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.

The Impact of Interventions to Improve Sleep on Delirium in the ICU: A Systematic Review and Research Framework.

OBJECTIVE: This study aimed to assess whether interventions targeted at improving sleep in the ICU were associated with reductions in ICU delirium. Secondary outcomes include duration of delirium and ICU length of stay. DATA SOURCES: MEDLINE, CINAHL, Web of Science, Scopus, WorldCat, and International Pharmaceutical Abstracts were searched from inception to January 2016. STUDY SELECTION: Studies investigating any type of sleep intervention (nonpharmacologic or pharmacologic) and assessing the impact on ICU delirium were included. Any type of study design was permitted so long as the delirium assessment was made at least daily with a validated delirium assessment tool. DATA EXTRACTION: The following data were extracted: first author, year of publication, study design, ICU type, components of sleep intervention, use of sleep assessment tool, patient age, sex, severity of illness, sleep measures, delirium assessment tool, incidence of delirium, duration of delirium, and ICU length of stay. The incidence of delirium was used to compare rates of ICU delirium across studies. Methodologic quality of included studies was evaluated using the Effective Public Health Practice Project quality assessment tool. DATA SYNTHESIS: Of 488 citations screened, 10 studies were identified for inclusion in the final review; six of which demonstrated a statistically significant reduction in the incidence of ICU delirium associated with sleep intervention. Four studies assessed duration of delirium; of which, three reported a shorter duration of delirium with sleep intervention. Two studies associated sleep intervention with a reduced ICU length of stay. In regard to quality assessment and risk of bias, only one study was assessed as strong. Multiple identified confounders and the significant qualitative assessment of heterogeneity limit both the conclusions that can be drawn from these findings and the quantitative pooling of data. CONCLUSIONS: Although sleep interventions seem to be a promising approach for improving delirium-related outcomes, studies are limited by bias issues, varying methodologies, and multiple confounders, making the evidence base for this conclusion limited at best. Future studies would benefit from a systematic approach to studying the link between sleep intervention and delirium-related outcomes, which is outlined in the context of reviewing the existing literature.

Sleep in the intensive care unit.

Sleep is an important physiologic process, and lack of sleep is associated with a host of adverse outcomes. Basic and clinical research has documented the important role circadian rhythm plays in biologic function. Critical illness is a time of extreme vulnerability for patients, and the important role sleep may play in recovery for intensive care unit (ICU) patients is just beginning to be explored. This concise clinical review focuses on the current state of research examining sleep in critical illness. We discuss sleep and circadian rhythm abnormalities that occur in ICU patients and the challenges to measuring alterations in circadian rhythm in critical illness and review methods to measure sleep in the ICU, including polysomnography, actigraphy, and questionnaires. We discuss data on the impact of potentially modifiable disruptors to patient sleep, such as noise, light, and patient care activities, and report on potential methods to improve sleep in the setting of critical illness. Finally, we review the latest literature on sleep disturbances that persist or develop after critical illness.

Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Bronchiolitis obliterans syndrome (BOS) is a form of chronic graft vs. host disease (cGVHD) and a highly morbid pulmonary complication after allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the prevalence and risk factors for BOS and cGVHD in a cohort of HSCT recipients, including those who received reduced intensity conditioning (RIC) HSCT. Between January 1, 2000 and June 30, 2010, all patients who underwent allogeneic HSCT at our institution (n = 1854) were retrospectively screened for the development of BOS by PFT criteria. We matched the BOS cases with two groups of control patients: (1) patients who had concurrent cGVHD without BOS and (2) those who developed neither cGVHD nor BOS. Comparisons between BOS patients and controls were conducted using t-test or Fisher's exact tests. Multivariate regression analysis was performed to examine factors associated with BOS diagnosis. All statistical analyses were performed using SAS 9.2. We identified 89 patients (4.8%) meeting diagnostic criteria for BOS at a median time of 491 days (range: 48-2067) after HSCT. Eighty-six (97%) of our BOS cohort had extra-pulmonary cGVHD. In multivariate analysis compared to patients without cGVHD, patients who received busulfan-based conditioning, had unrelated donors, and had female donors were significantly more likely to develop BOS, while ATG administration was associated with a lower risk of BOS. Our novel results suggest that busulfan conditioning, even in RIC transplantation, could be an important risk factor for BOS and cGVHD.

Delirium and sleep disturbances in the intensive care unit: can we do better?

PURPOSE OF REVIEW: Delirium in the ICU affects as many as 60-80% of mechanically ventilated patients and a smaller but substantial percentage of other critically ill patients. Poor sleep quality has been consistently observed in critically ill patients. These problems are associated with worse ICU outcomes and, in many cases, delirium and poor sleep quality may be related. This review will summarize the recent literature relevant to both the problems and provide a potential pathway toward improvement. RECENT FINDINGS: Many cases of delirium and the poor sleep experienced by ICU patients may be iatrogenic. How critical care practitioners prescribe sedatives and analgesics and, perhaps more broadly, how all medications are administered to critically ill patients, may be at the root of some of these problems. Reducing the administration of some commonly used ICU medications, especially some sedatives and anticholinergic medications, and keeping patients more awake and actively engaged in their care during the day may lead to better outcomes. SUMMARY: It is our responsibility to apply the best available, evidence-based medicine to our practice. Adherence to new guidelines for the treatment of pain, agitation, and delirium may be the best pathway toward reducing delirium, improving sleep quality, and improving related outcomes.

Effectiveness of Nebulized Tranexamic Acid in Patients with Moderate-to-Massive Hemoptysis at a Tertiary Academic Medical Center.

Introduction: The management of severe hemoptysis mainly consists of invasive interventional procedures, including angiographic bronchial artery embolization, various endobronchial interventions, and sometimes surgery. However, there are limited effective noninvasive medical therapies available. The objective of this analysis was to evaluate the effectiveness and safety of nebulized tranexamic acid (TXA) administration compared with conventional management in patients with hemoptysis. Methods: This Institutional Review Board-approved, single-center, retrospective matched cohort study was performed from January 1, 2018 to March 31, 2021. Electronic health record data were used to identify all adult inpatients with hemoptysis (International Classification of Diseases, Tenth Revision, code R04.2). All patients who received ≥1 dose of nebulized TXA were matched with up to five controls based on available severity criteria (hemoptysis severity, need for mechanical ventilation, and sequential organ failure assessment score at the time of hemoptysis diagnosis) with coarsened exact matching. The primary outcome was the need for invasive interventions for the management of hemoptysis. Secondary outcomes included time to hemoptysis resolution, duration of mechanical ventilation, hemoptysis recurrence, and hospital length of stay. Results: A total of 14 patients were treated with nebulized TXA; they were matched with 58 controls. Patients were 59.7% male, had a median age of 65.5 years, with airway disease (36.1%) being the major etiology of hemoptysis. There was no difference in the number of patients who required an invasive intervention between the TXA (35.7%) versus control group (56.9%), p = 0.344. Additionally, no difference was found in the time to hemoptysis resolution (p = 0.050), duration on mechanical ventilation (p = 0.128), hemoptysis recurrence (p = 1.000), or hospital length of stay (p = 0.139). Conclusions: In patients with hemoptysis, nebulized TXA may be considered as a noninvasive option for the management of hemoptysis. However, a larger analysis is warranted to determine the impact of nebulized TXA on invasive interventions for management.

Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis.

PURPOSE: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP. METHODS AND MATERIALS: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual. RESULTS: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism. CONCLUSIONS: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP.

Sleep Assessment in Critically Ill Adults: Established Methods and Emerging Strategies.

Sleep is a biological mandate with an integral role in optimizing functions that maintain psychological and physical health. During critical illness, however, sleep may be disrupted at best and elusive at worst. Sleep improvement efforts and research endeavors evaluating interventions to improve sleep in critically ill adults are hampered by limited methods available to measure sleep in this setting. This narrative review summarizes available modalities for sleep assessment in the ICU, describes new ICU sleep assessment methods under development, and highlights features of the ideal ICU sleep measurement tool. DATA SOURCES: The most relevant literature and author experiences were assessed for inclusion from PubMed and textbooks. STUDY SELECTION: The authors selected studies for inclusion by consensus. DATA EXTRACTION: The authors reviewed each study and selected appropriate data for inclusion by consensus. DATA SYNTHESIS: Currently available tools to measure sleep in critically ill adults have important flaws. Subjective measurements are limited by recall bias, the inability of many patients to communicate, and poorly correlate with objective measures when completed by surrogates. Actigraphy does not consider the effects of sedating medications or myopathy leading to an over estimation of sleep time. Polysomnography, the gold standard for sleep assessment, is limited by interpretation issues and practical application concerns. Single and multiple channel electroencephalogram devices offer real-time physiologic data and are more practical to use than polysomnography but are limited by the scope of sleep-specific information they can measure and poorly characterize the circadian system. CONCLUSIONS: A measurement tool that offers real-time sleep and circadian assessment and is practical for broad application in the ICU does not exist. Newer sleep assessment devices have shown promise in measuring physiologic data in real time; when used in combination with other assessment modalities, and analyzed by computational techniques, they may revolutionize sleep monitoring in the ICU.

Impact of COVID-19 on Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Introduction: To evaluate the impact of Sars-Cov-2 infection on mortality and immune checkpoint inhibitor (ICI) toxicity in patients with cancer receiving ICIs compared to those not receiving ICIs. Methods: We conducted a retrospective matched cohort study of 25 patients receiving ICIs within 1 year of coronavirus disease 2019 (COVID-19) diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute/Mass General Brigham. Cases were matched 1:1 with controls based on age, sex, and anticancer therapy within the prior 6 months. Results: Seven of 25 (28%) patients receiving ICIs died from COVID-19 as compared with nine of 25 (36%) controls. Through multivariable analysis adjusting for age, sex, and anticancer therapy, ICI use was not associated with increased risk for COVID-19 death (OR [odds ratio] 0.36, 95% CI 0.07-1.87). Determinants of mortality included age (OR 1.14, 95% CI 1.03-1.27) and chronic obstructive pulmonary disease (OR 12.26, 95% CI 1.76-85.14). Statin use was protective against mortality (OR 0.08, 95% CI 0.01-0.63). Two patients experienced persistent immune-related adverse events (irAEs) (hypophysitis); one had new-onset irAE (hypothyroidism) during their COVID-19 course. Patients with ICIs had significantly higher platelet (p = 0.017) and D-dimer (p = 0.037) levels. Elevated troponin levels (p = 0.01) were associated with COVID-19 death in patients using ICI. Conclusion: There is insufficient evidence to conclude COVID-19-related outcomes are associated with ICIs, and we did not observe an increased risk of COVID-19-related death associated with ICIs. The potential protective effect of statin therapy and role of laboratory biomarkers warrant further investigation.

Characterization of Nocturnal Neuroactive Medication Use and Related Sleep Documentation in Critically Ill Adults.

We retrospectively characterized scheduled, newly initiated, nocturnal neuroactive medication use, and related clinician documentation, in a cohort of consecutive adults admitted greater than or equal to 24 hours to seven different medical/surgical ICUs at two academic centers who had not received a scheduled nocturnal neuroactive medication prior to admission, over a 5-month period (April 1, 2017, to August 31, 2017). A total of 207 different newly initiated, scheduled nocturnal neuroactive medication orders were written (melatonin agonist 101 [48.8%], antipsychotic 80 [38.6%], antidepressant 17 [8.2%], benzodiazepine 9 [4.3%]) in 189 (9.7%) of the 1,955 patients. Among the 1,553 nights, the 189 patients spent in the ICU, a scheduled nocturnal neuroactive medication was administered on 1,103 (71%), an "as needed" nocturnal neuroactive medication was solely administered on 183 (11.8%), delirium occurred on 736 (47.4%), and nurses were twice as likely as physicians (28.8% vs 11.4%; p < 0.0001) to document a note about sleep quality. Among the 69.8% of patients discharged to the floor, and the 64.5% from the hospital, the scheduled nocturnal neuroactive medication was continued in 85.6% and 87.3%, respectively. Scheduled nocturnal neuroactive medication initiation is common, often continued beyond hospital discharge, and poorly documented.

Patients' and Their Caregivers' Interest in Learning About Post-ICU Syndrome and Seeking Help for It.

Critical Illness Recovery Programs report low attendance. We aimed to provide information about postintensive care syndrome and to learn which patients would pursue help in a Critical Illness Recovery Clinic. All patients who checked in to our Lung Center were given a survey regarding their ICU experience and offered information about postintensive care syndrome and an appointment in the clinic. Nine hundred and twenty respondents reported having had an ICU experience: 37% of former ICU patients reported difficulty returning to their normal lives afterward compared with 21% who were family or close friends of a former ICU patient. Only 5% requested information and less than 1% requested a dedicated appointment. More than one of three former ICU patients and one in five close friends or relatives of former ICU patients reported difficulty returning to their normal lives after their ICU experience. Very few pursued the opportunity to learn more about it or seek help.

Evaluation of the Efficacy and Safety of Inhaled Epoprostenol and Inhaled Nitric Oxide for Refractory Hypoxemia in Patients With Coronavirus Disease 2019.

OBJECTIVES: The objectives of this study were to evaluate the efficacy and safety of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019. DESIGN: Retrospective single-center study. SETTING: ICUs at a large academic medical center in the United States. PATIENTS: Thirty-eight adult critically ill patients with coronavirus disease 2019 and refractory hypoxemia treated with either inhaled epoprostenol or inhaled nitric oxide for at least 1 hour between March 1, 2020, and June 30, 2020. INTERVENTIONS: Electronic chart review. MEASUREMENTS AND MAIN RESULTS: Of 93 patients screened, 38 were included in the analysis, with mild (4, 10.5%), moderate (24, 63.2%), or severe (10, 26.3%), with acute respiratory distress syndrome. All patients were initiated on inhaled epoprostenol as the initial pulmonary vasodilator and the median time from intubation to initiation was 137 hours (68-228 h). The median change in Pao2/Fio2 was 0 (-12.8 to 31.6) immediately following administration of inhaled epoprostenol. Sixteen patients were classified as responders (increase Pao2/Fio2 > 10%) to inhaled epoprostenol, with a median increase in Pao2/Fio2 of 34.1 (24.3-53.9). The mean change in Pao2 and Spo2 was -0.55 ± 41.8 and -0.6 ± 4.7, respectively. Eleven patients transitioned to inhaled nitric oxide with a median change of 11 (3.6-24.8) in Pao2/Fio2. A logistic regression analysis did not identify any differences in outcomes or characteristics between the responders and the nonresponders. Minimal adverse events were seen in patients who received either inhaled epoprostenol or inhaled nitric oxide. CONCLUSIONS: We found that the initiation of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019, on average, did not produce significant increases in oxygenation metrics. However, a group of patients had significant improvement with inhaled epoprostenol and inhaled nitric oxide. Administration of inhaled epoprostenol or inhaled nitric oxide may be considered in patients with severe respiratory failure secondary to coronavirus disease 2019.