Anesthesiology
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Randomized Controlled Trial Clinical Trial
The role of cytochrome P450 3A4 in alfentanil clearance. Implications for interindividual variability in disposition and perioperative drug interactions.
There is considerable unexplained variability in alfentanil pharmacokinetics, particularly systemic clearance. Alfentanil is extensively metabolized in vivo, and thus systemic clearance depends on hepatic biotransformation. Cytochrome P450 3A4 was previously shown to be the predominant P450 isoform responsible for human liver microsomal alfentanil metabolism in vitro. This investigation tested the hypothesis that P450 3A4 is responsible for human alfentanil metabolism and clearance in vivo. ⋯ Modulation of P450 3A4 activity by rifampin and troleandomycin significantly altered alfentanil clearance and disposition. These results strongly suggest that P450 3A4 is the major isoform of P450 responsible for clinical alfentanil metabolism and clearance. This observation, combined with the known population variability in P450 3A4 activity, provides a mechanistic explanation for the interindividual variability in alfentanil disposition. Furthermore, known susceptibility of human P450 3A4 activity to induction and inhibition provides a conceptual framework for understanding and predicting clinical alfentanil drug interactions. Finally, human liver microsomal alfentanil metabolism in vitro is confirmed as an excellent model for human alfentanil metabolism in vivo.
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Randomized Controlled Trial Clinical Trial
Intracuff pressures do not predict laryngopharyngeal discomfort after use of the laryngeal mask airway.
The laryngeal mask airway (LMA) is a large foreign body that exerts pressure on the pharyngeal mucosa, which may lead to throat discomfort. To determine whether intracuff pressures are associated with such discomfort, a randomized, double-blind study was performed to determine the effect of high versus low intracuff pressures. ⋯ Differences in LMA intracuff pressures did not influence either the incidence or severity of laryngopharyngeal complaints.
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Gender-dependent differences in cytochrome P450 activity, drug metabolism, drug elimination, and their clinical consequences are increasingly apparent. P450 3A4 is the most abundant P450 isoform in the human liver and is responsible for metabolizing a vast and diverse assortment of therapeutic agents, including opioids, benzodiazepines, and local anesthetics. P450, 3A4 activity is higher in women, influenced by steroid hormone levels, and is speculated to vary during the menstrual cycle. This investigation tested the hypothesis that P450 3A4 activity varies during the menstrual cycle. Alfentanil clearance was used as a metabolic probe for P450 3A4 activity. ⋯ Alfentanil clearances were not different on menstrual cycle days 2, 13, and 21, strongly suggesting no change in P450 3A4 activity. Menstrual cycle differences in alfentanil clearances do not contribute to interindividual variability in alfentanil disposition in women. If other P450 3A4 substrates are comparable, then menstrual cycle variability in their metabolism may not be a consideration in dosing or in the design of pharmacokinetic investigations.
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Intraoperative blood pressure lability may be related to risk factors, hypovolemia, light anesthesia, and morbid outcomes, but the measurements of lability in previous studies have been limited by imprecise and infrequent data collection methods. Computerized intraoperative data acquisition systems have provided an opportunity to readdress the issue of intraoperative blood pressure lability with more abundant and precise data. This study sought to derive and validate an algorithm (expert system) to measure mean arterial pressure (MAP) lability. ⋯ One potential application of expert systems to anesthesia practice is a "smart alarm" to detect blood pressure lability. It may also provide a better tool to assess the relation between lability and outcome than has been available previously.
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Randomized Controlled Trial Multicenter Study Clinical Trial
Remifentanil versus remifentanil/midazolam for ambulatory surgery during monitored anesthesia care.
This study was designed to define the appropriate dose of remifentanil hydrochloride alone or combined with midazolam to provide satisfactory comfort and maintain adequate respiration for a monitored anesthesia care setting. ⋯ Remifentanil alone or combined with midazolam provided adequate analgesia and maintained adequate respiration at the doses reported. The low dose of remifentanil combined with 2 mg midazolam, compared with remifentanil alone, resulted in fewer side effects, slightly greater sedation, and less anxiety.