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Interventions that lead to earlier liberation from mechanical ventilation can improve patient outcomes. This guideline, a collaborative effort between the American Thoracic Society and the American College of Chest Physicians, provides evidence-based recommendations to optimize liberation from mechanical ventilation in critically ill adults. Two methodologists performed evidence syntheses to summarize available evidence relevant to key questions about liberation from mechanical ventilation. The methodologists appraised the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach and summarized the results in evidence profiles. The guideline panel then formulated recommendations after considering the balance of desirable consequences (benefits) versus undesirable consequences (burdens, adverse effects, and costs), the certainty in the evidence, and the feasibility and acceptability of various interventions. Recommendations were rated as strong or conditional. The guideline panel made four conditional recommendations related to rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. The recommendations were for acutely hospitalized adults mechanically ventilated for more than 24 hours to receive protocolized rehabilitation directed toward early mobilization, be managed with a ventilator liberation protocol, be assessed with a cuff leak test if they meet extubation criteria but are deemed high risk for postextubation stridor, and be administered systemic steroids for at least 4 hours before extubation if they fail the cuff leak test. The American Thoracic Society/American College of Chest Physicians recommendations are intended to support healthcare professionals in their decisions related to liberating critically ill adults from mechanical ventilation.

RATIONALE:Intensive care unit (ICU) delirium is highly prevalent and a potentially avoidable hospital complication. The current cost of ICU delirium is unknown. OBJECTIVES:To specify the association between the daily occurrence of delirium in the ICU with costs of ICU care accounting for time-varying illness severity and death. RESEARCH DESIGN:We performed a prospective cohort study within medical and surgical ICUs in a large academic medical center. SUBJECTS:We analyzed critically ill patients (N=479) with respiratory failure and/or shock. MEASURES:Covariates included baseline factors (age, insurance, cognitive impairment, comorbidities, Acute Physiology and Chronic Health Evaluation II Score) and time-varying factors (sequential organ failure assessment score, mechanical ventilation, and severe sepsis). The primary analysis used a novel 3-stage regression methodfirst, estimation of the cumulative cost of delirium over 30 ICU days and then costs separated into those attributable to increased resource utilization among survivors and those that were avoided on the account of delirium’s association with early mortality in the ICU. RESULTS:The patient-level 30-day cumulative cost of ICU delirium attributable to increased resource utilization was $17,838 (95% confidence interval, $11,132–$23,497). A combination of professional, dialysis, and bed costs accounted for the largest percentage of the incremental costs associated with ICU delirium. The 30-day cumulative incremental costs of ICU delirium that were avoided due to delirium-associated early mortality was $4654 (95% confidence interval, $2056–7869). CONCLUSIONS:Delirium is associated with substantial costs after accounting for time-varying illness severity and could be 20% higher (∼$22,500) if not for its association with early ICU mortality.

Abstract Rationale Acute kidney injury may contribute to distant organ dysfunction. Few studies have examined kidney injury as a risk factor for delirium and coma. Objectives To examine whether acute kidney injury is associated with delirium and coma in critically ill adults. Methods In a prospective cohort study of intensive care unit patients with respiratory failure and/or shock, we examined the association between acute kidney injury and daily mental status using multinomial transition models adjusting for demographics, nonrenal organ failure, sepsis, prior mental status, and sedative exposure. Acute kidney injury was characterized daily using the difference between baseline and peak serum creatinine and staged according to Kidney Disease Improving Global Outcomes criteria. Mental status (normal vs. delirium vs. coma) was assessed daily with the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale. Measurements and Main Results Among 466 patients, stage 2 acute kidney injury was a risk factor for delirium (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.07–2.26) and coma (OR, 2.04; 95% CI, 1.25–3.34) as was stage 3 injury (OR for delirium, 2.56; 95% CI, 1.57–4.16) (OR for coma, 3.34; 95% CI, 1.85–6.03). Daily peak serum creatinine (adjusted for baseline) values were also associated with delirium (OR, 1.35; 95% CI, 1.18–1.55) and coma (OR, 1.44; 95% CI, 1.20–1.74). Renal replacement therapy modified the association between stage 3 acute kidney injury and daily peak serum creatinine and both delirium and coma. Conclusions Acute kidney injury is a risk factor for delirium and coma during critical illness.

This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society and the American College of Chest Physicians. A multidisciplinary panel posed six clinical questions in a Population, Intervention, Comparator, and Outcomes format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, the confidence in the evidence, the certainty about how much the public values the main outcomes, the magnitude and balance of desirable and undesirable outcomes, the resources and costs associated with the intervention, the impact on health disparities, and the acceptability and feasibility of the intervention. Evidence-based recommendations were formulated and graded initially by subcommittees and then modified after full-panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation. The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and Chest.

Background Delirium is a frequent manifestation of acute brain dysfunction and is associated with cognitive impairment. The hypothesized mechanism of brain dysfunction during critical illness is centered on neuroinflammation, regulated in part by the cholinergic system. Point-of-care serum cholinesterase enzyme activity measurements serve as a real-time index of cholinergic activity. We hypothesized that cholinesterase activity during critical illness would be associated with delirium in the intensive care unit (ICU) and cognitive impairment after discharge. Methods We enrolled adults with respiratory failure and/or shock and measured plasma acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity on days 1, 3, 5, and 7 after enrollment. AChE values were also normalized per gram of hemoglobin (AChE/Hgb). We assessed for coma and delirium twice daily using the Richmond Agitation Sedation Scale and the Confusion Assessment Method for the ICU to evaluate daily mental status (delirium, coma, normal) and days alive without delirium or coma. Cognitive impairment, disability, and health-related quality of life were assessed at up to 6 months post-discharge. We used multivariable regression to determine whether AChE, AChE/Hgb, and BChE activity were associated with outcomes after adjusting for relevant covariates. Results We included 272 critically ill patients who were a median (IQR) age 56 (39–67) years and had a median Sequential Organ Failure Assessment score at enrollment of 8 (5–11). Higher daily AChE levels were associated with increased odds of being delirious versus normal mental status on the same day (Odds Ratio [95% Confidence Interval] 1.64 [1.11, 2.43]; P  = 0.045). AChE/Hgb and BChE activity levels were not associated with delirious mental status. Lower enrollment BChE was associated with fewer days alive without delirium or coma ( P  = 0.048). AChE, AChE/Hgb, and BChE levels were not significantly associated with cognitive impairment, disability, or quality of life after discharge. Conclusion Cholinesterase activity during critical illness is associated with delirium but not with outcomes after discharge, findings that may reflect mechanisms of acute brain organ dysfunction. Trial Registration: NCT03098472. Registered 31 March 2017.

Background Antipsychotics are used to treat delirium in the intensive care unit (ICU) despite unproven efficacy. We hypothesized that atypical antipsychotic treatment in the ICU is a risk factor for antipsychotic prescription at discharge, a practice that might increase risk since long-term use is associated with increased mortality. Methods After excluding patients on antipsychotics prior to admission, we examined antipsychotic use in a prospective cohort of ICU patients with acute respiratory failure and/or shock. We collected data on medication use from medical records and assessed patients for delirium using the Confusion Assessment Method for the ICU. Using multivariable logistic regression, we analyzed whether age, delirium duration, atypical antipsychotic use, and discharge disposition (each selected a priori) were independent risk factors for discharge on an antipsychotic. We also examined admission Acute Physiology and Chronic Health Evaluation (APACHE) II score, haloperidol use, and days of benzodiazepine use in post hoc analyses. Results After excluding 18 patients due to prior antipsychotic use and three who withdrew, we included 500 patients. Among 208 (42%) treated with an antipsychotic, median (interquartile range) age was 59 (49–69) years and APACHE II score was 26 (22–32), characteristics that were similar among antipsychotic nonusers. Antipsychotic users were more likely than nonusers to have had delirium (93% vs. 61%, p  < 0.001). Of the 208 antipsychotic users, 172 survived to hospital discharge, and 42 (24%) of these were prescribed an antipsychotic at discharge. Treatment with an atypical antipsychotic was the only independent risk factor for antipsychotic prescription at discharge (odds ratio 17.6, 95% confidence interval 4.9 to 63.3; p  < 0.001). Neither age, delirium duration, nor discharge disposition were risk factors ( p  = 0.11, 0.38, and 0.12, respectively) in the primary regression model, and post hoc analyses found APACHE II ( p  = 0.07), haloperidol use ( p  = 0.16), and days of benzodiazepine use ( p  = 0.31) were also not risk factors for discharge on an antipsychotic. Conclusions In this study, antipsychotics were used to treat nearly half of all antipsychotic-naïve ICU patients and were prescribed at discharge to 24% of antipsychotic-treated patients. Treatment with an atypical antipsychotic greatly increased the odds of discharge with an antipsychotic prescription, a practice that should be examined carefully during medication reconciliation since these drugs carry “black box warnings” regarding long-term use.

•Many trials are conducted on patients at high risk of death.•Among these trials, functional patient outcomes are increasingly important.•When patients die, functional outcomes are “truncated due to death”.•Authors seldom state whether patients who die are included in treatment comparisons.•Most often, comparisons include only survivors, with potentially misleading results.•Recommendations are provided for reporting in these trials. This structured methodology review evaluated statistical approaches used in randomized controlled trials (RCTs) enrolling patients at high risk of death and makes recommendations for reporting future RCTs. Using PubMed, we searched for RCTs published in five general medicine journals from January 2014 to August 2019 wherein mortality was ≥10% in at least one randomized group. We abstracted primary and secondary outcomes, statistical analysis methods, and patient samples evaluated (all randomized patients vs. “survivors only”). Of 1947 RCTs identified, 434 met eligibility criteria. Of the eligible RCTs, 91 (21%) and 351 (81%) had a primary or secondary functional outcome, respectively, of which 36 (40%) and 263 (75%) evaluated treatment effects among “survivors only”. In RCTs that analyzed all randomized patients, the most common methods included use of ordinal outcomes (e.g., modified Rankin Scale) or creating composite outcomes (primary: 41 of 91 [45%]; secondary: 57 of 351 [16%]). In RCTs enrolling patients at high risk of death, statistical analyses of functional outcomes are frequently conducted among “survivors only,” for which conclusions might be misleading. Given the growing number of RCTs conducted among patients hospitalized with COVID-19 and other critical illnesses, standards for reporting should be created.

Abstract Rationale The incidence and risk factors of post-traumatic stress disorder (PTSD) related to the intensive care unit (ICU) experience have not been reported in a mixed veteran and civilian cohort. Objectives To describe the incidence and risk factors for ICU-related PTSD in veterans and civilians. Methods This is a prospective, observational, multicenter cohort enrolling adult survivors of critical illness after respiratory failure and/or shock from three Veterans Affairs and one civilian hospital. After classifying those with/without preexisting PTSD (i.e., PTSD before hospitalization), we then assessed all subjects for ICU-related PTSD at 3 and 12 months post hospitalization. Measurements and Main Results Of 255 survivors, 181 and 160 subjects were assessed for ICU-related PTSD at 3- and 12-month follow-up, respectively. A high probability of ICU-related PTSD was found in up to 10% of patients at either follow-up time point, whether assessed by PTSD Checklist Event-Specific Version (score ≥ 50) or item mapping using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). In the multivariable regression, preexisting PTSD was independently associated with ICU-related PTSD at both 3 and 12 months (P < 0.001), as was preexisting depression (P < 0.03), but veteran status was not a consistent independent risk factor for ICU-related PTSD (3-month P = 0.01, 12-month P = 0.48). Conclusions This study found around 1 in 10 ICU survivors experienced ICU-related PTSD (i.e., PTSD anchored to their critical illness) in the year after hospitalization. Preexisting PTSD and depression were strongly associated with ICU-related PTSD.

Prominent among the numerous events that contribute to the enhanced susceptibility of elderly patients to infection is the decline of immune function that accompanies aging. Elderly patients experience a marked decline in cell-mediated immune function and reduced humoral immune function. Age-dependent defects in T and B cell function are readily demonstrable in elderly patients, yet the essential elements of innate immunity are remarkably well preserved. The cytokine and chemokine signaling networks are altered in elderly patients and tends to favor a type 2 cytokine response over type 1 cytokine responses. The induction of proinflammatory cytokines after septic stimuli is not adequately controlled by anti-inflammatory mechanisms in elderly persons. This immune dysregulation is accompanied by a more pronounced procoagulant state in older patients. These molecular events function in concert to render elderly patients at excess risk for mortality from severe sepsis and septic shock.