Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations

Abstract

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.

Effectiveness of Antiplatelet Drugs Under Therapeutic Hypothermia: A Comprehensive Review

“…Structure of the cytochrome P450 enzyme and alteration of enzymatic function due to hypothermia. Mechanism can be listed: (i) therapeutic hypothermia can decrease the affinity of the substrates to apoprotein coat of the P450, (ii) during hypothermia drug metabolism may also be mediated via altered rate of redox reactions, and (iii) additionally, cooling process may cause alteration in nicotinamide adenine dinucleotide phosphate P450 reductase activity, cytochrome b5 activity, or the affinity of oxygen for the ferric iron, as well as changes in the lipid membrane fluidity . [Colour figure can be viewed at wileyonlinelibrary.com]…”

“…Mechanism can be listed: (i) therapeutic hypothermia can decrease the affinity of the substrates to apoprotein coat of the P450, (ii) during hypothermia drug metabolism may also be mediated via altered rate of redox reactions, and (iii) additionally, cooling process may cause alteration in nicotinamide adenine dinucleotide phosphate P450 reductase activity, cytochrome b5 activity, or the affinity of oxygen for the ferric iron, as well as changes in the lipid membrane fluidity. 41,55 [Colour figure can be viewed at wileyonlinelibrary.com] metabolism, hypothermia also affects drug excretion. Two mechanisms were put forward to explain this phenomenon-one is decreased renal blood flow leading to lower glomerular filtrating rate.…”

“…Finally, regarding all possible pathways, the interplay of TH and CA should be underlined. Anderson et al 55 concluded that CA may affect pharmacokinetics itself by attenuating specific CYP450 isoform function. As mentioned above, the third step of TH is passive rewarming.…”

Studies on long term behavioural changes in group-housed rat models of brain and spinal cord injury using an automated home cage recording system

“…Body temperature, which is infrequently studied can be a valuable indicator of homeostasis during surgery and post-operative care, could directly impact recovery from CNS injury. Furthermore, a large variability in body temperature, due to the inflammatory, cardiovascular and/or shock response, could impact drug testing outcomes (18). Therefore, regular monitoring across the light and dark phases is critical in studies involving neurotrauma models.…”

The Brain and Hypothermia—From Aristotle to Targeted Temperature Management

“…This included use in both adults and children in a variety of strategies (19-23). Relatively unique complications associated with the use of TH in TBI have included concerns with hemodynamic instability during re-warming which may be deleterious if ICP is elevated and concerns with the many drugs used to treat TBI and toxicities from them given the inhibition of cytochrome P-450-mediated drug metabolism by TH (24-26). Some have suggested the need to use isolated brain cooling to achieve benefit without side effects in TBI (27).…”