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)


  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.
  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.

Sunday, September 13, 2015

Sympathy for Ketamine: Is It Really a Sympathomimetic?

Probably not.

Ketamine, as we all know, is a popular yet polarizing drug in emergency medicine. For some, it's the drug of choice for any and every indication in the ED. For others, it's avoided at all costs since it causes brains, hearts and eyes to explode. With regards to exploding hearts, providers are often concerned that the drug should never be used in patients with cardiovascular disease because of the FACT that ketamine is a sympathomimetic. However, this FACT, often regarded as common knowledge and therefore not referenced (for instance, in the ACEP guideline for ketamine use in the ED) is not factual. In fact, it is based on data from the 60's and 70's that has been quoted for decades.

The practice of using review articles to cite review articles is generally regarded as poor form. For instance, a nice review paper of ketamine discussing many aspects of the drug states the following: 

"With the stimulation of noradrenergic neurons and the inhibition of catecholamine uptake, ketamine provokes a hyperadrenergic state (release of norepinephrine, dopamine, and serotonin). Inhibition of norepinephrine uptake is stereo specific: R(−) isomer only inhibits its neuronal uptake, while S(+) isomer also inhibits extra-neuronal uptake. There is a prolonged synaptic action, leading to an increased transfer of norepinephrine in the circulation."

The reference cited here is not a piece of literature supporting this argument, but rather, another review. Searching through this review, the referenced paper for the discussion of ketamine's "sympathetic activating actions" is another review, but this time, in German. Wunderbar!

So let's go back, back to the beginning.

As far as I can tell, the first investigation into the cardiovascular effects of ketamine occurred shortly after it's discovery. In 1969, Traber et al. described the involvement of the sympathetic nervous system in the pressor response to ketamine. (Traber DL, et al. Involvement of the sympathetic nervous system in the pressor response to ketamine. Anesth Analg. 1969;48(2):248-252). The investigators administered ketamine at 5 mg/kg, 10 mg/kg or 20 mg/kg doses to 12 mechanically ventilated dogs under epidural anesthesia. They followed the effects on MAP as a marker of sympathetic activation. From baseline, the 'low dose' 5 mg/kg dose did not produce any change in MAP from baseline. When the higher 10 and 20 mg/kg doses were administered, however, MAPs fell to a statistically significant margin. Furthermore, no changes in HR were observed. The authors concluded that the epidural anesthesia suppressed the ketamine pressor response, which is evidence that the response is mediated by the sympathetic nervous system. However, in models without spinal epidural anesthesia, there is evidence demonstrating similar findings (Bidwai AV, et al. The effects of ketamine on cardiovascular dynamics during halothane and enflurane anesthesia. Anesth Analg. 1975;54(5):588-592; Savege TM, et al. A comparison of some cardiorespiratory effects of althesin and ketamine when used for induction of anaesthesia in patients with cardiac disease. Br J Anaesth 1976 Nov;48(11):1071-81; Waxman K, et al. Cardiovascular effects of anesthetic induction with ketamine. Anesth Analg. 1980 May;59(5):355-8; Dewhirst E, et al. Cardiac arrest following ketamine administration for rapid sequence intubation. J Intensive Care Med. 2013 Nov-Dec; 28(6):375-9). While not formally addressed in the study, the KETASED study did not show (among other things) any difference in vasopressor use between etomidate and ketamine groups. If it was a sympathomimetic, one would expect to find some difference, but again, KETASED did not have a population large enough to detect such a finding, nor was it designed to do so.

While the cardiovascular effects reported in the historical literature suggest a cardiovascular neutral or depressant effect at above normal therapeutic dosing, reviews and texts may also state that ketamine increases norepinephrine transport into the peripheral circulation by inhibiting uptake and reuptake thereby increasing the concentration in the neuronal synapse. This argument is supported similarly by historical data (Baraka A, et al. Catecholamine levels after ketamine anesthesia in man. Anesth Analg. 1973; 52(2):198-200; Miletich DJ, et al. The effect of ketamine on catecholamine in the isolate perfused rat heart. Anesthesiology, 1973; 39(3):271-277). The human and animal models tested did not demonstrate clinical response to the increase in plasma norepinephrine or epinephrine. Furthermore, the current attitude toward plasma NE levels suggest they are (effectively) meaningless. (Goldstein DS, et al. Sources and Significance of Plasma Levels of Catechols and Their Metabolites in Humans. JPET June 2003; 305(3): 800-811).

Ultimately, the concern of sympathomimetic effects in a patient with cardiovascular disease would be that a drug, such as ketamine, would lead to an increase in myocardial oxygen demand and possibly lead to ischemia/necrosis. A 1979 paper examined this question in a dog model. Six dogs were anesthetized and mechanically ventilated and subsequently given doses of 5 mg/kg or 10 mg/kg of ketamine followed by a continuous infusion in 4 of the dogs. After the 5 mg/kg bolus, there was no change in HR or cardiac output but a decrease in MAP. For the 10 mg/kg bolus, CO and SV both increased by approximately 90%. While the investigators observed a 58% increase in myocardial oxygen consumption, there was an equal and associated increase in myocardial oxygen delivery and increased coronary blood flow. (Smith G, et al. The effects of ketamine on the canine coronary circulation. Anesthesia 1979;34:555-61). The leading theory argues that ketamine acts on voltage-gated calcium channels in a manner similar to calcium channel blockers (Baum, VC, et al. Ketamine inhibits transsarcolemmal calcium entry in guinea pig myocardium: direct evidence by single cell voltage clamp. Anesth Analg 1991; 73:804-807).

The evidence available makes it difficult to draw conclusions. While the evidence suggests ketamine is a sympathomimetic, the evidence arguing against it is of equally poor quality. Should ketamine be contraindicated in patients with cardiovascular disease? Perhaps. Is it often given to patients with an unknown history of such disease? Absolutely.

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