Therapeutic hypothermia, now more commonly referred to as targeted temperature management, has been shown to decrease the clearance of hepatically metabolized drugs, which puts the patient at an elevated risk to reach super/supra-therapeutic drug concentrations.(1) Empey et al demonstrated that the maximum capacity of phenytoin metabolism was decreased by approximately 50% in children with traumatic brain injury who were cooled versus those not cooled. These effects were seen four to five days following the end of the rewarming period.(2) Bjelland et al reported that the clearance of fentanyl was decreased by 45.5% during the hypothermic phase in cardiac arrest patients, which led to an increase in plasma fentanyl concentrations.(3) No subsequent decrease in these concentrations was seen after temperature recovery, which was attributed to the long half-life of fentanyl in relation to the short rewarming period.(4) Further, Hostler et al reported an 11.1% decrease in the systemic clearance of midazolam per degree Celsius in healthy volunteers.(5)
Overall, these effects on hepatic drug elimination approximated an 11% decrease in systemic clearance for 1°C change in body temperature.(5,6) Recent clinical and preclinical studies have verified these findings in mild hypothermia, although earlier investigations had suggested a much greater change. A discrepancy in the results of hypothermia-mediated effects can largely be attributed to changes in the hypothermia protocols. Many initial estimates were based on studies that cooled patients well below the clinically optimal temperature range and for much longer or shorter cooling periods. As guidelines have evolved to reflect the optimal benefit-to-risk ratio for active cooling, pharmacometric analysis has become more robust, using a population pharmacokinetic approach to evaluate the impact of temperature versus other potential covariates (e.g., disease severity) contributing to changes in drug disposition.
Another important observation in these studies is the effect of critical care injuries on metabolism. Studies have demonstrated that critical care injuries lead to alterations in drug metabolism and disposition.(7-9) Preclinical work in our lab has further demonstrated a combined effect of injury and hypothermia on drug pharmacokinetics and, in some cases, injury may be the predominant driver in pharmacokinetic changes.(10) Evidence of a combined injury and temperature effect on drug pharmacokinetics can be seen in a number of clinical studies where pharmacometric analysis failed to demonstrate a temperature-mediated change on drug clearance, but a decrease in clearance was still seen when results were compared to those in uninjured subjects. For example, pharmacometric analysis could not identify any (clinically relevant) effect of moderate therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates; however, a decrease in clearance was observed when results were compared to literature values of non-asphyxiated neonates.(11) Most hypothermia studies demonstrate a combined effect of injury and cooling on drug pharmacokinetics; therefore, future studies should focus on determining which factor is predominately driving changes in pharmacokinetics.
Current data suggest that both liver ischemia and targeted temperature management decrease hepatic metabolism in a cytochrome P-450 isoform-specific/drug-specific manner. The magnitude of the change in metabolism will likely be most important for drugs with long half-lives and narrow therapeutic windows. In particular, the prolonged duration of action of sedatives and hypnotics should be considered when evaluating neurological function after insult. Furthermore, specific drugs that require enzymatic activation (such as clopidogrel) and other pharmacokinetic processes (such as drug transport) are important areas for study.
1. Tortorici MA, Kochanek PM, Poloyac SM. 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(9):2196-2204.
2. Empey PE, de Mendizabal NV, Bell MJ, et al. Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury. Crit Care Med. 2013;41(10):2379-2387.
3. Bjelland TW, Klepstad P, Haugen BO, Nilsen T, Dale O. Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients. Drug Metab Dispos. 2013;41(1):214-223.
4. Bjelland TW, Klepstad P, Haugen BO, Nilsen T, Salvesen O, Dale O. Concentrations of remifentanil, propofol, fentanyl, and midazolam during rewarming from therapeutic hypothermia. Acta Anaesth Scand. 2014;58(6):709-715.
5. Hostler D, Zhou J, Tortorici MA, et al. Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. Drug Metab Dispos. 2010;38(5):781-788.
6. Caldwell JE, Heier T, Wright PM, et al. Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium. Anesthesiology. 2000;92(1):84-93.
7. Kalsotra A, Zhao J, Anakk S, Dash PK, Strobel HW. Brain trauma leads to enhanced lung inflammation and injury: evidence for role of P4504Fs in resolution. J Cereb Blood Flow Metab. 2007;27(5):963-974.
8. Toler SM, Young AB, McClain CJ, Shedlofsky SI, Bandyopadhyay AM, Blouin RA. Head injury and cytochrome P-450 enzymes. Differential effect on mRNA and protein expression in the Fischer-344 rat. Drug Metab Dispos. 1993;21(6):1064-1069.
9. Poloyac SM, Perez A, Blouin RA. Tissue specific alterations in the 6-hydroxylation of chlorzoxazone following traumatic brain injury in the rat. Drug Metab Dispos. 2000;29(3):296-298.
10. Zhou J, Empey PE, Bies RR, Kochanek PM, Poloyac SM. Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome P450 drug metabolism. Drug Metab Dispos. 2011;39(12):2209-2218.
11. van den Broek MP, Groenendaal F, Toet MC, et al. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin Pharmacokinet. 2012;51(10):671-679.