Induced Hypothermia and Adverse Drug Events: Staying Abreast of the Data

Samuel Poloyac, PharmD, PhD*
Associate Professor
University of Pittsburgh
School of Pharmacy
Pittsburgh, Pennsylvania, USA

Adverse drug events (ADEs) are a significant public health problem. A meta-analysis by Lazarou and colleagues found a serious adverse drug reaction incidence rate of 6.7% in U.S. hospitalized patients with 0.32% being fatal. This projected to two million patients and more than 100,000 deaths annually, thereby, estimating ADEs as the fourth to sixth leading causes of death.(1)

Intensive care patients are particularly susceptible to life-threatening ADEs.(2) The ADE Prevention Study Group reported a two-fold increased risk in intensive care unit (ICU) patients (19 events/1,000 patient days) compared to non-ICU patients (10 events/1,000 patient days).(3) The U.S. Food and Drug Administration’s Center for Drug Evaluation and Research published a guide for the pharmaceutical industry encouraging “routine and thorough evaluation of metabolism and interactions in vitro” prior to implementation of phase III studies.(4)

The same degree of stringent evaluation does not occur when a new non-pharmacologic therapy enters clinical practice. Frequently, nonpharmacologic approaches – such as induced hypothermia – are used without a full understanding of their effects on hepatic metabolism, creating the potential for therapy-drug interactions. Randomized control trials have demonstrated that induced hypothermia is neuroprotective in adults after ventricular fibrillatory arrest and in neonates with hypoxic-ischemic encephalopathy.(5,6) These results have led to the clinical implementation of induced hypothermia as the standard of care. Ongoing clinical trials will help determine the utility of induced hypothermia in a multitude of other disease states. With this increased clinical implementation and expanding treatment indications comes increased complexity related to the pharmacotherapeutic regimens employed in various patient populations.

Several preclinical and clinical studies have demonstrated that hypothermia produces significant reductions in the clearance of hepatically eliminated drugs. The magnitude of these reductions suggests that induced hypothermia produces clinically relevant increases in drug concentrations in critically ill patients. Specifically, adult patients receiving hypothermia after traumatic brain injury have been shown to have a five-fold elevation in midazolam concentrations as body temperature is reduced below 35°C.(7) A study of neonates receiving induced hypothermia after hypoxic-ischemic encephalopathy demonstrated that morphine concentrations above known toxic levels are observed more frequently in hypothermia-treated versus normothermic neonates.(8) Published preclinical studies by the University of Pittsburgh School of Pharmacy and others have demonstrated that alterations in drug elimination are partially mediated by changes in the activity of specific cytochrome P-450 enzymes during reduced body temperature.(9-11) The effects of mild hypothermia on other systems responsible for drug elimination, such as drug transporters and phase II metabolizing enzymes, are still largely unknown.

Critical care practitioners should understand that hypothermiamediated reductions in drug metabolism do not necessarily equate to alterations in drug response. The effects of hypothermic temperatures on drug receptor response also are largely unknown. In vitro studies have shown that the morphine receptor response is reduced under hypothermic temperatures,(12) suggesting that increased levels may not relate directly to increased response and toxicity. Conversely, the response to neuromuscular blockers appears to be related directly to drug concentrations without hypothermic changes in the pharmacodynamic response.(13) The net result of increased drug levels during hypothermia may or may not lead to a toxic response, depending on the agent administered. Clinicians would anticipate that hypothermia mediated changes in pharmacodynamic response would recover faster than the elevated drug levels, which take approximately five half lives to reach the new steady state concentration upon rewarming. This would suggest that the period during and shortly after rewarming could be the most likely time for drug toxicity. Research to determine specific dosage recommendations is lacking, and no dosing algorithms currently exist; the best practice is to be aware of the potential for a drug-therapy interaction both during and after induced hypothermia. This heightened awareness, which should include increased monitoring for drug levels, response and toxicity, is warranted to optimize the benefits and mitigate adverse events during and after induced hypothermia.

References:

1. Lazarou J, et al. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200-1205.

2. Rothschild JM, et al. The Critical Care Safety Study: The incidence and nature of adverse events and serious medical errors in intensive care. Crit Care Med. 2005;33:1694-1700.

3. Cullen DJ, et al. Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units. Crit Care Med. 1997;25:1289-1297.

4. U.S. Department of Health & Human Services. Drug Metabolism / Drug Interaction Studies in the Drug Development Process: Studies In Vitro.  FDA U.S. Food and Drug Administration Web site. Accessed December 15, 2009.|

5. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.

6. Bernard SA, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563.

7. Fukuoka N, et al. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia. Resuscitation. 2004;60:225-230.

8. Roka A, et al. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121:e844-849.

9. Tortorici MA, et al. Therapeutic hypothermia-induced pharmacokinetic alterations on CYP2E1 chlorzoxazone-mediated metabolism in a cardiac arrest rat model. Crit Care Med. 2006;34:785-791.

10. Tortorici MA, et al. Moderate hypothermia prevents cardiac arrest-mediated suppression of drug metabolism and induction of interleukin-6 in rats. Crit Care Med. 2009;37:263-269.

11. Tortorici MA, et al. Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med. 2007;35:2196-204.

12. Puig MM, et al. Effects of temperature on the interaction of morphine with opioid receptors. Br J Anaesth. 1987;59:1459-1464.

13. Caldwell JE, et al. Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium. Anesthesiology. 2000;92:84-93.


Disclosures:

* Author has no disclosures to report

To learn more about Induced Hypothermia, be sure to attend SCCM's Clinical Focus Conference on Hypothermia coming up in April 2010. For more information, please visit the Conference web page.