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Understanding pharmacoeconomic evaluation can empower clinicians to be stronger decision makers. However, cost-effectiveness analyses (CEAs) in critical care are sometimes not easy to understand and often not placed in context with other interventions. The purpose of this article is to clarify and simplify the CEA process using examples from critical care and severe sepsis. First discussed is cost-effectiveness as a framework for clinical decision making and how it compares to other types of economic evaluations. Then important considerations when conducting or reviewing CEAs are explored, such as perspective, discounting, sensitivity analysis, and grading of CEAs, as well as shortcomings and resistance to using CEAs. Next, applications of CEA in critical care and severe sepsis are reviewed. Included is the Food and Drug Administration-approved drug for severe sepsis, drotrecogin alfa (activated), as an example of a recently new critical care intervention that resulted in significant interest in understanding cost-effectiveness. Finally, CEAs of other medical and nonmedical interventions are placed in context with CEAs from critical care. Understanding pharmacoeconomic evaluation can empower clinicians to be stronger decision makers. CEAs provide decision makers a quantitative measure of the value of therapeutic options that can guide clinicians toward balancing the cost burdens of therapy with their profound effects and choosing between options that compete for funding.