Therapeutic hypothermia (HT) is frequently used in neonates with hypoxic-ischemic encephalopathy
and young infants during cardiopulmonary bypass (CPB). Hypothermia and CPB result in physiological changes
contributing to pharmacokinetic (PK) and pharmacodynamic (PD) changes. Changes in the absorption, the volume of distribution (Vd)
and the total body clearance (CL) of drugs used during hypothermia and CPB might lead to the interindividual PK variability resulting in
either insufficient or toxic plasma concentrations and have an impact on the biodisposition and action of drugs. Both under- or overdosing
of medicines in these critically ill patients may contribute to a worse overall outcome. Overall, hypothermia decreases CL but may
decrease or increase Vd by changing intravascular blood volume, organ perfusion and enzymatic metabolic processes. In addition, maturational
as well as organ specific changes may occur during hypothermia superimposed on the underlying disease and/or procedures such
as extracorporeal membrane oxygenation (ECMO) or CPB. This paper will provide an overview of variables and potential covariates
(e.g., asphyxia, sepsis, multiorgan dysfunction syndrome, cardiac arrest) determining the PK of frequently used drugs. In addition, the effects
of hypothermia on individual drugs are described as well as alternative ways for future study designs such as the use of population
PK-PD and opportunistic sampling. Ultimately, these investigations are warranted to obtain specific dosing nomograms of medicines for
use in clinical practice and to improve the treatment results of this vulnerable group of pediatric patients.
Keywords: Hypothermia, pharmacokinetics, pharmacodynamics, pharmacogenomics, developmental pharmacology, absorption, distribution,
metabolism, and excretion, neonates, infants, covariates, asphyxia, sepsis, multiorgan dysfunction syndrome, cardiac arrest.
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