Surveying sedation and analgesia practice in the pediatric intensive care unit: discomforting data raise further questions.

During the last decade, the pediatric critical care community has called for more rigorous testing of sedatives and analgesics in critically ill children, including delineation of the pharmacokinetics, pharmacodynamics, and putative adverse effects of sustained administration. Still, few studies have been conducted. Assessment of the effects of development and critical illness on drug metabolism and dosage requirements is limited. Reports of propofol’s adverse effects in mechanically ventilated children underscore the importance of pediatricspecific data (1). There is also concern that -aminobutyric-acid agonists and/or N-methyl-D-aspartate antagonists administered during synaptogenesis may adversely affect cerebral development (2). Moreover, despite routine use and years of experience with intravenous opioids, the recently reported association between morphine and adverse outcomes in premature neonates demonstrates the need for large, randomized, controlled studies in children, even for apparently routine agents (3). Understanding the current state of sedative and analgesic use in pediatric intensive care (PICU) patients is an important first step and a compelling reminder of the need for additional data. In this issue of Pediatric Critical Care Medicine, we read a report by Dr. Twite and colleagues (4) who surveyed 59 PICU fellowship directors in the United States regarding their use of sedatives, analgesics, and monitoring practices. Approximately two thirds of the 35 survey respondents reported using written sedation protocols (4). This compares with 6% reported by Marx et al. (5), 13% by Rhoney et al. (6), and 50% by Playfor et al. (7). Despite the increasing use of sedation protocols, 15–20% of PICUs do not routinely assess adequacy of sedation and analgesia using objective measures (4). The COMFORT score, the only sedation scoring tool validated in mechanically ventilated children (8), is used by only 20–48% of survey respondents (4, 7). This may reflect its inherent limitations and/or difficulty in its implementation. Additionally, approximately 30% of PICU patients are likely to receive paralytics (4), limiting the utility of objective scoring tools. Accordingly, practitioners frequently rely on changes in vital signs to monitor sedation. Unfortunately, these variables are unreliable (9). A more objective method of monitoring sedation depth is the bispectral index (BIS). BIS values are derived from processed electroencephalogram and quantify the hypnotic effects of sedatives and anesthetics. BIS correlates with COMFORT scores and discriminates between light and deep levels of sedation (10, 11). Although 20% of survey respondents reported using the BIS monitor (4), it is difficult to determine whether this reflects intermittent or routine use. The role of BIS deserves more study, particularly since BIS monitoring is hindered by motion artifact, poor correlation with fine gradations of sedation (10, 11), and inadequate evaluation of analgesia (12). Additional objective, validated monitoring tools are needed to guide titration of sedatives and analgesics in critically ill children. Dr. Twite and colleagues (4) report that the most commonly used sedatives and analgesics are midazolam, lorazepam, morphine, and fentanyl. Two thirds of survey respondents use continuous infusions (4). Although continuous infusions may maintain a more constant level of sedation and analgesia than intermittent dosing, significant accumulation (13, 14) and rapid development of tolerance and dependence (15, 16) may occur. Recent pharmacokinetic studies of midazolam and lorazepam have improved our understanding of the variability inherent in critically ill children and the effects of covariates such as renal failure, hepatic failure, and concomitant administration of CYP3A inhibitors (17, 18). Still, development of tolerance and dependence in critically ill children is poorly understood. Establishment of useful guidelines for sedation and analgesia will require a better understanding of developmental changes in the pharmacokinetics of sustained administration and more precise pharmacodynamic and tolerance data. Perhaps the most concerning findings reported by Dr. Twite and colleagues (4) are the adverse events. Almost all (94%) survey respondents reported symptoms of withdrawal in their patients (4); however, this proportion does not delineate the incidence of withdrawal in critically ill children. Despite increased awareness and avoidance measures, withdrawal clearly remains a significant problem. A better understanding of the risk factors for withdrawal and its prevention is needed. Additionally, survey respondents frequently reported movement disorders in their patients. Choreoathetoid movements have been associated with midazolam and fentanyl infusions in critically ill children (19, 20). The etiology of these movement disorders remains unclear but may be related to withdrawal. Although the incidence of movement disorders is unknown, two thirds of survey respondents reported seeing at least one case in 2002 (4). Less than 50% reported resolution of symptoms (4); however, the follow-up period is not specified. Resolution may take several months (20), and PICU physicians may not witness delayed recoveries. Studies are needed to determine the risk factors and incidence of long-term sequelae associated with sustained sedation and analgesia. Last, the effect of sedative and analgesic regimens on intensive care unit outcomes has been a current focus of study. In adults, daily interruption of sedative and analgesic infusions reduces the duration of mechanical ventilation, intensive care and hospital lengths of stay, and adverse recall of intensive care unit expe*See also p. 521.