Association Between Sleep and Functional Outcome in Critically Ill Patients

Association Between Sleep and Functional Outcome in Critically Ill Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association Between Sleep and Functional Outcome in Critically Ill Patients Rebecca Dutta, Leslie C West, Ajay Sampat, Machelle Wilson, Guillermo Palchik, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6977598/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Examine the association between sleep and clinical outcome in patients with acute brain injury and critical illness. Methods Retrospective analysis of critically ill patients who underwent continuous electroencephalography monitoring in an academic medical center from 2018–2020. Patients admitted with primary neurologic, medical, and surgical conditions were included. Clinical outcome was determined by the modified Rankin Scale (mRS < 3 represented favorable outcome). Statistical modeling of outcome included predictor variables controlling for anesthetic concentration, diagnosis, and sex. Results 262 patients were included of which 57% were male with a mean age of 58 years (range 18–91). Twenty-one percent of the total population achieved sleep (56/262). Of those achieving any sleep, 43% had good outcomes compared to only 26% who did not (χ² =10.99, p = 0.0009), controlling for diagnosis, sex, anesthetic level, and Acute Physiology and Chronic Health Evaluation score. Neurological patients attained sleep more often (27%) compared to those with other primary diagnoses (14%). In multivariable analysis, the effect of level of centrally acting anesthetics did not account for sleep differences between neurologic and non-neurological patients (χ² =3.5, p = 0.95). Conclusions Neurocritical patients slept more often, and obtaining any sleep was associated with better functional outcome when controlling disease severity. Further studies are needed to determine whether sleep augmentation and anesthetic use in critically ill patients impact functional outcomes. sleep stages critically ill outcome assessment electrophysiology Figures Figure 1 Introduction Sleep is a fundamental dynamic physiologic process essential for cognition, repair, and survival. Disruption of physiologic sleep may have significant implications in acute brain injury, functional recovery, and critical illness. Little is known about the impact of sleep during acute phases of critical illness and its relationship with outcome. Extrapolated data from healthy individuals on how sleep deprivation influences organ function exists; however, limited relevant studies have examined those who are critically ill. 1 Characterization of sleep in limited medical and surgical intensive care unit (ICU) populations has primarily focused on subjective measurement tools and polysomnography (PSG). 2 – 5 Measuring sleep in the ICU is inherently challenging and not synonymous with studying sleep physiology in a standardized laboratory setting. Polysomnography has not been validated for routine use in the critical care setting, but published 24-hour monitoring studies have supported our current understanding of sleep in the ICU. 4 Sleep fragmentation and frequent arousals are common and often attributed to intrinsic factors to being critically ill, mechanical ventilation, along with extrinsic factors (i.e., care interruptions, light, disruptive noise). 3 Short sleep periods with unusual sleep stage transitions have been observed along with substantial sleep fragmentation. In an observational ICU cohort study, patients slept only three minutes before waking based on PSG. 5 Moreover, critically ill patients have substantial circadian misalignment, sleeping primarily during daytime hours. 2 , 5 They have markedly abnormal sleep architecture predominantly composed of non-rapid eye movement (REM) light sleep stages (i.e. N1 and N2), reduced N3 slow wave stage, and nearly absent REM. 2 – 3 , 5 Limited evidence exists examining sleep in neurocritical patients. 6 In a small sample of patients with aneurysmal subarachnoid hemorrhage (SAH) that focused on an isolated sleep stage, 85% did not achieve normal N2 stage within 24 hours of admission while 77% did not sleep at all. 7 The absence of electroencephalographic (EEG) identification of any sleep architecture was associated with poor 3-month outcome. 7 Herein, we report the largest study of mixed-population (neurological, medical, surgical) critically ill patients examining electrophysiological sleep characteristics and their association with clinical outcomes. Methods We performed a retrospective analysis of consecutive critically ill patients who underwent continuous EEG (cEEG) monitoring at an academic medical center from January 2018 to December 2020. Adult patients aged 18 years or greater admitted to an ICU with an acute neurological, medical, or surgical condition were included. All underwent cEEG monitoring for at least 24 hours but no more than 7 days as part of routine care. Example indications for monitoring included evaluation for subclinical seizures, encephalopathy, or detection of delayed cerebral ischemia in patients with SAH. Electroencephalographic studies were independently reviewed by board-certified clinical neurophysiologists/epileptologists. Sleep was defined by American Academy of Sleep Medicine (AASM) electrophysiological criteria and documented if a patient achieved sleep for at least one hour throughout the continuous recording. Stage of sleep was defined as non-REM (NREM) stage N1, stage N2, stage N3 and Stage REM in accordance with standard EEG criteria. Primary admission diagnosis, Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission (Table 1), demographics, relevant medications (e.g., anesthetic/sedation), and EEG characteristics were collected. Centrally acting anesthetic-sedation of propofol or midazolam were collected and tiered in three categories based on dose (Table 2). If combined sedation was used, the patient was tiered into the appropriate medium or high level based on dose. Table 1 APACHE II Score APACHE II, Acute Physiology and Chronic Health Evaluation II. Diagnosis APACHE II Score Neurologic & Neurosurgical Diagnosis Average 14.97 Standard Deviation 6.40 Medical & Surgical Diagnosis Average 18.12 Standard Deviation 7.82 Total Average of APACHE II Score 16.22 Total Standard Dev of APACHE II Score 7.15 Acute Physiology and Chronic Health Evaluation, APACHE Table 2 Central Acting Anesthesia Dose by Dosage Tiers Microgram, mcg; kilogram, kg Tier Sedative Regimen None None Low dose Propofol < 20 mcg/kg/minute OR Midazolam < 2 mcg/kg/minute Moderate-to-high dose Combination of propofol and midazolam at any dose OR Propofol ≥ 20 mcg/kg/minute OR Midazolam ≥ 2 mcg/kg/minute Microgram, mcg; kilogram, kg The functional global outcome was assessed by hospital discharge modified Rankin Scale score (mRS; range: 0 = no symptoms, 6 = death) and dichotomized by good outcome (mRS < 3) versus poor (3–6). A score of less than three represented patients with no to minimal neurologic disability. 8 Statistical analysis Statistical analysis was performed to evaluate the effect of sleep on good outcome (mRS < 3). Differences between categorical variables were assessed using chi-square and between continuous variables using t tests or Wilcoxon rank sum tests where appropriate. Subsequent multivariable analysis was performed to evaluate the influence of sleep on outcome, accounting for level of anesthetic, and controlling for APACHE II scores, diagnosis, and sex. Sedation intensity was grouped into two categories based on average dose while undergoing cEEG monitoring (none/low level versus moderate/high levels) (Table 2). 9 All analyses were conducted using SAS® software version 9.4 for Windows® (SAS Institute Inc., Cary, NC). Standard Protocol Approvals, Registrations, and Patient Consents The University of California Davis Institutional Review Board reviewed and approved the study. The ethics board determined that participant consent was not required. All data were compiled in a secure customized Research Electronic Data Capture (REDCap) database. Results Patient Characteristics Two hundred sixty-two patients were included with a mean age of 58 years (range 18–91), and 57% were male. Sixty percent were admitted for a primary neurocritical or neurosurgical diagnosis whereas 40% of patients had medical or surgical critical conditions. Most patients (94%) received mechanical ventilation while undergoing cEEG monitoring with an average recording period of 53 hours. Primary neurological diagnoses included traumatic brain injury [TBI; traumatic subarachnoid hemorrhage (tSAH), subdural hemorrhage (SDH)], acute stroke [ischemic, spontaneous intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage aSAH)], and status epilepticus. Most primary non-neurologic critical illness diagnoses included respiratory failure, metabolic, toxic or infectious disturbance, sepsis, and cardiac arrest. Additional neurologic and non-neurological diagnoses are itemized in Table 3 . Patient Outcomes Twenty-one percent of all patients (56/262) achieved any sleep. Of those who slept, 21% achieved N1 only, 71% achieved N1 with N2, and only 7% achieved all 3 non-REM stages (N1 to N3). Neurologic patients attained sleep significantly more frequently compared to those with other primary diagnoses (Fig. 1 ). Thirty percent of all patients died during hospitalization. Those who achieved any sleep were more likely to have favorable functional outcomes compared to those who did not (p < 0.0004), as well as male sex (P < 0.0074) and non-neurologic diagnosis (P < 0.0011) in univariate analysis. When controlling for diagnosis, sex, anesthetic, and APACHE score [OR = 3.56, 95% CI (1.68, 7.58)], patients who slept in the ICU were 3.6 times more likely to have a good outcome. Furthermore, more favorable outcomes were predicted by those admitted with non-neurological diagnoses (OR = 4.21, 95% CI = (2.17,8.18)) and male sex [OR = 2.24, 95% CI(1.17,4.30)]. The APACHE score, however, did not influence outcome in multivariate analysis (χ² (1)=, 3.48, p = 0.062). Critical ill patients achieved sleep more often in the absence of centrally-acting (e.g. propofol, midazolam) anesthetic use (27.4%) and low level of sedation (26.7%). In contrast, only 6.7% of patients receiving moderate to high anesthetic levels had documented sleep. However, the intensity of anesthetic use did not impact outcome (χ²(2) = 0.11, P < 0.95). Discussion Little is known about the impact of sleep on clinical outcomes in survivors of critical illness, particularly in those with severe brain injury. We examined a broad spectrum of critical patients and identified key characteristics associated with sleep and functional outcomes. Very ill patients seldom sleep and when they do, achieve incomplete restful sleep (only lighter stages of NREM sleep, stages N1-N2). Importantly, attaining any sleep was associated with better functional outcomes. Surprisingly, sleep was identified more commonly in patients with primary brain injury compared to those admitted for other conditions. The difference in achieving sleep between those with neurologic or non-neurological disease did not result from sedative use. Sleep disturbances (primarily hypersomnia) can be seen from disturbance in the wakeful regions of the brain (i.e. reticular activating system, hypothalamus, areas surrounding third ventricle, thalamus) or due to hormonal imbalance (i.e. reduction in histamine and hypocretin concentrations, wake-promoting neurochemicals, are observed following TBI) which may explain some hypersomnia features. 10 , 11 We hypothesized that neurologically injured patients would achieve less sleep based on involvement of key anatomical structures. 12 However, those admitted for medical critical illness slept less often than those with neurocritical disease in our analysis. Diffuse systemic inflammatory processes, such as sepsis, may affect sleep more severely by disrupting blood-brain barrier integrity. 13 Furthermore, critical systemic illness may disrupt the normal circadian rhythm. 14 , 15 Patients who slept less in our cohort had poorer functional outcomes. Short and long-term effects of sleep loss may impair immune recovery while negatively impacting cardiovascular and pulmonary function. 1 Polysomnography (PSG) is a reliable outpatient method used to qualify, and quantify, sleep. However, PSG has not been validated to examine sleep in the ICU. Continuous electroencephalographic monitoring is increasingly used in the critically-ill and may serve as a useful surrogate biomarker for sleep characterization. Actigraphy, a non-invasive worn device measuring rest and activity cycles, has tested circadian rhythm timing and sleep-associated variables in the critical care setting. 17 – 21 However, this modality does not record cerebral electrophysiology, thus conclusions about sleep can only be extrapolated. Improved identification of sleep-associated variables, based on AASM standardized metrics, can be better characterized (i.e. sleep stages) by cEEG monitoring. 22 Recent critical care guidelines proposed early progressive mobilization to prevent delirium; importantly, the report underscored sleep promotion and minimizing sleep disruption as key strategies to impact survivor outcome. 21 Patients with prior brain injury are at risk of developing circadian rhythm dysfunction. Stroke and TBI survivors are 40% more likely to be diagnosed with a sleep disorder, and little is known about predisposing risks or impact of interventions to minimize sleep disruption in this population. 23 , 24 Other important variables that may influence sleep among the critically ill, such as the potential impact of continuous enteral feeding, require ongoing investigation. 25 , 26 We examined a diverse population of critically ill patients and evaluated the effect of commonly used sedatives on sleep. Expectedly, patients achieved sleep more often when these medications were not used; however, anesthetic administration did not exclusively predict why those with neurological injury achieved sleep more often compared to those without brain insults. Limitations Inherent limitations exist with any single center, retrospective study. However, uniformity in how clinical practice is administered and information collected should minimize data variability. Several useful clinical variables were not systematically recorded such as the Glasgow Coma Scale in medical and surgical patients, individual circadian sleep timing, or pre-existing sleep disorder diagnoses due to low prevalence. Study patients underwent cEEG monitoring for various clinical indications, generating a potential bias towards those with greater medical complexity who may have less “central neurologic reserve.” Examining how these variables as well as other pharmacologic therapies (i.e. anticonvulsants, antipsychotics, antimicrobials, opiates, tricyclics and other antidepressants) might influence sleep in future studies will be informative. Lastly, dexmedetomidine was an anesthetic infrequently used in our cohort and not analyzed independently—its application in delirium prevention in critically ill patients is becoming increasingly recognized. 27 Conclusion Most critically ill patients do not achieve electrophysiologic sleep and those that do reach N1/N2 stages only. However, achieving any sleep was associated with more favorable functional outcome, and neurological patients slept more often. Sleep appears to be an important variable in the critically ill even when reaching ‘lighter’ restorative stages. Further studies are needed to standardize measurements of sleep in the ICU, determine effective interventions that promote it, and examine the impact of sleep on critical care outcomes. Declarations Acknowledgement We thank our patients and their families for their participation and willingness to share results with the academic community. We dedicate this manuscript to the memory of our co-authors, Dr. Ajay Sampat and Dr. Machelle D. Wilson, who passed away during the course of this work. Dr. Sampat’s contributions, mentorship, and dedication to the field of Sleep Neurology is invaluable and was instrumental in completing this research. Dr. Wilson’s expertise in statistics and data analysis provided critical insight and strengthened the rigor of our work. We honor both of their legacies and lasting impact on our community. Details Page This is original work that has not been published elsewhere and is not under consideration by any other journal. The manuscript complies with all instructions to authors. Author contributions: LC West- Conceptualization, Methodology, Data curation, Formal analysis, Writing, Editing R Dutta- Methodology, Data curation, Formal analysis, Writing, Editing LC West and R Dutta contributed equally to the research and writeup of this work. AH Yee- Supervision, Conceptualization, Methodology, Data curation, Formal analysis, Writing, Reviewing and Editing MD Wilson- Statistical analysis, Data visualization, Reviewing and Editing GA Palchick- Conceptualization, Methodology, Reviewing and Editing A Sampat- Conceptualization, Methodology, Reviewing and Editing All authors have read and approved the manuscript and have no conflicts of interest to disclose. Disclosures: LC West reports no disclosures relevant to the manuscript, R Dutta reports no disclosures relevant to the manuscript, A Sampat reports no disclosures relevant to the manuscript, MD Wilson reports no disclosures relevant to the manuscript, GA Palchik reports no disclosures relevant to the manuscript, AH Yee received research grant funding from the American Osteopathic Association (grant #: 23151879) and serves as a neurology consultant for Janux Biotechnology. Ethical Compliance Statement: This research study was approved by the University of California Davis Institutional Review Board. Consent was waived for this review. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources: MD Wilson PhD was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR001860. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors confirm use of a reporting checklist (STROBE). References Chang VA, Owens RL, LaBuzetta JN. Impact of sleep deprivation in the neurological intensive care unit: a narrative review. Neurocritical Care. 2020;32:596-608. Freedman NS, Gazendam J, Levan L, Pack AI, Schwab RJ. Abnormal sleep/wake cycles and the effect of environmental noise on sleep disruption in the intensive care unit. American Journal of Respiratory and Critical Care Medicine. 2001;163:451-7. Friese RS, Diaz-Arrastia R, McBride D, Frankel H, Gentilello LM. Quantity and quality of sleep in the surgical intensive care unit: are our patients sleeping?. Journal of Trauma and Acute Care Surgery. 2007;63:1210-4. Franck L, Tourtier JP, Libert N, Grasser L, Auroy Y. How did you sleep in the ICU?. Critical Care. 2011;15:1-10. Elliott R, McKinley S, Cistulli P, Fien M. 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Non‐pharmacological interventions for sleep promotion in the intensive care unit. Cochrane Database of Systematic Reviews. 2015;10. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJ, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical Care Medicine. 2018;46:e825-73. Berry R, Quan S, Abreu AR for the American Academy of Sleep Medicine. The AASM Manual for the scoring of sleep and associated events: rules, terminology and technical specifications. American Academy of Sleep Medicine, Darien (IL) 2020. Version 2.6 Wickwire EM, Williams SG, Roth T, Capaldi VF, Jaffe M, Moline M, Motamedi GK, Morgan GW, Mysliwiec V, Germain A, Pazdan RM. Sleep, sleep disorders, and mild traumatic brain injury. What we know and what we need to know: findings from a national working group. Neurotherapeutics. 2016;13:403-17. Leng Y, Byers AL, Barnes DE, Peltz CB, Li Y, Yaffe K. Traumatic Brain Injury and Incidence Risk of Sleep Disorders in Nearly 200,000 US Veterans. Neurology. 2021;96:e1792-9. McKenna H, van der Horst GT, Reiss I, Martin D. Clinical chronobiology: a timely consideration in critical care medicine. Critical Care. 2018;22:1-10. Marra A, Ely EW, Pandharipande PP, Patel MB. The ABCDEF bundle in critical care. Critical care clinics. 2017;33:225-43. Skrobik Y, Duprey MS, Hill NS, Devlin JW. Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial. American journal of respiratory and critical care medicine. 2018;197:1147-56. Table 3 Table 3 is available in the Supplementary Files section. Supplementary Files Table3.docx SupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6977598","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":482567122,"identity":"c3834fac-1637-4137-be9f-dff46e242211","order_by":0,"name":"Rebecca 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Stage. \u003c/strong\u003eSleep stages for all ICU patients: 56 patients achieved electrophysiologic sleep of which 75% were diagnosed with a primary neurological condition.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6977598/v1/330cb4442715356e6d8620e0.png"},{"id":88373368,"identity":"0f2104a2-8124-4018-a917-ef30e6f07b83","added_by":"auto","created_at":"2025-08-05 20:05:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":659613,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6977598/v1/9a24c4cb-2316-4e14-b2a1-ddb649eb2d64.pdf"},{"id":86660369,"identity":"10d3ced0-3d90-4b15-a387-77889a4b5182","added_by":"auto","created_at":"2025-07-14 10:35:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15310,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6977598/v1/3e2ad8c63f936e5bf65fee42.docx"},{"id":86662327,"identity":"3a288114-6c74-4f82-a8f7-68d011cb5602","added_by":"auto","created_at":"2025-07-14 10:43:00","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":22455,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6977598/v1/650dbb4b92ccf3d822a4c341.docx"}],"financialInterests":"","formattedTitle":"Association Between Sleep and Functional Outcome in Critically Ill Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSleep is a fundamental dynamic physiologic process essential for cognition, repair, and survival. Disruption of physiologic sleep may have significant implications in acute brain injury, functional recovery, and critical illness. Little is known about the impact of sleep during acute phases of critical illness and its relationship with outcome. Extrapolated data from healthy individuals on how sleep deprivation influences organ function exists; however, limited relevant studies have examined those who are critically ill.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eCharacterization of sleep in limited medical and surgical intensive care unit (ICU) populations has primarily focused on subjective measurement tools and polysomnography (PSG).\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Measuring sleep in the ICU is inherently challenging and not synonymous with studying sleep physiology in a standardized laboratory setting. Polysomnography has not been validated for routine use in the critical care setting, but published 24-hour monitoring studies have supported our current understanding of sleep in the ICU.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Sleep fragmentation and frequent arousals are common and often attributed to intrinsic factors to being critically ill, mechanical ventilation, along with extrinsic factors (i.e., care interruptions, light, disruptive noise).\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Short sleep periods with unusual sleep stage transitions have been observed along with substantial sleep fragmentation. In an observational ICU cohort study, patients slept only three minutes before waking based on PSG.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Moreover, critically ill patients have substantial circadian misalignment, sleeping primarily during daytime hours.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e They have markedly abnormal sleep architecture predominantly composed of non-rapid eye movement (REM) light sleep stages (i.e. N1 and N2), reduced N3 slow wave stage, and nearly absent REM.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eLimited evidence exists examining sleep in neurocritical patients.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e In a small sample of patients with aneurysmal subarachnoid hemorrhage (SAH) that focused on an isolated sleep stage, 85% did not achieve normal N2 stage within 24 hours of admission while 77% did not sleep at all.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e The absence of electroencephalographic (EEG) identification of any sleep architecture was associated with poor 3-month outcome.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Herein, we report the largest study of mixed-population (neurological, medical, surgical) critically ill patients examining electrophysiological sleep characteristics and their association with clinical outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe performed a retrospective analysis of consecutive critically ill patients who underwent continuous EEG (cEEG) monitoring at an academic medical center from January 2018 to December 2020. Adult patients aged 18 years or greater admitted to an ICU with an acute neurological, medical, or surgical condition were included. All underwent cEEG monitoring for at least 24 hours but no more than 7 days as part of routine care. Example indications for monitoring included evaluation for subclinical seizures, encephalopathy, or detection of delayed cerebral ischemia in patients with SAH. Electroencephalographic studies were independently reviewed by board-certified clinical neurophysiologists/epileptologists. Sleep was defined by American Academy of Sleep Medicine (AASM) electrophysiological criteria and documented if a patient achieved sleep for at least one hour throughout the continuous recording. Stage of sleep was defined as non-REM (NREM) stage N1, stage N2, stage N3 and Stage REM in accordance with standard EEG criteria. Primary admission diagnosis, Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission (Table\u0026nbsp;1), demographics, relevant medications (e.g., anesthetic/sedation), and EEG characteristics were collected. Centrally acting anesthetic-sedation of propofol or midazolam were collected and tiered in three categories based on dose (Table\u0026nbsp;2). If combined sedation was used, the patient was tiered into the appropriate medium or high level based on dose.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eAPACHE II Score\u0026nbsp;\u003cbr\u003eAPACHE II, Acute Physiology and Chronic Health Evaluation II.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAPACHE II Score\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeurologic \u0026amp; Neurosurgical Diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAverage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e14.97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStandard Deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedical \u0026amp; Surgical Diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAverage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e18.12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStandard Deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Average of APACHE II Score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e16.22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Standard Dev of APACHE II Score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eAcute Physiology and Chronic Health Evaluation, APACHE\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eCentral Acting Anesthesia Dose by Dosage Tiers\u003cbr\u003eMicrogram, mcg; kilogram, kg\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTier\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSedative Regimen\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePropofol \u0026lt; 20 mcg/kg/minute OR Midazolam \u0026lt; 2 mcg/kg/minute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModerate-to-high dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombination of propofol and midazolam at any dose OR Propofol ≥ 20 mcg/kg/minute OR Midazolam ≥ 2 mcg/kg/minute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eMicrogram, mcg; kilogram, kg\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe functional global outcome was assessed by hospital discharge modified Rankin Scale score (mRS; range: 0 = no symptoms, 6 = death) and dichotomized by good outcome (mRS \u0026lt; 3) versus poor (3–6). A score of less than three represented patients with no to minimal neurologic disability.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eStatistical analysis was performed to evaluate the effect of sleep on good outcome (mRS \u0026lt; 3). Differences between categorical variables were assessed using chi-square and between continuous variables using \u003cem\u003et\u003c/em\u003e tests or Wilcoxon rank sum tests where appropriate. Subsequent multivariable analysis was performed to evaluate the influence of sleep on outcome, accounting for level of anesthetic, and controlling for APACHE II scores, diagnosis, and sex. Sedation intensity was grouped into two categories based on average dose while undergoing cEEG monitoring (none/low level versus moderate/high levels) (Table\u0026nbsp;2). \u003csup\u003e9\u003c/sup\u003e All analyses were conducted using SAS® software version 9.4 for Windows® (SAS Institute Inc., Cary, NC).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eStandard Protocol Approvals, Registrations, and Patient Consents\u003c/h3\u003e\n\u003cp\u003eThe University of California Davis Institutional Review Board reviewed and approved the study. The ethics board determined that participant consent was not required. All data were compiled in a secure customized Research Electronic Data Capture (REDCap) database.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient Characteristics\u003c/h2\u003e\n \u003cp\u003eTwo hundred sixty-two patients were included with a mean age of 58 years (range 18\u0026ndash;91), and 57% were male. Sixty percent were admitted for a primary neurocritical or neurosurgical diagnosis whereas 40% of patients had medical or surgical critical conditions. Most patients (94%) received mechanical ventilation while undergoing cEEG monitoring with an average recording period of 53 hours. Primary neurological diagnoses included traumatic brain injury [TBI; traumatic subarachnoid hemorrhage (tSAH), subdural hemorrhage (SDH)], acute stroke [ischemic, spontaneous intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage aSAH)], and status epilepticus. Most primary non-neurologic critical illness diagnoses included respiratory failure, metabolic, toxic or infectious disturbance, sepsis, and cardiac arrest. Additional neurologic and non-neurological diagnoses are itemized in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003ePatient Outcomes\u003c/h3\u003e\n\u003cp\u003eTwenty-one percent of all patients (56/262) achieved any sleep. Of those who slept, 21% achieved N1 only, 71% achieved N1 with N2, and only 7% achieved all 3 non-REM stages (N1 to N3). Neurologic patients attained sleep significantly more frequently compared to those with other primary diagnoses (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Thirty percent of all patients died during hospitalization.\u003c/p\u003e\n\u003cp\u003eThose who achieved any sleep were more likely to have favorable functional outcomes compared to those who did not (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0004), as well as male sex (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0074) and non-neurologic diagnosis (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0011) in univariate analysis. When controlling for diagnosis, sex, anesthetic, and APACHE score [OR\u0026thinsp;=\u0026thinsp;3.56, 95% CI (1.68, 7.58)], patients who slept in the ICU were 3.6 times more likely to have a good outcome. Furthermore, more favorable outcomes were predicted by those admitted with non-neurological diagnoses (OR\u0026thinsp;=\u0026thinsp;4.21, 95% CI = (2.17,8.18)) and male sex [OR\u0026thinsp;=\u0026thinsp;2.24, 95% CI(1.17,4.30)]. The APACHE score, however, did not influence outcome in multivariate analysis (\u0026chi;\u0026sup2; (1)=, 3.48, p\u0026thinsp;=\u0026thinsp;0.062). Critical ill patients achieved sleep more often in the absence of centrally-acting (e.g. propofol, midazolam) anesthetic use (27.4%) and low level of sedation (26.7%). In contrast, only 6.7% of patients receiving moderate to high anesthetic levels had documented sleep. However, the intensity of anesthetic use did not impact outcome (\u0026chi;\u0026sup2;(2)\u0026thinsp;=\u0026thinsp;0.11, P\u0026thinsp;\u0026lt;\u0026thinsp;0.95).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eLittle is known about the impact of sleep on clinical outcomes in survivors of critical illness, particularly in those with severe brain injury. We examined a broad spectrum of critical patients and identified key characteristics associated with sleep and functional outcomes. Very ill patients seldom sleep and when they do, achieve incomplete restful sleep (only lighter stages of NREM sleep, stages N1-N2). Importantly, attaining any sleep was associated with better functional outcomes.\u003c/p\u003e\u003cp\u003eSurprisingly, sleep was identified more commonly in patients with primary brain injury compared to those admitted for other conditions. The difference in achieving sleep between those with neurologic or non-neurological disease did not result from sedative use. Sleep disturbances (primarily hypersomnia) can be seen from disturbance in the wakeful regions of the brain (i.e. reticular activating system, hypothalamus, areas surrounding third ventricle, thalamus) or due to hormonal imbalance (i.e. reduction in histamine and hypocretin concentrations, wake-promoting neurochemicals, are observed following TBI) which may explain some hypersomnia features.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e We hypothesized that neurologically injured patients would achieve less sleep based on involvement of key anatomical structures.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e However, those admitted for medical critical illness slept less often than those with neurocritical disease in our analysis. Diffuse systemic inflammatory processes, such as sepsis, may affect sleep more severely by disrupting blood-brain barrier integrity.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Furthermore, critical systemic illness may disrupt the normal circadian rhythm.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003ePatients who slept less in our cohort had poorer functional outcomes. Short and long-term effects of sleep loss may impair immune recovery while negatively impacting cardiovascular and pulmonary function.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Polysomnography (PSG) is a reliable outpatient method used to qualify, and quantify, sleep. However, PSG has not been validated to examine sleep in the ICU. Continuous electroencephalographic monitoring is increasingly used in the critically-ill and may serve as a useful surrogate biomarker for sleep characterization. Actigraphy, a non-invasive worn device measuring rest and activity cycles, has tested circadian rhythm timing and sleep-associated variables in the critical care setting.\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e However, this modality does not record cerebral electrophysiology, thus conclusions about sleep can only be extrapolated. Improved identification of sleep-associated variables, based on AASM standardized metrics, can be better characterized (i.e. sleep stages) by cEEG monitoring.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eRecent critical care guidelines proposed early progressive mobilization to prevent delirium; importantly, the report underscored sleep promotion and minimizing sleep disruption as key strategies to impact survivor outcome.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Patients with prior brain injury are at risk of developing circadian rhythm dysfunction. Stroke and TBI survivors are 40% more likely to be diagnosed with a sleep disorder, and little is known about predisposing risks or impact of interventions to minimize sleep disruption in this population.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Other important variables that may influence sleep among the critically ill, such as the potential impact of continuous enteral feeding, require ongoing investigation.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eWe examined a diverse population of critically ill patients and evaluated the effect of commonly used sedatives on sleep. Expectedly, patients achieved sleep more often when these medications were not used; however, anesthetic administration did not exclusively predict why those with neurological injury achieved sleep more often compared to those without brain insults.\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eInherent limitations exist with any single center, retrospective study. However, uniformity in how clinical practice is administered and information collected should minimize data variability. Several useful clinical variables were not systematically recorded such as the Glasgow Coma Scale in medical and surgical patients, individual circadian sleep timing, or pre-existing sleep disorder diagnoses due to low prevalence. Study patients underwent cEEG monitoring for various clinical indications, generating a potential bias towards those with greater medical complexity who may have less \u0026ldquo;central neurologic reserve.\u0026rdquo;\u003c/p\u003e\u003cp\u003eExamining how these variables as well as other pharmacologic therapies (i.e. anticonvulsants, antipsychotics, antimicrobials, opiates, tricyclics and other antidepressants) might influence sleep in future studies will be informative. Lastly, dexmedetomidine was an anesthetic infrequently used in our cohort and not analyzed independently\u0026mdash;its application in delirium prevention in critically ill patients is becoming increasingly recognized.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMost critically ill patients do not achieve electrophysiologic sleep and those that do reach N1/N2 stages only. However, achieving any sleep was associated with more favorable functional outcome, and neurological patients slept more often. Sleep appears to be an important variable in the critically ill even when reaching \u0026lsquo;lighter\u0026rsquo; restorative stages. Further studies are needed to standardize measurements of sleep in the ICU, determine effective interventions that promote it, and examine the impact of sleep on critical care outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank our patients and their families for their participation and willingness to share results with the academic community. We dedicate this manuscript to the memory of our co-authors, Dr. Ajay Sampat and Dr. Machelle D. Wilson, who passed away during the course of this work. Dr. Sampat’s contributions, mentorship, and dedication to the field of Sleep Neurology is invaluable and was instrumental in completing this research. Dr. Wilson’s expertise in statistics and data analysis provided critical insight and strengthened the rigor of our work. We honor both of their legacies and lasting impact on our community.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDetails Page\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is original work that has not been published elsewhere and is not under consideration by any other journal. The manuscript complies with all instructions to authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLC West- Conceptualization, Methodology, Data curation, Formal analysis, Writing, Editing\u003c/p\u003e\n\u003cp\u003eR Dutta- \u0026nbsp;Methodology, Data curation, Formal analysis, Writing, Editing\u003c/p\u003e\n\u003cp\u003eLC West and R Dutta contributed equally to the research and writeup of this work.\u003c/p\u003e\n\u003cp\u003eAH Yee- Supervision, Conceptualization, Methodology, Data curation, Formal analysis, Writing, Reviewing and Editing\u003c/p\u003e\n\u003cp\u003eMD Wilson- Statistical analysis, Data visualization, Reviewing and Editing\u003c/p\u003e\n\u003cp\u003eGA Palchick- Conceptualization, Methodology, Reviewing and Editing\u003c/p\u003e\n\u003cp\u003eA Sampat- Conceptualization, Methodology, Reviewing and Editing\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the manuscript and have no conflicts of interest to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures:\u0026nbsp;\u003c/strong\u003eLC West reports no disclosures relevant to the manuscript, R Dutta reports no disclosures relevant to the manuscript, A Sampat reports no disclosures relevant to the manuscript, \u0026nbsp;MD Wilson reports no disclosures relevant to the manuscript, GA Palchik reports no disclosures relevant to the manuscript, AH Yee received research grant funding from the American Osteopathic Association (grant #: 23151879) and serves as a neurology consultant for Janux Biotechnology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Compliance Statement:\u0026nbsp;\u003c/strong\u003eThis research study was approved by the University of California Davis Institutional Review Board. Consent was waived for this review. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources:\u003c/strong\u003e MD Wilson PhD was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR001860. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.\u003c/p\u003e\n\u003cp\u003eThe authors confirm use of a reporting checklist (STROBE).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChang VA, Owens RL, LaBuzetta JN. Impact of sleep deprivation in the neurological intensive care unit: a narrative review. Neurocritical Care. 2020;32:596-608.\u003c/li\u003e\n\u003cli\u003eFreedman NS, Gazendam J, Levan L, Pack AI, Schwab RJ. Abnormal sleep/wake cycles and the effect of environmental noise on sleep disruption in the intensive care unit. American Journal of Respiratory and Critical Care Medicine. 2001;163:451-7.\u003c/li\u003e\n\u003cli\u003eFriese RS, Diaz-Arrastia R, McBride D, Frankel H, Gentilello LM. Quantity and quality of sleep in the surgical intensive care unit: are our patients sleeping?. Journal of Trauma and Acute Care Surgery. 2007;63:1210-4.\u003c/li\u003e\n\u003cli\u003eFranck L, Tourtier JP, Libert N, Grasser L, Auroy Y. How did you sleep in the ICU?. Critical Care. 2011;15:1-10.\u003c/li\u003e\n\u003cli\u003eElliott R, McKinley S, Cistulli P, Fien M. Characterisation of sleep in intensive care using 24-hour polysomnography: an observational study. Critical Care. 2013;17:1-10.\u003c/li\u003e\n\u003cli\u003eForeman B, Westwood AJ, Claassen J, Bazil CW. Sleep in the neurological intensive care unit: feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction. Journal of Clinical Neurophysiology. 2015;32:66-74.\u003c/li\u003e\n\u003cli\u003eClaassen J, Hirsch LJ, Frontera JA, Fernandez A, Schmidt M, Kapinos G, Wittman J, Connolly ES, Emerson RG, Mayer SA. Prognostic significance of continuous EEG monitoring in patients with poor-grade subarachnoid hemorrhage. Neurocritical care. 2006;4:103-12.\u003c/li\u003e\n\u003cli\u003eVan Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, Van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604-7.\u003c/li\u003e\n\u003cli\u003eMukhopadhyay A, Tai BC, Remani D, Phua J, Cove ME, Kowitlawakul Y. Age related inverse dose relation of sedatives and analgesics in the intensive care unit. Plos One. 2017; 28;12.\u003c/li\u003e\n\u003cli\u003eCastriotta RJ \u0026amp; Murth JN. Sleep disorders in patients with traumatic brain injury. CNS drugs, 2011 25(3), 175-185. \u003c/li\u003e\n\u003cli\u003eMantua J, Grillakis A, Sahfouz SH, Taylor MR, Brager AJ, Yarnell AM, Balkin TJ, Capaldi VF Simonelli G. A systematic review and meta-analysis of sleep architecture and chronic traumatic brain injury. Sleep Medicine Reviews. 2018; 41:61-77.\u003c/li\u003e\n\u003cli\u003eAoun R, Rawal H, Attarian H, Sahni A. Impact of traumatic brain injury on sleep: an overview. Nature and Science of Sleep, 2019; 11: 131.\u003c/li\u003e\n\u003cli\u003eOpp MR, George A, Ringgold KM, Hansen KM, Bullock KM, Banks WA. Sleep fragmentation and sepsis differentially impact blood\u0026ndash;brain barrier integrity and transport of tumor necrosis factor-\u0026alpha; in aging. Brain, Behavior, and Immunity. 2015; 11;1,50:259-65.\u003c/li\u003e\n\u003cli\u003eTruong KK, Lam MT, Grandner MA, Sassoon CS, Malhotra A. Timing matters: circadian rhythm in sepsis, obstructive lung disease, obstructive sleep apnea, and cancer. Annals of the American Thoracic Society. 2016;13,7:1144-54.\u003c/li\u003e\n\u003cli\u003eMaas MB, Iwanaszko M, Lizza BD, Reid KJ, Braun RI, Zee PC. Circadian gene expression rhythms during critical illness. Critical Care Medicine. 2020; 1;48, 12:e1294-9.\u003c/li\u003e\n\u003cli\u003eRichards KC, O\u0026rsquo;Sullivan PS, Phillips RL. Measurement of sleep in critically ill patients. Journal of Nursing Measurement. 2000;8:131-44.\u003c/li\u003e\n\u003cli\u003eJeffs EL, Darbyshire JL. Measuring sleep in the intensive care unit: a critical appraisal of the use of subjective methods. Journal of Intensive Care Medicine. 2019;34:751-60.\u003c/li\u003e\n\u003cli\u003eDuclos C, Dumont M, Paquet J, Blais H, Van der Maren S, Menon DK, Bernard F, Gosselin N. Sleep-wake disturbances in hospitalized patients with traumatic brain injury: association with brain trauma but not with an abnormal melatonin circadian rhythm. Sleep. 2020;43:1-9.\u003c/li\u003e\n\u003cli\u003eTiruvoipati R, Mulder J, Haji K. Improving Sleep in Intensive Care Unit: An Overview of Diagnostic and Therapeutic Options. Journal of Patient Experience. 2020;7:697-702.\u003c/li\u003e\n\u003cli\u003eHu RF, Jiang XY, Chen J, Zeng Z, Chen XY, Li Y, Huining X, Evans DJ, Wang S. Non‐pharmacological interventions for sleep promotion in the intensive care unit. Cochrane Database of Systematic Reviews. 2015;10.\u003c/li\u003e\n\u003cli\u003eDevlin JW, Skrobik Y, G\u0026eacute;linas C, Needham DM, Slooter AJ, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical Care Medicine. 2018;46:e825-73.\u003c/li\u003e\n\u003cli\u003eBerry R, Quan S, Abreu AR for the American Academy of Sleep Medicine. The AASM Manual for the scoring of sleep and associated events: rules, terminology and technical specifications. American Academy of Sleep Medicine, Darien (IL) 2020. Version 2.6 \u003c/li\u003e\n\u003cli\u003eWickwire EM, Williams SG, Roth T, Capaldi VF, Jaffe M, Moline M, Motamedi GK, Morgan GW, Mysliwiec V, Germain A, Pazdan RM. Sleep, sleep disorders, and mild traumatic brain injury. What we know and what we need to know: findings from a national working group. Neurotherapeutics. 2016;13:403-17.\u003c/li\u003e\n\u003cli\u003eLeng Y, Byers AL, Barnes DE, Peltz CB, Li Y, Yaffe K. Traumatic Brain Injury and Incidence Risk of Sleep Disorders in Nearly 200,000 US Veterans. Neurology. 2021;96:e1792-9.\u003c/li\u003e\n\u003cli\u003eMcKenna H, van der Horst GT, Reiss I, Martin D. Clinical chronobiology: a timely consideration in critical care medicine. Critical Care. 2018;22:1-10.\u003c/li\u003e\n\u003cli\u003eMarra A, Ely EW, Pandharipande PP, Patel MB. The ABCDEF bundle in critical care. Critical care clinics. 2017;33:225-43.\u003c/li\u003e\n\u003cli\u003eSkrobik Y, Duprey MS, Hill NS, Devlin JW. Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial. American journal of respiratory and critical care medicine. 2018;197:1147-56.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 3","content":"\u003cp\u003eTable 3 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"sleep stages, critically ill, outcome assessment, electrophysiology","lastPublishedDoi":"10.21203/rs.3.rs-6977598/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6977598/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eExamine the association between sleep and clinical outcome in patients with acute brain injury and critical illness.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eRetrospective analysis of critically ill patients who underwent continuous electroencephalography monitoring in an academic medical center from 2018\u0026ndash;2020. Patients admitted with primary neurologic, medical, and surgical conditions were included. Clinical outcome was determined by the modified Rankin Scale (mRS\u0026thinsp;\u0026lt;\u0026thinsp;3 represented favorable outcome). Statistical modeling of outcome included predictor variables controlling for anesthetic concentration, diagnosis, and sex.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e262 patients were included of which 57% were male with a mean age of 58 years (range 18\u0026ndash;91). Twenty-one percent of the total population achieved sleep (56/262). Of those achieving any sleep, 43% had good outcomes compared to only 26% who did not (χ\u0026sup2; =10.99, p\u0026thinsp;=\u0026thinsp;0.0009), controlling for diagnosis, sex, anesthetic level, and Acute Physiology and Chronic Health Evaluation score. Neurological patients attained sleep more often (27%) compared to those with other primary diagnoses (14%). In multivariable analysis, the effect of level of centrally acting anesthetics did not account for sleep differences between neurologic and non-neurological patients (χ\u0026sup2; =3.5, p\u0026thinsp;=\u0026thinsp;0.95).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eNeurocritical patients slept more often, and obtaining any sleep was associated with better functional outcome when controlling disease severity. Further studies are needed to determine whether sleep augmentation and anesthetic use in critically ill patients impact functional outcomes.\u003c/p\u003e","manuscriptTitle":"Association Between Sleep and Functional Outcome in Critically Ill Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 10:26:56","doi":"10.21203/rs.3.rs-6977598/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4dce12fb-25c4-40ac-9bfa-c41b26531e74","owner":[],"postedDate":"July 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-05T19:57:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-14 10:26:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6977598","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6977598","identity":"rs-6977598","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}