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.

Would You Rather: Quantifying TBI Survivor Perceptions of Functional Status via Their Surrogates.

OBJECTIVE: To quantify health utilities of the Glasgow Outcome Scale-Extended (GOSE) states after actual Traumatic Brain Injury (TBI). BACKGROUND: Recovery after TBI is measured using the GOSE, a validated clinical trial endpoint. A recent public survey quantified the health utilities of some GOSE states after hypothetical TBI as worse than death. However, no health utilities exist for disability after actual TBI. METHODS: This national computer-adaptive survey followed EQUATOR-CHERRIES guidelines and recruited adult TBI survivors (injury>1 y prior) via their available surrogates. Using a standard gamble approach in randomized order, participants gave preferences for post-TBI categorical health states ranging from GOSE 2-8. We calculated median [interquartile range, IQR] health utilities for each GOSE state, from -1 (worse than death) to 1 (full health), with 0 as reference (death, GOSE 1). RESULTS: Of 515 eligible, 298 surrogates (58%) consented and completed the scenarios on TBI survivors' behalf. TBI survivors had a current median GOSE 5 [3-7]. GOSE 2, GOSE 3, and GOSE 4 were rated worse than death by 89%, 64%, and 38%, respectively. The relationship was nonlinear, and intervals were unequal between states, with a bimodal distribution for GOSE 4. CONCLUSIONS: In this index study of actual post-TBI disability, poor neurologic outcomes represented by GOSE 2-4 were perceived as worse than death by at least one in three survivors. Similar to previously reported public perceptions after a hypothetical TBI, these long-term perceptions may inform earlier post-TBI shared decision making, as well as help shape value-based research and quality of care. LEVEL OF EVIDENCE: II, Economic & Value-based Evaluations.

Surrogate Perception of Disability after Hospitalization for Traumatic Brain Injury.

BACKGROUND: The Glasgow Outcome Scale Extended (GOSE) is a measure of recovery after traumatic brain injury (TBI). Public surveys rate some GOSE states as worse than death. Direct family experience caring for patients with TBI may impact views of post-TBI disability. STUDY DESIGN: We conducted a national cross-sectional computer-adaptive survey of surrogates of TBI dependents incurring injury more than 1 year earlier. Using a standard gamble approach in randomized order, surrogates evaluated preferences for post-TBI GOSE states from GOSE 2 (bedridden, unaware) to GOSE 8 (good recovery). We calculated median (interquartile range [IQR]) health utilities for each post-TBI state, ranging from -1 to 1, with 0 as reference (death = GOSE 1), and assessed sociodemographic associations using proportional odds logistic regression modeling. RESULTS: Of 515 eligible surrogates, 298 (58%) completed scenarios. Surrogates were median aged 46 (IQR 35 to 60), 54% married, with Santa Clara strength of faith 14 (10 to 18). TBI dependents had a median GOSE5 (3 to 7). Median (IQR) health utility ratings for GOSE 2, GOSE 3, and GOSE 4 were -0.06 (-0.50 to -0.01), -0.01 (-0.30 to 0.45), and 0.30 (-0.01 to 0.80), rated worse than death by 91%, 65%, and 40%, respectively. Surrogates rated GOSE 4 (daily partial help) worse than the general population. Married surrogates rated GOSE 4 higher (p < 0.01). Higher strength of faith was associated with higher utility scores across GOSE states (p = 0.034). CONCLUSIONS: In this index study of surrogate perceptions about disability after TBI, poor neurologic outcomes-vegetative, needing all-day or partial daily assistance-were perceived as worse than death by at least 1 in 3 surrogates. Surrogate perceptions differed from the unexposed public. Long-term perceptions about post-TBI disability may inform earlier, tailored shared decision-making after neurotrauma.

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. Objective: To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. Design, Setting, and Participants: An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Interventions: Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Main Outcomes and Measures: Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. Results: A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. Conclusions and Relevance: The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. Trial Registration: ClinicalTrials.gov Identifier: NCT01211522.

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.

Prehospital Time Following Traumatic Injury Is Independently Associated With the Need for In-Hospital Blood and Early Mortality for Specific Injury Types.

OBJECTIVE: Treating traumatic hemorrhage is time sensitive. Prehospital care and transport modes (eg, helicopter and ground) may influence in-hospital events. We hypothesized that prehospital time (on-scene time [OST] and total prehospital time [TPT]) and transport mode are associated with same-day transfusion and mortality. Furthermore, we sought to identify regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. METHODS: We obtained prehospital, in-hospital, and trauma registry data from an 8-center cohort of adult nonburn trauma patients from 2017 to 2022 directly transported from the scene to the hospital and having an Injury Severity Score (ISS) > 9 for the Task Order 1 project of the Linking Investigators in Trauma and Emergency Services research network. We excluded patients missing prehospital times, patients < 18 years of age, patients from interfacility transfers, and recipients of prehospital blood. Our same-day outcomes were in-hospital transfusions within 4 hours and 24-hour mortality. Each outcome was adjusted using multivariable logistic regression for covariates of prehospital phases (OST and TPT), mode of transport (helicopter and ground), age, sex, ISS, Glasgow Coma Scale motor subscale score < 6, and field hypotension (systolic blood pressure < 90 mm Hg). We evaluated the association of prehospital time on outcomes for scene missions by transport mode across severe injury patterns defined by Abbreviated Injury Scale > 2 body regions. RESULTS: Of 78,198 subjects, 34,504 were eligible for the study with a mean age of 47.6 ± 20.3 years, ISS of 18 ± 11, OST of 15.9 ± 9.5 minutes, and TPT of 48.7 ± 20.3 minutes. Adjusted for injury severity and demographic factors, transport type significantly modified the relationship between prehospital time and outcomes. The association of OST and TPT with the odds of 4-hour transfusion was absent for the ground emergency medical services (GEMS) cohort and present for the helicopter emergency medical services (HEMS) ambulance cohort, whereas these times were associated with decreased 24-hour mortality for both transport types. When stratifying by injury to most anatomic regions, OST and TPT were associated with a decreased need for 4-hour transfusions in the GEMS cohort. However, OST was associated with increased early transfusion only among patients with severe injuries of the thorax, and this association persisted after adjusting additionally for injury type (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.00-1.05; P = .02). The presence of polytrauma supported an association between prehospital time and decreased 24-hour mortality for the GEMS cohort (OST: OR = 0.97; 95% CI, 0.95-0.99; P < .01; TPT: OR = 0.99; 95% CI, 0.98-0.99; P = .02), whereas no injuries showed significant association of helicopter prehospital time on mortality after adjustment. CONCLUSION: We determined that transport type affects the relationship between prehospital time and hospital outcomes (4-hour transfusion: positive relationship for HEMS and negative for GEMS, 24-hour mortality: negative for both transport types). Furthermore, we identified regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. Of these regions, most notable were severe isolated injuries to the thorax that supported a positive relationship between HEMS OST and 4-hour transfusions and polytrauma that showed a negative relationship between GEMS OST or TPT and 24-hour mortality after adjustment.

Differences in Health Professionals' Engagement With Electronic Health Records Based on Inpatient Race and Ethnicity.

Importance: US health professionals devote a large amount of effort to engaging with patients' electronic health records (EHRs) to deliver care. It is unknown whether patients with different racial and ethnic backgrounds receive equal EHR engagement. Objective: To investigate whether there are differences in the level of health professionals' EHR engagement for hospitalized patients according to race or ethnicity during inpatient care. Design, Setting, and Participants: This cross-sectional study analyzed EHR access log data from 2 major medical institutions, Vanderbilt University Medical Center (VUMC) and Northwestern Medicine (NW Medicine), over a 3-year period from January 1, 2018, to December 31, 2020. The study included all adult patients (aged ≥18 years) who were discharged alive after hospitalization for at least 24 hours. The data were analyzed between August 15, 2022, and March 15, 2023. Exposures: The actions of health professionals in each patient's EHR were based on EHR access log data. Covariates included patients' demographic information, socioeconomic characteristics, and comorbidities. Main Outcomes and Measures: The primary outcome was the quantity of EHR engagement, as defined by the average number of EHR actions performed by health professionals within a patient's EHR per hour during the patient's hospital stay. Proportional odds logistic regression was applied based on outcome quartiles. Results: A total of 243 416 adult patients were included from VUMC (mean [SD] age, 51.7 [19.2] years; 54.9% female and 45.1% male; 14.8% Black, 4.9% Hispanic, 77.7% White, and 2.6% other races and ethnicities) and NW Medicine (mean [SD] age, 52.8 [20.6] years; 65.2% female and 34.8% male; 11.7% Black, 12.1% Hispanic, 69.2% White, and 7.0% other races and ethnicities). When combining Black, Hispanic, or other race and ethnicity patients into 1 group, these patients were significantly less likely to receive a higher amount of EHR engagement compared with White patients (adjusted odds ratios, 0.86 [95% CI, 0.83-0.88; P < .001] for VUMC and 0.90 [95% CI, 0.88-0.92; P < .001] for NW Medicine). However, a reduction in this difference was observed from 2018 to 2020. Conclusions and Relevance: In this cross-sectional study of inpatient EHR engagement, the findings highlight differences in how health professionals distribute their efforts to patients' EHRs, as well as a method to measure these differences. Further investigations are needed to determine whether and how EHR engagement differences are correlated with health care outcomes.

Modifiable in-hospital factors for 12-month global cognition, post-traumatic stress disorder symptoms, and depression symptoms in adults hospitalized with COVID-19.

BACKGROUND: We sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months. METHODS: This was a multi-center prospective cohort study in adult hospitalized patients with acute COVID-19. The following in-hospital factors were assessed: delirium; frequency of in-person and virtual visits by friends and family; and hydroxychloroquine, corticosteroid, and remdesivir administration. Twelve-month global cognition was characterized by the MOCA-Blind. Twelve-month PTSD and depression were characterized using the PTSD Checklist for the DSM-V and Hospital Anxiety Depression Scale, respectively. FINDINGS: Two hundred three patients completed the 12-month follow-up assessments. Remdesivir use was associated with significantly higher cognition at 12 months based on the MOCA-Blind (adjusted odds ratio [aOR] = 1.98, 95% CI: 1.06, 3.70). Delirium was associated with worsening 12-month PTSD (aOR = 3.44, 95% CI: 1.89, 6.28) and depression (aOR = 2.18, 95% CI: 1.23, 3.84) symptoms. Multiple virtual visits per day during hospitalization was associated with lower 12-month depression symptoms compared to those with less than daily virtual visits (aOR = 0.40, 95% CI: 0.19, 0.85). CONCLUSION: Potentially modifiable factors associated with better long-term outcomes included remdesivir use (associated with better cognitive function), avoidance of delirium (associated with less PTSD and depression symptoms), and increased virtual interactions with friends and family (associated with less depression symptoms).

Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). BACKGROUND: Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. METHODS: This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16-64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. RESULTS: Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (- 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes. CONCLUSION: Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

Perceived Utility of Intracranial Pressure Monitoring in Traumatic Brain Injury: A Seattle International Brain Injury Consensus Conference Consensus-Based Analysis and Recommendations.

BACKGROUND: Intracranial pressure (ICP) monitoring is widely practiced, but the indications are incompletely developed, and guidelines are poorly followed. OBJECTIVE: To study the monitoring practices of an established expert panel (the clinical working group from the Seattle International Brain Injury Consensus Conference effort) to examine the match between monitoring guidelines and their clinical decision-making and offer guidance for clinicians considering monitor insertion. METHODS: We polled the 42 Seattle International Brain Injury Consensus Conference panel members' ICP monitoring decisions for virtual patients, using matrices of presenting signs (Glasgow Coma Scale [GCS] total or GCS motor, pupillary examination, and computed tomography diagnosis). Monitor insertion decisions were yes, no, or unsure (traffic light approach). We analyzed their responses for weighting of the presenting signs in decision-making using univariate regression. RESULTS: Heatmaps constructed from the choices of 41 panel members revealed wider ICP monitor use than predicted by guidelines. Clinical examination (GCS) was by far the most important characteristic and differed from guidelines in being nonlinear. The modified Marshall computed tomography classification was second and pupils third. We constructed a heatmap and listed the main clinical determinants representing 80% ICP monitor insertion consensus for our recommendations. CONCLUSION: Candidacy for ICP monitoring exceeds published indicators for monitor insertion, suggesting the clinical perception that the value of ICP data is greater than simply detecting and monitoring severe intracranial hypertension. Monitor insertion heatmaps are offered as potential guidance for ICP monitor insertion and to stimulate research into what actually drives monitor insertion in unconstrained, real-world conditions.

The Ethics of Discharge Planning After Violent Injury.

INTRODUCTION: Victims of violence (VoV) are at disproportionate risk for future violence, making consideration of patient safety by Emergency Medicine (EM) physicians and Trauma Surgeons (TS) essential when discharge planning (DP) for VoV. Practice patterns and ethical perspectives in DP for VoV, and their respective scenario- and specialty-specific variations, are unknown. METHODS: We surveyed 118 EM and 37 TS physicians at a level 1 trauma center. Three clinical scenarios were presented (intimate partner violence, elder abuse, gun violence), each followed by four questions assessing practices and ethical dilemmas in DP. Responses were compared using Chi-Square testing. RESULTS: Response rate was 51.6%. EM physicians more frequently supported patient autonomy to proceed with a potentially unsafe discharge plan after an episode of Intimate Partner Violence (P = .013) and believed that admission could facilitate change in the victim's social situation after an episode of Elder Abuse (P = .026). TS physicians were more likely to offer social admission, providing additional time to navigate safe discharge planning (P = .003), less likely to see social admission as an inappropriate use of limited resources (P = .030) and less likely to support patient autonomy to proceed with a potentially unsafe discharge (P = .003) after gun-related violence. CONCLUSION: There appears to exist scenario- and specialty-specific variability in the practice patterns and ethical perspectives of EM and TS physicians when discharge planning for victims of violence. These findings highlight the need for further evaluation of specific factors underlying variability by situation and specialty, and their implications for patient-centered outcomes.

Prognostication and Goals of Care Decisions in Severe Traumatic Brain Injury: A Survey of The Seattle International Severe Traumatic Brain Injury Consensus Conference Working Group.

Abstract Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the Seattle International severe traumatic Brain Injury Consensus Conference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a "nihilism guard." More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.

Prevalence and Risk Factors for Intensive Care Unit Delirium After Traumatic Brain Injury: A Retrospective Cohort Study.

BACKGROUND: Delirium remains understudied after traumatic brain injury (TBI). We sought to identify independent predictors of delirium among intensive care unit (ICU) patients with TBI. METHODS: This single-center retrospective cohort study evaluated adult patients with TBI requiring ICU admission. Outcomes included delirium days within the first 14 days, as assessed by the Confusion Assessment Method-ICU (CAM-ICU). Models were adjusted for age, sex, insurance, Marshall head computed tomography classification, presence of subarachnoid hemorrhage (SAH), Injury Severity Score (ISS), need for cardiopulmonary resuscitation, maximum admission Glasgow Coma motor score, glucose level, hemoglobin level, and pupil reactivity. RESULTS: Delirium prevalence was 60%, with a median duration of 4 days (interquartile range: 2-8) among ICU patients with TBI (n = 2,664). Older age, higher ISS, maximum motor score < 6, Marshall class II-IV, and SAH were associated with risk of increased delirium duration (all p < 0.001). CONCLUSIONS: In this large cohort, ICU delirium after TBI affected three of five patients for a median duration of 4 days. Age, general injury severity, motor score, and features of intracranial hemorrhage were predictive of more TBI-associated delirium days. Given the high prevalence of ICU delirium after TBI and its impact on hospitalization, further work is needed to understand the impact of delirium and TBI on outcomes and to determine whether delirium risk can be minimized.

Quantitative EEG signatures of delirium and coma in mechanically ventilated ICU patients.

OBJECTIVE: To identify quantitative electroencephalography (EEG)-based indicators of delirium or coma in mechanically ventilated patients. METHODS: We prospectively enrolled 28 mechanically ventilated intensive care unit (ICU) patients to undergo 24-hour continuous EEG, 25 of whom completed the study. We assessed patients twice daily using the Richmond Agitation-Sedation Scale (RASS) and Confusion Assessment Method for the ICU (CAM-ICU). We evaluated the spectral profile, regional connectivity and complexity of 5-minute EEG segments after each assessment. We used penalized regression to select EEG metrics associated with delirium or coma, and compared mixed-effects models predicting delirium with and without the selected EEG metrics. RESULTS: Delta variability, high-beta variability, relative theta power, and relative alpha power contributed independently to EEG-based identification of delirium or coma. A model with these metrics achieved better prediction of delirium or coma than a model with clinical variables alone (Akaike Information Criterion: 36 vs 43, p = 0.006 by likelihood ratio test). The area under the receiver operating characteristic curve for an ad hoc hypothetical delirium score using these metrics was 0.94 (95%CI 0.83-0.99). CONCLUSIONS: We identified four EEG metrics that, in combination, provided excellent discrimination between delirious/comatose and non-delirious mechanically ventilated ICU patients. SIGNIFICANCE: Our findings give insight to neurophysiologic changes underlying delirium and provide a basis for pragmatic, EEG-based delirium monitoring technology.

Dynamic predictors of in-hospital and 3-year mortality after traumatic brain injury: A retrospective cohort study.

BACKGROUND: Mortality risks after Traumatic Brain Injury (TBI) are understudied in critical illness. We sought to identify risks of mortality in critically ill patients with TBI using time-varying covariates. METHODS: This single-center, six-year (2006-2012), retrospective cohort study measured demographics, injury characteristics, and daily data of acute TBI patients in the Intensive Care Unit (ICU). Time-varying Cox proportional hazards models assessed in-hospital and 3-year mortality. RESULTS: Post-TBI ICU patients (n = 2664) experienced 20% in-hospital mortality (n = 529) and 27% (n = 706) 3-year mortality. Glasgow Coma Scale motor subscore (hazard ratio (HR) 0.58, p < 0.001), pupil reactivity (HR 3.17, p < 0.001), minimum glucose (HR 1.44, p < 0.001), mSOFA score (HR 1.81, p < 0.001), coma (HR 2.26, p < 0.001), and benzodiazepines (HR 1.38, p < 0.001) were associated with in-hospital mortality. At three years, public insurance (HR 1.78, p = 0.011) and discharge disposition (HR 4.48, p < 0.001) were associated with death. CONCLUSIONS: Time-varying characteristics influenced in-hospital mortality post-TBI. Socioeconomic factors primarily affect three-year mortality.

Assessment of safety and effectiveness of non-neurosurgical management for minimal traumatic brain injury (TBI).

BACKGROUND: Patients with mild traumatic brain injury (TBI) and intracranial hemorrhage often receive neurosurgical consultation. However, only a small proportion of patients require intervention. Our hypothesis is that low-risk minimal TBI patients managed without immediate neurosurgical consultation will have a reasonable safety and effectiveness outcome profile. METHODS: A non-neurosurgical management protocol for adult minimal TBI was implemented at a level I trauma center as an interdisciplinary quality-improvement initiative in November 2018. Minimal TBI was defined as Glasgow Coma Scale (GCS) of 15 secondary to blunt mechanism, without anticoagulant or antiplatelet therapy, and isolated pneumocephalus and/or traumatic subarachnoid hemorrhage on head CT imaging. Safety was assessed by in-hospital mortality, neurosurgical interventions, and ED revisits within two weeks of discharge. Effectiveness was assessed by neurosurgical consult rate and length of stay. Outcomes were compared 8-months pre- and post-protocol implementation. RESULTS: A total of 97 patients were included, of which 49 were pre-protocol and 48 were post-protocol There was no difference in rates of in-hospital mortality [0 (0%) vs 0 (0%)], neurosurgical procedure [1 (2.1%) vs 0 (0%)], operations [0 (0%) vs 0 (0%)], and ED revisits [1 (2.0%) vs 2 (4.2%), p = 0.985] between the periods. There was a significant reduction in neurosurgical consults post-protocol implementation (92% vs 29%, p<0.001). CONCLUSION: A protocol for minimal TBI patients effectively reduced neurosurgical consultation without changes in safety profile. Such an interdisciplinary management protocol for low-risk neurotrauma can effectively utilize the neurosurgery consult services by stratifying neurologically stable TBI patient.

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases.

BACKGROUND: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2. METHODS: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. RESULTS: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient's medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. CONCLUSIONS: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Association between cholinesterase activity and critical illness brain dysfunction.

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.