The Changing Landscape of ICU Sedation

INTUBATION AND MECHANICAL VENTILATION ARE ESSENtial components of modern intensive care. However, they are also uncomfortable and often intolerable for the patient. Therefore, intensive care clinicians typically prescribe sedation for ventilated patients, hoping to ensure comfort and yet avoid excess or prolonged unconsciousness. Two decades ago, the typical approach was to provide sedation via continuous infusion, with a focus on ensuring comfort and with little awareness of the adverse effects of excessive sedative use in the intensive care unit (ICU). However, as reports emerged showing such infusions could unnecessarily prolong the duration of mechanical ventilation and intensive care, a variety of evidence-based sedation algorithms for mechanically ventilated patients evolved. Nursing-directed drug titration algorithms and daily sedation interruption (“sedation holiday”) are 2 common strategies currently used. Compared with traditional usual care, both of these strategies reduce the duration of mechanical ventilation and length of stay in the ICU and hospital. However, the 2 strategies are quite different from each other and it is unclear which is better. Two small studies reported divergent results, with one favoring daily sedative interruption and the other favoring algorithmic titration by bedside nurses. In this issue of JAMA, Mehta and colleagues present the results of a large multicenter clinical trial conducted among critically ill patients receiving mechanical ventilation in 16 tertiary care medical and surgical ICUs in Canada and the United States. The authors compared protocolized sedation (209 patients) vs protocolized sedation plus daily sedation interruption (214 patients) and used benzodiazepines (midazolam or lorazepam) for sedation and opiates (fentanyl, morphine, or hydromorphone) for analgesia. There were no significant differences between the protocolized sedation and the protocolized sedation plus daily interruption groups in time to extubation (median, 7 days) or length of ICU stay (median, 10 days) or hospital stay (median, 20 days). In addition, there were no differences in the rates of unintentional removal of medical devices, ICU delirium, diagnostic neuroimaging, or tracheostomy. Patients randomized to daily sedation interruption received more midazolam and fentanyl and had higher perceived nurse (although not respiratory therapist) workload scores. This study was conducted by experienced ICU clinical investigators in a large, multicenter format. The study design was methodologically sound, with the potential for relatively widespread applicability. Interpretation of the results of this trial requires consideration of several interrelated issues. First, the rapidly changing critical care evidence base can influence interpretation and relevance of trial results, particularly large trials that may take years to design and complete. This trial began enrolling patients in January 2008. At the time the trial was designed (presumably 2007 or earlier), the use of benzodiazepines for ICU sedation was common. The Society of Critical Care Medicine (SCCM) Sedative and Analgesia Guidelines from 2002 recommended benzodiazepines (lorazepam) for sedation of most patients; however, more recent evidence suggests that benzodiazepines may not be the optimal agents for ICU sedation. The updated 2012 Evidence-Based SCCM Guidelines for the Management of Pain, Agitation and Delirium will be published later this year. An overview of these guidelines presented at the 2012 SCCM Congress meeting included a recommendation that non-benzodiazepine sedatives (eg, propofol or dexmedetomidine) are preferable to benzodiazepines (eg, midazolam or lorazepam). Second, in the first trial of daily sedation interruption in 2000, the average daily dose for patients randomized to midazolam was 47 mg in the sedation interruption group vs 58 mg in the control group (P=.05). In contrast, in the current trial, these average daily doses were 102 mg vs 82 mg, respectively (P=.04). This is important because the average daily dose of 102 mg of midazolam for the sedation interruption group was more than twice that recorded in the original trial. In addition, the group assigned to daily sedative interruption in the current trial received significantly more midazolam than the control group did. Given the propensity for midazolam to accumulate in ICU patients receiving prolonged administration, it is possible that such higher midazolam doses may have offset the effects of sedation interruption.

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