Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations.
Targeted temperature management (TTM) has been shown to reduce mortality and improve neurological outcomes in out-of-hospital cardiac arrest (CA) patients and in neonates with hypoxic-ischemic encephalopathy (HIE). TTM has also been associated with adverse drug events in the critically ill patient due to its effect on drug pharmacokinetics (PKs) and pharmacodynamics (PDs). We aim to evaluate the current literature on the effect of TTM on drug PKs and PDs following CA. MEDLINE/PubMed databases were searched for publications, which include the MeSH terms hypothermia, drug metabolism, drug transport, P450, critical care, cardiac arrest, hypoxic-ischemic encephalopathy, pharmacokinetics, and pharmacodynamics between July 2006 and October 2015. Twenty-three studies were included in this review. The studies demonstrate that hypothermia impacts PK parameters and increases concentrations of cytochrome-P450-metabolized drugs in the cooling and rewarming phase. Furthermore, the current data demonstrate a combined effect of CA and hypothermia on drug PK. Importantly, these effects can last greater than 4-5 days post-treatment. Limited evidence suggests hypothermia-mediated changes in the Phase II metabolism and the Phase III transport of drugs. Hypothermia also has been shown to potentially decrease the effect of specific drugs at the receptor level. Therapeutic hypothermia, as commonly deployed/applied during TTM, alters PK, and elevates concentrations of several commonly used medications. Hypothermia-mediated effects are an important factor when dosing and monitoring patients undergoing TTM treatment.
1 Department of Pharmaceutical Sciences, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania.
Kacey B
KB
Anderson
1 Department of Pharmaceutical Sciences, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania.
Samuel M
SM
Poloyac
2 Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.
Patrick M
PM
Kochanek
3 Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania.
Philip E
PE
Empey
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D001833:Body Temperature Regulation; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D006323:Heart Arrest / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007036:Hypothermia, Induced / Q000009:adverse effects / Q000379:methods*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D017694:Rewarming; D012307:Risk Factors; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D010975:Platelet Aggregation Inhibitors
cardiac arrest; drug interactions; drug metabolism; mild hypothermia; targeted temperature management