In this randomized controlled trial of mechanically ventilated medical ICU patients, patients managed with a wake up and breathe protocol, which paired daily spontaneous awakening trials (i.e., interruption of sedatives) with spontaneous breathing trials, experienced similar long-term cognitive, psychological, functional, and quality-of-life outcomes as those managed with usual care. Additionally, patients in the intervention group were less likely to report significant functional decline 1 year after ICU discharge than patients in the control group. Our results, along with those of a recent randomized trial of light versus deep sedation (32
), challenge the suspicion that decreasing sedation—even temporarily each morning—might be harmful to patients' long-term psychological and overall well-being. This concern likely fuels resistance to daily interruption of sedation and drives the common global practice of heavy and prolonged sedation in the ICU. In light of the previously published benefits of the wake up and breathe protocol, including a 14% absolute survival advantage and 4-day reductions in ICU and hospital lengths of stay (8
), our study's findings should usher in a new approach to the management of mechanically ventilated patients.
Cognitive impairment was pervasive among survivors in our trial, affecting 79% and 71% of patients able to undergo testing at 3- and 12-month follow-up, respectively. Symptoms of depression and PTSD, impaired functional status, and reduced quality of life were also common, although not as prevalent as cognitive impairment. These results are consistent with previous research showing that survivors of critical illness are at high risk for long-term cognitive, psychological, and functional disability (13
). To date, at least a dozen prospective cohort publications have assessed cognitive and/or psychological outcomes in patients who survived critical illness managed in medical, surgical, or trauma ICUs (35
). The prevalence of cognitive impairment reported in these studies has varied considerably, with deficits observed in 20 to 75% of patients up to a year or more after discharge. The rates of impairment observed in the ABC Trial are in the upper end of these ranges, possibly due to the advanced age of many patients included in this investigation. Whereas earlier studies included populations with average ages between 45 and 55 years, the median age among patients enrolled in the long-term component of the ABC Trial was 66 years, with one-quarter of these patients 75 years of age or older. Although not yet shown in ICU cohorts, human and animal studies suggest that advanced age is a risk factor for cognitive impairment after traumatic brain injury, coronary artery bypass graft surgery, and hypoxemia for a variety of reasons, including decreased cognitive or brain reserve (48
). Based on the Short IQCODE, only 10% of our patients had preexisting cognitive impairment, implying that the high prevalence of cognitive impairment during follow-up is due to development of an ICU-acquired cognitive insult. Our conservative definition of cognitive impairment—designed to ensure that patients classified with long-term cognitive impairment had clinically significant deficits—required a degree of cognitive deficits that would be detectable to patients in their daily life as well as to their surrogates. These effects may be amplified for those patients with concomitant depression or PTSD.
Notable strengths of our trial include a randomized study design, the breadth of outcomes assessed, higher follow-up rates than those achieved in earlier similar studies, and blinding of the investigator who conducted all follow-up evaluations. Randomization in a clinical trial facilitates equal distribution of potential confounders, both measured and unmeasured. Thus, potential confounding of the trial results due to preexisting cognitive impairment—which was balanced between treatment groups, according to a validated surrogate instrument—should be reduced through appropriate randomization. Similar to the comprehensive methods used in some cardiac bypass surgery and stroke trials (48
), the cognitive battery used in our trial tested a broad range of cognitive domains. Individual instruments in the battery were selected because they are psychometrically robust and yet tolerable to patients, giving the battery a balance of methodological rigor and feasibility (54
Because the wake up and breathe protocol reduced the likelihood of death, which was a common outcome in this critical care trial, our analyses of outcomes among patients tested could be significantly confounded by the differential mortality in the two groups. If risk factors for death (e.g., older age and ICU delirium) also increased the risk of long-term cognitive impairment, patients who might have died if not managed with the intervention were likely at high risk for poor cognitive outcomes; the survival benefit increased the number of such patients in the intervention group, potentially biasing the trial toward the null and against our finding improved cognitive outcomes in the intervention group. Other limitations include the single-center design (which limits generalizability to populations similar to those we enrolled and reduces sample size), incomplete follow-up, the use of self-report questionnaires for some outcomes rather than formal diagnostic instruments (which were too time-consuming to administer to patients who also completed an extensive battery of cognitive tests), and our inability to directly assess premorbid cognitive or psychological function. In studies of ICU survivors, investigators have used the Posttraumatic Stress Scale-10 more often than any other measurement of PTSD symptoms (33
), but this self-report questionnaire was based on the PTSD criteria outlined in the now-outdated third edition of the Diagnostic and Statistical Manual of Mental Disorders
) rather than the more expansive criteria included in the current DSM-IV-TR (56
). As with most critical care trials, patients could not be identified before their acute critical illness and thus could not be directly assessed for preexisting cognitive or psychological dysfunction. Thus, a surrogate questionnaire rather than direct testing was used to assess for baseline cognitive impairment according to previously published ICU methodology (54
). The results of the validated Short IQCODE questionnaire (16
) indicate that baseline cognitive impairment was evenly distributed between treatment groups, as would be expected in a randomized trial. Unfortunately, no comparable surrogate-based method exists to reliably assess for preexisting depression or PTSD. Finally, the current study was not powered to prove differences or equivalence for some outcomes; sample size was based on estimated improvements in short-term outcomes, and no power calculations were performed regarding potential effects on the long-term outcomes presented herein. Nevertheless, the results do not allude to any long-term harm associated with the intervention, and a very large trial would be needed to demonstrate noninferiority for any psychological outcomes, one that would likely be deemed unethical as patients in the control group would be exposed to increased risk for worse in-hospital outcomes as well as for death (8
In conclusion, our trial found that, compared with usual care sedation and ventilation weaning practices, a wake up and breathe protocol that pairs daily spontaneous awakening trials (i.e., interruption of sedatives) with spontaneous breathing trials for the management of mechanically ventilated medical ICU patients resulted in similar cognitive, psychological, functional, and quality-of-life outcomes among patients tested 3 and 12 months after their ICU stay. Despite widespread concerns regarding the potential long-term risks of interrupting or reducing sedation in the ICU, the wake up and breathe approach results in improved short- and long-term outcomes and does not increase the risk of adverse cognitive, psychological, or other outcomes.