Systemic inflammation and delirium during critical illness.

PURPOSE: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness. METHODS: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1ß), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives. RESULTS: Among 991 participants with a median age (interquartile range, IQR) of 62 [53-72] years and enrollment SOFA of 9 [7-11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4-2.3]), IL-8 (1.3 [1.1-1.5]), IL-10 (1.5 [1.2-1.8]), TNF-α (1.2 [1.0-1.4]), and TNFR1 (1.3 [1.1-1.6]) and lower concentrations of protein C (0.7 [0.6-0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1-1.7]), IFN-γ (1.3 [1.1-1.5]), IL-6 (2.3 [1.8-3.0]), IL-8 (1.8 [1.4-2.3]), and IL-10 (1.5 [1.2-2.0]) and lower concentrations of protein C (0.6 [0.5-0.8]) were associated with coma the following day. IL-1ß, IL-12, and MMP-9 were not associated with mental status. CONCLUSION: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness.

In-hospital catatonia, delirium, and coma and mortality: Results from the delirium and catatonia prospective cohort investigation.

BACKGROUND: Catatonia, a form of acute brain dysfunction typically linked with severe affective and psychotic disorders, occurs in critical illness with delirium and coma. Delirium and coma are associated with mortality, though catatonia's relationship with mortality is unclear. We aim to describe whether catatonia, delirium, and coma are associated with mortality. METHODS: We enrolled a convenience cohort of critically ill adults (N = 378) at an academic medical center. We assessed catatonia, delirium, and coma using the Bush-Francis Catatonia Rating Scale, the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale, respectively. We tested the associations between previous day brain dysfunction state occurrence with in-hospital and one-year mortality using multivariable time-dependent risk models. Additionally, we tested the association between brain dysfunction duration and one-year mortality. RESULTS: Catatonia was not associated with death on the day after diagnosis during hospitalization, and neither previous catatonia occurrence nor duration was associated with one-year mortality. Delirium was not associated with death on any day following diagnosis during hospitalization, and neither previous delirium occurrence nor duration was associated with one-year mortality. The occurrence of coma was associated with death on any day after diagnosis during hospitalization (HR 2.30,CI 1.19-4.44,p = 0.014), as well as through one year following hospital discharge (HR 1.68,CI 1.09-2.59,p = 0.02). CONCLUSIONS: Coma, but neither catatonia nor delirium, was associated with future day in-hospital and one-year mortality. More research is needed to understand catatonia's clinical impact. Delirium results differ from existing literature likely due to cohort demographics and size. Coma results highlight the prognostic significance of suppressed arousal while critically ill.

Rehabilitation for People with Respiratory Disease and Frailty: An Official American Thoracic Society Workshop Report.

People with respiratory disease have increased risk of developing frailty, which is associated with worse health outcomes. There is growing evidence of the role of rehabilitation in managing frailty in people with respiratory disease. However, several challenges remain regarding optimal methods of identifying frailty and delivering rehabilitation for this population. The aims of this American Thoracic Society workshop were to outline key definitions and concepts around rehabilitation for people with respiratory disease and frailty, synthesize available evidence, and explore how programs may be adapted to align to the needs and experiences of this population. Across two half-day virtual workshops, 20 professionals from diverse disciplines, professions, and countries discussed key developments and identified opportunities for future research, with additional input via online correspondence. Participants highlighted a "frailty rehabilitation paradox" whereby pulmonary rehabilitation can effectively reduce frailty, but programs are challenging for some individuals with frailty to complete. Frailty should not limit access to rehabilitation; instead, the identification of frailty should prompt comprehensive assessment and tailored support, including onward referral for additional specialist input. Exercise prescriptions that explicitly consider symptom burden and comorbidities, integration of additional geriatric or palliative care expertise, and/or preemptive planning for disruptions to participation may support engagement and outcomes. To identify and measure frailty in people with respiratory disease, tools should be selected on the basis of sensitivity, specificity, responsiveness, and feasibility for their intended purpose. Research is required to expand understanding beyond the physical dimensions of frailty and to explore the merits and limitations of telerehabilitation or home-based pulmonary rehabilitation for people with chronic respiratory disease and frailty.

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.

Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study.

BACKGROUND: To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae. METHODS: This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression. FINDINGS: Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation-Sedation Scale score while on invasive mechanical ventilation was -4 (-5 to -3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU. INTERPRETATION: Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19. FUNDING: None. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Inflammation and Coagulation during Critical Illness and Long-Term Cognitive Impairment and Disability.

Rationale: The biological mechanisms of long-term cognitive impairment and disability after critical illness are unclear.Objectives: To test the hypothesis that markers of acute inflammation and coagulation are associated with subsequent long-term cognitive impairment and disability.Methods: We obtained plasma samples from adults with respiratory failure or shock on Study Days 1, 3, and 5 and measured concentrations of CRP (C-reactive protein), IFN-γ, IL-1ß, IL-6, IL-8, IL-10, IL-12, MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), soluble TNF receptor 1, and protein C. At 3 and 12 months after discharge, we assessed global cognition, executive function, and activities of daily living. We analyzed associations between markers and outcomes using multivariable regression, adjusting for age, sex, education, comorbidities, baseline cognition, doses of sedatives and opioids, stroke risk (in cognitive models), and baseline disability scores (in disability models).Measurements and Main Results: We included 548 participants who were a median (interquartile range) of 62 (53-72) years old, 88% of whom were mechanically ventilated, and who had an enrollment Sequential Organ Failure Assessment score of 9 (7-11). After adjusting for covariates, no markers were associated with long-term cognitive function. Two markers, CRP and MMP-9, were associated with greater disability in basic and instrumental activities of daily living at 3 and 12 months. No other markers were consistently associated with disability outcomes.Conclusions: Markers of systemic inflammation and coagulation measured early during critical illness are not associated with long-term cognitive outcomes and demonstrate inconsistent associations with disability outcomes. Future studies that pair longitudinal measurement of inflammation and related pathways throughout the course of critical illness and during recovery with long-term outcomes are needed.

Surgery and Anesthesia Exposure Is Not a Risk Factor for Cognitive Impairment After Major Noncardiac Surgery and Critical Illness.

OBJECTIVE: The aim of this study was to determine whether surgery and anesthesia exposure is an independent risk factor for cognitive impairment after major noncardiac surgery associated with critical illness. SUMMARY OF BACKGROUND DATA: Postoperative cognitive impairment is a prevalent individual and public health problem. Data are inconclusive as to whether this impairment is attributable to surgery and anesthesia exposure versus patients' baseline factors and hospital course. METHODS: In a multicenter prospective cohort study, we enrolled ICU patients with major noncardiac surgery during hospital admission and with nonsurgical medical illness. At 3 and 12 months, we assessed survivors' global cognitive function with the Repeatable Battery for the Assessment of Neuropsychological Status and executive function with the Trail Making Test, Part B. We performed multivariable linear regression to study the independent association of surgery/anesthesia exposure with cognitive outcomes, adjusting initially for baseline covariates and subsequently for in-hospital covariates. RESULTS: We enrolled 1040 patients, 402 (39%) with surgery/anesthesia exposure. Median global cognition scores were similar in patients with surgery/anesthesia exposure compared with those without exposure at 3 months (79 vs 80) and 12 months (82 vs 82). Median executive function scores were also similar at 3 months (41 vs 40) and 12 months (43 vs 42). Surgery/anesthesia exposure was not associated with worse global cognition or executive function at 3 or 12 months in models incorporating baseline or in-hospital covariates (P > 0.2). Higher baseline education level was associated with better global cognition at 3 and 12 months (P < 0.001), and longer in-hospital delirium duration was associated with worse global cognition (P < 0.02) and executive function (P < 0.01) at 3 and 12 months. CONCLUSIONS: Cognitive impairment after major noncardiac surgery and critical illness is not associated with the surgery and anesthesia exposure but is predicted by baseline education level and in-hospital delirium.

Implementing delirium screening in the ICU: secrets to success.

OBJECTIVE: To review delirium screening tools available for use in the adult ICU and PICU, to review evidence-based delirium screening implementation, and to discuss common pitfalls encountered during delirium screening in the ICU. DATA SOURCES: Review of delirium screening literature and expert opinion. RESULTS: Over the past decade, tools specifically designed for use in critically ill adults and children have been developed and validated. Delirium screening has been effectively implemented across many ICU settings. Keys to effective implementation include addressing barriers to routine screening, multifaceted training such as lectures, case-based scenarios, one-on-one teaching, and real-time feedback of delirium screening, and interdisciplinary communication through discussion of a patient's delirium status during bedside rounds and through documentation systems. If delirium is present, clinicians should search for reversible or treatable causes because it is often multifactorial. CONCLUSION: Implementation of effective delirium screening is feasible but requires attention to implementation methods, including a change in the current ICU culture that believes delirium is inevitable or a normal part of a critical illness, to a future culture that views delirium as a dangerous syndrome which portends poor clinical outcomes and which is potentially modifiable depending on the individual patients circumstances.

Preventing delirium in the intensive care unit.

Delirium in the intensive care unit (ICU) is exceedingly common, and risk factors for delirium among the critically ill are nearly ubiquitous. Addressing modifiable risk factors including sedation management, deliriogenic medications, immobility, and sleep disruption can help to prevent and reduce the duration of this deadly syndrome. The ABCDE approach to critical care is a bundled approach that clinicians can implement for many patients treated in their ICUs to prevent the adverse outcomes associated with delirium and critical illness.

Optimising the recognition of delirium in the intensive care unit.

Delirium affects up to 80% of critically ill patients and negatively influences patient outcome. Consensus guidelines advocate that a validated screening tool like the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC) be used to identify delirium rather than a subjective approach. The CAM-ICU and ICDSC have the most rigorous psychometric data to support their use. The differences between these two instruments are far less important to the outcome of patients than the regular and reliable use of either in routine ICU care. Implementation of a large-scale delirium screening effort is both feasible and sustainable and should be accompanied by both didactic and bedside education. An ICU clinical road map should be used on a daily basis that promotes delirium assessment, establishes a targeted sedation goal and defines the analgesic/sedative regimen that is best suited to maintain patient comfort, prevent delirium and promote wakefulness.