CHICAGO--Letting critically ill patients on a ventilator "wake up" each day by interrupting their sedative infusions appears to decrease the duration of mechanical ventilation and length of stay in the intensive care unit (ICU). "The effect is really quite dramatic," said Jesse B. Hall, MD, a professor in the section of pulmonary and critical care at the University of Chicago and one of the authors of the study. "In a randomized controlled trial, this intervention reduced ventilator time by more than two days and ICU time by more than three days."[1]

Critically ill, mechanically ventilated patients usually receive continuous sedative infusions for agitation, anxiety, or discomfort. However, continuous sedative infusion has been shown to be an independent predictor of a prolonged need for mechanical ventilation and an increased duration of ICU and hospital stay.[2] It also makes it difficult for the physician to perform and interpret physical and neurologic examinations and to recognize mental status changes. The present study suggests that daily interruption of sedative infusions provides adequate sedation while minimizing these adverse effects.

HOW PATIENTS WERE AWAKENED

The study included 128 mechanically ventilated adults who were receiving sedative infusions. The most common causes of critical illness were acute respiratory distress syndrome, pulmonary edema, chronic obstructive pulmonary disease, ventilatory failure, and sepsis.

Patients were randomized to one of two sedation strategies: daily interruption of sedative infusions starting 48 hours after study entry (the intervention group) or continuous sedative infusion with interruption only at the ICU team's discretion (the control group). Within each group, patients were randomized to propofol or midazolam. In all cases, sedation was accompanied by morphine infusion for analgesia. Nurses adjusted sedative doses as needed to achieve a 3 or 4 on the Ramsay sedation scale--meaning that the patients either were drowsy but responded to commands or were asleep but responded to stimuli quickly.[3]

In the intervention group, an investigator stopped the sedative and morphine infusions each day until the patients were awake or became uncomfortable or agitated enough that the infusions had to be resumed. To be considered awake, patients had to be able to do at least three of the following tasks on request: open their eyes, follow an investigator with their eyes, squeeze a hand, and stick out their tongue.

SURPRISING FINDINGS

"We were surprised that daily interruption of sedative infusions had such a large impact," Dr. Hall told PULMONARY REVIEWS. The intervention group, he reported, needed mechanical ventilation for a median of only 4.9 days, as compared with 7.3 days in the control group. The median length of ICU stay was 6.4 days in the intervention group versus 9.9 days in the control group. Both of these differences were statistically significant. However, the difference in total hospital stay--13.3 and 16.9 days, respectively--did not reach significance.

As expected, the proportion of days that the patients had been awake at any time was markedly higher in the intervention group than in the control group (85.5% vs 9%). Therefore, since patients with interrupted sedation were usually awake at some point during the day, the investigators were better able to perform daily neurologic examinations. This led to a reduced need for brain scans, lumbar punctures, and other diagnostic tests used to detect new neurologic injury.

Daily sedative interruption also reduced the total sedative dose among midazolam recipients by almost 50%. There was no such reduction among those given propofol, however, probably because plasma propofol concentrations drop very quickly when infusions are stopped. As a result, propofol recipients did not spend a significant amount of time off the drug (mean daily sedation, 22.8 hours vs 18.7 hours for midazolam recipients).

Only seven patients in the intervention group never woke up during their ICU stay, as compared with 15 patients in the control group. "Of these patients, six in the intervention group and 13 in the control group died in a coma; the others were transferred to facilities equipped to provide long-term ventilation," the study authors noted.

No significant differences emerged between the two groups in rates of other adverse events. These adverse events, which included patients removing central venous catheters, the need for neuromuscular blockade, and patients dislodging their endotracheal tubes, were uncommon. In-hospital mortality rates were also similar (36% in the intervention group and 46.7% in the control group).

"There was a very strong trend nearly reaching significance toward more patients in the intervention group going home," noted Dr. Hall. Fifty-nine percent of the intervention group, versus 40% of the control group, were discharged to their homes.

A WAKE-UP CALL

"We can thank [these authors] for a superb study," noted John E. Heffner, MD, in an accompanying editorial.[4] However, "this investigation may represent not so much a call for daily wake-ups of patients undergoing mechanical ventilation as a wake-up call for practitioners in the intensive care unit to examine practices of sedation more critically."

Physicians need to better ensure the use of the lowest effective sedative doses for the shortest possible time in critically ill patients on mechanical ventilation, explained Dr. Heffner, associate dean and professor of medicine at the Medical University of South Carolina in Charleston. Appropriate dosing throughout the ICU stay may prevent the need to suddenly discontinue sedative infusions, he suggested.

"Although the incidence of patients' removal of their own endotracheal tubes or central venous catheters did not increase [with sedative interruption], the authors emphasized the low power of their study for assessing safety," added Dr. Heffner. In fact, the study failed to evaluate several important adverse events. These included the cardiovascular effects and possible psychological distress to patients that daily awakenings may cause.

However, Dr. Heffner applauds this study as an important step toward understanding the proper use of sedation in the ICU--an area, he notes, for which few hard data exist.

--Timothy Begany

References
1. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342:1471-1477.
2. Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114:541-548.
3. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ. 1974;2:656-659.
4. Heffner JE. A wake-up call in the intensive care unit. [editorial] N Engl J Med. 2000;342:1520-1522.

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