Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

A Systematic Review of Risk Factors for Sleep Disruption in Critically Ill Adults.

OBJECTIVES: Numerous risk factors for sleep disruption in critically ill adults have been described. We performed a systematic review of all risk factors associated with sleep disruption in the ICU setting. DATA SOURCES: PubMed, EMBASE, CINAHL, Web of Science, Cochrane Central Register for Controlled Trials, and Cochrane Database of Systematic Reviews. STUDY SELECTION: English-language studies of any design published between 1990 and April 2018 that evaluated sleep in greater than or equal to 10 critically ill adults (> 18 yr old) and investigated greater than or equal to 1 potential risk factor for sleep disruption during ICU stay. We assessed study quality using Newcastle-Ottawa Scale or Cochrane Risk of Bias tool. DATA EXTRACTION: We abstracted all data independently and in duplicate. Potential ICU sleep disruption risk factors were categorized into three categories based on how data were reported: 1) patient-reported reasons for sleep disruption, 2) patient-reported ratings of potential factors affecting sleep quality, and 3) studies reporting a statistical or temporal association between potential risk factors and disrupted sleep. DATA SYNTHESIS: Of 5,148 citations, we included 62 studies. Pain, discomfort, anxiety/fear, noise, light, and ICU care-related activities are the most common and widely studied patient-reported factors causing sleep disruption. Patients rated noise and light as the most sleep-disruptive factors. Higher number of comorbidities, poor home sleep quality, home sleep aid use, and delirium were factors associated with sleep disruption identified in available studies. CONCLUSIONS: This systematic review summarizes all premorbid, illness-related, and ICU-related factors associated with sleep disruption in the ICU. These findings will inform sleep promotion efforts in the ICU and guide further research in this field.

Methodologic Innovation in Creating Clinical Practice Guidelines: Insights From the 2018 Society of Critical Care Medicine Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption Guideline Effort.

OBJECTIVES: To describe novel guideline development strategies created and implemented as part of the Society of Critical Care Medicine's 2018 clinical practice guidelines for pain, agitation (sedation), delirium, immobility (rehabilitation/mobility), and sleep (disruption) in critically ill adults. DESIGN: We involved critical illness survivors from start to finish, used and expanded upon Grading of Recommendations, Assessment, Development and Evaluation methodology for making recommendations, identified evidence gaps, and developed communication strategies to mitigate challenges. SETTING/SUBJECTS: Thirty-two experts from five countries, across five topic-specific sections; four methodologists, two medical librarians, four critical illness survivors, and two Society of Critical Care Medicine support staff. INTERVENTIONS: Unique approaches included the following: 1) critical illness survivor involvement to help ensure patient-centered questions and recommendations; 2) qualitative and semiquantitative approaches for developing descriptive statements; 3) operationalizing a three-step approach to generating final recommendations; and 4) systematic identification of evidence gaps. MEASUREMENTS AND MAIN RESULTS: Critical illness survivors contributed to prioritizing topics, questions, and outcomes, evidence interpretation, recommendation formulation, and article review to ensure that their values and preferences were considered in the guidelines. Qualitative and semiquantitative approaches supported formulating descriptive statements using comprehensive literature reviews, summaries, and large-group discussion. Experts (including the methodologists and guideline chairs) developed and refined guideline recommendations through monthly topic-specific section conference calls. Recommendations were precirculated to all members, presented to, and vetted by, most members at a live meeting. Final electronic voting provided links to all forest plots, evidence summaries, and "evidence to decision" frameworks. Written comments during voting captured dissenting views and were integrated into evidence to decision frameworks and the guideline article. Evidence gaps, reflecting clinical uncertainty in the literature, were identified during the evidence to decision process, live meeting, and voting and formally incorporated into all written recommendation rationales. Frequent scheduled "check-ins" mitigated communication gaps. CONCLUSIONS: Our multifaceted, interdisciplinary approach and novel methodologic strategies can help inform the development of future critical care clinical practice guidelines.

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.

OBJECTIVE: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. DESIGN: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017. METHODS: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. RESULTS: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. CONCLUSIONS: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

Burst suppression on processed electroencephalography as a predictor of postcoma delirium in mechanically ventilated ICU patients.

OBJECTIVES: Many patients, due to a combination of illness and sedatives, spend a considerable amount of time in a comatose state that can include time in burst suppression. We sought to determine if burst suppression measured by processed electroencephalography during coma in sedative-exposed patients is a predictor of post-coma delirium during critical illness. DESIGN: Observational convenience sample cohort. SETTING: Medical and surgical ICUs in a tertiary care medical center. PATIENTS: Cohort of 124 mechanically ventilated ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Depth of sedation was monitored twice daily using the Richmond Agitation-Sedation Scale and continuously monitored by processed electroencephalography. When noncomatose, patients were assessed for delirium twice daily using Confusion Assessment Method for the ICU. Multiple logistic regression and Cox proportional hazards regression were used to assess associations between time in burst suppression and both prevalence and time to resolution of delirium, respectively, adjusting for time in deep sedation and a principal component score consisting of Acute Physiology and Chronic Health Evaluation II score and cumulative doses of sedatives while comatose. Of the 124 patients enrolled and monitored, 55 patients either never had coma or never emerged from coma, yielding 69 patients for whom we performed these analyses; 42 of these 69 (61%) had post-coma delirium. Most patients had burst suppression during coma, although often short-lived (median [interquartile range] time in burst suppression, 6.4 [1-58] min). After adjusting for covariates, even this short time in burst suppression independently predicted a higher prevalence of post-coma delirium (odds ratio, 4.16; 95% CI, 1.27-13.62; p = 0.02) and a lower likelihood (delayed) resolution of delirium (hazard ratio, 0.78; 95% CI, 0.53-0.98; p = 0.04). CONCLUSIONS: Time in burst suppression during coma, as measured by processed electroencephalography, was an independent predictor of prevalence and time to resolution of postcoma/post-deep sedation delirium. These findings of this single-center investigation support lighter sedation strategies.

Atypical sleep in ventilated patients: empirical electroencephalography findings and the path toward revised ICU sleep scoring criteria.

OBJECTIVES: Standard sleep scoring criteria may be unreliable when applied to critically ill patients. We sought to quantify typical and atypical polysomnographic findings in critically ill patients and to begin development and reliability testing of methodology to characterize the atypical polysomnographic tracings that confound standard sleep scoring criteria. DESIGN: Prospective convenience sample. SETTING: Two academic, tertiary care medical centers. PATIENTS: Thirty-seven critically ill, mechanically ventilated, medical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mechanically ventilated subjects were monitored by continuous polysomnography. After noting frequent atypical polysomnographic findings (i.e., lack of stage N2 markers, the presence of polymorphic delta, burst suppression, or isoelectric electroencephalography), attempts to use standard sleep scoring criteria alone were abandoned. Atypical polysomnographic findings were characterized and used to develop a modified scoring system. Polysomnographic data were scored manually via this revised scoring scheme. Of 37 medical ICU patients enrolled, 36 experienced atypical sleep, which accounted for 85% of all recorded data, with 5.1% normal sleep and 9.4% wake. Coupling observed patient arousal levels with polysomnographic characteristics revealed that standard polysomnographic staging criteria did not reliably determine the presence or absence of sleep. Rapid eye movement occurred in only five patients (14%). The revised scoring system incorporating frequently seen atypical characteristics yielded very high interrater reliability (weighted κ = 0.80; bootstrapped 95% CI, [0.48, 0.89]). CONCLUSIONS: Analysis of polysomnographic data revealed profound deficiencies in standard scoring criteria due to a predominance of atypical polysomnographic findings in ventilated patients. The revised scoring scheme proved reliable in sleep staging and may serve as a building block in future work.

Liberation and animation: strategies to minimize brain dysfunction in critically ill patients.

Acute brain dysfunction, usually manifested as delirium, occurs in up to 80% of critically ill patients. Delirium increases costs of hospitalizations and affects short-term outcomes such as duration of mechanical ventilation, intensive care unit (ICU) length of stay, and the hospital length of stay. Long-term consequences-cognitive impairment and increased risk of death-can be devastating. For adequate recognition and management it is imperative to implement a successful delirium monitoring and assessment strategy. A liberation and animation strategy can reduce both the incidence and the duration of delirium. Liberation aims to reduce the harmful effects of sedative exposure through use of target-based sedation protocols, spontaneous awakening trials, and proper choice of sedative as well as liberation from the ventilator and the ICU. Animation refers to early mobilization, which reduces delirium and improves neurocognitive outcomes. Delirium is a serious problem with important consequences and can be prevented or improved using the information that we have learned in the last decade.

Bench-to-bedside review: delirium in ICU patients - importance of sleep deprivation.

Delirium occurs frequently in critically ill patients and has been associated with both short-term and long-term consequences. Efforts to decrease delirium prevalence have been directed at identifying and modifying its risk factors. One potentially modifiable risk factor is sleep deprivation. Critically ill patients are known to experience poor sleep quality with severe sleep fragmentation and disruption of sleep architecture. Poor sleep while in the intensive care unit is one of the most common complaints of patients who survive critical illness. The relationship between delirium and sleep deprivation remains controversial. However, studies have demonstrated many similarities between the clinical and physiologic profiles of patients with delirium and sleep deprivation. This article aims to review the literature, the clinical and neurobiologic consequences of sleep deprivation, and the potential relationship between sleep deprivation and delirium in intensive care unit patients. Sleep deprivation may prove to be a modifiable risk factor for the development of delirium with important implications for the acute and long-term outcome of critically ill patients.

Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality.

OBJECTIVES: This study investigates the possibility of a relationship between oversedation and mortality in mechanically ventilated patients. The presence of burst suppression, a pattern of severely decreased brain wave activity on the electroencephalogram, may be unintentionally induced by heavy doses of sedatives. Burst suppression has never been studied as a potential risk factor for death in patients without a known neurologic disorder or injury. DESIGN: Post hoc analysis of a prospectively observational cohort study. SETTING: Medical intensive care units of a tertiary care, university-based medical center. PATIENTS: A total of 125 mechanically ventilated, adult, critically ill patients. MEASUREMENTS AND MAIN RESULTS: A validated arousal scale (Richmond Agitation-Sedation Scale) was used to measure sedation level, and the bispectral index monitor was used to capture electroencephalogram data. Burst suppression occurred in 49 of 125 patients (39%). For analysis, the patients were divided into those with burst suppression (49 of 125, 39%) and those without burst suppression (76 of 125, 61%). All baseline variables were similar between the two groups, with the overall cohort demonstrating a high severity of illness (Acute Physiology and Chronic Health Evaluation II scores of 27.4 +/- 8.2) and 98% receiving sedation. Of those with burst suppression, 29 of 49 (59%) died within 6 months compared with 25 of 76 (33%) who did not demonstrate burst suppression. Using time-dependent Cox regression to adjust for clinically important covariates (age, Charlson comorbidity score, baseline dementia, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, coma, and delirium), patients who experienced burst suppression were found to have a statistically significant higher 6-month mortality [Hazard's ratio = 2.04, 95% confidence interval, 1.12-3.70, p = 0.02]. CONCLUSION: The presence of burst suppression, which was unexpectedly high in this medical intensive care unit population, was an independent predictor of increased risk of death at 6 months. This association should be studied prospectively on a larger scale in mechanically ventilated, critically ill patients.

Measuring sleep in critically ill patients: beware the pitfalls.

Survivors of critical illness frequently report poor sleep while in the intensive care unit (ICU), and sleep deprivation has been hypothesized to lead to emotional distress, ICU delirium and neurocognitive dysfunction, prolongation of mechanical ventilation, and decreased immune function. Thus, the careful study of sleep in the ICU is essential to understanding possible relationships with adverse clinical outcomes. Such research, however, must be conducted using sleep measurement techniques that have important limitations in this unique setting. Polysomnography (PSG) is considered the gold standard but is cumbersome, time consuming, and expensive. As such, alternative methods of sleep measurement such as actigraphy, processed electroencephalography monitors, and subjective observation are often used. Though helpful in some instances, data obtained using these methods can often be inaccurate and misleading. Even PSG itself must be interpreted with caution in this population due to effects of critical illness and associated treatments.

Delirium: is sleep important?

Delirium and poor sleep quality are common and often co-exist in hospitalised patients. A link between these disorders has been hypothesised but whether this link is a cause-and-effect relationship or simply an association resulting from shared mechanisms is yet to be determined. Potential shared mechanisms include: abnormalities of neurotransmitters, tissue ischaemia, inflammation and sedative exposure. Sedatives, while decreasing sleep latency, often cause a decrease in slow wave sleep and stage rapid eye movement (REM) sleep and therefore may not provide the same restorative properties as natural sleep. Mechanical ventilation, an important cause of sleep disruption in intensive care unit (ICU) patients, may lead to sleep disruption not only from the discomfort of the endotracheal tube but also as a result of ineffective respiratory efforts and by inducing central apnoea events if not properly adjusted for the patient's physiologic needs. When possible, efforts should be made to optimise the patient-ventilator interaction to minimise sleep disruptions.

Sedation and sleep disturbances in the ICU.

Sedation in the ICU is, paradoxically, both a cause and a potential treatment for the sleep disruption almost universally observed in the critically ill. A patient-focused sedation strategy that minimizes unnecessary medication, avoids medication withdrawal, addresses the specific impediments to sleep, and serves as an adjunct to attentive environmental control may ultimately serve patients best.

Sedation and sleep disturbances in the ICU.

The need for compassionate care of the critically ill often compels clinicians to treat these patients with pharmacologic sedation. Although patients may appear to be asleep under the influence of these sedating medications, the relationship between sleep and sedation is complex and not fully understood. These medications exert their effects at different points along the central nervous system's natural sleep pathway, leading to similarities and differences between the two states. This relationship is important because critically ill patients sleep poorly and this phenomenon has been linked to poor intensive care unit outcomes. Therefore, greater awareness of the effects of these medications on sleep may lead to sedation protocols that further improve outcomes. This article reviews the relationship between sedation and sleep from physiologic and clinical perspectives.