Effects of Hypothermia on the Disposition of Morphine, Midazolam, Fentanyl, and Propofol in Intensive Care Unit Patients

Abstract

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 (t 1/2 ) was significantly higher, while total clearance (CL tot ) was significantly lower (median [semiinterquartile range (s-iqr)]): t 1/2 , 266 (43) versus 168 (11) minutes, P < 0.01; CL tot , 1201 (283) versus 1687 (200) ml/min, P < 0.01. No significant differences were seen for midazolam. CL tot 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, t 1/2 of morphine was significantly higher during TH. CL tot 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

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

“…The median morphine clearance was estimated from a subset of patients with samples available at each time point [0.69 mL/(min$kg) vs. 0.89 mL/(min$kg)]; however, the hypothermic group never reached steady state preventing the calculation of a steady-state morphine Cl in this group. Bjelland et al (2013) (28) L]. Collectively, these two clinical studies in adults and neonates indicate that hypothermia decreases morphine Cl, which is likely due to a decrease in the Phase II metabolic glucuronidation pathway.…”

“…In contrast to many of the drugs discussed so far which undergo Phase I CYP450 metabolism, morphine undergoes Phase II glucuronidation. Since our previous review, two clinical studies have demonstrated an effect of hypothermia on morphine concentrations and PK (Roka et al, 2008;Bjelland et al, 2013). Roka et al (2008) found significantly higher morphine concentrations in hypothermic neonates with HIE as compared with normothermic neonates with HIE.…”

“…Hostler et al (2010) randomized six healthy volunteers to (Hostler et al, 2010). Bjelland et al (2013) investigated the effects of hypothermia on the disposition of midazolam along with several other sedatives and anesthetics (fentanyl, morphine, and propofol) in patients suffering from CA. A total of 15 CA patients who underwent hypothermic treatment to 33-34°C were enrolled in this case-control study and matched to critically ill patients in the ICU, who did not receive hypothermia (n = 8).…”

“…Based on the well-stirred model of hepatic drug clearance, the elimination of a high-clearance drug such as fentanyl should be predominately affected by changes in hepatic blood flow (Pang and Rowland, 1977). Bjelland et al (2013) reported a 45.5% decrease in the median total clearance of fentanyl in 14 CA patients versus eight case-control-matched critically-ill patients (36-38°C) [median (semi-interquartile range): 726 (230) vs. 1331 (678); p < 0.05]. In a subsequent study, Bjelland et al (2014) reported no change in fentanyl concentrations from the hypothermia to rewarming phases.…”

“…In the same study that investigated midazolam PK by Bjelland et al (2013), the authors also investigated propofol Bjelland et al (2014) investigated the concentrations of propofol during rewarming in 14 CA patients. The concentration of propofol decreased 3.1% per degree Celsius increase in body temperature (*12.4% total change in concentration from 33°C to 37°C) during rewarming.…”