Refractory primary cardiac arrhythmias

Adverse drug events are a significant clinical problem with an estimated incidence rate of 6.7% in hospitalized patients, which projects to 2 million affected patients annually (1). In critically ill patients, adverse drug events are particularly problematic due to an approximate two-fold increased incidence and often life-threatening implications of these events (2, 3). In particular, adverse drug reactions with nitrates, opiates, and benzodiazepines are common in intensive care unit patients and can complicate ventilator weaning, which also increases the length of stay (4). Adverse drug events are highly problematic in critically ill children due to an inability to clinically identify such events from disease pathogenesis. Furthermore, few studies have been conducted to evaluate drug disposition and response in children. Determining optimal drug dosing through therapeutic concentration monitoring, understanding metabolic degradation/elimination, and adjusting for developmental changes in drug disposition and response are woefully understudied in critically ill children. Frequently, these relationships are inappropriately extrapolated from healthy children or adult subjects. It is well recognized that alterations in hepatic elimination by the cytochrome P450 (CYP) enzyme system are a significant contributor to adverse drug events in adults and children. The CYP3A4/5 isoforms are the major human enzymes responsible for the elimination of >60% of drugs that rely on hepatic metabolism (5), including midazolam, fentanyl, amiodarone, morphine, carbamazepine, vecuronium, and several calcium channel blockers (6, 7). Midazolam is a commonly used benzodiazepine in critically ill patients and is also a validated probe for the cytochrome P450 3A4/5 activity. Monohydroxylation of midazolam is predominantly catalyzed by the CYP3A4/5 isoforms and is required for elimination (8), thereby allowing 1-hydroxymidazolam formation to serve as a surrogate marker for CYP3A4/5 functional activity in humans (9). In addition, midazolam has a low to intermediate extraction by liver enzymes, which implies that the hepatic clearance of midazolam is predominantly dependent on CYP enzyme activity and the degree of protein binding, rather than hepatic blood flow, which is the predominant factor in the elimination of high extraction ratio drugs (10). Functional expression of the CYP3A4 isoform is down-regulated after activation of the acute phase response. The cytokine response, interleukin-6 in particular, has been implicated as a primary mechanism of decreased CYP expression in these models (11, 12). Despite the wealth of preclinical literature demonstrating CYP3A4 down-regulation during the inflammatory response, few studies have demonstrated that similar reductions in CYP3A4 activity occur in humans after infectious or critical insult. Even fewer studies exist that evaluate such alterations in critically ill children. In this issue of Pediatric Critical Care Medicine, Vet and colleagues (13) have provided insight into this understudied area of research by evaluating the effect of critical illness and inflammation on midazolam therapy in children. Previously, this group utilized the same pharmacometric modeling techniques to estimate midazolam clearance in pediatric intensive care unit patients (14). The major finding of the current study was a significant, albeit modest (r2 = .245), negative association between increased pediatric logistic organ dysfunction score and weight-adjusted or unadjusted midazolam clearance in these children. Although it is expected that multiple-organ failure would reduce the systemic clearance of midazolam, the observed reduction in midazolam clearance was not associated with either the COMFORT score or the overall dose of midazolam administered. This lack of association with dose suggests that the children with the highest pediatric logistic organ dysfunction score and the lowest clearance still required similar doses of midazolam on the basis of COMFORT scoring of behavioral and physiologic symptoms of distress. This result implies that the degree of reduced midazolam clearance did not impact the overall midazolam dosing, likely due to the greater need for pharmacologic management of these critically ill children. The study also provides potential clinical evidence of cytokine-mediated alterations in CYP3A4/5 functional activity. The data suggest that the observed reduction in clearance is mediated by a reduction in CYP3A4/5 functional activity with increasing organ dysfunction via cytokine-mediated down-regulation of CYP3A4/5 expression. Although it is possible that the reduction in clearance is mediated by reduced CYP3A4/5 activity, it is also plausible that altered protein binding and/or concomitant medications may be contributors to the observed association. One limitation of the presented study is that the concentrations of the 1-hydroxymidazolam metabolite were not assessed in either plasma or urine samples. Evaluation of the 1-hydroxymidazolam/midazolam ratio and/or the formation clearance of 1-hydroxymidazolam along with free drug concentration measurements would allow for the determination of whether the observed differences in clearance are truly due to decreases in CYP3A4/5 metabolic activity. Furthermore, future studies with larger cohorts of patients for complete covariate analyses, including assessment of cytokine levels, will better characterize the wide degree of variability in midazolam clearance observed in this patient population. Finally, the results by Vet and colleagues (13) demonstrate that there is a high degree of variance in midazolam clearance within this vulnerable patient population. Although ∼25% of the variance in midazolam clearance was explained by the pediatric logistic organ dysfunction score, much of the remaining 10- to 20-fold variance in midazolam clearance remains unexplained. Indeed, similar degrees of variance have been observed in other assessments of drug levels in critically ill children (15). The observation of decreased clearance with increasing pediatric logistic organ dysfunction score illustrates the paradox of clinical care for critically ill children. The sickest children are likely to have the poorest ability to metabolize drugs, and yet these same patients are the ones that require the greatest degree of pharmacologic intervention for survival. Striking the delicate balance between appropriate pharmacologic management without producing adverse drug events is a considerable challenge in pediatric critical care medicine and is a challenge that will not be adequately met without future, more extensive clinical research to guide such decisions. Samuel M. Poloyac, PharmD, PhD University of Pittsburgh School of Pharmacy, Pharmaceutical Sciences Pittsburgh, PA