The influence of targeted temperature management on the pharmacokinetics of drugs administered during and after cardiac arrest: a systematic review

Objective: Pharmacokinetic parameters of drugs are widely investigated under normothermic conditions and normal hemodynamic parameters. The European Resuscitation Council recommends the use of targeted temperature management (TTM) with a target temperature of 34 degrees C in cardiac arrest (CA) patients. The aim of this literature review is to investigate the influence of CA combined with TTM on the pharmacokinetics of drugs. Results of preclinical and clinical studies are compared with each other. Only the most important drugs, administered during CA in emergency setting, were studied. Methods: A literature search was conducted within PubMed and Google Scholar. The search terms included 'therapeutic hypothermia', 'TTM', 'drug metabolism', 'pharmacokinetics during hypothermia', 'cardiac arrest/etiology'. In Pubmed, MeSH-terms were also included: 'myocardial infarction/therapy', 'heart arrest/complications' and 'hypothermia'. To search for preclinical studies: the search terms 'pigs' and 'swine' were used. After the primary shift of relevant findings, further articles were found through references of these (snowballing method), as well as through related articles as suggested by the databases. Results: Due to the reduced cardiac output during TTM, most of the distribution volume (V-D) of drugs included in this literature study is decreased. Only the V-D of chlorzoxazone in CA rats and midazolam in non-CA patients are significantly increased during respectively deep and mild hypothermia. The renal, hepatic and biliary clearance of drugs administered during CA/TTM/hypothermia are decreased. Discussion: The combination of a decreased V-D and a decrease in the metabolization/excretion of drugs during CA/TTM result in higher plasma concentrations compared to the plasma concentrations during CA without TTM.