when preceded by successful endoscopic therapy.20
In both trials, CI omeprazole resulted in a statistically significant lower incidence of rebleeding in comparison to H2RA therapy or placebo. Furthermore, this finding was evident not only for the critical 72 hours following diagnosis, but also persisted for up to 1 month when patients were provided with oral maintenance PPI therapy following the infusion. However, the ability to extrapolate the results of these trials to the management of patients presenting with an acute GI bleed in the United States may be debated. Intravenous omeprazole is not available in the United States, thus requiring one to assume similar outcomes with the use of IV pantoprazole. In addition, these studies were conducted in a predominantly Asian population. It has been postulated that Asian individuals possess a smaller parietal cell mass in comparison to that of Americans, potentially confounding the use of a similar dosage regimen between these two populations.4,20 Nevertheless, until the results of trials evaluating IV pantoprazole in the management of acute peptic ulcer bleeds become available, the trials of Lin and Lau serve as the only sources to guide current therapy.
Some of the earlier trials evaluating IV PPIs for the treatment of acute GI bleeds did not demonstrate a significant reduction in the incidence of rebleeding when compared against placebo or H2RAs. However, many of these studies employed intermittent bolus dosing in contrast to CI.4 Intermittent bolus dosing may give rise to incomplete inhibition of parietal cell pump reserves, thus leading to suboptimal acid suppression.17 In addition, the manner in which endoscopic treatment was employed in previous trials should also be evaluated as a possible limitation. For example, only patients with an active spurting bleed received endoscopic treatment in the study conducted by Hasselgan and colleagues. Thus, early hemostasis was not achieved in other high-risk patients, such as those with an active oozing bleed or a NBVV.

Administration and Cost:
The standard concentration of IV pantoprazole is 80 mg/100 mL (0.8 mg/ml), with a 12-hour expiration. The 80 mg IV bolus should be administered over at least 15 minutes. The use of an in-line filter provided with the product is required, and IV pantoprazole should not be administered simultaneously through the same line as other IV solutions. The cost of IV pantoprazole is in Table 3.

Conclusion:
Acute GI bleeds secondary to PUD remain a prominent issue. Current evidence supports the use of an 80 mg IV bolus of pantoprazole followed by a CI of 8 mg/hr for a total of 72 hours to minimize the incidence of rebleeding following successful endoscopic treatment in high-risk patients with a Type I or II ulcer. However, the need for surgical intervention and overall mortality is generally unaltered. Once the patient is tolerating other medications by mouth, the patient should be switched to oral PPI therapy. Currently, an IV formulation of lansoprazole (Prevacid®) is being reviewed for FDA-approval.

CCF Formulary:
The use of IV pantoprazole at CCF is restricted to staff physicians from the Department of Gastroenterology for the treatment of an acute GI bleed secondary to PUD or a hypersecretory condition, such as ZES. According to the CCF Adult IV Guidelines, CI pantoprazole should only be initiated within a designated ICU and continued for no longer than 72 hours.23 However, if the patient is transferred to a non-ICU area before the 72-hour infusion is completed, the infusion may be continued on all nursing units. Finally, a drug use evaluation is currently being conducted to collect data on how IV pantoprazole is being used at CCF and if the current formulary restrictions are being followed.
The article's author and the CCF Department of Pharmacy Drug Information Center would like to thank Jeffrey P. Gonzales, Pharm.D., BCPS, for his input and review of the article.

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