Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin

Warfarin (Coumadin) is a potent drug that when used judiciously and monitored closely, leads to substantial reductions in morbidity and mortality from thromboembolic events. However, even with careful monitoring, initiation of warfarin dosing is associated with highly variable responses between individuals and challenges achieving and maintaining levels within the narrow therapeutic range that can lead to adverse drug events. Variants of two genes, CYP2C9 and VKORC1, account for 30 -50% of the variability in dosing of warfarin; thus, many believe that testing of these genes will aid in warfarin dosing recommendations. Evidence about this test is evolving rapidly, as is its translation into clinical practice. In an effort to address this situation, a multidisciplinary expert group was organized in November 2006 to evaluate the role of CYP2C9 and VKORC1 testing in altering warfarin-related therapeutic goals and reduction of adverse drug events. A recently completed Rapid-ACCE (Analytical, Clinical Validity, Clinical Utility, and Ethical, Legal, and Social Implications) Review, commissioned to inform this work group, was the foundation for this analysis. From this effort, specific recommendations for the appropriate use of CYP2C9 and VKORC1 testing were developed and are presented here. The group determined that the analytical validity of these tests has been met, and there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin. However, there is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients. Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing. Although the routine use of warfarin genotyping is not endorsed by this work group at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful, and warranted, in There is perhaps no drug whose therapeutic range is functionally as narrow as that of warfarin. Warfarin has a very large marketplace with over 30 million prescriptions in the United States in 2004, including up to a million new patients initiated on therapy each year. Although effective in reducing thrombotic events, warfarin's use is associated with 800 reports to the From th

Brain resuscitation in the drowning victim

Item does not contain fulltextDrowning is a leading cause of accidental death. Survivors may sustain severe neurologic morbidity. There is negligible research specific to brain injury in drowning making current clinical management non-specific to this disorder. This review represents an evidence-based consensus effort to provide recommendations for management and investigation of the drowning victim. Epidemiology, brain-oriented prehospital and intensive care, therapeutic hypothermia, neuroimaging/monitoring, biomarkers, and neuroresuscitative pharmacology are addressed. When cardiac arrest is present, chest compressions with rescue breathing are recommended due to the asphyxial insult. In the comatose patient with restoration of spontaneous circulation, hypoxemia and hyperoxemia should be avoided, hyperthermia treated, and induced hypothermia (32-34 degrees C) considered. Arterial hypotension/hypertension should be recognized and treated. Prevent hypoglycemia and treat hyperglycemia. Treat clinical seizures and consider treating non-convulsive status epilepticus. Serial neurologic examinations should be provided. Brain imaging and serial biomarker measurement may aid prognostication. Continuous electroencephalography and N20 somatosensory evoked potential monitoring may be considered. Serial biomarker measurement (e.g., neuron specific enolase) may aid prognostication. There is insufficient evidence to recommend use of any specific brain-oriented neuroresuscitative pharmacologic therapy other than that required to restore and maintain normal physiology. Following initial stabilization, victims should be transferred to centers with expertise in age-specific post-resuscitation neurocritical care. Care should be documented, reviewed, and quality improvement assessment performed. Preclinical research should focus on models of asphyxial cardiac arrest. Clinical research should focus on improved cardiopulmonary resuscitation, re-oxygenation/reperfusion strategies, therapeutic hypothermia, neuroprotection, neurorehabilitation, and consideration of drowning in advances made in treatment of other central nervous system disorders