Association of anaesthesia provider sex with perioperative complications: a two-centre retrospective cohort study.

BACKGROUND: Previous studies suggested that surgeon sex is associated with differential patient outcomes. Whether this also applies to anaesthesia providers is unclear. We hypothesised that female sex of the primary anaesthesia provider is associated with lower risk of perioperative complications. METHODS: The first case for all adult patients undergoing anaesthesia care between 2008 and 2022 at two academic healthcare networks in the USA was included in this retrospective cohort study. The primary exposure was the sex of the anaesthesia provider who spent the most time in the operating theatre during the case. The primary outcome was intraoperative complications, defined as hypotension (mean arterial blood pressure <55 mm Hg for ≥5 cumulative minutes) or hypoxaemia (oxygen saturation <90% for >2 consecutive minutes). The co-primary outcome was 30-day adverse postoperative events (including complications, readmission, and mortality). Analyses were adjusted for a priori defined confounders. RESULTS: Among 364,429 included patients, 57,550 (15.8%) experienced intraoperative complications and 55,168 (15.1%) experienced adverse postoperative events. Care by female compared with male anaesthesia providers was associated with lower risk of intraoperative complications (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI] 0.94-0.97, P<0.001), which was magnified among non-trainees (aOR 0.84, 95% CI 0.82-0.87, P-for-interaction <0.001). Anaesthesia provider sex was not associated with the composite of adverse postoperative events (aOR 1.00, 95% CI 0.98-1.02, P=0.88). CONCLUSIONS: Care by a female anaesthesia provider was associated with a lower risk of intraoperative complications, which was magnified among non-trainees. Future studies should investigate underlying mechanisms.

DANGER Signals Activate G -Protein Receptor Kinases Suppressing Neutrophil Function and Predisposing to Infection After Tissue Trauma.

OBJECTIVE: Injured tissue predisposes the subject to local and systemic infection. We studied injury-induced immune dysfunction seeking novel means to reverse such predisposition. BACKGROUND: Injury mobilizes primitive "DANGER signals" [danger-associated molecular patterns (DAMPs)] activating innate immunocyte (neutrophils, PMN) signaling and function. Mitochondrial formyl peptides activate G -protein coupled receptors (GPCR) like formyl peptide receptor-1. Mitochondrial DNA and heme activate toll-like receptors (TLR9 and TLR2/4). GPCR kinases (GRKs) can regulate GPCR activation. METHODS: We studied human and mouse PMN signaling elicited by mitochondrial DAMPs (GPCR surface expression; protein phosphorylation, or acetylation; Ca 2+ flux) and antimicrobial functions [cytoskeletal reorganization, chemotaxis (CTX), phagocytosis, bacterial killing] in cellular systems and clinical injury samples. Predicted rescue therapies were assessed in cell systems and mouse injury-dependent pneumonia models. RESULTS: Mitochondrial formyl peptides activate GRK2, internalizing GPCRs and suppressing CTX. Mitochondrial DNA suppresses CTX, phagocytosis, and killing through TLR9 through a novel noncanonical mechanism that lacks GPCR endocytosis. Heme also activates GRK2. GRK2 inhibitors like paroxetine restore functions. GRK2 activation through TLR9 prevented actin reorganization, implicating histone deacetylases (HDACs). Actin polymerization, CTX, bacterial phagocytosis, and killing were also rescued, therefore, by the HDAC inhibitor valproate. Trauma repository PMN showed GRK2 activation and cortactin deacetylation, which varied with severity and was most marked in patients developing infections. Either GRK2 or HDAC inhibition prevented loss of mouse lung bacterial clearance, but only the combination rescued clearance when given postinjury. CONCLUSIONS: Tissue injury-derived DAMPs suppress antimicrobial immunity through canonical GRK2 activation and a novel TLR-activated GRK2-pathway impairing cytoskeletal organization. Simultaneous GRK2/HDAC inhibition rescues susceptibility to infection after tissue injury.

Association Between Unmet Nonmedication Needs After Hospital Discharge and Readmission or Death Among Acute Respiratory Failure Survivors: A Multicenter Prospective Cohort Study.

OBJECTIVES: To characterize early unmet nonmedication discharge needs (UDNs), classified as durable medical equipment (DME), home health services (HHS), and follow-up medical appointments (FUAs) and explore their association with 90-day readmission and mortality among survivors of acute respiratory failure (ARF) who were discharged home. DESIGN: Prospective multicenter cohort study. SETTING: Six academic medical centers across United States. PARTICIPANTS: Adult survivors of ARF who required an ICU stay and were discharged home from hospital. INTERVENTIONS: None. Exposure of interest was the proportion of UDN for the following categories: DME, HHS, and FUA ascertained within 7-28 days after hospital discharge. MEASUREMENTS AND MAIN RESULTS: Two hundred eligible patients were recruited between January 2019 and August 2020. One-hundred ninety-five patients were included in the analytic cohort: 118 were prescribed DME, 134 were prescribed HHS, and 189 needed at least one FUA according to discharge plans. 98.4% (192/195) had at least one identified nonmedication need at hospital discharge. Median (interquartile range) proportion of unmet needs across three categories were 0 (0-15%) for DME, 0 (0-50%) for HHS, and 0 (0-25%) for FUA, and overall was 0 (0-20%). Fifty-six patients (29%) had 90-day death or readmission. After adjusting for prespecified covariates, having greater than the median level of unmet needs was not associated with an increased risk of readmission or death within 90 days of discharge (risk ratio, 0.89; 0.51-1.57; p = 0.690). Age, hospital length of stay, Acute Physiology and Chronic Health Evaluation II severity of illness score, and Multidimensional Scale Perceived Social Support score were associated with UDN. CONCLUSIONS: UDN were common among survivors of ARF but not significantly associated a composite outcome of 90-day readmission or death. Our results highlight the substantial magnitude of UDN and identifies areas especially vulnerable to lapses in healthcare coordination.

Discharge Disposition and Loss of Independence Among Survivors of COVID-19 Admitted to Intensive Care: Results From the SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS).

OBJECTIVES: To describe incidence and risk factors of loss of previous independent living through nonhome discharge or discharge home with health assistance in survivors of intensive care unit (ICU) admission for coronavirus disease 2019 (COVID-19). DESIGN: Multicenter observational study including patients admitted to the ICU from January 2020 till June 30, 2021. HYPOTHESIS: We hypothesized that there is a high risk of nonhome discharge in patients surviving ICU admission due to COVID-19. SETTING: Data were included from 306 hospitals in 28 countries participating in the SCCM Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 registry. PATIENTS: Previously independently living adult ICU survivors of COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was nonhome discharge. Secondary outcome was the requirement of health assistance among patients who were discharged home. Out of 10 820 patients, 7101 (66%) were discharged alive; 3791 (53%) of these survivors lost their previous independent living status, out of those 2071 (29%) through nonhome discharge, and 1720 (24%) through discharge home requiring health assistance. In adjusted analyses, loss of independence on discharge among survivors was predicted by patient age ≥ 65 years (adjusted odds ratio [aOR] 2.78, 95% confidence interval [CI] 2.47-3.14, P < .0001), former and current smoking status (aOR 1.25, 95% CI 1.08-1.46, P = .003 and 1.60 (95% CI 1.18-2.16), P = .003, respectively), substance use disorder (aOR 1.52, 95% CI 1.12-2.06, P = .007), requirement for mechanical ventilation (aOR 4.17, 95% CI 3.69-4.71, P < .0001), prone positioning (aOR 1.19, 95% CI 1.03-1.38, P = .02), and requirement for extracorporeal membrane oxygenation (aOR 2.28, 95% CI 1.55-3.34, P < .0001). CONCLUSIONS: More than half of ICU survivors hospitalized for COVID-19 are unable to return to independent living status, thereby imposing a significant secondary strain on health care systems worldwide.

Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients.

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality. RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality. CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

Association of hypothyroidism with outcomes in hospitalized adults with COVID-19: Results from the International SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS): COVID-19 Registry.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is associated with high rates of morbidity and mortality. Primary hypothyroidism is a common comorbid condition, but little is known about its association with COVID-19 severity and outcomes. This study aims to identify the frequency of hypothyroidism in hospitalized patients with COVID-19 as well as describe the differences in outcomes between patients with and without pre-existing hypothyroidism using an observational, multinational registry. METHODS: In an observational cohort study we enrolled patients 18 years or older, with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between March 2020 and February 2021. The primary outcomes were (1) the disease severity defined as per the World Health Organization Scale for Clinical Improvement, which is an ordinal outcome corresponding with the highest severity level recorded during a patient's index COVID-19 hospitalization, (2) in-hospital mortality and (3) hospital-free days. Secondary outcomes were the rate of intensive care unit (ICU) admission and ICU mortality. RESULTS: Among the 20,366 adult patients included in the study, pre-existing hypothyroidism was identified in 1616 (7.9%). The median age for the Hypothyroidism group was 70 (interquartile range: 59-80) years, and 65% were female and 67% were White. The most common comorbidities were hypertension (68%), diabetes (42%), dyslipidemia (37%) and obesity (28%). After adjusting for age, body mass index, sex, admission date in the quarter year since March 2020, race, smoking history and other comorbid conditions (coronary artery disease, hypertension, diabetes and dyslipidemia), pre-existing hypothyroidism was not associated with higher odds of severe disease using the World Health Organization disease severity index (odds ratio [OR]: 1.02; 95% confidence interval [CI]: 0.92, 1.13; p = .69), in-hospital mortality (OR: 1.03; 95% CI: 0.92, 1.15; p = .58) or differences in hospital-free days (estimated difference 0.01 days; 95% CI: -0.45, 0.47; p = .97). Pre-existing hypothyroidism was not associated with ICU admission or ICU mortality in unadjusted as well as in adjusted analysis. CONCLUSIONS: In an international registry, hypothyroidism was identified in around 1 of every 12 adult hospitalized patients with COVID-19. Pre-existing hypothyroidism in hospitalized patients with COVID-19 was not associated with higher disease severity or increased risk of mortality or ICU admissions. However, more research on the possible effects of COVID-19 on the thyroid gland and its function is needed in the future.

Association between unmet medication needs after hospital discharge and readmission or death among acute respiratory failure survivors: the addressing post-intensive care syndrome (APICS-01) multicenter prospective cohort study.

INTRODUCTION: Survivors of acute respiratory failure (ARF) commonly experience long-lasting physical, cognitive, and/or mental health impairments. Unmet medication needs occurring immediately after hospital discharge may have an important effect on subsequent recovery. METHODS AND ANALYSIS: In this multicenter prospective cohort study, we enrolled ARF survivors who were discharged directly home from their acute care hospitalization. The primary exposure was unmet medication needs. The primary outcome was hospital readmission or death within 3 months after discharge. We performed a propensity score analysis, using inverse probability weighting for the primary exposure, to evaluate the exposure-outcome association, with an a priori sample size of 200 ARF survivors. RESULTS: We enrolled 200 ARF survivors, of whom 107 (53%) were female and 77 (39%) were people of color. Median (IQR) age was 55 (43-66) years, APACHE II score 20 (15-26) points, and hospital length of stay 14 (9-21) days. Of the 200 participants, 195 (98%) were in the analytic cohort. One hundred fourteen (57%) patients had at least one unmet medication need; the proportion of medication needs that were unmet was 6% (0-15%). Fifty-six (29%) patients were readmitted or died by 3 months; 10 (5%) died within 3 months. Unmet needs were not associated (risk ratio 1.25; 95% CI 0.75-2.1) with hospital readmission or death, although a higher proportion of unmet needs may have been associated with increased hospital readmission (risk ratio 1.7; 95% CI 0.96-3.1) and decreased mortality (risk ratio 0.13; 95% CI 0.02-0.99). DISCUSSION: Unmet medication needs are common among survivors of acute respiratory failure shortly after discharge home. The association of unmet medication needs with 3-month readmission and mortality is complex and requires additional investigation to inform clinical trials of interventions to reduce unmet medication needs. Study registration number: NCT03738774 . The study was prospectively registered before enrollment of the first patient.

Sedative polypharmacy mediates the effect of mechanical ventilation on delirium in critically ill COVID-19 patients: A retrospective cohort study.

BACKGROUND: Polypharmacy of sedatives (PP) is a potentially modifiable, iatrogenic risk factor for ICU delirium. The extent to which sedative PP influenced development of high rates of delirium among critically ill COVID-19 patients is unknown. We tested the hypothesis that PP, defined as the use of four or more classes of intravenous agents, is a mediator in the causal pathway of mechanical ventilation and delirium. METHODS: Retrospective cohort study of adults admitted with a primary diagnosis of RT-PCR+ for SARS-CoV2 to ICUs of a tertiary-level academic medical center between February 2020 and April 2021. Mediation analysis was conducted with bootstrap estimation to assess whether an association between mechanical ventilation and delirium was mediated by PP. Analyses were adjusted for potential confounders related to mechanical ventilation, mediator, and outcome, including age, gender, vasopressor use, median RASS scores, SOFA score within 24 h of admission, and maximum CRP levels. RESULTS: A total of 212 patients were included in the analysis. Of total patients, 72.6%(154/212) of patients had delirium (CAM-ICU+) during ICU stay. 54.7%(116/212) patients received PP. Mechanical ventilation (OR 3.81 [1.16-12.52]) and PP (OR 7.38 [2.4-22.68]) were identified as risk factors for development of ICU delirium after adjusting for prespecified confounders. PP acts as a mediator in the causal pathway between mechanical ventilation and delirium. 39% (95% CI: 17%-94%) of the effect of mechanical ventilation on delirium was mediated through PP. CONCLUSION: PP mediates approximately 39% of the effect of mechanical ventilation on delirium, which is clinically and statistically significant. Studies should assess whether mitigating PP could lead to reduction in ICU delirium. IMPLICATION STATEMENT: PP of sedatives (defined as use of four or more intravenous agents) mediates approximately 39% of the effect of mechanical ventilation on development of ICU delirium. Avoidance of sedative PP may represent a viable strategy for reduction of ICU delirium.

Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

SARS-CoV-2 infection increases risk of acute kidney injury in a bimodal age distribution.

BACKGROUND: Hospitalized patients with SARS-CoV2 develop acute kidney injury (AKI) frequently, yet gaps remain in understanding why adults seem to have higher rates compared to children. Our objectives were to evaluate the epidemiology of SARS-CoV2-related AKI across the age spectrum and determine if known risk factors such as illness severity contribute to its pattern. METHODS: Secondary analysis of ongoing prospective international cohort registry. AKI was defined by KDIGO-creatinine only criteria. Log-linear, logistic and generalized estimating equations assessed odds ratios (OR), risk differences (RD), and 95% confidence intervals (CIs) for AKI and mortality adjusting for sex, pre-existing comorbidities, race/ethnicity, illness severity, and clustering within centers. Sensitivity analyses assessed different baseline creatinine estimators. RESULTS: Overall, among 6874 hospitalized patients, 39.6% (n = 2719) developed AKI. There was a bimodal distribution of AKI by age with peaks in older age (≥60 years) and middle childhood (5-15 years), which persisted despite controlling for illness severity, pre-existing comorbidities, or different baseline creatinine estimators. For example, the adjusted OR of developing AKI among hospitalized patients with SARS-CoV2 was 2.74 (95% CI 1.66-4.56) for 10-15-year-olds compared to 30-35-year-olds and similarly was 2.31 (95% CI 1.71-3.12) for 70-75-year-olds, while adjusted OR dropped to 1.39 (95% CI 0.97-2.00) for 40-45-year-olds compared to 30-35-year-olds. CONCLUSIONS: SARS-CoV2-related AKI is common with a bimodal age distribution that is not fully explained by known risk factors or confounders. As the pandemic turns to disproportionately impacting younger individuals, this deserves further investigation as the presence of AKI and SARS-CoV2 infection increases hospital mortality risk.

Anesthetics to Prevent Lung Injury in Cardiac Surgery: A Randomized Controlled Trial.

OBJECTIVES: To investigate if sevoflurane based anesthesia is superior to propofol in preventing lung inflammation and preventing postoperative pulmonary complications. DESIGN: Randomized controlled trial. SETTING: Single tertiary care university hospital. PARTICIPANTS: Forty adults undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were randomized in a 1:1 ratio to anesthetic maintenance with sevoflurane or propofol. MEASUREMENTS AND MAIN RESULTS: Blood and bronchoalveolar lavage fluid was sampled before and after bypass to measure pulmonary inflammation using a biomarker panel. The change in bronchoalveolar lavage concentration of tumor necrosis factor alpha (TNFα) was the primary outcome. Secondary outcomes included lung inflammation defined as changes in other biomarkers and postoperative pulmonary complications. There were no significant differences between groups in the change in bronchoalveolar lavage TNFα concentration (median [IQR] change, 17.24 [1.11-536.77] v 101.51 [1.47-402.84] pg/mL, sevoflurane v propofol, p = 0.31). There was a significantly lower postbypass concentration of plasma interleukin 8 (median [IQR], 53.92 [34.5-55.91] v 66.92 [53.03-94.44] pg/mL, p = 0.04) and a significantly smaller postbypass increase in the plasma receptor for advanced glycosylation end products (median [IQR], 174.59 [73.59-446.06] v 548.22 [193.15-852.39] pg/mL, p = 0.03) in the sevoflurane group compared with propofol. The incidence of postoperative pulmonary complications was 100% in both groups, with high rates of pleural effusion (17/18 [94.44%] v 19/22 [86.36%], p = 0.39) and hypoxemia (16/18 [88.88%] v 22/22 [100%], p = 0.11). CONCLUSIONS: Sevoflurane anesthesia during cardiac surgery did not consistently prevent lung inflammation or prevent postoperative pulmonary complications compared to propofol. There were significantly lower levels of 2 plasma biomarkers specific for lung injury and inflammation in the sevoflurane group.

Outcomes of Patients With Coronavirus Disease 2019 Receiving Organ Support Therapies: The International Viral Infection and Respiratory Illness Universal Study Registry.

OBJECTIVES: To describe the outcomes of hospitalized patients in a multicenter, international coronavirus disease 2019 registry. DESIGN: Cross-sectional observational study including coronavirus disease 2019 patients hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between February 15, 2020, and November 30, 2020, according to age and type of organ support therapies. SETTING: About 168 hospitals in 16 countries within the Society of Critical Care Medicine's Discovery Viral Infection and Respiratory Illness University Study coronavirus disease 2019 registry. PATIENTS: Adult hospitalized coronavirus disease 2019 patients who did and did not require various types and combinations of organ support (mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was hospital mortality. Secondary outcomes were discharge home with or without assistance and hospital length of stay. Risk-adjusted variation in hospital mortality for patients receiving invasive mechanical ventilation was assessed by using multilevel models with hospitals as a random effect, adjusted for age, race/ethnicity, sex, and comorbidities. Among 20,608 patients with coronavirus disease 2019, the mean (± sd) age was 60.5 (±17), 11,1887 (54.3%) were men, 8,745 (42.4%) were admitted to the ICU, and 3,906 (19%) died in the hospital. Hospital mortality was 8.2% for patients receiving no organ support (n = 15,001). The most common organ support therapy was invasive mechanical ventilation (n = 5,005; 24.3%), with a hospital mortality of 49.8%. Mortality ranged from 40.8% among patients receiving only invasive mechanical ventilation (n =1,749) to 71.6% for patients receiving invasive mechanical ventilation, vasoactive drugs, and new renal replacement therapy (n = 655). Mortality was 39% for patients receiving extracorporeal membrane oxygenation (n = 389). Rates of discharge home ranged from 73.5% for patients who did not require organ support therapies to 29.8% for patients who only received invasive mechanical ventilation, and 8.8% for invasive mechanical ventilation, vasoactive drugs, and renal replacement; 10.8% of patients older than 74 years who received invasive mechanical ventilation were discharged home. Median hospital length of stay for patients on mechanical ventilation was 17.1 days (9.7-28 d). Adjusted interhospital variation in mortality among patients receiving invasive mechanical ventilation was large (median odds ratio 1.69). CONCLUSIONS: Coronavirus disease 2019 prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation.

Healthcare disparities among anticoagulation therapies for severe COVID-19 patients in the multi-site VIRUS registry.

Here we analyze hospitalized andintensive care unit coronavirus disease 2019 (COVID-19) patient outcomes from the international VIRUS registry (https://clinicaltrials.gov/ct2/show/NCT04323787). We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have a higher mortality-rate (390 of 1012 = 39%) compared to patients administered enoxaparin but not unfractionated heparin (270 of 1939 = 14%), presenting a risk ratio of 2.79 (95% confidence interval [CI]: [2.42, 3.16]; p = 4.45e-52). This difference persists even after balancing on a number of covariates including demographics, comorbidities, admission diagnoses, and method of oxygenation, with an increased mortality rate on discharge from the hospital of 37% (268 of 733) for unfractionated heparin versus 22% (154 of 711) for enoxaparin, presenting a risk ratio of 1.69 (95% CI: [1.42, 2.00]; p = 1.5e-8). In these balanced cohorts, a number of complications occurred at an elevated rate for patients administered unfractionated heparin compared to patients administered enoxaparin, including acute kidney injury, acute cardiac injury, septic shock, and anemia. Furthermore, a higher percentage of Black/African American COVID patients (414 of 1294 [32%]) were noted to receive unfractionated heparin compared to White/Caucasian COVID patients (671 of 2644 [25%]), risk ratio 1.26 (95% CI: [1.14, 1.40]; p = 7.5e-5). After balancing upon available clinical covariates, this difference in anticoagulant use remained statistically significant (311 of 1047 [30%] for Black/African American vs. 263 of 1047 [25%] for White/Caucasian, p = .02, risk ratio 1.18; 95% CI: [1.03, 1.36]). While retrospective studies cannot suggest any causality, these findings motivate the need for follow-up prospective research into the observed racial disparity in anticoagulant use and outcomes for severe COVID-19 patients.

Intraoperative Oxygen Concentration and Neurocognition after Cardiac Surgery.

BACKGROUND: Despite evidence suggesting detrimental effects of perioperative hyperoxia, hyperoxygenation remains commonplace in cardiac surgery. Hyperoxygenation may increase oxidative damage and neuronal injury leading to potential differences in postoperative neurocognition. Therefore, this study tested the primary hypothesis that intraoperative normoxia, as compared to hyperoxia, reduces postoperative cognitive dysfunction in older patients having cardiac surgery. METHODS: A randomized double-blind trial was conducted in patients aged 65 yr or older having coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 100 patients were randomized to one of two intraoperative oxygen delivery strategies. Normoxic patients (n = 50) received a minimum fraction of inspired oxygen of 0.35 to maintain a Pao2 above 70 mmHg before and after cardiopulmonary bypass and between 100 and 150 mmHg during cardiopulmonary bypass. Hyperoxic patients (n = 50) received a fraction of inspired oxygen of 1.0 throughout surgery, irrespective of Pao2 levels. The primary outcome was neurocognitive function measured on postoperative day 2 using the Telephonic Montreal Cognitive Assessment. Secondary outcomes included neurocognitive function at 1, 3, and 6 months, as well as postoperative delirium, mortality, and durations of mechanical ventilation, intensive care unit stay, and hospital stay. RESULTS: The median age was 71 yr (interquartile range, 68 to 75), and the median baseline neurocognitive score was 17 (16 to 19). The median intraoperative Pao2 was 309 (285 to 352) mmHg in the hyperoxia group and 153 (133 to 168) mmHg in the normoxia group (P < 0.001). The median Telephonic Montreal Cognitive Assessment score on postoperative day 2 was 18 (16 to 20) in the hyperoxia group and 18 (14 to 20) in the normoxia group (P = 0.42). Neurocognitive function at 1, 3, and 6 months, as well as secondary outcomes, were not statistically different between groups. CONCLUSIONS: In this randomized controlled trial, intraoperative normoxia did not reduce postoperative cognitive dysfunction when compared to intraoperative hyperoxia in older patients having cardiac surgery. Although the optimal intraoperative oxygenation strategy remains uncertain, the results indicate that intraoperative hyperoxia does not worsen postoperative cognition after cardiac surgery.

Prevention of Early Postoperative Decline: A Randomized, Controlled Feasibility Trial of Perioperative Cognitive Training.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction (POCD) are common after cardiac surgery and contribute to an increased risk of postoperative complications, longer length of stay, and increased hospital mortality. Cognitive training (CT) may be able to durably improve cognitive reserve in areas deficient in delirium and POCD and, therefore, may potentially reduce the risk of these conditions. We sought to determine the feasibility and potential efficacy of a perioperative CT program to reduce the incidence of postoperative delirium and POCD in older cardiac surgery patients. METHODS: Randomized controlled trial at a single tertiary care center. Participants included 45 older adults age 60-90 undergoing cardiac surgery at least 10 days from enrollment. Participants were randomly assigned in a 1:1 fashion to either perioperative CT via a mobile device or a usual care control. The primary outcome of feasibility was evaluated by enrollment patterns and adherence to protocol. Secondary outcomes of postoperative delirium and POCD were assessed using the Confusion Assessment Method and the Montreal Cognitive Assessment, respectively. Patient satisfaction was assessed via a postoperative survey. RESULTS: Sixty-five percent of eligible patients were enrolled. Median (interquartile range [IQR]) adherence (as a percentage of prescribed minutes played) was 39% (20%-68%), 6% (0%-37%), and 19% (0%-56%) for the preoperative, immediate postoperative, and postdischarge periods, respectively. Median (IQR) training times were 245 (136-536), 18 (0-40), and 122 (0-281) minutes for each period, respectively. The incidence of postoperative delirium (CT group 5/20 [25%] versus control 3/20 [15%]; P = .69) and POCD (CT group 53% versus control 37%; P = .33) was not significantly different between groups for either outcome in this limited sample. CT participants reported a high level of agreement (on a scale of 0-100) with statements that the program was easy to use (median [IQR], 87 [75-97]) and enjoyable (85 [79-91]). CT participants agreed significantly more than controls that their memory (median [IQR], 75 [54-82] vs 51 [49-54]; P = .01) and thinking ability (median [IQR], 78 [64-83] vs 50 [41-68]; P = .01) improved as a result of their participation in the study. CONCLUSIONS: A CT program designed for use in the preoperative period is an attractive target for future investigations of cognitive prehabilitation in older cardiac surgery patients. Changes in the functionality of the program and enrichment techniques may improve adherence in future trials. Further investigation is necessary to determine the potential efficacy of cognitive prehabilitation to reduce the risk of postoperative delirium and POCD.

Patent foramen ovale and long-term risk of ischaemic stroke after surgery.

AIMS: Pre-operatively diagnosed patent foramen ovale (PFO) is associated with an increased risk of ischaemic stroke within 30 days after surgery. This study aimed to assess the PFO-attributable ischaemic stroke risk beyond the perioperative period. METHODS AND RESULTS: This observational study of adult patients without history of stroke undergoing non-cardiac surgery with general anaesthesia examined the association of PFO with ischaemic stroke 1 and 2 years after surgery using multivariable logistic regression. Of the 144 563 patients included, a total of 1642 (1.1%) and 2376 (1.6%) ischaemic strokes occurred within 1 and 2 years after surgery, 54 (4.7%) and 76 (6.6%) among patients with PFO, and 1588 (1.1%) and 2300 (1.6%) among patients without PFO, respectively. The odds of ischaemic stroke within 1 and 2 years after surgery were increased in patients with PFO: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.51-2.69; P < 0.001 and aOR 2.10, 95% CI 1.64-2.68; P < 0.001, respectively. Among patients who underwent contrast transoesophageal echocardiography, the frequency of PFO was 27%, and the increased stroke risk in patients with PFO was robust (aOR 3.80, 95% CI 1.76-8.23; P = 0.001 for year 1). The PFO-attributable risk was mitigated by post-operative prescription of combination antithrombotic therapy (odds ratio 0.41, 95% CI 0.22-0.75; P for interaction = 0.004). CONCLUSION: Patients with PFO are vulnerable to ischaemic stroke for an extended period of time after surgery. Physicians should consider implementing PFO screening protocols in patients scheduled for major non-cardiac surgery.

Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: Adjusting positive end-expiratory pressure (PEEP) to offset pleural pressure might attenuate lung injury and improve patient outcomes in acute respiratory distress syndrome (ARDS). Objective: To determine whether PEEP titration guided by esophageal pressure (PES), an estimate of pleural pressure, was more effective than empirical high PEEP-fraction of inspired oxygen (Fio2) in moderate to severe ARDS. Design, Setting, and Participants: Phase 2 randomized clinical trial conducted at 14 hospitals in North America. Two hundred mechanically ventilated patients aged 16 years and older with moderate to severe ARDS (Pao2:Fio2 ≤200 mm Hg) were enrolled between October 31, 2012, and September 14, 2017; long-term follow-up was completed July 30, 2018. Interventions: Participants were randomized to PES-guided PEEP (n = 102) or empirical high PEEP-Fio2 (n = 98). All participants received low tidal volumes. Main Outcomes and Measures: The primary outcome was a ranked composite score incorporating death and days free from mechanical ventilation among survivors through day 28. Prespecified secondary outcomes included 28-day mortality, days free from mechanical ventilation among survivors, and need for rescue therapy. Results: Two hundred patients were enrolled (mean [SD] age, 56 [16] years; 46% female) and completed 28-day follow-up. The primary composite end point was not significantly different between treatment groups (probability of more favorable outcome with PES-guided PEEP: 49.6% [95% CI, 41.7% to 57.5%]; P = .92). At 28 days, 33 of 102 patients (32.4%) assigned to PES-guided PEEP and 30 of 98 patients (30.6%) assigned to empirical PEEP-Fio2 died (risk difference, 1.7% [95% CI, -11.1% to 14.6%]; P = .88). Days free from mechanical ventilation among survivors was not significantly different (median [interquartile range]: 22 [15-24] vs 21 [16.5-24] days; median difference, 0 [95% CI, -1 to 2] days; P = .85). Patients assigned to PES-guided PEEP were significantly less likely to receive rescue therapy (4/102 [3.9%] vs 12/98 [12.2%]; risk difference, -8.3% [95% CI, -15.8% to -0.8%]; P = .04). None of the 7 other prespecified secondary clinical end points were significantly different. Adverse events included gross barotrauma, which occurred in 6 patients with PES-guided PEEP and 5 patients with empirical PEEP-Fio2. Conclusions and Relevance: Among patients with moderate to severe ARDS, PES-guided PEEP, compared with empirical high PEEP-Fio2, resulted in no significant difference in death and days free from mechanical ventilation. These findings do not support PES-guided PEEP titration in ARDS. Trial Registration: ClinicalTrials.gov Identifier NCT01681225.

Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial.

Importance: Postoperative delirium is common following cardiac surgery and may be affected by choice of analgesic and sedative. Objective: To evaluate the effect of postoperative intravenous (IV) acetaminophen (paracetamol) vs placebo combined with IV propofol vs dexmedetomidine on postoperative delirium among older patients undergoing cardiac surgery. Design, Setting, and Participants: Randomized, placebo-controlled, factorial clinical trial among 120 patients aged 60 years or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries at a US center. Enrollment was September 2015 to April 2018, with follow-up ending in April 2019. Interventions: Patients were randomized to 1 of 4 groups receiving postoperative analgesia with IV acetaminophen or placebo every 6 hours for 48 hours and postoperative sedation with dexmedetomidine or propofol starting at chest closure and continued for up to 6 hours (acetaminophen and dexmedetomidine: n = 29; placebo and dexmedetomidine: n = 30; acetaminophen and propofol: n = 31; placebo and propofol: n = 30). Main Outcomes and Measures: The primary outcome was incidence of postoperative in-hospital delirium by the Confusion Assessment Method. Secondary outcomes included delirium duration, cognitive decline, breakthrough analgesia within the first 48 hours, and ICU and hospital length of stay. Results: Among 121 patients randomized (median age, 69 years; 19 women [15.8%]), 120 completed the trial. Patients treated with IV acetaminophen had a significant reduction in delirium (10% vs 28% placebo; difference, -18% [95% CI, -32% to -5%]; P = .01; HR, 2.8 [95% CI, 1.1-7.8]). Patients receiving dexmedetomidine vs propofol had no significant difference in delirium (17% vs 21%; difference, -4% [95% CI, -18% to 10%]; P = .54; HR, 0.8 [95% CI, 0.4-1.9]). There were significant differences favoring acetaminophen vs placebo for 3 prespecified secondary outcomes: delirium duration (median, 1 vs 2 days; difference, -1 [95% CI, -2 to 0]), ICU length of stay (median, 29.5 vs 46.7 hours; difference, -16.7 [95% CI, -20.3 to -0.8]), and breakthrough analgesia (median, 322.5 vs 405.3 µg morphine equivalents; difference, -83 [95% CI, -154 to -14]). For dexmedetomidine vs propofol, only breakthrough analgesia was significantly different (median, 328.8 vs 397.5 µg; difference, -69 [95% CI, -155 to -4]; P = .04). Fourteen patients in both the placebo-dexmedetomidine and acetaminophen-propofol groups (46% and 45%) and 7 in the acetaminophen-dexmedetomidine and placebo-propofol groups (24% and 23%) had hypotension. Conclusions and Relevance: Among older patients undergoing cardiac surgery, postoperative scheduled IV acetaminophen, combined with IV propofol or dexmedetomidine, reduced in-hospital delirium vs placebo. Additional research, including comparison of IV vs oral acetaminophen and other potentially opioid-sparing analgesics, on the incidence of postoperative delirium is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02546765.

Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome.

OBJECTIVES: Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance. DESIGN: Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the FIO2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome. SETTING: Five academic centers in the United States. PATIENTS: Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome. INTERVENTIONS: Aerosolized budesonide/formoterol versus placebo bid for up to 5 days. MEASUREMENTS AND MAIN RESULTS: Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group (p = 0.02) and independent of shock (p = 0.04). Categorical change in S/F improved (p = 0.01) but not after adjustment for shock (p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%). CONCLUSIONS: Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition.

RATIONALE: Estimates of the incidence of the acute respiratory distress syndrome (ARDS) in high- and middle-income countries vary from 10.1 to 86.2 per 100,000 person-years in the general population. The epidemiology of ARDS has not been reported for a low-income country at the level of the population, hospital, or intensive care unit (ICU). The Berlin definition may not allow identification of ARDS in resource-constrained settings. OBJECTIVES: To estimate the incidence and outcomes of ARDS at a Rwandan referral hospital using the Kigali modification of the Berlin definition: without requirement for positive end-expiratory pressure, hypoxia cutoff of SpO2/FiO2 less than or equal to 315, and bilateral opacities on lung ultrasound or chest radiograph. METHODS: We screened every adult patient for hypoxia at a public referral hospital in Rwanda for 6 weeks. For every patient with hypoxia, we collected data on demographics and ARDS risk factors, performed lung ultrasonography, and evaluated chest radiography when available. MEASUREMENTS AND MAIN RESULTS: Forty-two (4.0%) of 1,046 hospital admissions met criteria for ARDS. Using various prespecified cutoffs for the SpO2/FiO2 ratio resulted in almost identical hospital incidence values. Median age for patients with ARDS was 37 years, and infection was the most common risk factor (44.1%). Only 30.9% of patients with ARDS were admitted to an ICU, and hospital mortality was 50.0%. Using traditional Berlin criteria, no patients would have met criteria for ARDS. CONCLUSIONS: ARDS seems to be a common and fatal syndrome in a hospital in Rwanda, with few patients admitted to an ICU. The Berlin definition is likely to underestimate the impact of ARDS in low-income countries, where resources to meet the definition requirements are lacking. Although the Kigali modification requires validation before widespread use, we hope this study stimulates further work in refining an ARDS definition that can be consistently used in all settings.