Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest

Bjelland, Thor Wilhelm; Hjertner, Øyvind; Klepstad, Pål; Kaisen, Kjell; Dale, Ola; Haugen, Bjørn Olav

doi:10.1016/j.resuscitation.2010.07.002

Cited by 62 publications

(51 citation statements)

References 30 publications

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“…Unlike the majority of drugs administered in the ICU, clopidogrel is administered orally and depends on metabolic activation by CYP2C19 as well as other CYP450 enzymes. Bjelland et al (2010) investigated the effect of hypothermia on the clopidogrel's efficacy to inhibit platelets. In this prospective study, 25 CA patients received hypothermia (33-34°C) for 24 hours.…”

Section: Effect Of Ttm On Pharmacodynamicsmentioning

confidence: 99%

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

Anderson

Poloyac

Kochanek

et al. 2016

Therapeutic Hypothermia and Temperature Management

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Targeted temperature management (TTM) has been shown to reduce mortality and improve neurological outcomes in out-of-hospital cardiac arrest (CA) patients and in neonates with hypoxic-ischemic encephalopathy (HIE). TTM has also been associated with adverse drug events in the critically ill patient due to its effect on drug pharmacokinetics (PKs) and pharmacodynamics (PDs). We aim to evaluate the current literature on the effect of TTM on drug PKs and PDs following CA. MEDLINE/PubMed databases were searched for publications, which include the MeSH terms hypothermia, drug metabolism, drug transport, P450, critical care, cardiac arrest, hypoxic-ischemic encephalopathy, pharmacokinetics, and pharmacodynamics between July 2006 and October 2015. Twenty-three studies were included in this review. The studies demonstrate that hypothermia impacts PK parameters and increases concentrations of cytochrome-P450-metabolized drugs in the cooling and rewarming phase. Furthermore, the current data demonstrate a combined effect of CA and hypothermia on drug PK. Importantly, these effects can last greater than 4-5 days post-treatment. Limited evidence suggests hypothermia-mediated changes in the Phase II metabolism and the Phase III transport of drugs. Hypothermia also has been shown to potentially decrease the effect of specific drugs at the receptor level. Therapeutic hypothermia, as commonly deployed/applied during TTM, alters PK, and elevates concentrations of several commonly used medications. Hypothermia-mediated effects are an important factor when dosing and monitoring patients undergoing TTM treatment.

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Section: Effect Of Ttm On Pharmacodynamicsmentioning

confidence: 99%

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

Anderson

Poloyac

Kochanek

et al. 2016

Therapeutic Hypothermia and Temperature Management

View full text Add to dashboard Cite

show abstract

“…Bjelland et al showed that after therapeutic hypothermia the effect of clopidogrel is non-existent in the first day of treatment and during the third day the recovery in partial [63]. Also there is evidence that bioavailability of clopidogrel is reduced in hemodynamic unstable patients after successful cardio-pulmonary resuscitation [64].…”

Section: Mechanisms For Anti-platelet Drugs Resistance In Critically mentioning

confidence: 99%

Anti-platelet Therapy Resistance – Concept, Mechanisms and Platelet Function Tests in Intensive Care Facilities

Mărginean

Bănescu

Scridon

et al. 2016

The Journal of Critical Care Medicine

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It is well known that critically ill patients require special attention and additional consideration during their treatment and management. The multiple systems and organ dysfunctions, typical of the critical patient, often results in different patterns of enteral absorption in these patients. Anti-platelet drugs are the cornerstone in treating patients with coronary and cerebrovascular disease. Dual anti-platelet therapy with aspirin and clopidogrel is the treatment of choice in patients undergoing elective percutaneous coronary interventions and is still widely used in patients with acute coronary syndromes. However, despite the use of dual anti-platelet therapy, some patients continue to experience cardiovascular ischemic events. Recurrence of ischemic events is partly attributed to the fact that some patients have poor inhibition of platelet reactivity despite treatment. These patients are considered low-or nonresponders to therapy. The underlying mechanisms leading to resistance are not yet fully elucidated and are probably multifactorial, cellular, genetic and clinical factors being implicated. Several methods have been developed to asses platelet function and can be used to identify patients with persistent platelet reactivity, which have an increased risk of thrombosis. In this paper, the concept of anti-platelet therapy resistance, the underlying mechanisms and the methods used to identify patients with low responsiveness to anti-platelet therapy will be highlighted with a focus on aspirin and clopidogrel therapy and addressing especially critically ill patients.

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“…However, these studies were performed in vitro, in animals, children, and healthy volunteers, which are settings that limit their validity with regard to adult patients treated with TH after cardiac arrest. However, the existing evidence suggests that hypothermia can induce clinically significant PK changes that increase the risk of detrimental oversedation; thus more knowledge on drug disposition during TH is needed (Koren et al, 1987;Polderman, 2004;Pedersen et al, 2007;Tortorici et al, 2007;Bjelland et al, 2010). We have therefore explored the disposition of morphine, midazolam, fentanyl, and propofol during TH following cardiac arrest in man.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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

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Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest

Cited by 62 publications

References 30 publications

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

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

Anti-platelet Therapy Resistance – Concept, Mechanisms and Platelet Function Tests in Intensive Care Facilities

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

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