Dmd045567 214..223

Therapeutic hypothermia (TH) may induce pharmacokinetic changes that may affect the level of sedation. We have compared the disposition of morphine, midazolam, fentanyl, and propofol in TH with normothermia in man. Fourteen patients treated with TH following cardiac arrest (33–34°C) were compared with eight matched critically ill patients (36–38°C). Continuous infusions of morphine and midazolam were stopped and replaced with infusions of fentanyl and propofol to describe elimination and start of infusion pharmacokinetics, respectively. Serial serum and urine samples were collected for 6–8 hours for validated quantification and subsequent pharmacokinetic analysis. During TH, morphine elimination half-life (t1/2) was significantly higher, while total clearance (CLtot) was significantly lower (median [semiinterquartile range (s-iqr)]): t1/2, 266 (43) versus 168 (11) minutes, P < 0.01; CLtot, 1201 (283) versus 1687 (200) ml/min, P < 0.01. No significant differences were seen for midazolam. CLtot of fentanyl and propofol was significantly lower in hypothermic patients [median (s-iqr)]: fentanyl, 726 (230) versus 1331 (678) ml/min, P < 0.05; propofol, 2046 (305) versus 2665 (223) ml/min, P < 0.05. Compared with the matched, normothermic intensive care unit patients, t1/2 of morphine was significantly higher during TH. CLtot was lower during TH for morphine, fentanyl, and propofol but not for midazolam. Reducing the infusion rates of morphine, fentanyl, and propofol during TH is encouraged