Effects of Sedative Interruption in Critically Ill, Mechanically Ventilated Patients Receiving Midazolam or Propofol

• Objective: To assess the impact of daily interruption of sedative infusions on duration of mechanical ventilation and length of stay (LOS) in patients receiving either midazolam and morphine or propofol and morphine. • Design: Randomized controlled trial. • Setting and participants: 128 mechanically ventilated adult patients receiving continuous sedative infusions in a medical intensive care unit (ICU). • Methods: Patients were randomized to receive either midazolam or propofol along with morphine infusions. Half the patients in each group had their sedatives discontinued every day until they were awake, while the other half had their sedatives discontinued at the discretion of the ICU team. • Outcome measures: Primary outcomes were duration of mechanical ventilation, ICU LOS, and hospital LOS. Other measures included total dose of sedative and opiate administered, neurologic tests performed to assess unexplained mental status changes, and adverse events. • Results: Median duration of mechanical ventilation was 5.5 days in the midazolam group versus 5.6 days in the propofol group (P = 0.45). Median ICU LOS was 6.7 days in the midazolam group versus 7.1 days in the propofol group (P = 0.60). Neurologic tests were used in 18% of midazolam patients compared with 16% in the propofol group (P = 0.94). Adverse events occurred in 7.6% of the midazolam group and 3.2% of the propofol group (P = 0.49). Similar results were seen when propofol and midazolam were compared in subgroups assigned to daily sedative interruption and to interruption only at the discretion of the ICU team. • Conclusion: Daily interruption of sedative infusions is a safe and practical approach to managing mechanically ventilated patients receiving midazolam or propofol. The method of drug administration may be more important than the particular drug used for sedation in the ICU. Critically ill patients needing mechanical ventilation typically are given intravenous infusions of sedatives for pain, anxiety, and agitation. Opiates are most commonly used as analgesics, while benzodiazepines and propofol are typically used to treat anxiety and agitation. Midazolam, a short-acting benzodiazepine, and propofol have been evaluated in several clinical trials, and in the growing body of literature on sedation in the intensive care unit (ICU), they are the most commonly compared drugs in head-to-head trials [1,2]. Several authors have reported that time for recovery from sedation is shorter with propofol compared with midazolam [3–5]. Propofol’s pharmacokinetic profile has been proposed as the mechanism behind patients’ rapid clinical recovery from the drug [6]. Because propofol is lipid soluble, it has a very high volume of distribution, resulting in short-lived sedative effects as the drug is redistributed from plasma to tissue. However, the rapid recovery seen with propofol may be attenuated by concomitant opiate administration [6,7]. The increased time for recovery seen with midazolam may be explained by the drug’s pharmacokinetics, which are significantly altered in critical illness. A number of reports have described impaired midazolam metabolism in critically ill patients, with accumulation of both parent drug and active metabolites that may prolong altered mental status [8–12]. Sedatives such as midazolam and propofol are often administered to critically ill patients by continuous infusion [13–15]. However, there is increasing evidence that this practice may extend the duration of mechanical ventilation and length of stay (LOS) [15,16]. We have recently described a strategy of daily interruption of sedative infusions as a method for minimizing these adverse effects. Interrupting sedative infusions to