Monday, September 21, 2015

Use Pantoprazole Intermittently and Cancel the Infusion for Upper GI Bleed

A common controversy of late has been whether lower doses of proton pump inhibitors (PPIs) can be used in the high-risk upper gastrointestinal bleeding (UGIB) patient after endoscopy instead of the standard high-dose PPI bolus, followed by a 72-hour continuous infusion. The continuous infusion use stems from  guidelines formed after an international consensus conference on nonvariceal UGIB management that were published in 2010.1 There is the additional question of whether we should even be using PPIs prior to endoscopy in the first place, which The Skeptics’ Guide to EM has previously discussed. More often than not, when we come across an UGIB there is a pantoprazole 80 mg bolus followed by an 8 mg per hour infusion ordered and the common rebuttal is “GI is going to ask me to order it.”

Mortality in these UGIB patients is between 10-14% and is caused by peptic ulcers in two-thirds of cases, the other third compromises mostly of gastritis, duodenitis, Mallory-Weiss tears, malignancy, arteriovenous malformations, and esophageal varices.1 The Rockall risk scoring system and emergency medicine-focused Blatchford score can be used to assess a high-risk of rebleeding and the need for clinical intervention, respectively.2,3 Of course there are times in the emergency department our minds are made up pretty quickly on a patient’s GI bleed severity (hematemesis, melena, hematochezia, hemodynamics) and need for emergent interventions. For your high-risk UGIB patient, the mainstay of treatment without controversy is endoscopic therapy with epinephrine and an additional modality (heater probe, argon plasma, clips, bipolar) which will provide hemostasis in 70-90% of patients.4,5 So where is the PPI role in this? The thought is to start a PPI and alkalinize the GI to allow the clot to form and stabilize with the antagonism of the Na/K-ATPase pump on parietal cells, which decreases gastric acid secretion and increases intragastric pH > 6. This in turn improves hemostasis by decreasing pepsin activity, which would normally block the hemostasis process by degrading fibrin clots.6

In the United States, intravenous (IV) pantoprazole is the drug of choice, but it should be mentioned that IV pantoprazole is currently on a national shortage. There are numerous studies that were not available or included in the 2010 guidelines that investigated PPI intermittent and continuous infusion dosing strategies.  There are at least eight relatively recent randomized controlled trials that compared high-dose continuous infusions versus intermittent dosing of IV pantoprazole for patients who are at a high-risk of rebleeding after endoscopy.7-14 There were 1,224 patients analyzed in these trials and indicated that there was a lack of superiority between regimens. No statistical or clinical differences were found between treatment groups in regards to rebleeding rates, hospital length of stay, units of packed red blood cells (PRBC) transfused, urgent surgery, or mortality in seven trials.7-13 A 2015 study from Turkey actually found a decreased rate of rebleeding and PRBC use in the intermittent group compared to the continuous infusion group and no difference in length of stay, urgent surgery, or death.14 This could have been a form of selection bias where the sickest patients were given the higher-dosed regimen or potentially due to a smaller sample size. All pantoprazole groups in each study had a bolus dose ranging from 40 to 80 mg. Three trials compared pantoprazole 40 mg IV every 24 hours,7,13,14 four trials compared 40 mg every 12 hours,8-10,12 and one looked into an every 6 hour regimen11 to the standard 8 mg per hour continuous infusion. After 3 days, each trial used different regimens in regards to route of administration, frequency, and duration of pantoprazole.

Of note, none of these studies were performed in the United States, but rather European and Asian countries. The largest study (n = 474) involving 11 hospitals in Italy used omeprazole or pantoprazole.14 Omeprazole is not available in the intravenous formulation in the United States.

During this time of IV pantoprazole shortage, it should be noted that a standard bolus and continuous infusion regimen uses 7 vials of pantoprazole per day, 21 vials total for the 72-hour regimen, and requires nursing time and resources to continue the infusion with a new infusion due every 5 hours. The drug cost at our institution for this 72-hour regimen is $58.72. For three days of therapy using a bolus followed by once daily dosing, our drug cost is $8.52 and every 12 hours would be $17.04. This is assuming prices do not increase with the shortage, which is counterintuitive to my Economics 101 course freshman year of college. In addition to costs, PPIs also have potential for increased risk of infection and drug-drug interactions.15

Next time you think or are told “GI is going to ask me to order it” consider this data and using a pantoprazole 40 mg IV daily or 40 mg IV every 12 hour regimen. These regimens can be used with support showing no increased risk of rebleeding after endoscopic treatment, length of stay, PRBC use, urgent surgery, or mortality. These regimens may also decrease potential adverse effects from pantoprazole, increase nursing satisfaction, and reduce healthcare costs.

Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Phoenix, Arizona

Peer Reviewed by: Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)


References

  1. Barkun AN, Bardou M, Kuipers EJ, et al. International Consensus Recommendations on the Management of Patients with Nonvariceal Upper Gastrointestinal Bleeding. Ann Intern Med. 2010;152(2):101-113
  2. Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal haemorrhage. Gut. 1996;38:316-321
  3. Chen IC, Hung MS, Chiu TF, et al. Risk scoring systems to predict need for clinical intervention for patients with nonvariceal upper gastrointestinal tract bleeding. Am J Emerg Med. 2007; 25:774-9
  4. Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345-360.
  5. Songur Y, Balkarli A, Acarturk G, et al. Comparison of infusion or low-dose proton pump inhibitor treatments in upper gastrointestinal system bleeding. Eur J Intern Med. 2011;22(2):200-204. 
  6. Medscape. Peptic Ulcer Disease. Accessed on 9/12/15. http://misc.medscape.com/pi/android/medscapeapp/html/A181753-business.html
  7. Chen CC, Lee JY, Fang YJ, et al. Randomised clinical trial: high-dose vs. standard-dose proton pump inhibitors for the prevention of recurrent haemorrhage after combined endoscopic haemostasis of bleeding peptic ulcers. Aliment Pharmacol Ther. 2012;35(8):894-903.
  8. Ucbilek E, Sezgin O, Altintas E. Low dose bolus pantoprazole following successful endoscopic treatment for acute peptic ulcer bleeding is effective: a randomized, prospective, double blind, double dummy pilot study. Gastroenterology. 2013;144(suppl 1):S506.
  9. Yamada S, Wongwanakul P. Randomized controlled trial of high dose bolus versus continuous intravenous infusion pantoprazole as an adjunct therapy to therapeutic endoscopy in massive bleeding peptic ulcer. J Med Assoc Thai. 2012;95(3):349-357.
  10. Hung WK, Li VK, Chung CK, et al. Randomized trial comparing pantoprazole infusion, bolus and no treatment on gastric pH and recurrent bleeding in peptic ulcers. ANZ J Surg. 2007;77(8):677-681.
  11. Hsu YC, Perng CL, Yang TH, et al. A randomized controlled trial comparing two different dosages of infusional pantoprazole in peptic ulcer bleeding. Br J Clin Pharmacol. 2010;69(3):245-251.
  12. Yüksel I, Ataseven H, Köklü S, et al. Intermittent versus continuous pantoprazole infusion in peptic ulcer bleeding: a prospective randomized study. Digestion. 2008;78(1):39-43.
  13. Choi KD, Kim N, Jang IJ, et al. Optimal dose of intravenous pantoprazole in patients with peptic ulcer bleeding requiring endoscopic hemostasis in Korea.J Gastroenterol Hepatol. 2009;24(10):1617-1624.
  14. Andriulli A, Loperido S, Focareta R, et al. High- versus low-dose proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding: a multicentre, randomized study. Am J Gastroenterol. 2008;103(12):3011-8.
  15. Abraham NS. Proton Pump Inhibitors: potential adverse effects. Curr Opin Gastroenterol. 2012;28(6):615-620.