Effect of Hypothermia Physiology on Drug Metabolism and Toxicity in Forensic Cases: A Narrative Scoping Review and Interpretive Framework

Abstract

Background: Background: Hypothermia is a clinically and forensically important physiological state in which reduced core body temperature alters cardiovascular function, hepatic enzyme activity, renal clearance, tissue perfusion, protein binding, and central nervous system responsiveness. In forensic cases, these changes may modify both the actual toxicity of drugs during life and the interpretation of postmortem drug concentrations after death. Aim: To evaluate the effect of hypothermia physiology on drug metabolism, drug toxicity, and postmortem toxicological interpretation in forensic cases, with emphasis on mechanisms relevant to alcohol, sedatives, opioids, antidepressants, antipsychotics, cardiovascular drugs, and polypharmacy. Methodology: A narrative scoping review was conducted using published literature from forensic toxicology, clinical pharmacokinetics, targeted temperature management, accidental hypothermia, postmortem redistribution, and drug-related death interpretation. Evidence was synthesized into mechanistic domains: absorption, distribution, metabolism, excretion, pharmacodynamic sensitivity, postmortem redistribution, and forensic interpretation. The results are presented as seven structured tables with interpretive inferences. Results: Hypothermia reduces hepatic enzymatic metabolism, particularly temperature-dependent cytochrome P450-mediated biotransformation; decreases hepatic and renal blood flow; delays gastrointestinal absorption; alters protein binding and tissue distribution; and increases pharmacodynamic vulnerability to central nervous system and respiratory depressants. These effects are especially important for opioids, benzodiazepines, sedative-hypnotics, antidepressants, antipsychotics, ethanol, and drugs with narrow therapeutic indices. Postmortem interpretation is complicated by redistribution, sampling-site variability, impaired premortem metabolism, delayed clearance, decomposition, and overlap between hypothermia biomarkers and drug or ethanol effects. Conclusion: Hypothermia should be considered an active modifier of drug toxicity rather than a passive background condition. In forensic cases, a drug concentration that appears therapeutic or borderline toxic under normothermic assumptions may become lethal in the presence of hypothermia-induced metabolic suppression, impaired clearance, altered consciousness, and respiratory depression. Interpretation should integrate scene findings, core-temperature history where available, autopsy findings, vitreous biochemistry, peripheral blood toxicology, drug class, tolerance, comorbidity, and postmortem interval.