Effect of level of sedation on outcomes in critically ill adult patients: a systematic review of clinical trials with meta-analysis and trial sequential analysis.

Background: Sedation is routinely administered to critically ill patients to alleviate anxiety, discomfort, and patient-ventilator asynchrony. However, it must be balanced against risks such as delirium and prolonged intensive care stays. This study aimed to investigate the effects of different levels of sedation in critically ill adults. Methods: Systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials including critically ill adults admitted to the intensive care unit. CENTRAL, MEDLINE, Embase, LILACS, and Web of Science were searched from their inception to 13 June 2023. Risks of bias were assessed using the Cochrane risk of bias tool. Primary outcome was all-cause mortality. Aggregate data were synthesised with meta-analyses and TSA, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO: CRD42023386960. Findings: Fifteen trials randomising 4352 patients were included, of which 13 were assessed high risk of bias. Meta-analyses comparing lighter to deeper sedation showed no evidence of a difference in all-cause mortality (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.83-1.06; p = 0.28; 15 trials; moderate certainty evidence), serious adverse events (RR 0.99, CI 0.92-1.06; p = 0.80; 15 trials; moderate certainty evidence), or delirium (RR 1.01, 95% CI 0.94-1.09; p = 0.78; 11 trials; moderate certainty evidence). TSA showed that when assessing mortality, a relative risk reduction of 16% or more between the compared interventions could be rejected. Interpretation: The level of sedation has not been shown to affect the risks of death, delirium, and other serious adverse events in critically ill adult patients. While TSA suggests that additional trials are unlikely to significantly change the conclusion of the meta-analyses, the certainty of evidence was moderate. This suggests a need for future high-quality studies with higher methodological rigor. Funding: None.

Achieving Goals of Care Decisions in Chronic Critical Illness: A Multi-Institutional Qualitative Study.

BACKGROUND: Physicians, patients, and families alike perceive a need to improve how goals of care (GOC) decisions occur in chronic critical illness (CCI), but little is currently known about this decision-making process. RESEARCH QUESTION: How do intensivists from various health systems facilitate decision-making about GOC for patients with CCI? What are barriers to, and facilitators of, this decision-making process? STUDY DESIGN AND METHODS: We conducted semistructured interviews with a purposeful sample of intensivists from the United States and Canada using a mental models approach adapted from decision science. We analyzed transcripts inductively using qualitative description. RESULTS: We interviewed 29 intensivists from six institutions. Participants across all sites described GOC decision-making in CCI as a complex, longitudinal, and iterative process that involved substantial preparatory work, numerous stakeholders, and multiple family meetings. Intensivists required considerable time to collect information on prior events and conversations, and to arrive at a prognostic consensus with other involved physicians prior to meeting with families. Many intensivists stressed the importance of scheduling multiple family meetings to build trust and relationships prior to explicitly discussing GOC. Physician-identified barriers to GOC decision-making included 1-week staffing models, limited time and cognitive bandwidth, difficulty eliciting patient values, and interpersonal challenges with care team members or families. Potential facilitators included scheduled family meetings at regular intervals, greater interprofessional involvement in decisions, and consistent messaging from care team members. INTERPRETATION: Intensivists described a complex time- and labor-intensive group process to achieve GOC decision-making in CCI. System-level interventions that improve how information is shared between physicians and decrease logistical and relational barriers to timely and consistent communication are key to improving GOC decision-making in CCI.

A multicenter, randomized, doubleblind, placebo-controlled trial of amantadine to stimulate awakening in comatose patients resuscitated from cardiac arrest.

OBJECTIVE: We hypothesized that the administration of amantadine would increase awakening of comatose patients resuscitated from cardiac arrest. METHODS: We performed a prospective, randomized, controlled pilot trial, randomizing subjects to amantadine 100 mg twice daily or placebo for up to 7 days. The study drug was administered between 72 and 120 hours after resuscitation and patients with absent N20 cortical responses, early cerebral edema, or ongoing malignant electroencephalography patterns were excluded. Our primary outcome was awakening, defined as following two-step commands, within 28 days of cardiac arrest. Secondary outcomes included length of stay, awakening, time to awakening, and neurologic outcome measured by Cerebral Performance Category at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher exact tests and time to awakening and hospital length of stay using Wilcoxon rank sum tests. RESULTS: After 2 years, we stopped the study due to slow enrollment and lapse of funding. We enrolled 14 subjects (12% of goal enrollment), seven in the amantadine group and seven in the placebo group. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.6%) and placebo groups (n=3, 42.9%; P>0.99). There were no differences in secondary outcomes. Study medication was stopped in three subjects (21.4%). Adverse events included a recurrence of seizures (n=2; 14.3%), both of which occurred in the placebo group. CONCLUSION: We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.

Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement From the American Heart Association and Neurocritical Care Society.

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement from the American Heart Association and Neurocritical Care Society.

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

Standardizing post-cardiac arrest care across rural-urban settings - qualitative findings on proposed post-cardiac arrest learning community intervention.

BACKGROUND: Standardization of post-cardiac arrest care between emergency department arrival and intensive care unit admission can be challenging, particularly for rural centers, which can experience significant delays in interfacility transfer. One approach to addressing this issue is to form a post-cardiac arrest learning community (P-CALC) consisting of emergency department (ED) and intensive care unit (ICU) physicians and nurses who use data, shared resources, and collaboration to improve post-cardiac arrest care. MaineHealth, the largest regional health system in Maine, launched its P-CALC in 2022. OBJECTIVE: To explore P-CALC participants' perspectives on current post-cardiac arrest care, attitudes toward implementing a P-CALC intervention, perceived barriers and facilitators to intervention implementation, and implementation strategies. METHODS: We conducted semi-structured, individual, qualitative interviews with 16 staff from seven system EDs spanning the rural-urban spectrum. Directed content analysis was used to discern key themes in transcribed interviews. RESULTS: Participants highlighted site- and system-level factors influencing current post-cardiac arrest care. They expressed both positive attitudes and concerns about the P-CALC intervention. Multiple facilitators and barriers were identified in regard to the intervention implementation. Five proposed implementation strategies emerged as important factors to move the intervention forward. CONCLUSIONS: Implementation of a P-CALC intervention to effect system-wide improvements in post-cardiac arrest care is complex. Understanding providers' perspectives on current care practices, feasibility of quality improvement, and potential intervention impacts is essential for program development.

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients.

IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

Sedation and shivering management after cardiac arrest.

Management of sedation and shivering during targeted temperature management (TTM) after cardiac arrest is limited by a dearth of high-quality evidence to guide clinicians. Data from general intensive care unit (ICU) populations can likely be extrapolated to post-cardiac arrest patients, but clinicians should be mindful of key differences that exist between these populations. Most importantly, the goals of sedation after cardiac arrest are distinct from other ICU patients and may also involve suppression of shivering during TTM. Drug metabolism and clearance are altered considerably during TTM when a low goal temperature is used, which can delay accurate neuroprognostication. When neuromuscular blockade is used to prevent shivering, sedation should be deep enough to prevent awareness and providers should be aware that this can mask clinical manifestations of seizures. However, excessively deep or prolonged sedation is associated with complications including delirium, infections, increased duration of ventilatory support, prolonged ICU length of stay, and delays in neuroprognostication. In this manuscript, we review sedation and shivering management best practices in the post-cardiac arrest patient population.

External validation of the CREST model to predict early circulatory-etiology death after out-of-hospital cardiac arrest without initial ST-segment elevation myocardial infarction.

BACKGROUND: The CREST model is a prediction model, quantitating the risk of circulatory-etiology death (CED) after cardiac arrest based on variables available at hospital admission, and intend to guide the triage of comatose patients without ST-segment-elevation myocardial infarction after successful cardiopulmonary resuscitation. This study assessed performance of the CREST model in the Target Temperature Management (TTM) trial cohort. METHODS: We retrospectively analyzed data from resuscitated out-of-hospital cardiac arrest (OHCA) patients in the TTM-trial. Demographics, clinical characteristics, and CREST variables (history of coronary artery disease, initial heart rhythm, initial ejection fraction, shock at admission and ischemic time > 25 min) were assessed in univariate and multivariable analysis. The primary outcome was CED. The discriminatory power of the logistic regression model was assessed using the C-statistic and goodness of fit was tested according to Hosmer-Lemeshow. RESULTS: Among 329 patients eligible for final analysis, 71 (22%) had CED. History of ischemic heart disease, previous arrhythmia, older age, initial non-shockable rhythm, shock at admission, ischemic time > 25 min and severe left ventricular dysfunction were variables associated with CED in univariate analysis. CREST variables were entered into a logistic regression model and the area under the curve for the model was 0.73 with adequate calibration according to Hosmer-Lemeshow test (p = 0.602). CONCLUSIONS: The CREST model had good validity and a discrimination capability for predicting circulatory-etiology death after resuscitation from cardiac arrest without ST-segment elevation myocardial infarction. Application of this model could help to triage high-risk patients for transfer to specialized cardiac centers.

Decreased circulating CD73 and adenosine deaminase are associated with disease severity in hospitalized patients with COVID-19.

OBJECTIVE: SARS-CoV-2 infection has been shown to result in increased circulating levels of adenosine triphosphate and adenosine diphosphate and decreased levels of adenosine, which has important anti-inflammatory activity. The goal of this pilot project was to assess the levels of soluble CD73 and soluble Adenosine Deaminase (ADA) in hospitalized patients with COVID-19 and determine if levels of these molecules are associated with disease severity. METHODS: Plasma from 28 PCR-confirmed hospitalized COVID-19 patients who had varied disease severity based on WHO classification (6 mild/moderate, 10 severe, 12 critical) had concentrations of both soluble CD73 and ADA determined by ELISA. These concentrations were compared to healthy control plasma that is commercially available and was biobanked prior to the start of the pandemic. Additionally, outcomes such as WHO ordinal scale for disease severity, ICU admission, needed for invasive ventilation, hospital length of stay, and development of thrombosis during admission were used as markers of disease severity. RESULTS: Our results show that both CD73 and ADA are decreased during SARS-CoV-2 infection. The level of circulating CD73 is directly correlated to the severity of the disease defined by the need for ICU admission, invasive ventilation, and hospital length of stay. Low level of CD73 is also associated with clinical thrombosis, a severe complication of SARS-CoV-2 infection. CONCLUSION: Our study indicates that adenosine metabolism is down-regulated in patients with COVID-19 and associated with severe infection. Further large-scale studies are warranted to investigate the role of the adenosinergic anti-inflammatory CD73/ADA axis in protection against COVID-19.

The number of circulating CD26 expressing cells is decreased in critical COVID-19 illness.

We evaluated the number of CD26 expressing cells in peripheral blood of patients with COVID-19 within 72 h of admission and on day 4 and day 7 after enrollment. The majority of CD26 expressing cells were presented by CD3+ CD4+ lymphocytes. A low number of CD26 expressing cells were found to be associated with critical-severity COVID-19 disease. Conversely, increasing numbers of CD26 expressing T cells over the first week of standard treatment was associated with good outcomes. Clinically, the number of circulating CD26 cells might be a marker of recovery or the therapeutic efficacy of anti-COVID-19 treatment. New therapies aimed at preserving and increasing the level of CD26 expressing T cells may prove useful in the treatment of COVID-19 disease.

Cardiac Arrest Treatment Center Differences in Sedation and Analgesia Dosing During Targeted Temperature Management.

BACKGROUND: Sedation and analgesia are recommended during targeted temperature management (TTM) after cardiac arrest, but there are few data to provide guidance on dosing to bedside clinicians. We evaluated differences in patient-level sedation and analgesia dosing in an international multicenter TTM trial to better characterize current practice and clinically important outcomes. METHODS: A total 950 patients in the international TTM trial were randomly assigned to a TTM of 33 °C or 36 °C after resuscitation from cardiac arrest in 36 intensive care units. We recorded cumulative doses of sedative and analgesic drugs at 12, 24, and 48 h and normalized to midazolam and fentanyl equivalents. We compared number of medications used, dosing, and titration among centers by using multivariable models, including common severity of illness factors. We also compared dosing with time to awakening, incidence of clinical seizures, and survival. RESULTS: A total of 614 patients at 18 centers were analyzed. Propofol (70%) and fentanyl (51%) were most frequently used. The average dosages of midazolam and fentanyl equivalents were 0.13 (0.07, 0.22) mg/kg/h and 1.16 (0.49, 1.81) µg/kg/h, respectively. There were significant differences in number of medications (p < 0.001), average dosages (p < 0.001), and titration at all time points between centers (p < 0.001), and the outcomes of patients in these centers were associated with all parameters described in the multivariate analysis, except for a difference in the titration of sedatives between 12 and 24 h (p = 0.40). There were associations between higher dosing at 48 h (p = 0.003, odds ratio [OR] 1.75) and increased titration of analgesics between 24 and 48 h (p = 0.005, OR 4.89) with awakening after 5 days, increased titration of sedatives between 24 and 48 h with awakening after 5 days (p < 0.001, OR > 100), and increased titration of sedatives between 24 and 48 h with a higher incidence of clinical seizures in the multivariate analysis (p = 0.04, OR 240). There were also significant associations between decreased titration of analgesics and survival at 6 months in the multivariate analysis (p = 0.048). CONCLUSIONS: There is significant variation in choice of drug, dosing, and titration when providing sedation and analgesics between centers. Sedation and analgesia dosing and titration were associated with delayed awakening, incidence of clinical seizures, and survival, but the causal relation of these findings cannot be proven.

Community consultation for Exception from Informed consent (EFIC) before and during the COVID-19 pandemic.

Aim: Describe community consultation and surrogate consent rates for two Exception From Informed Consent (EFIC) trials for out-of-hospital cardiac arrest (OOHCA) - before and during the COVID-19 pandemic. Methods: The PEARL study (2016-2018) randomized OOHCA patients without ST-elevation to early cardiac catheterization or not. Community consultation included flyers, radio announcements, newspaper advertisements, mailings, and in-person surveys at basketball games and ED waiting rooms. The PROTECT trial (2021-present) randomizes OOHCA survivors to prophylactic ceftriaxone or placebo; the community consultation plan during the pandemic included city council presentations, social media posts, outpatient flyers, but no in-person encounters. Demographics for PROTECT community consultation were compared to PEARL and INTCAR registry data, with p-value < 0.05 considered significant. Results: PEARL surveyed 1,362 adults, including 64 % ≥60 years old, 96 % high school graduates or beyond; research acceptance rate was 92 % for the community and 76 % for personal level. PROTECT initially obtained 221 surveys from electronic media - including fewer males (28 % vs 72 %,p < 0.001) and those > 60 years old (14 % vs 53 %;p < 0.001) compared to INTCAR. These differences prompted a revised community consultation plan, targeting 79 adult in-patients with cardiac disease which better matched PEARL and INTCAR data: the majority were ≥ 60 years old (66 %) and male (54 %). Both PEARL and PROTECT enrolled more patients using surrogate consent vs EFIC (57 %, 61 %), including 71 % as remote electronic consents during PROTECT. Conclusions: Community consultation for EFIC studies changed with the COVID-19 pandemic, resulting in different demographic patterns. We describe effective adaptations to community consultation and surrogate consent during the pandemic.

Opioid Prescribing Patterns Before, During, and After Critical Illness: An Observational Study.

OBJECTIVES: The association between opioid therapy during critical illness and persistent opioid use after discharge is understudied relative to ICU opioid exposure and modifiable risk factors. Our objectives were to compare persistent opioid use after discharge among patients with and without chronic opioid use prior to admission (OPTA) and identify risk factors associated with persistent use. DESIGN: Retrospective cohort study. SETTING: Medical, trauma/surgical, or neurologic ICU at an academic hospital. PARTICIPANTS: Adult patients surviving hospital admission. INTERVENTIONS: Opioid use during the ICU and post-ICU stays. MEASUREMENTS AND MAIN RESULTS: The primary outcome was persistent opioid use accounting for greater than 70% of days 4-6 months after discharge. Among 2,975 included patients, 257 (8.6%) were classified as OPTA, and 305 (10.2%) persistently filled opioid prescriptions, including 186/257 (72%) OPTA and 119/2,718 (4.4%) with no chronic opioid fills prior to admission. Among all patients, OPTA was strongly associated with persistent opioid use (odds ratio, 57.2 [95% CI, 41.4-80.0]). Multivariable logistic regression revealed that male sex, surgical procedure, and ICU opioid-free days were associated with reduced persistent opioid use for OPTA patients. Age and ICU opioid-free days were associated with reduced persistent opioid use for non-OPTA patients. Total ICU opioid dose and dose per day of ICU exposure were not associated with persistent use for either group. CONCLUSIONS: In this mixed cohort of ICU patients, 10.2% persistently filled opioid prescriptions 4-6 months after discharge. Although ICU opioid doses were not associated with persistent use, duration of ICU opioid administration is a modifiable risk factor that may reduce persistent opioid use after critical illness.

Influence of circulatory shock at hospital admission on outcome after out-of-hospital cardiac arrest.

Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006-2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1-2) versus poor (CPC 3-5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46-0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome.

Prospective Validation of Sedation Scale Scores That Identify Light Sedation: A Pilot Study.

BACKGROUND: Intensive care unit (ICU) sedation guidelines recommend targeting a light sedation level, but light sedation has no accepted definition, and inconsistent levels have been proposed. OBJECTIVE: To determine Sedation-Agitation Scale and Richmond Agitation-Sedation Scale scores that best describe patients' ability to follow voice commands. METHODS: This prospective, observational pilot study enrolled a convenience sample of ICU patients receiving mechanical ventilation. Pairs of trained investigators evaluated scores on the Sedation-Agitation Scale and Richmond Agitation-Sedation Scale and ability to follow commands before and up to 2 hours after sedation lightening in a blind, independent, simultaneous fashion. Positive predictive values (PPVs) and likelihood ratios (LRs) of Sedation-Agitation Scale and Richmond Agitation-Sedation Scale scores associated with light sedation (ability to follow at least 3 commands) were calculated. RESULTS: Ninety-six assessments (50 before and 46 after lightening of sedation) were performed in medical ICU patients. Scores best associated with ability to follow at least 3 commands were Sedation-Agitation Scale score of 4 (PPV, 0.88; 95% CI, 0.70-0.98; LR, 14.0) and Richmond Agitation-Sedation Scale score of -1 (PPV, 0.81; 95% CI, 0.61-0.93; LR, 10.7), superior to previously recommended thresholds of Sedation-Agitation Scale score of 3 (PPV, 0.62; 95% CI, 0.48-0.75; LR, 3.1) and Richmond Agitation-Sedation Scale score of -3 (PPV, 0.52; 95% CI, 0.39-0.64; LR, 2.0). CONCLUSIONS: The level of sedation most associated with the ability to follow commands appears higher than previously recommended. Further study is needed regarding the effects of sedation level on ICU patients' ability to follow commands and assessment of delirium, pain, and patient preferences.

Ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arresT (PROTECT): study protocol for a randomized, placebo-controlled trial.

BACKGROUND: Pneumonia is the most common infection after out-of-hospital cardiac arrest (OHCA) occurring in up to 65% of patients who remain comatose after return of spontaneous circulation. Preventing infection after OHCA may (1) reduce exposure to broad-spectrum antibiotics, (2) prevent hemodynamic derangements due to local and systemic inflammation, and (3) prevent infection-associated morbidity and mortality. METHODS: The ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arrest (PROTECT) trial is a randomized, placebo-controlled, single-center, quadruple-blind (patient, treatment team, research team, outcome assessors), non-commercial, superiority trial to be conducted at Maine Medical Center in Portland, Maine, USA. Ceftriaxone 2 g intravenously every 12 h for 3 days will be compared with matching placebo. The primary efficacy outcome is incidence of early-onset pneumonia occurring < 4 days after mechanical ventilation initiation. Concurrently, T cell-mediated inflammation bacterial resistomes will be examined. Safety outcomes include incidence of type-one immediate-type hypersensitivity reactions, gallbladder injury, and Clostridioides difficile-associated diarrhea. The trial will enroll 120 subjects over approximately 3 to 4 years. DISCUSSION: The PROTECT trial is novel in its (1) inclusion of OHCA survivors regardless of initial heart rhythm, (2) use of a low-risk antibiotic available in the USA that has not previously been tested after OHCA, (3) inclusion of anti-inflammatory effects of ceftriaxone as a novel mechanism for improved clinical outcomes, and (4) complete metagenomic assessment of bacterial resistomes pre- and post-ceftriaxone prophylaxis. The long-term goal is to develop a definitive phase III trial powered for mortality or functional outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT04999592 . Registered on August 10, 2021.

Evaluation of Free Valproate Concentration in Critically Ill Patients.

Protein binding of valproate is variable in ICU patients, and the total valproate concentration does not predict the free valproate concentration, even when correcting for albumin. We sought to quantify valproate free concentration among ICU patients, identify risk factors associated with an increasing free valproate concentration, and evaluate the association between free valproate concentration with potential adverse drug effect. DESIGN: Retrospective multicenter cohort study. SETTING: Two academic medical centers. PATIENTS: Patients greater than or equal to 18 years of age with concomitant free and total valproate concentrations collected in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifty-six patients were included in the study, with a median age of 56 years (42-70) and 65% of patients were male. The median total valproate concentration was 53 µg/mL (38-70 µg/mL), the free valproate concentration was 12 µg/mL (7-20 µg/mL), and the free fraction was 23.6% (17.0-33.9%). Therapeutic discordance between the free and total valproate concentration occurred in 70% of patients. On multivariable analysis, increased free valproate concentration was associated with higher total valproate concentration (per 5 µg/mL increase, increase 1.72 µg/mL, 95% CI, 1.48-1.96) and lower serum albumin (per 1 g/dL decrease, increase 4.60 µg/mL, 95% CI, 2.71-6.49). There was no association between free valproate concentration and adverse effects. CONCLUSIONS: The valproate total and free concentration was discordant in the majority of patients (70%). Increased valproate free concentration was associated with hypoalbuminemia and total valproate concentration. Clinical decisions based on total valproate concentration may be incorrect for many ICU patients. Prospective, controlled studies are needed to confirm these findings and their clinical relevance.

Women receive less targeted temperature management than men following out-of-hospital cardiac arrest due to early care limitations - A study from the CARES Investigators.

BACKGROUND: Women experience worse neurological outcomes following out-of-hospital cardiac arrest (OHCA). It is unknown whether sex disparities exist in the use of targeted temperature management (TTM), a standard of care treatment to improve neurological outcomes. METHODS: We performed a retrospective study of prospectively collected patients who survived to hospital admission following OHCA from the Cardiac Arrest Registry to Enhance Survival from 2013 through 2019. We compared receipt of TTM by sex in a mixed-effects model adjusted for patient, arrest, neighborhood, and hospital factors, with the admitting hospital modeled as a random intercept. RESULTS: Among 123,419 patients, women had lower rates of shockable rhythms (24.4 % vs. 39.2%, P < .001) and lower rates of presumed cardiac aetiologies for arrest (74.3% vs. 81.1%, P < .001). Despite receiving a similar rate of TTM in the field (12.1% vs. 12.6%, P = .02), women received less TTM than men upon admission to the hospital (41.6% vs. 46.4%, P < .001). In an adjusted mixed-effects model, women were less likely than men to receive TTM (Odds Ratio 0.91, 95% Confidence Interval 0.89 to 0.94). Among the 27,729 patients with data indicating the reason for not using TTM, a higher percentage of women did not receive TTM due to Do-Not-Resuscitate orders/family requests (15.1% vs. 11.4%, p < .001) and non-shockable rhythms (11.1% vs. 8.4%, p < .001). CONCLUSIONS: We found that women received less TTM than men, likely due to early care limitations and a preponderance of non-shockable rhythms.

DEspRhigh neutrophils are associated with critical illness in COVID-19.

SARS-CoV-2 infection results in a spectrum of outcomes from no symptoms to widely varying degrees of illness to death. A better understanding of the immune response to SARS-CoV-2 infection and subsequent, often excessive, inflammation may inform treatment decisions and reveal opportunities for therapy. We studied immune cell subpopulations and their associations with clinical parameters in a cohort of 26 patients with COVID-19. Following informed consent, we collected blood samples from hospitalized patients with COVID-19 within 72 h of admission. Flow cytometry was used to analyze white blood cell subpopulations. Plasma levels of cytokines and chemokines were measured using ELISA. Neutrophils undergoing neutrophil extracellular traps (NET) formation were evaluated in blood smears. We examined the immunophenotype of patients with COVID-19 in comparison to that of SARS-CoV-2 negative controls. A novel subset of pro-inflammatory neutrophils expressing a high level of dual endothelin-1 and VEGF signal peptide-activated receptor (DEspR) at the cell surface was found to be associated with elevated circulating CCL23, increased NETosis, and critical-severity COVID-19 illness. The potential to target this subpopulation of neutrophils to reduce secondary tissue damage caused by SARS-CoV-2 infection warrants further investigation.