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1.
Drug Metab Dispos ; 41(1): 214-23, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23115086

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 [semi-interquartile 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.


Subject(s)
Fentanyl/pharmacokinetics , Hypothermia, Induced , Intensive Care Units , Midazolam/pharmacokinetics , Morphine/pharmacokinetics , Propofol/pharmacokinetics , Aged , Case-Control Studies , Female , Fentanyl/blood , Fentanyl/urine , Half-Life , Heart Arrest/therapy , Humans , Limit of Detection , Male , Midazolam/blood , Midazolam/urine , Middle Aged , Morphine/blood , Morphine/urine , Propofol/blood , Propofol/urine , Prospective Studies
2.
Resuscitation ; 81(12): 1627-31, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20727659

ABSTRACT

BACKGROUND: The platelet inhibitor clopidogrel is administered to patients treated with therapeutic hypothermia following cardiac arrest due to acute coronary syndromes. Interactions with proton pump inhibitors and genetics are factors with a known potential to attenuate the platelet inhibition of clopidogrel. In patients treated with therapeutic hypothermia, reduced gastrointestinal function and hypothermia may also reduce the effect of clopidogrel. To investigate the net platelet inhibition of clopidogrel, we have measured the platelet reactivity index in patients treated with therapeutic hypothermia. METHODS AND RESULTS: Twenty-five Caucasian patients treated with clopidogrel and therapeutic hypothermia were prospectively included. Therapeutic hypothermia was defined as 33-34°C and delivered for 24h. Clopidogrel loading doses (300-600 mg) were administered enterally the day of admission and followed by 75 mg daily. Blood samples were collected on day 1 (n=25) and day 3 (n=16). The samples were analysed for inhibition by clopidogrel with a vasodilator stimulated phosphoprotein phosphorylation kit. On day 1 and day 3, platelet reactivity index was 0.77±0.09 and 0.57±0.16, respectively. The number of patients with a satisfactory antiplatelet effect (defined as platelet reactivity index <0.5) were 0 (0%) and 5 (31%), respectively. CONCLUSION: In patients treated with therapeutic hypothermia after cardiac arrest, the effect of clopidogrel on platelets was virtually nonexistent on day 1 after administration, with some improvement on day 3.


Subject(s)
Heart Arrest/therapy , Hypothermia, Induced , Platelet Aggregation Inhibitors/pharmacology , Ticlopidine/analogs & derivatives , Acute Coronary Syndrome/complications , Clopidogrel , Female , Humans , Male , Middle Aged , Prospective Studies , Ticlopidine/pharmacology
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