Tortorici Michael A, Kochanek Patrick M, Poloyac Samuel M
University of Pittsburgh School of Pharmacy, Department of Pharmaceutical Sciences, Pittsburgh, PA, USA.
Crit Care Med. 2007 Sep;35(9):2196-204. doi: 10.1097/01.ccm.0000281517.97507.6e.
Therapeutic hypothermia has been shown to decrease neurologic damage in patients experiencing out-of-hospital cardiac arrest. In addition to being treated with hypothermia, critically ill patients are treated with an extensive pharmacotherapeutic regimen. The effects of hypothermia on drug disposition increase the probability for unanticipated toxicity, which could limit its putative benefit. This review examines the effects of therapeutic hypothermia on the disposition, metabolism, and response of drugs commonly used in the intensive care unit, with a focus on the cytochrome P450 enzyme system.
A MEDLINE/PubMed search from 1965 to June 2006 was conducted using the search terms hypothermia, drug metabolism, P450, critical care, cardiac arrest, traumatic brain injury, and pharmacokinetics.
Twenty-one studies were included in this review. The effects of therapeutic hypothermia on drug disposition include both the effects during cooling and the effects after rewarming on drug metabolism and response. The studies cited in this review demonstrate that the addition of mild to moderate hypothermia decreases the systemic clearance of cytochrome P450 metabolized drugs between approximately 7% and 22% per degree Celsius below 37degreesC during cooling. The addition of hypothermia decreases the potency and efficacy of certain drugs.
This review provides evidence that the therapeutic index of drugs is narrowed during hypothermia. The magnitude of these alterations indicates that intensivists must be aware of these alterations in order to maximize the therapeutic efficacy of this modality. In addition to increased clinical attention, future research efforts are essential to delineate precise dosing guidelines and mechanisms of the effect of hypothermia on drug disposition and response.
治疗性低温已被证明可减少院外心脏骤停患者的神经损伤。除接受低温治疗外，重症患者还接受广泛的药物治疗方案。低温对药物处置的影响增加了意外毒性的可能性，这可能会限制其假定的益处。本综述探讨治疗性低温对重症监护病房常用药物的处置、代谢和反应的影响，重点关注细胞色素P450酶系统。
使用搜索词“低温”、“药物代谢”、“P450”、“重症监护”、“心脏骤停”、“创伤性脑损伤”和“药代动力学”对1965年至2006年6月的MEDLINE/PubMed进行搜索。
本综述纳入了21项研究。治疗性低温对药物处置的影响包括降温期间的影响以及复温后对药物代谢和反应的影响。本综述引用的研究表明，在降温期间，每低于37摄氏度1度，轻度至中度低温会使细胞色素P450代谢药物的全身清除率降低约7%至22%。低温会降低某些药物的效力和疗效。
本综述提供的证据表明，低温期间药物的治疗指数会变窄。这些改变的程度表明，重症监护医生必须意识到这些改变，以便最大限度地提高这种治疗方式的疗效。除了增加临床关注外，未来的研究工作对于确定精确的给药指南以及低温对药物处置和反应的影响机制至关重要。
