Early physical rehabilitation dosage in the Intensive Care Unit predicts hospital outcomes after critical COVID-19.

Objective : to examine the relationship between physical rehabilitation parameters including a novel approach to quantifying dosage with hospital outcomes for patients with critical COVID-19. Design: Retrospective practice analysis from March 5, 2020, to April 15, 2021. Setting: Intensive care units (ICU) at four medical institutions Patients: n = 3,780 adults with ICU admission and diagnosis of COVID-19 Interventions: We measured the physical rehabilitation treatment delivered in ICU and patient outcomes: 1) mortality; 2) discharge disposition; and 3) physical function at hospital discharge measured by the Activity Measure-Post Acute Care (AM-PAC) "6-Clicks" (6-24, 24=greater functional independence). Physical rehabilitation dosage was defined as the average mobility level scores in the first three sessions (a surrogate measure of intensity) multiplied by the rehabilitation frequency (PT + OT frequency in hospital). Measurements and Main Results: The cohort was a mean 64 ± 16 years old, 41% female, mean BMI of 32 ± 9 kg/m 2 and 46% (n=1739) required mechanical ventilation. For 2191 patients with complete data, rehabilitation dosage and AM-PAC at discharge were moderately, positively associated (Spearman's rho [r] = 0.484, p < 0.001). Multivariate linear regression (model adjusted R 2 = 0.68, p <0.001) demonstrates mechanical ventilation (ß = -0.86, p = 0.001), average mobility score in first three sessions (ß = 2.6, p <0.001) and physical rehabilitation dosage (ß = 0.22, p = 0.001) were predictive of AM-PAC scores at discharge when controlling for age, sex, BMI, and ICU LOS. Conclusions: Greater physical rehabilitation exposure early in the ICU is associated with physical function at hospital discharge.

Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.

Oxygen-Saturation Targets and Cognitive and Functional Outcomes in Mechanically Ventilated Adults.

Rationale: Among mechanically ventilated critically ill adults, the PILOT (Pragmatic Investigation of Optimal Oxygen Targets) trial demonstrated no difference in ventilator-free days among lower, intermediate, and higher oxygen-saturation targets. The effects on long-term cognition and related outcomes are unknown.Objectives: To compare the effects of lower (90% [range, 88-92%]), intermediate (94% [range, 92-96%]), and higher (98% [range, 96-100%]) oxygen-saturation targets on long-term outcomes.Methods: Twelve months after enrollment in the PILOT trial, blinded neuropsychological raters conducted assessments of cognition, disability, employment status, and quality of life. The primary outcome was global cognition as measured using the Telephone Montreal Cognitive Assessment. In a subset of patients, an expanded neuropsychological battery measured executive function, attention, immediate and delayed memory, verbal fluency, and abstraction.Measurements and Main Results: A total of 501 patients completed follow-up, including 142 in the lower, 186 in the intermediate, and 173 in the higher oxygen target groups. Median (interquartile range) peripheral oxygen saturation values in the lower, intermediate, and higher target groups were 94% (91-96%), 95% (93-97%), and 97% (95-99%), respectively. Telephone Montreal Cognitive Assessment score did not differ between lower and intermediate (adjusted odds ratio [OR], 1.36 [95% confidence interval (CI), 0.92-2.00]), intermediate and higher (adjusted OR, 0.90 [95% CI, 0.62-1.29]), or higher and lower (adjusted OR, 1.22 [95% CI, 0.83-1.79]) target groups. There was also no difference in individual cognitive domains, disability, employment, or quality of life.Conclusions: Among mechanically ventilated critically ill adults who completed follow-up at 12 months, oxygen-saturation targets were not associated with cognition or related outcomes.

Thinking Clearly: The History of Brain Dysfunction in Critical Illness.

Brain dysfunction during critical illness (ie, delirium and coma) is extremely common, and its lasting effect has only become increasingly understood in the last two decades. Brain dysfunction in the intensive care unit (ICU) is an independent predictor of both increased mortality and long-term impairments in cognition among survivors. As critical care medicine has grown, important insights regarding brain dysfunction in the ICU have shaped our practice including the importance of light sedation and the avoidance of deliriogenic drugs such as benzodiazepines. Best practices are now strategically incorporated in targeted bundles of care like the ICU Liberation Campaign's ABCDEF Bundle.

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial.

Importance: Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors. Objective: To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial. Design, Setting, and Participants: This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022. Interventions: The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo. Main Outcomes and Measures: Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization. Results: After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups. Conclusions and Relevance: In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors. Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Early posthospitalization recovery after extracorporeal membrane oxygenation in survivors of COVID-19.

OBJECTIVE: We sought to determine the influence of venovenous extracorporeal membrane oxygenation (ECMO) on outcomes of mechanically ventilated patients with COVID-19 during the first 120 days after hospital discharge. METHODS: Five academic centers conducted a retrospective analysis of mechanically ventilated patients with COVID-19 admitted during March through May 2020. Survivors had access to a multidisciplinary postintensive care recovery clinic. Physical, psychological, and cognitive deficits were measured using validated instruments and compared based on ECMO status. RESULTS: Two hundred sixty two mechanically ventilated patients were compared with 46 patients cannulated for venovenous ECMO. Patients receiving ECMO were younger and traveled farther but there was no significant difference in gender, race, or body mass index. ECMO patients were mechanically ventilated for longer durations (median, 26 days [interquartile range, 19.5-41 days] vs 13 days [interquartile range, 7-20 days]) and were more likely to receive inhaled pulmonary vasodilators, neuromuscular blockade, investigational COVID-19 therapies, blood transfusions, and inotropes. Patients receiving ECMO experienced greater bleeding and clotting events (P < .01). However, survival at discharge was similar (69.6% vs 70.6%). Of the 217 survivors, 65.0% had documented follow-up within 120 days. Overall, 95.5% were residing at home, 25.7% had returned to work or usual activity, and 23.1% were still using supplemental oxygen; these rates did not differ significantly based on ECMO status. Rates of physical, psychological, and cognitive deficits were similar. CONCLUSIONS: Our data suggest that COVID-19 survivors experience significant physical, psychological, and cognitive deficits following intensive care unit admission. Despite a more complex critical illness course, longer average duration of mechanical ventilation, and longer average length of stay, patients treated with venovenous ECMO had similar survival at discharge and outcomes within 120 days of discharge.

Cognitive Outcomes in the Pragmatic Investigation of optimaL Oxygen Targets (CO-PILOT) trial: protocol and statistical analysis plan.

INTRODUCTION: Long-term cognitive impairment is one of the most common complications of critical illness among survivors who receive mechanical ventilation. Recommended oxygen targets during mechanical ventilation vary among international guidelines. Different oxygen targets during mechanical ventilation have the potential to alter long-term cognitive function due to cerebral hypoxemia or hyperoxemia. Whether higher, intermediate or lower SpO2 targets are associated with better cognitive function at 12-month follow-up is unknown. METHODS AND ANALYSIS: The Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial is an ongoing pragmatic, cluster-randomised, cluster-crossover trial comparing the effect of a higher SpO2 target (target 98%, goal range 96%-100%), an intermediate SpO2 target (target 94%, goal range 92%-96%) and a lower SpO2 target (target 90%, goal range 88%-92%) on clinical outcomes in mechanically ventilated patients admitted to the medical intensive care unit at a single centre in the USA. For this ancillary study of long-term Cognitive Outcomes (CO-PILOT), survivors of critical illness who are in the PILOT trial and who do not meet exclusion criteria for CO-PILOT are approached for consent. The anticipated number of patients for whom assessment of long-term cognition will be performed in CO-PILOT is 612 patients over 36 months of enrolment. Cognitive, functional and quality of life assessments are assessed via telephone interview at approximately 12 months after enrolment in PILOT. The primary outcome of CO-PILOT is the telephone version of the Montreal Cognitive Assessment. A subset of patients will also complete a comprehensive neuropsychological telephone battery to better characterise the cognitive domains affected. ETHICS AND DISSEMINATION: The CO-PILOT ancillary study was approved by the Vanderbilt Institutional Review Board. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.

Oxygen as an Essential Medicine.

Supplemental oxygen is an essential medication in critical care. The optimal oxygen dose delivery system remains unclear, however. The "dose" and "delivery" of oxygen carry significant importance for resource-limited settings, such as low- and middle-income countries (LMICs). Regrettably, LMICS often experience significant inequities in oxygen supply and demand, with major impacts on preventable mortality. These inequities have become particularly prominent during the global COVID-19 pandemic, highlighting the need for additional investment and research into the best methods to utilize supplemental oxygen and ensure stable access to medical oxygen.

Physiologic responses to exercise in survivors of critical illness: an exploratory pilot study.

BACKGROUND: ICU survivors suffer from impaired physical function and reduced exercise capacity, yet the underlying mechanisms are poorly understood. The goal of this exploratory pilot study was to investigate potential mechanisms of exercise limitation using cardiopulmonary exercise testing (CPET) and 6-min walk testing (6MWT). METHODS: We enrolled adults aged 18 years or older who were treated for respiratory failure or shock in medical, surgical, or trauma ICUs at Vanderbilt University Medical Center (Nashville, TN, United States). We excluded patients with pre-existing cardiac dysfunction, a contraindication to CPET, or the need for supplemental oxygen at rest. We performed CPET and 6MWT 6 months after ICU discharge. We measured standard CPET parameters in addition to two measures of oxygen utilization during exercise (VO2-work rate slope and VO2 recovery half-time). RESULTS: We recruited 14 participants. Low exercise capacity (i.e., VO2Peak < 80% predicted) was present in 11 out of 14 (79%) with a median VO2Peak of 12.6 ml/kg/min [9.6-15.1] and 6MWT distance of 294 m [240-433]. In addition to low VO2Peak, CPET findings in survivors included low oxygen uptake efficiency slope, low oxygen pulse, elevated chronotropic index, low VO2-work rate slope, and prolonged VO2 recovery half-time, indicating impaired oxygen utilization with a hyperdynamic heart rate and ventilatory response, a pattern seen in non-critically ill patients with mitochondrial myopathies. Worse VO2-work rate slope and VO2 recovery half-time were strongly correlated with worse VO2Peak and 6MWT distance, suggesting that exercise capacity was potentially limited by impaired muscle oxygen utilization. CONCLUSIONS: These exploratory data suggest ICU survivors may suffer from impaired muscular oxygen metabolism due to mitochondrial dysfunction that impairs exercise capacity long-term. These findings should be further characterized in future studies that include direct assessments of muscle mitochondrial function in ICU survivors.

In-Hospital Depressed Level of Consciousness and Long-Term Functional Outcomes in ICU Survivors.

OBJECTIVES: Among critically ill patients, acutely depressed level of consciousness is associated with mortality, but its relationship to long-term outcomes such as disability and physical function is unknown. We investigated the relationship of level of consciousness during hospitalization with long-term disability and physical function in ICU survivors. DESIGN: Multi-center observational cohort study. SETTING: Medical or surgical ICUs at five U.S. centers. PATIENTS: Adult survivors of respiratory failure or shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Depressed level of consciousness during hospitalization was defined using the Richmond Agitation Sedation Scale (RASS) score (including all negative scores) by calculating the area under the curve using linear interpolation. Sedative-associated level of consciousness was similarly defined for all hospital days that sedation was received. We measured disability in basic activities of daily living (BADLs), instrumental activities of daily living (IADLs), discharge destination, and self-reported physical function. In separate models, we evaluated associations between these measures of level of consciousness and outcomes using multivariable regression, adjusted for age, sex, race, body mass index, education level, comorbidities, baseline frailty, baseline IADLs and BADLs, hospital type (civilian vs veteran), modified mean daily Sequential Organ Failure Assessment score, duration of severe sepsis, duration of mechanical ventilation, and hospital length of stay. Of the 1,040 patients enrolled in the ICU, 781 survived to hospital discharge. We assessed outcomes in 624 patients at 3 months and 527 patients at 12 months. After adjusting for covariates, there was no association between depressed level of consciousness (total or sedation-associated) with BADLs or IADLs at either 3- or 12-month follow-up. There was also no association with self-reported physical function at 3 or 12 months or with discharge destination. CONCLUSIONS: Depressed level of consciousness, as defined by the RASS, was not associated with disability or self-reported physical function. Future studies should investigate additional modifiable in-hospital risk factors for disability and poor physical function following critical illness.

Effects of social influence and implementation climate and leadership on nurse-led early mobility behaviours in critical care.

INTRODUCTION: Early mobility (EM), initiating and advancing physical activity in the earliest days of critical illness, has been described as the most difficult component of the ABCDEF bundle to implement and coordinate. Successful implementation of EM in clinical practice requires multiple targeted implementation strategies. OBJECTIVE: Describe the associations of nurses' EM attitudes, subjective norms, perceived behavioural control, intention, and implementation climate and leadership with self-reported and documented EM behaviour in the intensive care unit (ICU). DESIGN: This was a two-site, descriptive, cross-sectional study to explore nurses' perception of the factors influencing EM adherence. SETTING: Three ICUs (medical, surgical and cardiovascular) in an academic medical centre and two ICUs (medical/surgical and cardiovascular) in a regional medical centre in middle Tennessee. PATIENTS: Critically ill adults. INTERVENTIONS: None. MAIN OUTCOME MEASURES: A 34-item investigator-developed survey, Implementation Leadership Scale, and Implementation Climate Scale were administered to ICU nurses. Survey development was informed by a Theory of Planned Behavior based elicitation study and implementation science frameworks. RESULTS: The academic medical centre had markedly lower EM documentation. We found no difference in nurses' EM attitudinal beliefs, social influence, facilitators, and barriers at both sites. Nurses perceived moderate social influence to perform EM similarly across sites and considerable control over their ability to perform EM. We did note site differences for implementation climate and leadership and objective EM adherence with the regional community medical centre demonstrating statistically significant relationships of implementation climate and leadership with self-report and documented EM behaviours. CONCLUSIONS: We identified contextual differences in implementation climate and leadership influence when comparing nurse EM behaviours. Streamlined documentation, leadership advocacy for interprofessional coordination and manpower support, and multicomponent context-based implementation strategies could contribute to better EM adherence.

Establishing Medicaid incentives for liberating nursing home patients from ventilators.

BACKGROUND: Chronic ventilator use in Tennessee nursing homes surged following 2010 increases in respiratory care payment rates. Tennessee's Medicaid program implemented multiple policies between 2014 and 2017 to promote ventilator liberation in 11 nursing homes, including quality reporting, on-site monitoring, and pay-for-performance incentives. METHODS: Using repeated cross-sectional analysis of Medicare and Medicaid nursing home claims (2011-2017), hospital discharge records (2010-2017), and nursing home quality reports (2015-2017), we examined how service use changed as Tennessee implemented policies designed to promote ventilator liberation in nursing homes. We measured the annual number of nursing home patients with ventilator-related service use; discharge destination of ventilated inpatients and percent of nursing home patients liberated from ventilators. RESULTS: Between 2011 and 2014, the number of Medicare SNF and Medicaid nursing home patients with ventilator use increased more than sixfold. Among inpatients with prolonged mechanical ventilation, discharges to home decreased as discharges to nursing homes increased. As Tennessee implemented policy changes, ventilator-related service use moderately declined in nursing homes from a peak of 198 ventilated Medicare SNF patients in 2014 to 125 in 2017 and from 182 Medicaid patients with chronic ventilator use in 2014 to 145 patients in 2017. Nursing home weaning rates peaked at 49%-52% in 2015 and 2016, but declined to 26% by late 2017. Median number of days from admission to wean declined from 81 to 37 days. CONCLUSIONS: This value-based approach demonstrates the importance of designing payment models that target key patient outcomes like ventilator liberation.

Nutritional Risk at intensive care unit admission and outcomes in survivors of critical illness.

BACKGROUND AND AIMS: Risk factors for poor outcomes after critical illness are incompletely understood. While nutritional risk is associated with mortality in critically ill patients, its association with disability, cognitive, and health-related quality of life is unclear in survivors of critical illness. This study's objective was to determine whether greater nutritional risk at ICU admission is associated with greater disability, worse cognition, and worse HRQOL at 3 and 12-month follow-up. METHODS: We enrolled adults (≥18 years of age) with respiratory failure or shock treated in medical and surgical intensive care units from two U.S. centers. We measured nutritional risk using the modified Nutrition Risk in Critically Ill (mNUTRIC) score (range 0-9 [highest risk]) at intensive care unit admission. We measured associations between mNUTRIC scores and discharge destination, disability in basic activities of daily living (ADLs) using the Katz ADL, instrumental ADLs using the Functional Activities Questionnaire (FAQ), global cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), executive function using the Trail Making Test Part B (Trails B), and health-related quality of life using the SF-36, adjusting for sex, education, BMI, baseline frailty, disability, and cognition, severity of illness, days of delirium, coma, and mechanical ventilation. RESULTS: Of the 821 patients enrolled in the ICU, 636 patients survived to hospital discharge. We assessed outcomes in 448 of 535 survivors (84%) at 3 months and 382 of 476 survivors (80%) at 12 months. Higher mNUTRIC scores predicted greater odds of discharge to an institution (OR 2.0, 95% CI: 1.6 to 2.6; P < 0.01). Higher mNUTRIC scores were associated with a trend towards greater disability in basic activities of daily living (IRR 1.3, 95% CI 1.0 to 1.7) at 3 months that did not reach significance (p = 0.09) with no association demonstrated at 12 months. There were no associations between mNUTRIC scores and FAQ, RBANS, or Trails B scores. mNUTRIC scores were inconsistently associated with SF-36 physical and mental component scale scores. CONCLUSIONS: Greater nutritional risk at ICU admission is associated with disability in survivors of critical illness. Future studies should evaluate interventions in those at high nutritional risk as a means to speed recovery.

ICU Survivorship-The Relationship of Delirium, Sedation, Dementia, and Acquired Weakness.

The advent of modern critical care medicine has revolutionized care of the critically ill patient in the last 50 years. The Society of Critical Care Medicine (was formed in recognition of the challenges and need for specialized treatment for these fragile patients. As the specialty has grown, it has achieved impressive scientific advances that have reduced mortality and saved lives. With those advances, however, came growing recognition that the burden of critical illness did not end at the doorstep of the hospital. Delirium, once thought to be a mere by-product of critical illness, was found to be an independent predictor of mortality, prolonged mechanical ventilation, and long-lasting cognitive impairment. Similarly, deep sedation and immobility, so often used to keep patients "comfortable" and to facilitate mechanical ventilation and recovery, worsen mortality and lead to the development of ICU-acquired weakness. The realization that these outcomes are inextricably linked to one another and how we manage our patients has helped us recognize the need for culture change. We, as a specialty, now understand that although celebrating the successes of survival, we now also have a duty to focus on those who survive their diseases. Led by initiatives such as the ICU Liberation Campaign of the Society of Critical Care Medicine, the natural progression of the field is now focused on getting patients back to their homes and lives unencumbered by disability and impairment. Much work remains to be done, but the futures of our most critically ill patients will continue to benefit if we leverage and build on the history of our first 50 years.

Prevention and Management of Delirium in the Intensive Care Unit.

Delirium is a debilitating form of brain dysfunction frequently encountered in the intensive care unit (ICU). It is associated with increased morbidity and mortality, longer lengths of stay, higher hospital costs, and cognitive impairment that persists long after hospital discharge. Predisposing factors include smoking, hypertension, cardiac disease, sepsis, and premorbid dementia. Precipitating factors include respiratory failure and shock, metabolic disturbances, prolonged mechanical ventilation, pain, immobility, and sedatives and adverse environmental conditions impairing vision, hearing, and sleep. Historically, antipsychotic medications were the mainstay of delirium treatment in the critically ill. Based on more recent literature, the current Society of Critical Care Medicine (SCCM) guidelines suggest against routine use of antipsychotics for delirium in critically ill adults. Other pharmacologic interventions (e.g., dexmedetomidine) are under investigation and their impact is not yet clear. Nonpharmacologic interventions thus remain the cornerstone of delirium management. This approach is summarized in the ABCDEF bundle (Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment). The implementation of this bundle reduces the odds of developing delirium and the chances of needing mechanical ventilation, yet there are challenges to its implementation. There is an urgent need for ongoing studies to more effectively mitigate risk factors and to better understand the pathobiology underlying ICU delirium so as to identify additional potential treatments. Further refinements of therapeutic options, from drugs to rehabilitation, are current areas ripe for study to improve the short- and long-term outcomes of critically ill patients with delirium.

Publisher Correction: Delirium.

An Erratum to this paper has been published: https://doi.org/10.1038/s41572-020-00236-z.

Asthma-chronic obstructive pulmonary disease overlap syndrome.

Overlap of asthma and chronic obstructive lung disease (ACO) in patients with obstructive lung disease is growing in recognition, though there is no consistent agreement on the diagnostic criteria for the disease process. Patients with ACO have distinct clinical characteristics and trajectories, which are representative of a heterogenous, multifactorial, and incompletely understood inflammatory pathophysiology. Current treatment strategies are focused on titration of inhaled therapies such as long-acting bronchodilators, with increasing interest in the use of targeted biologic therapies aimed at the underlying inflammatory mechanisms. Future directions for research will focus on elucidating the varied inflammatory signatures leading to ACO, the development of consistent diagnostic criteria and biomarkers of disease, and improving the clinical management with an eye toward targeted therapies.