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Potentially Modifiable Risk Factors for Long-Term Cognitive Impairment After Critical Illness: A Systematic Review

      Abstract

      Long-term cognitive impairment is common in survivors of critical illness. Little is known about the etiology of this serious complication. We sought to summarize current scientific knowledge about potentially modifiable risk factors during intensive care unit (ICU) treatment that may play a substantial role in the development of long-term cognitive impairment. All searches were run on October 1, 2017. The search strategy included Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central Register of Controlled Trials and Database of Abstracts of Reviews of Effect, Scopus, and Web of Science, and included MeSH headings and keywords related to intensive care, critical care, and cognitive disorders. Searches were restricted to adult subjects. Inclusion required follow-up cognitive evaluation at least 2 months after ICU discharge. Studies assessing patients with cardiac arrest, traumatic brain injury, and cardiac surgery history were excluded. The search strategy resulted in 3180 studies. Of these, 28 studies (.88%) met our inclusion criteria and were analyzed. Delirium and duration of delirium were associated with long-term cognitive impairment after ICU admission in 6 of 9 studies in which this factor was analyzed. Weaker and more inconsistent associations have been reported with hypoglycemia, hyperglycemia, fluctuations in serum glucose levels, and in-hospital acute stress symptoms. Instead, most of the studies did not find significant associations between long-term cognitive impairment and mechanical ventilation; use of sedatives, vasopressors, or analgesic medications; enteral feeding; hypoxia; extracorporeal membrane oxygenation; systolic blood pressure; pulse rate; or length of ICU stay. Prolonged delirium may be a risk factor for long-term cognitive impairment after critical illness, though this association has not been entirely consistent across studies. Other potentially preventable factors have not been shown to have strong or consistent associations with long-term cognitive dysfunction in survivors of critical illness.

      Abbreviations and Acronyms:

      ARDS (acute respiratory distress syndrome), ICU (intensive care unit)
      Article Highlights
      • Long-term cognitive impairment is common in survivors of critical illness. It can be greatly taxing to patients and their families, and it has enormous societal cost, with a total estimate of $18 billion per year.
      • Little is known about the etiology of this serious complication. Available evidence suggests that prolonged delirium is the potentially modifiable factor most strongly associated with post–intensive care unit (ICU) cognitive impairment. Weaker and more inconsistent associations have been reported with hypoglycemia, hyperglycemia, fluctuations in serum glucose levels, and in-hospital acute stress symptoms. Instead, most of the studies did not find significant associations between long-term cognitive impairment and mechanical ventilation; use of sedatives, vasopressors, or analgesic medications; enteral feeding; hypoxia; extracorporeal membrane oxygenation; systolic blood pressure; pulse rate; or length of ICU stay.
      • High-quality research on a large cohort of critically ill patients is necessary to better characterize potentially modifiable risk factors for persistent cognitive impairment after ICU hospitalization.
      Long-term cognitive impairment after critical illness remains a significant public health burden. Each year, millions of patients are treated in intensive care units (ICUs) across the United States, and many of them end up being cognitively impaired.
      • Karnatovskaia L.V.
      • Johnson M.M.
      • Benzo R.P.
      • Gajic O.
      The spectrum of psychocognitive morbidity in the critically ill: a review of the literature and call for improvement.
      The incidence of cognitive decline after critical illness has been highly variable (4%-64%) in different studies.
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      • Jackson J.C.
      • Obremskey W.
      • Bauer R.
      • et al.
      Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage.
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      • Duning T.
      • van den Heuvel I.
      • Dickmann A.
      • et al.
      Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.
      Cognitive impairment after ICU admission can be greatly taxing to patients and their families, and it has enormous societal cost, with a total estimate of $18 billion per year.
      • Langa K.M.
      • Chernew M.E.
      • Kabeto M.U.
      • et al.
      National estimates of quality and cost of informal care giver for the elderly with dementia.
      • Rockwood K.
      • Brown M.
      • Merry H.
      • Sketris I.
      • Fisk J.
      Vascular Cognitive Impairment Investigators of the Canadian Study of Health and Aging
      Societal cost of vascular cognitive impairment in older adults.
      To date, a number of studies have evaluated the incidence of long-term cognitive impairment after critical illness.
      • Wolters A.E.
      • Slooter A.J.
      • van der Kooi A.W.
      • van Dijk D.
      Cognitive impairment after intensive care unit admission: a systematic review.
      However, risk factors, particularly preventable ones, are not well understood. We sought to summarize current knowledge about potentially modifiable risk factors during ICU treatment that may influence the development of long-term cognitive impairment.

      Patients and Methods

      With the assistance of an expert librarian, we developed search strategies and applied them to Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central Register of Controlled Trials and Database of Abstracts of Reviews of Effects, Scopus, and Web of Science. All searches were run on October 1, 2017. There were no restrictions on publication date; searches were restricted to adult subjects. The search strategy included MeSH headings and keywords related to intensive care, critical care, and cognitive disorders (Supplemental Table 1, available online at http://www.mayoclinicproceedings.org). Each study abstract was evaluated independently by 2 investigators. We excluded studies in languages other than English, case reports and case series with less than 10 patients, animal studies, reviews, comments, editorials, letters to the editor, studies that assessed cognitive function only within 2 months of ICU discharge, and studies focused on patients admitted to the ICU because of cardiac arrest, traumatic brain injury, or cardiac surgery history.
      To compare and reconcile independent evaluations, we used Covidence, an online tool for systematic reviews.
      Covidence. Accelerate your systematic review.
      This software allows searches of abstracts and full texts to be uploaded and evaluated by each investigator blinded to the other evaluator's determinations. Disagreements are flagged for resolution. We resolved such cases using third reviewer adjudication. After screening abstracts, full texts were obtained and evaluated in the same way. We then abstracted data from each study using a standardized form. Because the primary aim of our systematic review was to evaluate potentially modifiable risk factors during the ICU stay, we focused on ICU exposures such as delirium and duration of delirium, mechanical ventilation and duration of mechanical ventilation; use of sedatives, analgesic medications, or vasopressors; extracorporeal membrane oxygenation; presence of in-hospital acute stress symptoms; blood product transfusion; blood loss; hematocrit level; hypoglycemia, hyperglycemia, and fluctuations in blood glucose levels; enteral feeding; hypoxia; and length of ICU stay. We used the Downs and Black checklist
      • Downs S.H.
      • Black N.
      The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
      to assess the quality of each included study.

      Results

      Our search strategy identified 3180 studies. Of these, 28 studies met our inclusion criteria. Details are provided in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram shown in the Figure.
      Figure thumbnail gr1
      FigureThe search flow diagram. ICU = intensive care unit.
      Of the 28 included studies, 13 evaluated patients admitted to mixed (medical and surgical) ICUs, 6 included patients from medical ICUs, 7 studied patients from surgical or trauma ICUs, and the remaining 2 studies did not report the type of ICU. Study designs were prospective observational in 23 articles, retrospective in 3, case-control in 1, and randomized controlled trial in 1. Study design and characteristics are summarized in Table 1.
      • Ambrosino N.
      • Bruletti G.
      • Scala V.
      • Porta R.
      • Vitacca M.
      Cognitive and perceived health status in patient with chronic obstructive pulmonary disease surviving acute on chronic respiratory failure: a controlled study.
      • de Azevedo J.R.
      • Montenegro W.S.
      • Rodrigues D.P.
      • et al.
      Long-term cognitive outcomes among unselected ventilated and non-ventilated ICU patients.
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      • Girard T.D.
      • Jackson J.C.
      • Pandharipande P.P.
      • et al.
      Delirium as a predictor of long-term cognitive impairment in survivors of critical illness.
      • Gunther M.L.
      • Morandi A.
      • Krauskopf E.
      • et al.
      VISIONS Investigation, VISualizing Icu SurvivOrs
      The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study.
      • Hope A.A.
      • Morrison R.S.
      • Du Q.
      • Wallenstein S.
      • Nelson J.E.
      Risk factors for long-term brain dysfunction after chronic critical illness.
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      • Hopkins R.O.
      • Weaver L.K.
      • Chan K.J.
      • Orme Jr., J.F.
      Quality of life, emotional, and cognitive function following acute respiratory distress syndrome.
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      • Hopkins R.O.
      • Weaver L.K.
      • Collingridge D.
      • Parkinson R.B.
      • Chan K.J.
      • Orme Jr., J.
      Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome.
      • Jackson J.C.
      • Archer K.R.
      • Bauer R.
      • et al.
      A prospective investigation of long-term cognitive impairment and psychological distress in moderately versus severely injured trauma intensive care unit survivors without intracranial hemorrhage.
      • Jackson J.C.
      • Girard T.D.
      • Gordon S.M.
      • et al.
      Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.
      • Jones C.
      • Griffiths R.D.
      • Slater T.
      • Benjamin K.S.
      • Wilson S.
      Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness.
      • Mikkelsen M.E.
      • Christie J.D.
      • Lanken P.N.
      • et al.
      The adult respiratory distress syndrome cognitive outcomes study long-term neuropsychological function in survivors of acute lung injury.

      Mitchell ML, Shum DHK, Mihala G, Murfield JE, Aitken LM. Long term cognitive impairment and delirium in intensive care: a prospective cohort study [published online ahead of print July 20, 2017]. Aust Crit Care. https://doi.org/10.1016/j.aucc.2017.07.002.

      • Morandi A.
      • Rogers B.P.
      • Gunther M.L.
      • et al.
      The relationship between delirium duration, white matter integrity and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging.
      • Needham D.M.
      • Dinglas V.D.
      • Morris P.E.
      • et al.
      NIH NHLBI ARDS Network
      Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding EDEN trial follow-up.
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      • Richards J.E.
      • Guillamondegui O.D.
      • Archer K.R.
      • Jackson J.C.
      • Ely E.W.
      • Obremskey W.T.
      The association of reamed intramedullary nailing and long-term cognitive impairment.
      • de Rooij S.E.
      • Govers A.C.
      • Korevaar J.C.
      • Giesbers A.W.
      • Levi M.
      • de Jonge E.
      Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment.
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      • Semmler A.
      • Widmann C.N.
      • Okulla T.
      • et al.
      Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.
      • Woon F.L.
      • Dunn C.B.
      • Hopkins R.O.
      Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests.
      • van den Boogaard M.
      • Schoonhoven L.
      • Evers A.W.
      • van der Hoeven J.G.
      • van Achterberg T.
      • Pickkers P.
      Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning.
      Table 1Study Design and Characteristics
      Reference, yearStudy designSettingCasesControlsCognitive evaluation/time of cognitive assessmentDefinition of cognitive impairment
      Ambrosino et al,
      • Ambrosino N.
      • Bruletti G.
      • Scala V.
      • Porta R.
      • Vitacca M.
      Cognitive and perceived health status in patient with chronic obstructive pulmonary disease surviving acute on chronic respiratory failure: a controlled study.
      2002
      Prospective controlled cohort studyRespiratory ICU63 Patients with COPD at their first episode of acute or chronic respiratory failure required mechanical ventilation34 Stable patients with COPD receiving long-term oxygen therapyMMS at discharge and 3 and 6 mo after ICU dischargeMaximum score is 30; score <24 indicates cognitive impairment
      de Azevedo et al,
      • de Azevedo J.R.
      • Montenegro W.S.
      • Rodrigues D.P.
      • et al.
      Long-term cognitive outcomes among unselected ventilated and non-ventilated ICU patients.
      2017
      Prospective observational cohort studyMedical and surgical ICUs206 ICU survivors with cognitive impairment207 ICU survivors without cognitive impairmentFTT, RAVLT, clock-drawing test, verbal fluency test, MMSE1.5 SD below the mean on 2 of the index scores or 2 SD below the mean on 1 of the index scores—mild cognitive impairment; 1.5 SD below the mean on ≥3 of the index scores or 2 SD below the mean on ≥2 of the index scores—severe cognitive impairment
      Davydow et al,
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      2013
      Prospective cohort studyMedical and surgical ICUs120 Nontraumatic ICU patients completed cognitive evaluation 12 mo after dischargePatients with IHASS vs those without IHASS (specific number, not reported)Modified Telephone Interview for Cognitive Status at 12 mo after ICU dischargeNot precisely defined/cognitive impairment was assessed using a cutoff score of ≥3 errors on the 6-item cognitive screen. Maximum possible score is 39, with higher scores indicating better cognitive status
      Duning et al,
      • Duning T.
      • van den Heuvel I.
      • Dickmann A.
      • et al.
      Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.
      2010
      Case-control studySurgical ICU37 Patients with hypoglycemia37 Patients with hypoglycemia vs matched controls (those without hypoglycemia)Battery of validated neuropsychological tests investigating 5 areas of cognitive functioning at least 1 y after ICU dischargeTest results were compared with the published normative data
      • Lezak M.D.
      Neuropsychological Assestment. 4th ed.
      Girard et al,
      • Girard T.D.
      • Jackson J.C.
      • Pandharipande P.P.
      • et al.
      Delirium as a predictor of long-term cognitive impairment in survivors of critical illness.
      2010
      Prospective control studyMedical ICU65 Patients who experienced delirium during the ICU stay12 Patients without deliriumIn-person cognitive evaluation by neuropsychologists at 3 and 12 mo after discharge; comprehensive battery of 9 neuropsychological tests designed to measure 7 main domains of cognitive functioning used for the assessment2 cognitive test scores 1.5 SD below the mean or 1 cognitive test score 2 SD below the mean—mild to moderate cognitive impairment. ≥3 cognitive test scores 1.5 SD below the mean or ≥2 cognitive test scores 2 SD below the mean—severe cognitive impairment. Scores better than 1.5 SD below the mean on all 9 tests—no cognitive impairment
      Gunther et al,
      • Gunther M.L.
      • Morandi A.
      • Krauskopf E.
      • et al.
      VISIONS Investigation, VISualizing Icu SurvivOrs
      The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study.
      2012
      Prospective cohort studyMedical and surgical ICUs47 ICU survivors with respiratory failure or shockComparison was made using the RBANSRBANS at 12 mo after ICU discharge≤69, extremely low; 70-79, borderline; 80-89, low average; 90-109, average; 110-119, high average; 120-129, superior; ≥130, very superior
      Hope et al,
      • Hope A.A.
      • Morrison R.S.
      • Du Q.
      • Wallenstein S.
      • Nelson J.E.
      Risk factors for long-term brain dysfunction after chronic critical illness.
      2013
      Prospective cohort studyRespiratory ICU108 Patients with cognitive impairment after chronic critical illness59 Patients without cognitive impairment after chronic critical illnessTelephone Confusion Assessment Method at 6 mo after dischargeToo cognitively impaired for the telephone Confusion Assessment Method or delirious by telephone—alive with brain dysfunction

      Not delirious by the telephone Confusion Assessment Method —alive without brain dysfunction
      Hopkins et al,
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      1999
      Retrospective studyMedical and surgical ICUs30 Patients with cognitive impairment36 Patients without cognitive impairmentBattery of neuropsychological tests (WAIS-R, WMS-R, RAVLT, ROCF, immediate recall and 30-min delayed recall, TMT Parts A and B, verbal fluency test) at 1 y after discharge≥2 cognitive test scores that were >1.5 SD or 1 test score that was >2 SD below the normative population mean values
      Hopkins et al,
      • Hopkins R.O.
      • Weaver L.K.
      • Chan K.J.
      • Orme Jr., J.F.
      Quality of life, emotional, and cognitive function following acute respiratory distress syndrome.
      2004
      Prospective longitudinal outcome studyMedical and surgical ICUs30 ARDS ICU survivors with cognitive sequelae36 ARDS ICU survivors without cognitive sequelaeNeuropsychological tests (WAIS-R, WMS-R, RAVLT, ROCF, TMT Parts A and B, verbal fluency test) at 1 y after hospital dischargeScores on ≥2 neuropsychological tests that were >1.5 SD or 1 test score that was >2 SD below the normative population mean
      Hopkins et al,
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      2010
      Prospective studyShock-Trauma

      Intermountain Respiratory ICU
      55 ARDS survivors who have reached 1 y follow-upNormative population meanWAIS-R, WMS-R, RAVLT, ROCF (copy, immediate recall, and 30-min delayed recall), TMT Parts A and B at 1 y after entry into the ARDS studyCompared with normative population data
      Hopkins et al,
      • Hopkins R.O.
      • Weaver L.K.
      • Collingridge D.
      • Parkinson R.B.
      • Chan K.J.
      • Orme Jr., J.
      Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome.
      2005
      Longitudinal prospective cohort studyType of ICU was not reported66 ARDS survivors who have reached 1 y follow-up; 62 ARDS survivors who have reached 2 y follow-upNormative population meanWAIS-R, WMS-R, RAVLT, ROCF (copy, immediate recall, and 30-min delayed recall), TMT Parts A and B, verbal fluency test at 2 y after hospital discharge≥2 neuropsychological tests scored ≥1.5 SDs below the mean or ≥1 tests scored ≥2 SDs below the mean
      Jackson et al,
      • Jackson J.C.
      • Archer K.R.
      • Bauer R.
      • et al.
      A prospective investigation of long-term cognitive impairment and psychological distress in moderately versus severely injured trauma intensive care unit survivors without intracranial hemorrhage.
      2011
      Prospective cohort studyTrauma ICU71 Severely injured trauma ICU survivors37 Moderately injured trauma ICU survivorsComprehensive battery of neuropsychological tests (MMSE, ROCF, TMT Parts A and B, Digit Span subtest, Digit Symbol subtest, FAS, IQCODE-SF) at 1 y after hospital dischargeCognitive impairment was defined as having 2 neuropsychological test scores that were 1.5 SD below the mean or 1 neuropsychological test score that was 2 SD below the mean
      Jackson et al,
      • Jackson J.C.
      • Obremskey W.
      • Bauer R.
      • et al.
      Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage.
      2007
      Prospective observational pilot studyTrauma ICU58 Adult ICU survivors without intracranial hemorrhage with injury severity score >25Normative population meanComprehensive battery of cognitive instruments (MMSE, ROCF, TMT Parts A and B, Digit Span subtest, Digit Symbol subtest, FAS, IQCODE-SF) at 12 and 24 mo after ICU discharge2 neuropsychological test scores that were 1.5 SD below the mean or 1 neuropsychological test score that was 2 SD below the mean were defined as cognitively impaired
      Jackson et al,
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      2003
      Prospective cohort studyMedical ICU11 Cognitively impaired and mechanically ventilated ICU patients23 Cognitively normal and mechanically ventilated ICU patientsBattery of neuropsychological tests (APACHE II, CAM-ICU, GCS, GDS-SF, MMSE, RASS, SOFA) at 6 mo after ICU discharge2 neuropsychological test scores that were at least 2 SD below the norm-referenced mean or 3 scores that were at least 1.5 SD below the norm-referenced mean
      Jackson et al,
      • Jackson J.C.
      • Girard T.D.
      • Gordon S.M.
      • et al.
      Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.
      2010
      Single-center randomized trialMedical ICU89 Patients undergoing a wake-up and breathe protocol that paired daily spontaneous breathing trials91 Patients with usual care (patient-targeted sedation) and undergoing a spontaneous breathing trial protocolBattery of neuropsychological tests (Digit Span subtest, Digit Symbol subtest—Coding, MMSE, RAVLT, ROCF, TMT Parts A and B, verbal fluency test, Psychological Assessments Awareness Questionnaire, BDI-II, PTSD-10 for the ICU, Functional Assessment Screening Questionnaire, Katz ADL, SF-36)≥2 neuropsychological tests scored ≥1.5 SDs below the mean or ≥1 tests scored ≥2 SDs below the mean
      Jones et al,
      • Jones C.
      • Griffiths R.D.
      • Slater T.
      • Benjamin K.S.
      • Wilson S.
      Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness.
      2006
      Prospective studyMedical and surgical ICUs16 Nondelirious ICU patients who underwent tracheal intubation and without sedationComparison was made according to the CANTABCANTAB at 1 wk after ICU discharge, on the general ward, and 2 mo after dischargeNot reported
      Mikkelsen et al,
      • Mikkelsen M.E.
      • Christie J.D.
      • Lanken P.N.
      • et al.
      The adult respiratory distress syndrome cognitive outcomes study long-term neuropsychological function in survivors of acute lung injury.
      2012
      Prospective multicenter cohort studyType of ICU was not reported41 Acute lung injury survivors with cognitive impairment34 Acute lung injury survivors without cognitive impairmentTelephone-administered battery of standardized neuropsychological testsScore that was >2 SD below the normative population data
      Mitchell et al,

      Mitchell ML, Shum DHK, Mihala G, Murfield JE, Aitken LM. Long term cognitive impairment and delirium in intensive care: a prospective cohort study [published online ahead of print July 20, 2017]. Aust Crit Care. https://doi.org/10.1016/j.aucc.2017.07.002.

      2017
      Prospective cohort studyMedical and surgical ICUs15 ICU survivors who experienced delirium during the ICU stay64 ICU survivors without delirium during the ICU stayRBANS, TMT Parts A and B, MMSE1.5 SD below the mean on 2 of the index scores or 2 SD below the mean on one of the index scores—mild cognitive impairment; 1.5 SD below the mean on ≥3 of the index scores or 2 SD below the mean on ≥2 of the index scores—severe cognitive impairment
      Morandi et al,
      • Morandi A.
      • Rogers B.P.
      • Gunther M.L.
      • et al.
      The relationship between delirium duration, white matter integrity and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging.
      2012
      Two-center prospective cohort studyMedical, surgical, and cardiac ICUs47 Adult patients admitted to ICUs with respiratory failure or shockComparison was made using the RBANSRBANS at 3 and 12 mo after ICU dischargeNot reported
      Needham et al,
      • Needham D.M.
      • Dinglas V.D.
      • Morris P.E.
      • et al.
      NIH NHLBI ARDS Network
      Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding EDEN trial follow-up.
      2013
      Multicenter prospective longitudinal studyMedical ICU81 Adult ICU patients who survived acute lung injury and were receiving trophic feeding82 Adult ICU patients who survived acute lung injury and were receiving full enteral feedingHSCT, COWAT, Logical Memory I and Logical Memory II age-adjusted scaled scores, Digit Span subtest age-adjusted scaled score at 12 mo after discharge1 Cognitive test within the battery with a score at least 2 SDs below population norms or 2 tests with a score ≥1.5 SDs below population norms
      Pandharipande et al,
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      2013
      Prospective studyMedical and surgical ICUs448 Patients with respiratory failure, cardiogenic shock, or septic shock were cognitively evaluated at 3 mo after ICU discharge; 382 patients were evaluated at 12 mo after ICU discharge (59 died in between)Normative population meanRBANS at 3 and 12 mo after ICU dischargeGlobal cognition scores 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury) and scores 2 SD below the population means (similar to scores for patients with Alzheimer disease)
      Richards et al,
      • Richards J.E.
      • Guillamondegui O.D.
      • Archer K.R.
      • Jackson J.C.
      • Ely E.W.
      • Obremskey W.T.
      The association of reamed intramedullary nailing and long-term cognitive impairment.
      2011
      Prospective observational studyTrauma ICU59 Cognitively impaired trauma ICU patients with multiple trauma (Injury Severity Score>15) without evidence of intracranial hemorrhage49 Cognitively normal trauma ICU patients with multiple trauma (Injury Severity Score>15) without evidence of intracranial hemorrhageMMSE, RAVLT, ROCF, Digit Symbol subtest—Coding, TMT Parts A and B, Digit Span subtest at 1 y after hospital discharge2 Neuropsychological test scores 1.5 SD below the mean or 1 neuropsychological test score 2 SD below the mean
      de Rooij et al,
      • de Rooij S.E.
      • Govers A.C.
      • Korevaar J.C.
      • Giesbers A.W.
      • Levi M.
      • de Jonge E.
      Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment.
      2008
      Retrospective cohort studyMedical and surgical ICUs178 Patients who underwent planned surgery15 Patients who underwent unplanned surgery; 11 patients with medical treatment without surgeryIQCODE-SF at 1-6 y after ICU dischargeIQCODE-SF score >3.9, dementia; IQCODE-SF score 3.1-3.9, mild to moderate cognitive impairment; IQCODE-SF score <3.1, normal cognition
      Rothenhäusler et al,
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      2001
      Exploratory retrospective studyMultidisciplinary ICU11 ARDS survivors with cognitive impairment35 ARDS survivors without cognitive impairmentSKT at a median time of 6 y after ICU dischargeProfound cognitive impairment, 24-27; severe cognitive impairment, 19-23; moderate cognitive impairment, 14-18; mild cognitive impairment, 9-13; subthreshold, 5-8; no cognitive deficits, 0-4
      Semmler et al,
      • Semmler A.
      • Widmann C.N.
      • Okulla T.
      • et al.
      Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.
      2013
      Two-center prospective study with follow-upSurgical ICU25 Septic ICU survivors19 Nonseptic ICU survivorsNeuroCogFX (computerized assessment battery) at 6-24 mo after dischargeNot reported
      Torgersen et al,
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      2011
      Prospective studySurgical ICU28 ICU patients with >24 h ICU length of stay24 Surgical patients without ICU admissionMMSE at hospital discharge; CANTAB at 3 and 12 mo after dischargez Score below −2.0 SD on 2 out of 10 results or below −1.5 SD on 3 out of 10 results obtained from the CANTAB
      Woon et al,
      • Woon F.L.
      • Dunn C.B.
      • Hopkins R.O.
      Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests.
      2012
      Prospective studyShock trauma ICU and respiratory ICU53 ICU survivors who were mechanically ventilated for >48 h completed cognitive evaluation after dischargeNormative population meanMMSE and Mini-Cog at hospital discharge; WASI and standardized neurophysiological tests (SCWTGV, FTT, COWAT, WMT-III, LMS, CVLT, ROCF, WAIS-R, TNT Parts A and B, HSCT) at 6 mo after dischargeScores on ≥2 neuropsychological tests that were >1.5 SD or 1 test score that was >2 SD below the normative population mean
      van den Boogaard et al,
      • van den Boogaard M.
      • Schoonhoven L.
      • Evers A.W.
      • van der Hoeven J.G.
      • van Achterberg T.
      • Pickkers P.
      Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning.
      2012
      Prospective study4 Mixed ICUs171 Patients who were delirious during the ICU stay745 Patients who were not delirious during the ICU stayCognitive failure questionnaireTotal score 0-100, with higher scores indicating greater cognitive impairment
      APACHE II = Acute Physiology and Chronic Health Evaluation II; ARDS = acute respiratory distress syndrome; BDI- II = Beck Depression Inventory Two; CAM-ICU = Confusion Assessment Method for the Intensive Care Unit; CANTAB = Cambridge Neuropsychological Test Automated Battery; COPD = chronic obstructive pulmonary disease; COWAT = Controlled Oral Word Association Test; CVLT = California Verbal Learning Test; FAS = Verbal fluency test, generating as many possible words with F,A,S; FTT = finger tapping test; GCS = Glasgow Coma Scale; GDS-SF = Geriatric Depression Scale – Short Form; HSCT = Hayling Sentence Completion Test; ICU = intensive care unit; IHASS = in-hospital acute stress syndrome; IQCODE-SF = Informant Questionnaire on Cognitive Decline – Short Form; Katz ADL = Katz Activity of Daily Living; LMS = Logical Memory subtest; MMSE = Mini-Mental State Examination; PTSD = post traumatic stress disorder; RASS = Richmond Agitation-Sedation Scale; RAVLT = Rey Auditory Verbal Learning Test; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; ROCF = Rey-Osterrieth Complex Figure Test; SCWTGV = Stroop Color-Word Test-Golden Version; SF-36 = Short Form 36 SKT = short cognitive performance test for assessing deficits of memory and attention; SOFA = Sepsis-related Organ Failure Assessment; TMT Parts A and B = Trail Making Test Parts A and B; WAIS-R = Wechsler Adult Intelligence Scale – Revised; WASI = Wechsler Abbreviated Scale of Intelligence; WMS-R = Wechsler Memory Scale – Revised; WMT-III = Wechsler Memory Test—Third Edition.
      The definition of cognitive impairment varied in different studies, and there was a wide range of neuropsychological tools used to evaluate cognitive function (Table 1). Most of the studies performed both univariate and multivariate analyses adjusted for age and severity of acute illness. Outcome data for exposures are summarized in Table 2. Quality assessment is provided in Supplemental Table 2 (available online at http://www.mayoclinicproceedings.org). Overall, the studies meeting our inclusion criteria had a moderate risk of bias, primarily because of limitations in the measurement of the variables under investigation and the outcome as well as in the selection of the reported results.
      Table 2Outcome Data for Exposures
      ECMO = extracorporeal membrane oxygenation; HCT = hematocrit; ICU = intensive care unit.
      Reference, yearDelirium and duration of deliriumMechanical ventilation (MV) and duration of MVLength of ICU stayUse of sedatives or analgesic medicationsVasopressorsECMOIn-hospital acute stress symptomsBlood product transfusion, blood loss, or HCT levelHypoglycemia, hyperglycemia, or fluctuations in glucose levelsTrophic feeding vs enteral feedingHypoxiaPulse rate or systolic blood pressure
      Ambrosino et al,
      • Ambrosino N.
      • Bruletti G.
      • Scala V.
      • Porta R.
      • Vitacca M.
      Cognitive and perceived health status in patient with chronic obstructive pulmonary disease surviving acute on chronic respiratory failure: a controlled study.
      2001
      Not testedNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      de Azevedo et al,
      • de Azevedo J.R.
      • Montenegro W.S.
      • Rodrigues D.P.
      • et al.
      Long-term cognitive outcomes among unselected ventilated and non-ventilated ICU patients.
      2017
      An analysis adjusted for multiple variables was performed.
      No associationNot testedNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Davydow et al,
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      2013
      An analysis adjusted for multiple variables was performed.
      No associationNo associationNot testedNo associationNot testedNot testedPositive associationNo associationNot testedNot testedNot testedNot tested
      Duning et al,
      • Duning T.
      • van den Heuvel I.
      • Dickmann A.
      • et al.
      Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.
      2010
      A matched case-control design.
      Not testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedPositive associationNot testedNot testedNot tested
      Girard et al,
      • Girard T.D.
      • Jackson J.C.
      • Pandharipande P.P.
      • et al.
      Delirium as a predictor of long-term cognitive impairment in survivors of critical illness.
      2010
      An analysis adjusted for multiple variables was performed.
      Positive associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Gunther et al,
      • Gunther M.L.
      • Morandi A.
      • Krauskopf E.
      • et al.
      VISIONS Investigation, VISualizing Icu SurvivOrs
      The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study.
      2012
      An analysis adjusted for multiple variables was performed.
      Positive associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNo association
      Hope et al,
      • Hope A.A.
      • Morrison R.S.
      • Du Q.
      • Wallenstein S.
      • Nelson J.E.
      Risk factors for long-term brain dysfunction after chronic critical illness.
      2013
      An analysis adjusted for multiple variables was performed.
      Positive associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Hopkins et al,
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      2010
      An analysis adjusted for multiple variables was performed.
      Not testedPositive associationPositive associationNot testedNot testedNot testedNot testedNot testedPositive associationNot testedNot testedNot tested
      Hopkins et al,
      • Hopkins R.O.
      • Weaver L.K.
      • Chan K.J.
      • Orme Jr., J.F.
      Quality of life, emotional, and cognitive function following acute respiratory distress syndrome.
      2004
      Not testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNo associationNot tested
      Hopkins et al,
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      1999
      Not testedNo associationNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedPositive associationNot tested
      Hopkins et al,
      • Hopkins R.O.
      • Weaver L.K.
      • Collingridge D.
      • Parkinson R.B.
      • Chan K.J.
      • Orme Jr., J.
      Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome.
      2005
      Not testedNo associationNo associationNo associationNot testedNot testedNot testedNot testedNot testedNot testedNo associationNo association
      Jackson et al, 2011
      An analysis adjusted for multiple variables was performed.
      No associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot TestedNot testedNot testedNot tested
      Jackson et al,
      • Jackson J.C.
      • Obremskey W.
      • Bauer R.
      • et al.
      Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage.
      2007
      Not testedNo associationNot testedNot testedNot testedNot testedNot testedNo associationNot testedNot testedNot testedNot tested
      Jackson et al,
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      2003
      An analysis adjusted for multiple variables was performed.
      Not testedNo associationNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Jackson et al,
      • Jackson J.C.
      • Girard T.D.
      • Gordon S.M.
      • et al.
      Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.
      2010
      Randomized design.
      Not testedNot testedNot testedNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Jones et al,
      • Jones C.
      • Griffiths R.D.
      • Slater T.
      • Benjamin K.S.
      • Wilson S.
      Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness.
      2006
      Not testedNot testedPositive associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Mikkelsen et al,
      • Mikkelsen M.E.
      • Christie J.D.
      • Lanken P.N.
      • et al.
      The adult respiratory distress syndrome cognitive outcomes study long-term neuropsychological function in survivors of acute lung injury.
      2005
      Not testedNo associationNo associationNot testedNo associationNot testedNot testedNot testedNot testedNot testedPositive associationNo association
      Mitchell et al,

      Mitchell ML, Shum DHK, Mihala G, Murfield JE, Aitken LM. Long term cognitive impairment and delirium in intensive care: a prospective cohort study [published online ahead of print July 20, 2017]. Aust Crit Care. https://doi.org/10.1016/j.aucc.2017.07.002.

      2017
      An analysis adjusted for multiple variables was performed.
      Positive associationNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Morandi et al,
      • Morandi A.
      • Rogers B.P.
      • Gunther M.L.
      • et al.
      The relationship between delirium duration, white matter integrity and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging.
      2012
      Not testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Needham et al,
      • Needham D.M.
      • Dinglas V.D.
      • Morris P.E.
      • et al.
      NIH NHLBI ARDS Network
      Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding EDEN trial follow-up.
      2013
      Randomized design.
      Not testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNo associationNot testedNot tested
      Pandharipande et al,
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      2013
      An analysis adjusted for multiple variables was performed.
      Positive associationNot testedNot testedNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Richards et al,
      • Richards J.E.
      • Guillamondegui O.D.
      • Archer K.R.
      • Jackson J.C.
      • Ely E.W.
      • Obremskey W.T.
      The association of reamed intramedullary nailing and long-term cognitive impairment.
      2011
      An analysis adjusted for multiple variables was performed.
      Not testedPositive associationNot testedNot testedNot testedNot testedNot testedPositive associationNot testedNot testedNot testedNo association
      de Rooij et al,
      • de Rooij S.E.
      • Govers A.C.
      • Korevaar J.C.
      • Giesbers A.W.
      • Levi M.
      • de Jonge E.
      Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment.
      2008
      An analysis adjusted for multiple variables was performed.
      Not testedNot testedNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Rothenhäusler et al,
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      2001
      Not testedNo associationNo associationNot testedNot testedNo associationNot testedNot testedNot testedNot testedNot testedNot tested
      Semmler et al,
      • Semmler A.
      • Widmann C.N.
      • Okulla T.
      • et al.
      Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.
      2013
      Not testedNo associationNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Torgersen et al,
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      2011
      Not testedNo associationNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      Woon et al,
      • Woon F.L.
      • Dunn C.B.
      • Hopkins R.O.
      Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests.
      2012
      Not testedNo associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      van den Boogaard et al,
      • van den Boogaard M.
      • Schoonhoven L.
      • Evers A.W.
      • van der Hoeven J.G.
      • van Achterberg T.
      • Pickkers P.
      Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning.
      2012
      An analysis adjusted for multiple variables was performed.
      Positive associationNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot testedNot tested
      a ECMO = extracorporeal membrane oxygenation; HCT = hematocrit; ICU = intensive care unit.
      b An analysis adjusted for multiple variables was performed.
      c A matched case-control design.
      d Randomized design.

      Delirium and Duration of Delirium

      Acute delirium in the ICU has been highlighted as a predictor of subsequent cognitive impairment in several studies. Pandharipande et al
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      assessed 448 ICU patients diagnosed with respiratory failure, septic shock, or cardiogenic shock with cognitive evaluations 3 months after ICU discharge. A total of 382 patients survived and were reevaluated at 12 months. A significant proportion of patients remained cognitively impaired both at 3 and 12 months after ICU discharge (66% and 58%, respectively), and longer duration of delirium was found to be independently associated with worse cognitive performance at 3 and 12 months in tests of global cognition (P=.001 and P=.04) and executive function (P=.004 and P=.007).
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      A high rate of delirium during the ICU stay (84%) was reported in a prospective study conducted in 77 ICU patients with in-person cognitive evaluation by an expert 3 months and 12 months after ICU discharge. Duration of delirium was an independent risk factor for cognitive decline at both time points. After adjusting for preexisting cognitive impairment, age, severity of illness, education, severity of sepsis, treatment group, and total exposure to sedatives, longer duration of delirium was still associated with worse cognitive performance.
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      A 2-center prospective cohort study found that patients with longer duration of delirium had a greater degree of brain atrophy on magnetic resonance imaging obtained 3 months after discharge as well as worse cognitive performance at 12 months follow-up.
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      van den Boogaard et al
      • van den Boogaard M.
      • Schoonhoven L.
      • Evers A.W.
      • van der Hoeven J.G.
      • van Achterberg T.
      • Pickkers P.
      Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning.
      compared 171 patients who experienced delirium during the ICU stay with 745 ICU patients who had not developed delirium. Patients who experienced delirium exhibited worse performance in all cognitive dimensions. After adjusting for covariates, the difference between the groups remained significant.
      • van den Boogaard M.
      • Schoonhoven L.
      • Evers A.W.
      • van der Hoeven J.G.
      • van Achterberg T.
      • Pickkers P.
      Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning.
      Acute brain dysfunction during chronic critical illness, defined by the placement of tracheostomy tubes after at least 10 days of difficulty weaning from mechanical ventilation, was shown to be substantially associated with an increased risk of long-term cognitive impairment (odds ratio, 2.14; 95% CI, 1.02-4.52) in 1 prospective cohort study.
      • Hope A.A.
      • Morrison R.S.
      • Du Q.
      • Wallenstein S.
      • Nelson J.E.
      Risk factors for long-term brain dysfunction after chronic critical illness.
      Delirium in the ICU was positively associated with impaired information processing speed and executive functioning 6 months after discharge in adult ICU survivors who were ventilated for more than 12 hours during their ICU hospitalization.

      Mitchell ML, Shum DHK, Mihala G, Murfield JE, Aitken LM. Long term cognitive impairment and delirium in intensive care: a prospective cohort study [published online ahead of print July 20, 2017]. Aust Crit Care. https://doi.org/10.1016/j.aucc.2017.07.002.

      However, not all studies have found an association between delirium and subsequent cognitive impairment. Davydow et al
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      did not find a significant association between delirium and worse cognitive performance in 120 nontraumatic ICU patients who completed a Modified Telephone Interview for Cognitive Status 12 months after discharge. In another study conducted in 108 patients who completed a comprehensive battery of neuropsychological tests 12 months after discharge from a trauma ICU, delirium during ICU hospitalization (present in 23.2% of the patients) was not associated with long-term cognitive impairment.
      • Jones C.
      • Griffiths R.D.
      • Slater T.
      • Benjamin K.S.
      • Wilson S.
      Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness.
      In unselected population of 413 ventilated and nonventilated ICU patients, delirium did not seem to contribute the development of long-term cognitive impairment.
      • de Azevedo J.R.
      • Montenegro W.S.
      • Rodrigues D.P.
      • et al.
      Long-term cognitive outcomes among unselected ventilated and non-ventilated ICU patients.

      Mechanical Ventilation and Duration of Mechanical Ventilation

      The influence of mechanical ventilation during ICU hospitalization on long-term cognitive impairment was inconsistent across studies. Of the 28 studies included in our analysis, 14 evaluated the influence of mechanical ventilation on long-term cognitive impairment after ICU admission. Twelve of these studies did not find any significant association.
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      • Jackson J.C.
      • Obremskey W.
      • Bauer R.
      • et al.
      Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage.
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      • Ambrosino N.
      • Bruletti G.
      • Scala V.
      • Porta R.
      • Vitacca M.
      Cognitive and perceived health status in patient with chronic obstructive pulmonary disease surviving acute on chronic respiratory failure: a controlled study.
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      • Hopkins R.O.
      • Weaver L.K.
      • Collingridge D.
      • Parkinson R.B.
      • Chan K.J.
      • Orme Jr., J.
      Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome.
      • Jones C.
      • Griffiths R.D.
      • Slater T.
      • Benjamin K.S.
      • Wilson S.
      Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness.
      • Mikkelsen M.E.
      • Christie J.D.
      • Lanken P.N.
      • et al.
      The adult respiratory distress syndrome cognitive outcomes study long-term neuropsychological function in survivors of acute lung injury.
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      • Semmler A.
      • Widmann C.N.
      • Okulla T.
      • et al.
      Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.
      • Woon F.L.
      • Dunn C.B.
      • Hopkins R.O.
      Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests.
      Only 2 studies reported an association between mechanical ventilation and cognitive impairment. In a prospective observational study that evaluated 108 trauma ICU patients without evidence of intracranial hemorrhage, 57.4% of the patients were mechanically ventilated for a mean duration of 3.4 days. Duration of mechanical ventilation was shown to be significantly longer in patients with worse cognitive outcomes (P=.004).
      • Richards J.E.
      • Guillamondegui O.D.
      • Archer K.R.
      • Jackson J.C.
      • Ely E.W.
      • Obremskey W.T.
      The association of reamed intramedullary nailing and long-term cognitive impairment.
      In a retrospective study conducted in 66 acute respiratory distress syndrome (ARDS) survivors, intubation time longer than 23.6 days increased the odds of cognitive impairment by 1.8 times in multivariate analysis.
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.

      Use of Sedatives or Analgesic Medications

      Sedation and analgesia did not appear to influence the risk of long-term cognitive impairment. Pandharipande et al
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      did not find a consistent association between the use of sedatives or analgesic medications and cognitive impairment 3 and 12 months after ICU discharge. In a single-center randomized trial that compared 89 patients managed according to a protocol of daily sedation holidays paired with spontaneous breathing trials against 91 patients receiving usual care (patient-targeted sedation), the cognitive scores at 12 months follow-up were similar in both groups (P=.61).
      • Jackson J.C.
      • Girard T.D.
      • Gordon S.M.
      • et al.
      Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.
      The use of vasopressors,
      • Mikkelsen M.E.
      • Christie J.D.
      • Lanken P.N.
      • et al.
      The adult respiratory distress syndrome cognitive outcomes study long-term neuropsychological function in survivors of acute lung injury.
      benzodiazepines, opioids, antipsychotic agents, and antidepressant drugs did not play a significant role in the incidence of cognitive decline in 120 nontraumatic ICU patients.
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.

      In-Hospital Acute Stress Symptoms (Posttraumatic Stress Disorder Checklist – Civilian Version)

      The Modified Telephone Interview for Cognitive Status was used to evaluate a cognitive function in 120 nontraumatic ICU survivors 12 months after ICU discharge to assess the role of in-hospital acute stress symptoms in the development of cognitive impairment. The 17-item Posttraumatic Stress Disorder Checklist – Civilian version was used to evaluate the presence of in-hospital acute stress symptoms such as intrusive thoughts, nightmares, avoidance of thoughts, emotional numbing, impaired sleep, and hypervigilance. The investigators concluded that the presence of in-hospital acute stress symptoms was an independent risk factor for long-term cognitive decline (P=.03).
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.

      Blood Product Transfusion, Blood Loss, and Hematocrit Level

      Davydow et al
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      did not find any significant correlation between blood transfusion and persistent cognitive impairment in general ICU patients. Similarly, blood loss did not appear to have any effect on the risk of subsequent cognitive impairment in patients admitted to a trauma ICU.
      • Jackson J.C.
      • Obremskey W.
      • Bauer R.
      • et al.
      Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage.
      Meanwhile, another study in trauma patients found that hematocrit level in the emergency department (P=.03) and blood transfusion during the first 24 hours (P=.04) were more common in patients who subsequently had cognitive decline impairment.
      • Richards J.E.
      • Guillamondegui O.D.
      • Archer K.R.
      • Jackson J.C.
      • Ely E.W.
      • Obremskey W.T.
      The association of reamed intramedullary nailing and long-term cognitive impairment.

      Hypoglycemia, Hyperglycemia, and Fluctuations in Glucose Levels

      Glucose levels have been associated with cognitive impairment after the ICU stay in a few small studies. Duning et al
      • Duning T.
      • van den Heuvel I.
      • Dickmann A.
      • et al.
      Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.
      compared 37 ICU patients with hypoglycemia vs 37 matched controls without hypoglycemia to assess the influence of low serum glucose levels on long-term cognitive impairment. The results indicated that cognitive impairment was persistent in both groups, but cases performed worse in visuospatial skills (P=.01). Interestingly, hyperglycemia and fluctuations in blood glucose levels were significantly associated with worse outcomes in the same domain (P<.005 and P<.008, respectively).
      • Duning T.
      • van den Heuvel I.
      • Dickmann A.
      • et al.
      Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.
      A retrospective study conducted in 66 ARDS survivors found that blood glucose dysregulation, in particular moderate hyperglycemia, was associated with long-term cognitive impairment. Having a blood glucose level greater than 153.5 mg/dL (to convert to mmol/L, multiply by 0.0259) during ICU hospitalization was associated with a greater likelihood of having long-term cognitive impairment after ICU discharge.
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.

      Hypoxia

      Mikkelsen et al
      • Mikkelsen M.E.
      • Christie J.D.
      • Lanken P.N.
      • et al.
      The adult respiratory distress syndrome cognitive outcomes study long-term neuropsychological function in survivors of acute lung injury.
      compared acute lung injury survivors who developed cognitive impairment (n=41) with those who remained cognitively well (n=34) 12 months after ICU discharge. Lower partial pressure of oxygen during ICU admission was detected in patients with cognitive impairment (P<.02).
      • Mikkelsen M.E.
      • Christie J.D.
      • Lanken P.N.
      • et al.
      The adult respiratory distress syndrome cognitive outcomes study long-term neuropsychological function in survivors of acute lung injury.
      A small study by Hopkins et al
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      reported a significant correlation between cognitive impairment and hypoxemia in 17 ARDS survivors who experienced generalized cognitive decline 1 year after discharge. Yet, the same group of researchers later put into question the relationship between degree of acute hypoxemia and subsequent cognitive decline. When comparing the mean duration of oxygen desaturation less than 90% between 30 ARDS ICU survivors with cognitive impairment and 39 ARDS ICU survivors without cognitive impairment, they did not find any significant difference (110.6 and 113.8 hours, respectively) (P=.89).
      • Hopkins R.O.
      • Weaver L.K.
      • Chan K.J.
      • Orme Jr., J.F.
      Quality of life, emotional, and cognitive function following acute respiratory distress syndrome.
      Furthermore, although evaluating the influence of hypoxemia on neurocognitive sequelae in ARDS survivors 2 years after ICU discharge, they did not find any significant correlation and suggested that this may be due to cognitive recovery over time.
      • Hopkins R.O.
      • Weaver L.K.
      • Collingridge D.
      • Parkinson R.B.
      • Chan K.J.
      • Orme Jr., J.
      Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome.

      Length of ICU Stay

      Studies published so far have shown contradictory results on the relationship of the length of stay in the ICU and cognitive decline. Hopkins et al
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      reported that a total length of stay in the ICU longer than 27.4 days was associated with 2.7 times higher odds of cognitive decline. The length of stay in the ICU correlated with the degree of difficulty in problem solving 2 months after discharge in another small prospective study.
      • Hopkins R.O.
      • Weaver L.K.
      • Chan K.J.
      • Orme Jr., J.F.
      Quality of life, emotional, and cognitive function following acute respiratory distress syndrome.
      Conversely, most of the other studies did not find significant associations between the length of ICU stay and cognitive dysfunction.
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      • de Rooij S.E.
      • Govers A.C.
      • Korevaar J.C.
      • Giesbers A.W.
      • Levi M.
      • de Jonge E.
      Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment.
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      • Semmler A.
      • Widmann C.N.
      • Okulla T.
      • et al.
      Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.

      Discussion

      Long-term cognitive impairment after critical illness is a challenging research and clinical problem. To date, many studies have discussed this topic, yet little is truly known about potentially preventable risk factors for this disabling complication.
      Our review shows that delirium, particularly when prolonged, may be associated with an increased likelihood of persistent cognitive impairment after ICU hospitalization. Of the 9 studies that assessed the role of delirium in cognitive impairment, 6 reported a significant association.
      • Girard T.D.
      • Jackson J.C.
      • Pandharipande P.P.
      • et al.
      Delirium as a predictor of long-term cognitive impairment in survivors of critical illness.
      • Gunther M.L.
      • Morandi A.
      • Krauskopf E.
      • et al.
      VISIONS Investigation, VISualizing Icu SurvivOrs
      The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study.
      • Hope A.A.
      • Morrison R.S.
      • Du Q.
      • Wallenstein S.
      • Nelson J.E.
      Risk factors for long-term brain dysfunction after chronic critical illness.

      Mitchell ML, Shum DHK, Mihala G, Murfield JE, Aitken LM. Long term cognitive impairment and delirium in intensive care: a prospective cohort study [published online ahead of print July 20, 2017]. Aust Crit Care. https://doi.org/10.1016/j.aucc.2017.07.002.

      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      • van den Boogaard M.
      • Schoonhoven L.
      • Evers A.W.
      • van der Hoeven J.G.
      • van Achterberg T.
      • Pickkers P.
      Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning.
      Evidence linking other potentially preventable ICU factors with long-term cognitive impairment is much weaker or even more inconsistent. Because delirium is a significant and independent risk factor for developing cognitive impairment, putting an effort to prevent delirium in the ICU may be an important prevention strategy.
      For instance, mechanical ventilation and duration of mechanical ventilation were not significantly associated with cognitive impairment after critical illness in many studies,
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      • Jackson J.C.
      • Obremskey W.
      • Bauer R.
      • et al.
      Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage.
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      • Ambrosino N.
      • Bruletti G.
      • Scala V.
      • Porta R.
      • Vitacca M.
      Cognitive and perceived health status in patient with chronic obstructive pulmonary disease surviving acute on chronic respiratory failure: a controlled study.
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.

      Mitchell ML, Shum DHK, Mihala G, Murfield JE, Aitken LM. Long term cognitive impairment and delirium in intensive care: a prospective cohort study [published online ahead of print July 20, 2017]. Aust Crit Care. https://doi.org/10.1016/j.aucc.2017.07.002.

      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      • Semmler A.
      • Widmann C.N.
      • Okulla T.
      • et al.
      Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.
      • Woon F.L.
      • Dunn C.B.
      • Hopkins R.O.
      Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests.
      but still 2 studies found positive associations.
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      • Richards J.E.
      • Guillamondegui O.D.
      • Archer K.R.
      • Jackson J.C.
      • Ely E.W.
      • Obremskey W.T.
      The association of reamed intramedullary nailing and long-term cognitive impairment.
      One of them emphasized the influence of long duration of mechanical ventilation (>23 days),
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      yet 2 other studies did not find such correlation.
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      • Jackson J.C.
      • Archer K.R.
      • Bauer R.
      • et al.
      A prospective investigation of long-term cognitive impairment and psychological distress in moderately versus severely injured trauma intensive care unit survivors without intracranial hemorrhage.
      Most of the studies did not find an association between the length of ICU stay and cognitive dysfunction.
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      • Hopkins R.O.
      • Suchyta M.R.
      • Snow G.L.
      • Jephson A.
      • Weaver L.K.
      • Orme J.F.
      Blood glucose dysregulation and cognitive outcome in ARDS survivors.
      • de Rooij S.E.
      • Govers A.C.
      • Korevaar J.C.
      • Giesbers A.W.
      • Levi M.
      • de Jonge E.
      Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment.
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      • Semmler A.
      • Widmann C.N.
      • Okulla T.
      • et al.
      Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.
      Dysglycemia has been reported to be associated with subsequent cognitive decline, but the studies supporting this association are small and methodologically limited.
      • Duning T.
      • van den Heuvel I.
      • Dickmann A.
      • et al.
      Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.
      • Hopkins R.O.
      • Weawer L.K.
      • Pope D.
      • Orme J.F.
      • Bigler E.D.
      • Larson-LOHR V.
      Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
      Multiple other evaluated factors were not found to influence the likelihood of post-ICU cognitive impairment, including use of sedatives and analgesic medications, extracorporeal membrane oxygenation, trophic feeding, intraoperative hypotension, and hypoxia.
      • de Azevedo J.R.
      • Montenegro W.S.
      • Rodrigues D.P.
      • et al.
      Long-term cognitive outcomes among unselected ventilated and non-ventilated ICU patients.
      • Jackson J.C.
      • Girard T.D.
      • Gordon S.M.
      • et al.
      Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.
      • Needham D.M.
      • Dinglas V.D.
      • Morris P.E.
      • et al.
      NIH NHLBI ARDS Network
      Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding EDEN trial follow-up.
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      • Richards J.E.
      • Guillamondegui O.D.
      • Archer K.R.
      • Jackson J.C.
      • Ely E.W.
      • Obremskey W.T.
      The association of reamed intramedullary nailing and long-term cognitive impairment.
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      Although our study focused on the influence of potentially modifiable risk factors during critical illness on long-term cognitive impairment after discharge, it is pertinent to note that nonmodifiable factors, such as age, level of education, comorbidities, severity of illness and injury, and sepsis, can affect the risk of cognitive impairment. Age was significantly associated with long-term cognitive dysfunction in a prospective cohort study of 167 survivors of chronic critical illness.
      • Hope A.A.
      • Morrison R.S.
      • Du Q.
      • Wallenstein S.
      • Nelson J.E.
      Risk factors for long-term brain dysfunction after chronic critical illness.
      Yet, age was not significantly associated with cognitive impairment in several other studies.
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      • Jackson J.C.
      • Obremskey W.
      • Bauer R.
      • et al.
      Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage.
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      • Jackson J.C.
      • Archer K.R.
      • Bauer R.
      • et al.
      A prospective investigation of long-term cognitive impairment and psychological distress in moderately versus severely injured trauma intensive care unit survivors without intracranial hemorrhage.
      • Pandharipande P.P.
      • Girard T.D.
      • Jackson J.C.
      • et al.
      BRAIN-ICU Study Investigators
      Long-term cognitive impairment after critical illness.
      • de Rooij S.E.
      • Govers A.C.
      • Korevaar J.C.
      • Giesbers A.W.
      • Levi M.
      • de Jonge E.
      Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment.
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      Data on the relationship of age with cognitive impairment after ICU admission needs to be interpreted with caution because the higher rates of mortality in older patients may create a form of selection bias, by which only patients at lower risk of cognitive impairment get to survive. The severity of acute illness assessed by Sepsis-related Organ Failure Assessment, Acute Physiologic and Chronic Health Evaluation II, or Simplified Acute Physiology score did not appear to influence the risk of long-term cognitive impairment in most of the studies published so far.
      • Torgersen J.
      • Hole J.F.
      • Kvåle R.
      • Wentzel-Larsen T.
      • Flaatten H.
      Cognitive impairments after critical illness.
      • Jackson J.C.
      • Hart R.P.
      • Gordon S.M.
      • et al.
      Six-month neuropsychological outcome of medical intensive care unit patients.
      • Davydow D.S.
      • Zatzick D.
      • Hough C.L.
      • Katon W.J.
      In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission.
      • de Rooij S.E.
      • Govers A.C.
      • Korevaar J.C.
      • Giesbers A.W.
      • Levi M.
      • de Jonge E.
      Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment.
      • Rothenhäusler H.B.
      • Ehrentraut S.
      • Stoll C.
      • Schelling G.
      • Kapfhammer H.P.
      The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.
      However, Acute Physiologic and Chronic Health Evaluation II score was associated with long-term cognitive decline in 1 study of 108 survivors of chronic critical illness.
      • Hope A.A.
      • Morrison R.S.
      • Du Q.
      • Wallenstein S.
      • Nelson J.E.
      Risk factors for long-term brain dysfunction after chronic critical illness.
      In a large cohort of subjects who underwent serial cognitive evaluation, Iwashyna et al
      • Iwashyna T.J.
      • Ely E.W.
      • Smith D.M.
      • Langa K.M.
      Long-term cognitive imapirment and functional disability among survivors of severe sepsis.
      found that hospitalization for severe sepsis (though not necessarily in the ICU) was associated with new moderate or severe cognitive impairment.
      The literature on cognitive impairment after critical illness has marked limitations. None of the articles had addressed all issues, making it tough to draw effective conclusions. Chief among them is the lack of baseline assessment of cognitive function before ICU hospitalization in most studies. Most of the studies were also likely underpowered to assess for associations between possible risk factors and cognitive outcomes reliably. The discrepant results across studies may in part be caused by variable cognitive assessments, in terms of both definitions and timing. Also, most of the studies do not permit discrimination between transient and persistent cognitive impairment because they do not provide information on serial cognitive examinations at various times after discharge from the ICU. Overall, the included studies had moderate risk of bias, mostly related to limitations in the measurement of the examined variables and the end point as well as in the selection of the results reported.

      Conclusion

      The influence of potentially modifiable risk factors during ICU treatment on long-term cognitive impairment needs further investigation. Available evidence suggests that prolonged delirium is the potentially modifiable factor most strongly associated with post-ICU cognitive impairment. Yet, the literature on this important clinical problem is generally suboptimal and the results are inconsistent across studies. High-quality research on a large cohort of critically ill patients is necessary to better characterize potentially modifiable risk factors for persistent cognitive impairment after ICU hospitalization.

      Supplemental Online Material

      Supplemental material can be found online at: http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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