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Midazolam and fentanyl infusions are commonly used for prolonged sedation and analgesia in the pediatric intensive care setting. Tolerance and withdrawal are major concerns when these infusions are used for days or weeks. Here, we review the current approaches to prolonged pediatric sedation using midazolam and fentanyl and discuss newer strategies to avoid tolerance and withdrawal syndromes. We report the case of a pediatric burn patient who developed tolerance syndrome and a movement disorder in our institution. We also review the relevant literature and methods of minimizing tolerance and withdrawal. Prolonged sedation is often necessary in treating critically ill children, and tolerance and abstinence syndrome can complicate a successful recovery. Scoring systems can be used to minimize oversedation and to titrate effectively. “Drug cycling,” “wake-up protocols,” and weaning regimens, possibly combined with adjuvant drugs, are being implemented successfully. Such novel approaches may decrease the incidence of tolerance and withdrawal associated with prolonged sedative and analgesic use.