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To test the hypothesis that relatively lower clot strength on thromboelastography maximum amplitude (MA) is associated with development of venous thromboembolism (VTE) in critically ill patients with COVID-19. DESIGN: Prospective, observational cohort study. SETTING: Tertiary care, academic medical center in Nashville, TN. PATIENTS: Patients with acute respiratory failure from COVID-19 pneumonia admitted to the adult medical ICU without known VTE at enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ninety-eight consecutive critically ill adults with laboratory-confirmed COVID-19 were enrolled. Thromboelastography parameters and conventional coagulation parameters were measured on days 0 (within 48 hr of ICU admission), 3, 5, and 7 after enrollment. The primary outcome was diagnosis of VTE with confirmed deep venous thrombosis and/or pulmonary embolism by clinical imaging or autopsy. Twenty-six patients developed a VTE. Multivariable regression controlling for antiplatelet exposure and anticoagulation dose with death as a competing risk found that lower MA was associated with increased risk of VTE. Each 1 mm increase in enrollment and peak MA was associated with an 8% and 14% decrease in the risk of VTE, respectively (enrollment MA: subdistribution hazard ratio [SHR], 0.92; 95% CI, 0.87–0.97; p = 0.003 and peak MA: SHR, 0.86; 95% CI, 0.81–0.91; p < 0.001). Lower enrollment platelet counts and fibrinogen levels were also associated with increased risk of VTE (p = 0.002 and p = 0.01, respectively). Platelet count and fibrinogen level were positively associated with MA (multivariable model: adjusted R(2) = 0.51; p < 0.001). CONCLUSIONS: When controlling for the competing risk of death, lower enrollment and peak MA were associated with increased risk of VTE. Lower platelet counts and fibrinogen levels at enrollment were associated with increased risk of VTE. The association of diminished MA, platelet counts, and fibrinogen with VTE may suggest a relative consumptive coagulopathy in critically ill patients with COVID-19.

OBJECTIVES:. To determine if implementation of a standardized effective request process (ERP) can increase organ donation authorization rates. DESIGN:. A retrospective, observational study was performed using data acquired from the Midwest Transplant Network. chi-square test was used to analyze categorical data, with p value of less than 0.05 deemed significant. SETTING:. The Midwest Transplant Network located in Westwood, KS from January 1, 2013 to June 30, 2017. PATIENTS:. A total of 1,391 consecutive patients were identified as potential donors based on medical evaluation of the patient’s neurologic status, organ function, and established age criteria. INTERVENTIONS:. An ERP was used when discussing donation with 733 patients (53%), compared with no ERP usage with 658 patients (47%). MEASUREMENTS AND MAIN RESULTS:. A significant increase (30%) in donation rates was observed when an ERP was used. A comparative decrease in donation rates was observed whenever a breakdown in any of the four identified steps occurred. LIMITATIONS:. The data analyzed was gathered retrospectively. Due to the retrospective nature of our study, there is no way to determine delay in authorization times versus no delay. Although most population data information about the authorized donors was known, this information was limited in patients who declined. CONCLUSIONS:. With proper preparation and planning, the implementation of a standardized ERP may improve organ donation rates and increase the number of life-saving organs for transplant.

OBJECTIVES:. To compare the diagnostic value of clinical sepsis criteria to novel protein biomarkers in the burn patient. DESIGN:. Prospective observational study. SETTING:. American Burn Association verified Burn Center ICU. PATIENTS:. Burn patients (n = 24) and healthy volunteers (n = 10). INTERVENTIONS:. Enrolled burn patients (n = 24) were stratified based on whether or not they met a clinical definition of sepsis. Four separate clinical criteria for sepsis were analyzed for their diagnostic sensitivity and specificity, which were compared to a panel of protein biomarkers. The most significant protein biomarkers were further analyzed via the area under the receiver operating characteristic curves (AUROCs). MEASUREMENTS AND MAIN RESULTS:. Of the clinical criteria, SEPSIS-2 criteria led to the highest AUROC (0.781; p < 0.001), followed by the quick Sequential Organ Failure Assessment score (AUROC = 0.670; p = 0.022). Multiplexing revealed a number of inflammatory proteins (complement C5) and matrix metalloproteinases (MMP1, MMP7) that were significantly elevated in septic samples compared with both healthy controls and nonseptic burn samples. Furthermore, three proteins associated with endothelial dysfunction and glycocalyx shedding revealed diagnostic potential. Specifically, syndecan-1, p-selectin, and galectin-1 were all significantly elevated in sepsis, and all resulted in an AUROC greater than 0.7; analyzing the sum of these three markers led to an AUROC of 0.808. CONCLUSIONS:. These data reveal several potential biomarkers that may help with sepsis diagnosis in the burn patient. Furthermore, the role of endotheliopathy as a mechanistic etiology for sepsis after burns warrants further investigation.

OBJECTIVES:. Early mobilization of ICU patients has been reported to be safe and feasible. Recently, our ICU implemented out-of-the-ICU wheelchair excursions as a daily rehabilitation practice. The aim of this study is to investigate the safety of participation in the out-of-the-ICU program for early mobilization. DESIGN:. Retrospective cohort study. SETTING:. Single general ICU in a tertiary teaching hospital. PATIENTS:. Adult patients who were admitted to the ICU and underwent the out-of-the-ICU program as an early mobilization intervention was investigated. INTERVENTIONS:. The out-of-the-ICU activities include visiting indoor area, visiting our outdoor garden, and bathing. MEASUREMENTS AND MAIN RESULTS:. Medical records of ICU patients who participated in the out-of-the-ICU program were reviewed. The primary outcome was the occurrence rate of physical safety events, defined as unintentional removal of medical devices, patient agitation, a fall, or an injury. The secondary outcome was the occurrence rate of adverse physiologic changes, defined as hypotension, hypertension, bradycardia, tachycardia, desaturation, bradypnea, tachypnea, an increase in Fio2, or an increase in doses of vasoactive drugs. In total, 99 adult patients participated in the program, comprising a total of 423 out-of-the-ICU sessions. Among them, one session resulted in a physical safety event, the dislodgement of a tracheostomy tube. In 23 sessions, one or two adverse physiologic changes occurred. None of these events required additional treatment nor resulted in serious sequelae. CONCLUSIONS:. An out-of-the-ICU program can be provided safely to adult ICU patients, provided that it is supervised by a dedicated intensivist with an appropriately trained multiprofessional staff and equipment on-site. It appears to contribute to the promotion of humanizing intensive care.

Supplemental Digital Content is available in the text., OBJECTIVES: The reduced orthostatic tolerance (OT) that is characteristic of the female sex may be explained by multiple phenotypic differences between sexes. This study aimed to elucidate the mechanistic role of blood volume (BV) and oxygen carrying capacity on sex differences in OT. DESIGN: Experimental intervention. SETTING: University of Calgary, Main Campus, Calgary, AB, Canada. SUBJECTS: Healthy women and men (n = 90) throughout the adult lifespan (20–89 yr) matched by age and physical activity. INTERVENTIONS: Incremental lower body negative pressure (LBNP) in all individuals. Blood withdrawal and oxygen carrying capacity reduction in men to match with women’s levels. MEASUREMENTS AND MAIN RESULTS: Transthoracic echocardiography and central blood pressures were assessed throughout incremental LBNP for 1 hour or until presyncope. Blood uniformization resulted in a precise sex match of BV and oxygen carrying capacity (p ≥ 0.598). A third of women (14/45) and two thirds of men (31/45) prior to blood uniformization completed the orthostatic test without presyncopal symptoms (p-for-sex < 0.001). After blood uniformization, seven out of 45 men completed the test (p-for-sex = 0.081). Left ventricular end-diastolic volume (LVEDV) and stroke volume (SV) were progressively reduced with LBNP in both sexes, with women showing markedly lower volumes than men (p < 0.001). Blood uniformization did not eliminate sex differences in LVEDV and SV. CONCLUSIONS: Sex differences in OT are not present when BV and oxygen carrying capacity are experimentally matched between sexes throughout the adult lifespan.

OBJECTIVES:. Demonstrate the feasibility of weekly data collection and analysis of public health emergency (PHE) data. Assess fluctuations in, and challenges of, resource matching and potential effect on patient care for influenza in ICUs. DESIGN:. Multicenter prospective noninterventional study testing effectiveness of leveraging the Discovery Critical Care Research Network Program for Resilience and Emergency Preparedness (Discovery-PREP) in performing PHE research. A 20-question internet survey was developed to prospectively assess ICU influenza-related resource stress. An informatics tool was designed to track responses; data were analyzed within 24 hours of weekly survey completion by the team biostatistician for timely reporting. PARTICIPANTS:. Critical care and Emergency Medicine Discovery-PREP network investigators self-selected to participate in the voluntary query. SETTING:. ICUs of 13 hospitals throughout the United States, 12 academic, and one community. INTERVENTIONS:. ICU physicians were electronically surveyed weekly over 17 weeks during the influenza season (January 2018–April 2018). Responses were collected for 48 hours after each email query. MEASUREMENTS AND MAIN RESULTS:. The average weekly response among the sites was 79% (range, 65–100%). Significant stress, defined as alterations in ICU staffing and/or resource allocation, occurred in up to 41% of sites during the national peak of influenza activity. These alterations included changes in staffing, not accepting external patient transfers, and canceling elective surgery. During this same period, up to 17% of the sites indicated that these changes might not have been sufficient to prevent potentially avoidable patient harm. CONCLUSIONS:. This novel approach to querying ICU operational stress indicated that almost half of participating sites experienced critical care resource limitations during peak influenza season and required process and/or staffing changes to better balance resources with patient care demands. This weekly national reporting infrastructure could be adapted and expanded to better inform providers, hospital emergency management teams, and government leaders during PHEs.

Supplemental Digital Content is available in the text., Objectives: Plans for allocating scarce healthcare resources during the COVID-19 pandemic commonly involve the activation of institutional triage teams. These teams would be responsible for selecting patients who are most likely to survive to be prioritized to receive scarce resources. However, there is little empirical support for this approach. Design: High-fidelity triage-team simulation study. Setting: Healthcare institutions in Washington state. SUBJECTS: Triage teams, consisting of at least two senior clinicians and a bioethicist. INTERVENTIONS: Participants reviewed a limited amount of deidentified information for a diverse sample of critically ill patients. Teams then assigned each patient to one of five prioritization categories defined by likelihood of survival to hospital discharge. The process was refined based on observation and participant feedback after which a second phase of simulations was conducted. MEASUREMENTS AND MAIN RESULTS: Feasibility was assessed by the time required for teams to perform their task. Prognostic accuracy was assessed by comparing teams’ prediction about likelihood of survival to hospital discharge with real-world discharge outcomes. Agreement between the teams on prognostic categorization was evaluated using kappa statistics. Eleven triage team simulations (eight in phase 1 and three in phase 2) were conducted from December 2020 to February 2021. Overall, teams reviewed a median of 23 patient cases in each session (interquartile range [IQR], 17–29) and spent a median of 102 seconds (IQR, 50–268) per case. The concordance between expected survival and real-world survival to discharge was 71% (IQR, 64–76%). The overall agreement between teams for placement of patients into prognostic categories was moderate (weighted kappa = 0.53). Conclusions: These findings support the potential feasibility, accuracy, and effectiveness of institutional triage teams informed by a limited set of patient information items as part of a strategy for allocating scarce resources in healthcare emergencies. Additional work is needed to refine the process and adapt it to local contexts.

Supplemental Digital Content is available in the text., OBJECTIVES: To develop a physiologic grading system for the severity of acute encephalopathy manifesting as delirium or coma, based on EEG, and to investigate its association with clinical outcomes. DESIGN: This prospective, single-center, observational cohort study was conducted from August 2015 to December 2016 and October 2018 to December 2019. SETTING: Academic medical center, all inpatient wards. PATIENTS/SUBJECTS: Adult inpatients undergoing a clinical EEG recording; excluded if deaf, severely aphasic, developmentally delayed, non-English speaking (if noncomatose), or if goals of care focused primarily on comfort measures. Four-hundred six subjects were assessed; two were excluded due to technical EEG difficulties. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A machine learning model, with visually coded EEG features as inputs, was developed to produce scores that correlate with behavioral assessments of delirium severity (Confusion Assessment Method-Severity [CAM-S] Long Form [LF] scores) or coma; evaluated using Spearman R correlation; area under the receiver operating characteristic curve (AUC); and calibration curves. Associations of Visual EEG Confusion Assessment Method Severity (VE-CAM-S) were measured for three outcomes: functional status at discharge (via Glasgow Outcome Score [GOS]), inhospital mortality, and 3-month mortality. Four-hundred four subjects were analyzed (mean [sd] age, 59.8 yr [17.6 yr]; 232 [57%] male; 320 [79%] White; 339 [84%] non-Hispanic); 132 (33%) without delirium or coma, 143 (35%) with delirium, and 129 (32%) with coma. VE-CAM-S scores correlated strongly with CAM-S scores (Spearman correlation 0.67 [0.62–0.73]; p < 0.001) and showed excellent discrimination between levels of delirium (CAM-S LF = 0 vs ≥ 4, AUC 0.85 [0.78–0.92], calibration slope of 1.04 [0.87–1.19] for CAM-S LF ≤ 4 vs ≥ 5). VE-CAM-S scores were strongly associated with important clinical outcomes including inhospital mortality (AUC 0.79 [0.72–0.84]), 3-month mortality (AUC 0.78 [0.71–0.83]), and GOS at discharge (0.76 [0.69–0.82]). CONCLUSIONS: VE-CAM-S is a physiologic grading scale for the severity of symptoms in the setting of delirium and coma, based on visually assessed electroencephalography features. VE-CAM-S scores are strongly associated with clinical outcomes.

Supplemental Digital Content is available in the text., OBJECTIVES: To identify the epidemiology and outcome of adults and children with and without sepsis in a rural sub-Sahara African setting. DESIGN: A priori planned substudy of a prospective, before-and-after trial. SETTING: Rural, sub-Sahara African hospital. PATIENTS: One-thousand four-hundred twelve patients (adults, n = 491; children, n = 921) who were admitted to hospital because of an acute infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, clinical, laboratory data, danger signs, and the presence of sepsis (defined as a quick Sequential Organ Failure Assessment score count ≥ 2) at admission were extracted. Sepsis was observed in 69 adults (14.1%) and 248 children (26.9%). Sepsis patients differed from subjects without sepsis in several demographic and clinical aspects. Malaria was the most frequent type of infection in adults (66.7%) and children (63.7%) with sepsis, followed by suspected bacterial and parasitic infections other than malaria. Adults with sepsis more frequently developed respiratory failure (8.7% vs 2.1%; p = 0.01), had a higher in-hospital mortality (17.4% vs 8.3%; p < 0.001), were less often discharged home (81.2% vs 92.2%; p = 0.007), and had higher median (interquartile range) costs of care (30,300 [19,400–49,900] vs 42,500 Rwandan Francs [27,000–64,400 Rwandan Francs]; p = 0.004) than adults without sepsis. Children with sepsis were less frequently discharged home than children without sepsis (93.1% vs 96.4%; p = 0.046). Malaria and respiratory tract infections claimed the highest absolute numbers of lives. The duration of symptoms before hospital admission did not differ between survivors and nonsurvivors in adults (72 [24–168] vs 96 hr [72–168 hr]; p = 0.27) or children (48 [24–72] vs 36 [24–108 hr]; p = 0.8). Respiratory failure and coma were the most common causes of in-hospital death. CONCLUSIONS: In addition to suspected bacterial, viral, and fungal infections, malaria and other parasitic infections are common and important causes of sepsis in adults and children admitted to a rural hospital in sub-Sahara Africa. The in-hospital mortality associated with sepsis is substantial, primarily in adults.

Supplemental Digital Content is available in the text., OBJECTIVES: Differences and biases between directly measured intra-arterial blood pressure and intermittingly measured noninvasive blood pressure using an oscillometric cuff method have been reported in adults and children. At the bedside, clinicians are required to assign a confidence to a specific blood pressure measurement before acting upon it, and this is challenging when there is discordance between measurement techniques. We hypothesized that big data could define and quantify the relationship between noninvasive blood pressure and intra-arterial blood pressure measurements and how they can be influenced by patient characteristics, thereby aiding bedside decision-making. DESIGN: A retrospective analysis of cuff blood pressure readings with associated concurrent invasive arterial blood pressure measurements (452,195 noninvasive blood pressure measurements). SETTING: Critical care unit at The Hospital for Sick Children, Toronto. PATIENTS: Six-thousand two-hundred ninety-seven patients less than or equal to 18 years old, hospitalized in a critical care unit with an indwelling arterial line. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-dimensional distributions of intra-arterial blood pressure and noninvasive blood pressure were generated and the conditional distributions of intra-arterial blood pressure examined as a function of the noninvasive systolic, diastolic, or mean blood pressure. Modification of these distributions according to age and gender were examined using a multilevel mixed-effects model. For any given combination of patient age and noninvasive blood pressure, the expected distribution of intra-arterial blood pressure readings exhibited marked variability at the population level and a bias that significantly depended on the noninvasive blood pressure value and age. We developed an online tool that allows exploration of the relationship between noninvasive blood pressure and intra-arterial blood pressure and the conditional probability distributions according to age. CONCLUSIONS: A large physiologic dataset provides clinically applicable insights into the relationship between noninvasive blood pressure and intra-arterial blood pressure measurements that can help guide decision-making at the patient bedside.

Supplemental Digital Content is available in the text., OBJECTIVES: To characterize prehospital air medical transport sedation practices and test the hypothesis that modifiable variables related to the monitoring and delivery of analgesia and sedation are associated with prehospital deep sedation. DESIGN: Multicenter, retrospective cohort study. SETTING: A nationwide, multicenter (approximately 130 bases) air medical transport provider. PATIENTS: Consecutive, adult mechanically ventilated air medical transport patients treated in the prehospital environment (January 2015 to December 2020). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All data involving sedation (medications, monitoring) were recorded. Deep sedation was defined as: 1) Richmond Agitation-Sedation Scale of –3 to –5; 2) Ramsay Sedation Scale of 5 or 6; or 3) Glasgow Coma Scale of less than or equal to 9. Coma was defined as being unresponsive and based on median sedation depth: 1) Richmond Agitation-Sedation Scale of –5; 2) Ramsay of 6; or 3) Glasgow Coma Scale of 3. A total of 72,148 patients were studied. Prehospital deep sedation was observed in 63,478 patients (88.0%), and coma occurred in 42,483 patients (58.9%). Deeply sedated patients received neuromuscular blockers more frequently and were less likely to have sedation depth documented with a validated sedation depth scale (i.e., Ramsay or Richmond Agitation-Sedation Scale). After adjusting for covariates, a multivariable logistic regression model demonstrated that the use of longer-acting neuromuscular blockers (i.e., rocuronium and vecuronium) was an independent predictor of deep sedation (adjusted odds ratio, 1.28; 95% CI, 1.22–1.35; p < 0.001), while use of a validated sedation scale was associated with a lower odds of deep sedation (adjusted odds ratio, 0.29; 95% CI, 0.27–0.30; p < 0.001). CONCLUSIONS: Deep sedation (and coma) is very common in mechanically ventilated air transport patients and associated with modifiable variables related to the monitoring and delivery of analgesia and sedation. Sedation practices in the prehospital arena and associated clinical outcomes are in need of further investigation.

Supplemental Digital Content is available in the text., OBJECTIVES: To assess the effectiveness of a chaplain patient navigator in improving outcomes and reducing costs in the ICU setting. DESIGN: A randomized controlled trial at a large, urban, academic community hospital in Baltimore, Maryland. SETTING/PATIENTS: All patients admitted to the Johns Hopkins Bayview Medical Center Cardiac and Medical ICUs between March 2015 and December 2015. INTERVENTIONS: Patients in the intervention group were assigned a chaplain patient navigator to facilitate communication, offer support, and setup multidisciplinary family meetings. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were hospital and ICU length of stay. Secondary outcomes included total and ICU charges, 60- and 90-day readmission rates, and the number of palliative care consults. For all outcomes, patients were included in the intention-to-treat analyses only if they remained in the ICU greater than 24 hours. In total, 1,174 were randomly assigned to “usual care” (n = 573) or to the intervention (n = 601). In the intervention group, 44.8% (269/601) had meetings within 24 hours of admission and, of those patients, 32.8% (88/268) took part in the larger multidisciplinary family meeting 2–3 days later. The intervention group had longer mean adjusted hospital length of stay (7.78 vs 8.63 d; p ≤ 0.001) and mean ICU length of stay (3.65 vs 3.87 d; p = 0.029). In addition, they had greater total and ICU charges. There were no differences in other outcomes. Of note, only differences in total and ICU charges remained when controlling for case-mix index, which were greater in the intervention group. CONCLUSIONS: Although the chaplain patient navigator anecdotally enhanced communication, our study found an increase in hospital and ICU length of stay as well as cost. Since other studies have shown benefits in some clinical outcomes, projects focused on patient navigators may learn lessons from our study in order to better prioritize family meetings, gather indicators of communication quality, and identify the optimal patient navigator operational context.

Supplemental Digital Content is available in the text., BACKGROUND: Ischemia-reperfusion injury is common in critically ill patients, and directed therapies are lacking. Inhaled hydrogen gas diminishes ischemia-reperfusion injury in models of shock, stroke, and cardiac arrest. The purpose of this study was to investigate the safety of inhaled hydrogen gas at doses required for a clinical efficacy study. DESIGN: Prospective, single-arm study. SETTING: Tertiary care hospital. PATIENTS/SUBJECTS: Eight healthy adult participants. INTERVENTIONS: Subjects underwent hospitalized exposure to 2.4% hydrogen gas in medical air via high-flow nasal cannula (15 L/min) for 24 (n = 2), 48 (n = 2), or 72 (n = 4) hours. MEASUREMENTS AND MAIN RESULTS: Endpoints included vital signs, patient- and nurse-reported signs and symptoms (stratified according to clinical significance), pulmonary function testing, 12-lead electrocardiogram, mini-mental state examinations, neurologic examination, and serologic testing prior to and following exposure. All adverse events were verified by two clinicians external to the study team and an external Data and Safety Monitoring Board. All eight participants (18–30 yr; 50% female; 62% non-Caucasian) completed the study without early termination. No clinically significant adverse events occurred in any patient. Compared with baseline measures, there were no clinically significant changes over time in vital signs, pulmonary function testing results, Mini-Mental State Examination scores, neurologic examination findings, electrocardiogram measurements, or serologic tests for hematologic (except for clinically insignificant increases in hematocrit and platelet counts), renal, hepatic, pancreatic, or cardiac injury associated with hydrogen gas inhalation. CONCLUSIONS: Inhalation of 2.4% hydrogen gas does not appear to cause clinically significant adverse effects in healthy adults. Although these data suggest that inhaled hydrogen gas may be well tolerated, future studies need to be powered to further evaluate safety. These data will be foundational to future interventional studies of inhaled hydrogen gas in injury states, including following cardiac arrest.

Supplemental Digital Content is available in the text., OBJECTIVES: To compare the performance of Sequential Organ Failure Assessment, systemic inflammatory response syndrome, Red Flag Sepsis, and National Institute of Clinical Excellence sepsis risk stratification tools in the identification of patients at greatest risk of mortality from sepsis in nonintensive care environments. DESIGN: Secondary analysis of three annual 24-hour point-prevalence study periods. SETTING: The general wards and emergency departments of 14 acute hospitals across Wales. Studies were conducted on the third Wednesday of October in 2017, 2018, and 2019. PATIENTS: We screened all patients presenting to the emergency department and on the general wards. MEASUREMENTS AND MAIN RESULTS: We recruited 1,271 patients, of which 724 (56.9%) had systemic inflammatory response syndrome greater than or equal to 2, 679 (53.4%) had Sequential Organ Failure Assessment greater than or equal to 2, and 977 (76.9%) had Red Flag Sepsis. When stratified according to National Institute of Clinical Excellence guidelines, 450 patients (35.4%) were in the “High risk” category in comparison with 665 (52.3%) in “Moderate to High risk” and 156 (12.3%) in “Low risk” category. In a planned sensitivity analysis, we found that none of the tools accurately predicted mortality at 90 days, and Sequential Organ Failure Assessment and National Institute of Clinical Excellence tools showed only moderate discriminatory power for mortality at 7 and 14 days. Furthermore, we could not find any significant correlation with any of the tools at any of the mortality time points. CONCLUSIONS: Our data suggest that the sepsis risk stratification tools currently utilized in emergency departments and on the general wards do not predict mortality adequately. This is illustrated by the disparity in mortality risk of the populations captured by each instrument, as well as the weak concordance between them. We propose that future studies on the development of sepsis identification tools should focus on identifying predicator values of both the short- and long-term outcomes of sepsis.

Supplemental Digital Content is available in the text., Objectives: To prospectively describe 1-year outcomes, with a focus on functional outcome, cognitive outcome, and the burden of anxiety, depression, and post-traumatic stress disorder, in coronavirus disease 2019 patients managed with extracorporeal membrane oxygenation. Design: Prospective case series. Setting: Tertiary extracorporeal membrane oxygenation center in the United States. Patients: Adult coronavirus disease 2019 acute respiratory distress syndrome patients managed with extracorporeal membrane oxygenation March 1, 2020, to July 31, 2020. Interventions: Baseline variables, treatment measures, and short-term outcomes were obtained from the medical record. Survivors were interviewed by telephone, a year following the index intensive care admission. Functional outcome was assessed using the modified Rankin Scale and the World Health Organization Disability Assessment Scale 2.0. Cognitive status was assessed with the 5-minute Montreal Cognitive Assessment. The Hospital Anxiety and Depression Scale was used to screen for anxiety and depression. Screening for post-traumatic stress disorder was performed with the Posttraumatic Stress Disorder Checklist 5 instrument. Measurements and Main Results: Twenty-three patients were managed with extracorporeal membrane oxygenation, 14 (61%) survived to hospital discharge. Thirteen (57%) were alive at 1 year. One patient was dependent on mechanical ventilation, another intermittently required supplemental oxygen at 1 year. The median modified Rankin Scale score was 2 (interquartile range, 1–2), median World Health Organization Disability Assessment Scale 2.0 impairment score was 21% (interquartile range, 6–42%). Six of 12 previously employed individuals (50%) had returned to work, and 10 of 12 (83%) were entirely independent in activities of daily living. The median Montreal Cognitive Assessment score was 14 (interquartile range, 13–14). Of 10 patients assessed with Hospital Anxiety and Depression Scale, 4 (40%) screened positive for depression and 6 (60%) for anxiety. Four of 10 (40%) screened positive for post-traumatic stress disorder. Conclusions: Functional impairment was common a year following the use of extracorporeal membrane oxygenation in coronavirus disease 2019, although the majority achieved independence in daily living and about half returned to work. Long-term anxiety, depression, and post-traumatic stress disorder were common, but cognitive impairment was not.

Supplemental Digital Content is available in the text., OBJECTIVES: We hypothesized that low serum albumin would contribute to pulmonary edema formation, thereby independently increasing the risk of developing acute respiratory distress syndrome in critically ill patients. DESIGN: Retrospective analysis of prospective cohort. SETTING: Medical, surgical, and cardiovascular ICUs at Vanderbilt University Medical Center. PATIENTS: Patients (n = 993) with serum albumin measured for clinical reasons within 24 hours of study enrollment on ICU day 2 were included. MEASUREMENTS AND MAIN RESULTS: The primary outcome was presence of acute respiratory distress syndrome at any time during the first 4 days in the ICU, as defined by the Berlin definition. Secondary outcomes included ventilator-free days and ICU length of stay. In an unadjusted analysis, lower serum albumin levels were associated with a higher occurrence rate of acute respiratory distress syndrome (p < 0.001). In a multivariable analysis controlling for prespecified confounders, lower serum albumin was independently associated with an increased risk of acute respiratory distress syndrome (odds ratio, 1.48 per 1-g/dL decrease in albumin; 95% CI, 1.14–1.94; p = 0.004). Additionally, lower serum albumin was associated with increased mortality (odds ratio, 1.56 per 1-g/dL decrease in albumin; 95% CI, 1.19–2.04; p = 0.001), increased ICU length of stay (incidence rate ratio, 1.19; 95% CI, 1.15–1.23; p < 0.001), higher Sequential Organ Failure Assessment score (p < 0.001), and fewer ventilator-free days (incidence rate ratio, 1.21; 95% CI, 1.19–1.24; p < 0.001). CONCLUSIONS: Among adult ICU patients, lower serum albumin was independently associated with increased risk of acute respiratory distress syndrome after controlling for severity of illness and potential confounders. These findings support the hypothesis that low plasma oncotic pressure contributes to pulmonary edema formation in patients at risk for acute respiratory distress syndrome, independent of severity of illness.

Supplemental Digital Content is available in the text., OBJECTIVES: Patients with aneurysmal subarachnoid hemorrhage (ruptured brain aneurysm) often have reduced health-related quality of life at follow-up in multiple domains (e.g., cognitive function and social function). We tested the hypothesis that there are distinct patterns of patient outcomes across domains of health-related quality of life, “complex patient outcomes,” in survivors of subarachnoid hemorrhage. DESIGN: Patients with subarachnoid hemorrhage were prospectively identified. Clinical data were prospectively recorded. Health-related quality of life was prospectively assessed at 3-month follow-up using the National Institutes of Health Patient Reported Outcomes Measurement Information System and neuro-quality of life in the domains of mobility, cognitive function, satisfaction with social roles, and depression. We used k-means clustering to analyze prospectively recorded health-related quality of life data, identifying clusters of complex patient outcomes. Decision tree analysis identified index hospital stay factors predictive of a patient having a particular complex patient outcome at follow-up. SETTING: Academic medical center. PATIENTS: One hundred three survivors of subarachnoid hemorrhage. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 103 patients, of whom 75 (72.8%) were female, and mean age was 53.6 ± 13.4 years. There were three complex patient outcomes: health-related quality of life greater than 1 sd better than the U.S. mean across all domains (n = 23, 22.3%), health-related quality of life greater than 1 sd worse than U.S. mean across all domains (n = 26, 25.2%), and satisfaction with social roles greater than 0.5 sd worse than U.S. mean with cognitive function, depression, and mobility scores near the U.S. mean (n = 54, 52.4%). In decision tree analysis, hospital disposition and Hunt and Hess Grade were associated with complex patient outcome. CONCLUSIONS: Complex patient outcomes across multiple domains of health-related quality of life at follow-up after subarachnoid hemorrhage are distinct and may be predictable.

Supplemental Digital Content is available in the text., OBJECTIVES: Examine the safety and feasibility of a multimodal in-person or telehealth treatment program, administered in acute recovery phase for patients surviving critical coronavirus disease 2019. DESIGN: Pragmatic, pre-post, nonrandomized controlled trial with patients electing enrollment into one of the two recovery pathways. SETTING: ICU Recovery Clinic in an academic medical center. PATIENTS: Adult patients surviving acute respiratory failure due to critical coronavirus disease 2019. INTERVENTIONS: Patients participated in combined ICU Recovery clinic and 8 weeks of physical rehabilitation delivered: 1) in-person or 2) telehealth. Patients received medical care by an ICU Recovery Clinic interdisciplinary team and physical rehabilitation focused on aerobic, resistance, and respiratory muscle training. MEASUREMENTS AND MAIN RESULTS: Thirty-two patients enrolled with mean age 57 ± 12, 62% were male, and the median Sequential Organ Failure Assessment score was 9.5. There were no differences between the two groups except patients in telehealth pathway (n = 10) lived further from clinic than face-to-face patients (162 ± 60 vs 31 ± 47 kilometers, t = 6.06, p < 0.001). Four safety events occurred: one minor adverse event in the telehealth group, two minor adverse events, and one major adverse event in the in-person group. Three patients did not complete the study (two in-person and one telehealth). Six-minute walk distance increased to 101 ± 91 meters from pre to post (n = 29, t = 6.93, p < 0.0001), which was similar between the two groups (110 vs 80 meters, t = 1.34, p = 0.19). Self-reported levels of anxiety, depression, and distress were high in both groups with similar self-report quality of life. CONCLUSIONS: A multimodal treatment program combining care from an interdisciplinary team in an ICU Recovery Clinic with physical rehabilitation is safe and feasible in patients surviving the ICU for coronavirus disease 2019 acute respiratory failure.

Supplemental Digital Content is available in the text., OBJECTIVES: Psychologic sequelae after critical illness, part of the postintensive care syndrome, significantly decrease quality of life. A robustly effective treatment intervention is currently lacking. Virtual reality has beneficial effects on several non-ICU–related psychologic disorders. The aim of this study was to explore patient-related determinants of ICU-specific virtual reality, such as the timing of patients’ self-reported readiness to initiate virtual reality and the number of desired sessions and safety, and to explore the effects of ICU-specific virtual reality on mental health. DESIGN: A multicenter, randomized controlled feasibility study. SETTING: ICU at a university teaching hospital and a secondary care hospital in Rotterdam, The Netherlands. PATIENTS: Consecutive mechanically ventilated patients with sepsis or septic shock. INTERVENTIONS: Patients were randomly assigned (1:1) to receive ICU-specific virtual reality (ICU-specific virtual reality group) or exposure to a nature virtual reality environment (control virtual reality group). MEASUREMENT AND MAIN RESULTS: Explorative outcomes were feasibility, in terms of patient-related determinants, and safety. The effects of ICU-specific virtual reality on the psychologic components of postintensive care syndrome and quality of life were additionally studied. Fifty patients (median age: 61 yr; 21 [42%] female) were included. Patients in the ICU-specific virtual reality group felt ready to initiate the virtual reality intervention 10 days (median, 95% range, 5–21 d) after ICU discharge, and one session (median, 95% range, 1–6) was desired. ICU-specific virtual reality patients experienced higher immersion, cybersickness scores were low, and no changes in vital signs were observed. They also reported reduced posttraumatic stress disorder and depression scores and better mental health from 2 days until 1 month after initial exposure (Short Form-12 Mental Component Scale: ICU-specific virtual reality, 57 [36–67] vs control virtual reality, 47 [26–63]; p < 0.01). Six months after exposure, this effect was still present for posttraumatic stress disorder and depression, but not for mental quality of life. CONCLUSIONS: ICU-specific virtual reality is a feasible and acceptable novel intervention that could be used during recovery from an episode of critical illness in the ICU. A future, adequately powered study should confirm whether virtual reality is able to improve mental health and quality of life.

Supplemental Digital Content is available in the text., OBJECTIVES: Unbiased global metabolomic profiling has not been used to identify distinct subclasses in patients with early sepsis and sepsis-associated acute respiratory distress syndrome. In this study, we examined whether the plasma metabolome reflects systemic illness in early sepsis and in acute respiratory distress syndrome. DESIGN: Plasma metabolites were measured in subjects with early sepsis. SETTING: Patients were admitted from the emergency department to the ICU in a plasma sample collected within 24 hours of ICU admission. Metabolic profiling of 970 metabolites was performed by Metabolon (Durham, NC). Hierarchical clustering and partial least squares discriminant clustering were used to identify distinct clusters among patients with early sepsis and sepsis-associated acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among critically ill patients with early sepsis (n = 197), three metabolically distinct subgroups were identified, with metabolic subtype driven by plasma lipids. Group 1, with 45 subjects (23% of cohort), had increased 60-day mortality (odds ratio, 2; 95% CI, 0.99–4.0; p = 0.04 for group 1 vs all others). This group also had higher rates of vasopressor-dependent shock, acute kidney injury, and met Berlin acute respiratory distress syndrome criteria more often (all p < 0.05). Conversely, metabolic group 3, with 76 subjects (39% of cohort), had the lowest risk of 60-day mortality (odds ratio, 0.44; 95% CI, 0.22–0.86; p = 0.01) and lower rates of organ dysfunction as reflected in a lower Simplified Acute Physiology Score II (p < 0.001). In contrast, global metabolomic profiling did not separate patient with early sepsis with moderate-to-severe acute respiratory distress syndrome (n = 78) from those with sepsis without acute respiratory distress syndrome (n = 75). CONCLUSIONS: Plasma metabolomic profiling in patients with early sepsis identified three metabolically distinct groups that were characterized by different plasma lipid profiles, distinct clinical phenotypes, and 60-day mortality. Plasma metabolites did not distinguish patients with early sepsis who developed acute respiratory distress syndrome from those who did not.

Supplemental Digital Content is available in the text., OBJECTIVES: Hyper- and hypoinflammatory subphenotypes discovered in patients with acute respiratory distress syndrome predict clinical outcomes and therapeutic responses. These subphenotypes may be important in broader critically ill patient populations with acute respiratory failure regardless of clinical diagnosis. We investigated subphenotyping with latent class analysis in an inclusive population of acute respiratory failure, derived a parsimonious model for subphenotypic predictions based on a small set of variables, and examined associations with clinical outcomes. DESIGN: Prospective, observational cohort study. SETTING: Single-center, academic medical ICU. PATIENTS: Mechanically ventilated patients with acute respiratory failure. MEASUREMENTS AND MAIN RESULTS: We included 498 patients with acute respiratory failure (acute respiratory distress syndrome: 143, at-risk for acute respiratory distress syndrome: 198, congestive heart failure: 37, acute on chronic respiratory failure: 23, airway protection: 61, and multifactorial: 35) in our derivation cohort and measured 10 baseline plasma biomarkers. Latent class analysis considering clinical variables and biomarkers determined that a two-class model offered optimal fit (23% hyperinflammatory subphenotype). Distribution of hyperinflammatory subphenotype varied among acute respiratory failure etiologies (acute respiratory distress syndrome: 31%, at-risk for acute respiratory distress syndrome: 27%, congestive heart failure: 22%, acute on chronic respiratory failure 0%, airway protection: 5%, and multifactorial: 14%). Hyperinflammatory patients had higher Sequential Organ Failure Assessment scores, fewer ventilator-free days, and higher 30- and 90-day mortality (all p < 0.001). We derived a parsimonious model consisting of angiopoietin-2, soluble tumor necrosis factor receptor-1, procalcitonin, and bicarbonate and classified subphenotypes in a validation cohort (n = 139). Hyperinflammatory patients (19%) demonstrated higher levels of inflammatory biomarkers not included in the model (p < 0.01) and worse outcomes. CONCLUSIONS: Host-response subphenotypes are observable in a heterogeneous population with acute respiratory failure and predict clinical outcomes. Simple, biomarker-based models can offer prognostic enrichment in patients with acute respiratory failure. The differential distribution of subphenotypes by specific etiologies of acute respiratory failure indicates that subphenotyping may be more relevant in patients with hypoxemic causes of acute respiratory failure and not in patients intubated for airway protection or acute on chronic decompensation.

Supplemental Digital Content is available in the text., OBJECTIVES: To quantify short- and long-term psychologic distress, that is, symptoms of posttraumatic stress disorder, anxiety, and depression, and the health-related quality of life in coronavirus disease 2019 ICU survivors. DESIGN: A prospective, observational cohort study. SETTING: Postcoronavirus disease 2019 clinics of three hospitals in Rotterdam, the Netherlands. PATIENTS: Adult patients admitted for coronavirus disease 2019 to the ICU, who visited the postcoronavirus disease 2019 follow-up clinic. MEASURES AND MAIN RESULTS: The primary outcomes were psychologic distress and overall and mental health-related quality of life, assessed using the Impact of Event Scale-Revised, Hospital Anxiety and Depression Scale, Short-Form 36, and European Quality of Life 5D, 6 weeks, 3 months, and 6 months post hospital discharge. Second, we compared 3-month psychologic and mental health-related quality of life outcomes with a historical critical illness survivor cohort and overall and mental health-related quality of life with the Dutch population. We included 118 patients with a median age of 61 years (95% range, 36–77 yr) of whom 79 (68%) were male. At 6 weeks, 13 patients (23%) reported psychologic distress, copresence of probable psychiatric disorders was common, and no decline in psychologic distress was observed throughout follow-up. Coronavirus disease 2019 patients tend to suffer less from posttraumatic stress disorder and reported less severe symptoms of anxiety (Hospital Anxiety and Depression Scale Anxiety Score: 3 [0–17] vs 5 [0–16]; estimated mean difference 2.3 [95% CI, 0.0–4.7]; p = 0.05) and depression (Hospital Anxiety and Depression Scale Depression Score: 3 [0–15] vs 5 [0–16]; estimated mean difference 2.4 [95% CI, 0.1–2.4]; p = 0.04) than the historical critical illness cohort. Overall and mental health-related quality of life increased over time. Coronavirus disease 2019 ICU survivors reported better mental health-related quality of life than our historical cohort, but overall and mental health-related quality of life was still poorer than the Dutch population. CONCLUSIONS: Psychologic distress was common in coronavirus disease 2019 ICU survivors and remained similar until 6 months after hospital discharge. Health-related quality of life increased over time and was higher than in a historical cohort, but was lower than in the Dutch population. Our findings highlight that coronavirus disease 2019 ICU survivors should be monitored after ICU treatment to detect possible psychologic distress.

Supplemental Digital Content is available in the text., OBJECTIVES: Critically ill patients with coronavirus disease 2019 have variable mortality. Risk scores could improve care and be used for prognostic enrichment in trials. We aimed to compare machine learning algorithms and develop a simple tool for predicting 28-day mortality in ICU patients with coronavirus disease 2019. DESIGN: This was an observational study of adult patients with coronavirus disease 2019. The primary outcome was 28-day inhospital mortality. Machine learning models and a simple tool were derived using variables from the first 48 hours of ICU admission and validated externally in independent sites and temporally with more recent admissions. Models were compared with a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 using the area under the receiver operating characteristic curve and calibration. SETTING: Sixty-eight U.S. ICUs. PATIENTS: Adults with coronavirus disease 2019 admitted to 68 ICUs in the United States between March 4, 2020, and June 29, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study included 5,075 patients, 1,846 (36.4%) of whom died by day 28. eXtreme Gradient Boosting had the highest area under the receiver operating characteristic curve in external validation (0.81) and was well-calibrated, while k-nearest neighbors were the lowest performing machine learning algorithm (area under the receiver operating characteristic curve 0.69). Findings were similar with temporal validation. The simple tool, which was created using the most important features from the eXtreme Gradient Boosting model, had a significantly higher area under the receiver operating characteristic curve in external validation (0.78) than the Sequential Organ Failure Assessment score (0.69), National Early Warning Score (0.60), and CURB-65 (0.65; p < 0.05 for all comparisons). Age, number of ICU beds, creatinine, lactate, arterial pH, and Pao2/Fio2 ratio were the most important predictors in the eXtreme Gradient Boosting model. CONCLUSIONS: eXtreme Gradient Boosting had the highest discrimination overall, and our simple tool had higher discrimination than a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 on external validation. These models could be used to improve triage decisions and clinical trial enrichment.

OBJECTIVES:. Extracorporeal membrane oxygenator support is a powerful clinical tool that is currently enjoying a resurgence in popularity. Wider use of extracorporeal membrane oxygenator support is limited by its significant risk profile and extreme consumption of resources. This study examines the role of markers of liver dysfunction in predicting outcomes of adult patients requiring extracorporeal membrane oxygenator support. DESIGN:. Retrospective review. SETTING:. Large extracorporeal membrane oxygenator center, Chicago, IL. PATIENTS:. This study reports a single institution experience examining all adult patients for whom extracorporeal membrane oxygenator support was used over an 8-year period. Data were collected regarding patient demographics, details of extracorporeal membrane oxygenator support provided, laboratory data, and outcomes. Trends in liver function were examined for their ability to predict survival. INTERVENTION:. Extracorporeal membrane oxygenator support, critical care. MEASUREMENTS AND MAIN RESULTS:. Mean age was 50 years (range, 19–82 yr). There were 86 male patients (56.6%) and 66 female patients (43.4%). Indications for initiation of extracorporeal membrane oxygenator support included cardiac 76 patients (50.0%), respiratory 48 patients (31.6%), extracorporeal cardiopulmonary resuscitation 21 patients (13.3%), and combined cardiac/respiratory seven patients (4.6%). Mean duration of extracorporeal membrane oxygenator support was 17 days (range 1–223 d) or median 8 days (interquartile range, 4–17 d). Overall, in-hospital mortality was 56% (86/152). Forty-five percent of adult patients (68/152) surpassed at least one of the following established liver dysfunction thresholds: total bilirubin greater than 15 mg/dL, aspartate aminotransferase greater than 20× upper limit of normal, and alanine aminotransferase greater than 20× upper limit of normal. The multivariable logistic analysis yielded three significant findings associated with in-hospital mortality: highest total bilirubin greater than 15 (adjusted odds ratio = 4.40; 95% CI, 1.19–21.87; p = 0.04), age (adjusted odds ratio = 1.03; 95% CI, 1.00–1.05; p = 0.04), and highest lactate (adjusted odds ratio = 1.15; 95% CI, 1.06–1.26; p = 0.002). CONCLUSIONS:. Increases in age, highest total bilirubin, and lactate all correlated with in-hospital mortality in multivariable analysis of patients requiring extracorporeal membrane oxygenator support.

OBJECTIVES:. Family members commonly have inaccurate expectations of patient’s prognosis in ICU. Adding to classic oral information, a visual support, depicting day by day the evolution of the condition of the patient, improves the concordance in prognosis estimate between physicians and family members. The objective of this study was to evaluate the impact of this tool on symptoms of anxiety/depression of family members. DESIGN:. Bicenter prospective before-and-after study. SETTING:. A nonacademic and a university hospital. SUBJECTS:. Relatives of consecutive patients admitted in the two ICUs. INTERVENTIONS:. In the period “before,” family members received classic oral information, and in the period “after,” they could consult the visual support in the patient’s room. The primary endpoint was the Hospital Anxiety and Depression Scale score of relatives at day 5. Secondary outcomes were the prevalence of symptoms of anxiety (Hospital Anxiety and Depression Scale anxiety subscale score > 7) and depression (Hospital Anxiety and Depression Scale depression subscale score > 7) at day 5 and Hospital Anxiety and Depression Scale score at day 90. MEASUREMENTS AND MAIN RESULTS:. A total of 140 patients and their referent family members were included (77 in period before and 63 after). Characteristics of patients of the two groups were similar regarding age, reason for admission, Simplified Acute Physiology Score II at admission, and Sequential Organ Failure Assessment score at day 5. At day 5, median Hospital Anxiety and Depression Scale score was 17 (9–25) before and 15 (10–22) after the implementation of the visual support (p = 0.43). The prevalence of symptoms of anxiety and depression was similar in the two groups (66.2% and 49.4% before and 68.3% and 36.5% after [not significant], respectively). At day 90, median Hospital Anxiety and Depression Scale score was 11 before (7–16) and 9 (5–16) after the implementation of the tool (p = 0.38). CONCLUSIONS:. In this study, the use of a visual support tool dedicated to prognosis did not modify the level of stress of family members.

Supplemental Digital Content is available in the text., OBJECTIVES: To evaluate the link between early acute respiratory failure and functional morbidity in survivors using the plasma biomarkers interleukin-8, interleukin-1 receptor antagonist, thrombomodulin, and plasminogen activator inhibitor-1. We hypothesized that children with acute respiratory failure with higher levels of inflammation would have worse functional outcomes at discharge, as measured by Pediatric Overall Performance Category. DESIGN: Secondary analysis of the Genetic Variation and Biomarkers in Children with Acute Lung Injury (R01HL095410) study. SETTING: Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622) and the ancillary study (Biomarkers in Children with Acute Lung Injury). SUBJECTS: Children 2 weeks to 17 years requiring invasive mechanical ventilation for acute airways and/or parenchymal lung disease. Patients with an admission Pediatric Overall Performance Category greater than 3 (severe disability, coma, or brain death) were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among survivors, 387 patients had no worsening of Pediatric Overall Performance Category at discharge while 40 had worsening functional status, defined as any increase in Pediatric Overall Performance Category from baseline. There was no significant relationship between worsening of Pediatric Overall Performance Category and interleukin-8 or plasminogen activator inhibitor-1 on any day. There was no significant relationship between interleukin-1 receptor antagonist, or thrombomodulin, and worsening Pediatric Overall Performance Category on day 1. Plasma interleukin-1 receptor antagonist and thrombomodulin were significantly elevated on days 2 and 3 in those with worse functional status at discharge compared with those without. In multivariable analysis, interleukin-1 receptor antagonist and thrombomodulin were associated with a decline in functional status on days 2 and 3 after adjustment for age and highest oxygenation index. However, after adjusting for age and cardiovascular failure, only day 2 thrombomodulin levels were associated with a worsening in Pediatric Overall Performance Category. CONCLUSIONS: Higher levels of interleukin-1 receptor antagonist or thrombomodulin following intubation were associated with worse Pediatric Overall Performance Category scores at hospital discharge in children who survive acute respiratory failure. These data suggest that persistent inflammation may be related to functional decline.

OBJECTIVES:. We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN:. We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING:. A multisite international inpatient trial. PATIENTS:. A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS:. Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS:. For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60–0.68), and improved with addition of age (c-index, 0.66–0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65–0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68–0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59–0.69) and improved with addition of age (c-index, 0.63–0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS:. In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

Supplemental Digital Content is available in the text., OBJECTIVES: To measure the frequency of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis among decedents in hospitals of different sizes and teaching statuses. DESIGN: We performed a multicenter, retrospective cohort study. SETTING: Four large teaching hospitals, four affiliated small teaching hospitals, and nine affiliated nonteaching hospitals in the United States. PATIENTS: We included a sample of all adult inpatient decedents between August 2017 and August 2019. MEASUREMENTS AND MAIN RESULTS: We reviewed inpatient notes and categorized the immediately preceding circumstances as withdrawal of life-sustaining therapy for perceived poor neurologic prognosis, withdrawal of life-sustaining therapy for nonneurologic reasons, limitations or withholding of life support or resuscitation, cardiac death despite full treatment, or brain death. Of 2,100 patients, median age was 71 years (interquartile range, 60–81 yr), median hospital length of stay was 5 days (interquartile range, 2–11 d), and 1,326 (63%) were treated at four large teaching hospitals. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis occurred in 516 patients (25%) and was the sole contributing factor to death in 331 (15%). Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis was common in all hospitals: 30% of deaths at large teaching hospitals, 19% of deaths in small teaching hospitals, and 15% of deaths at nonteaching hospitals. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis happened frequently across all hospital units. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis contributed to one in 12 deaths in patients without a primary neurologic diagnosis. After accounting for patient and hospital characteristics, significant between-hospital variability in the odds of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis persisted. CONCLUSIONS: A quarter of inpatient deaths in this cohort occurred after withdrawal of life-sustaining therapy for perceived poor neurologic prognosis. The rate of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis occurred commonly in all type of hospital settings. We observed significant unexplained variation in the odds of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis across participating hospitals.

Supplemental Digital Content is available in the text., OBJECTIVES: To determine methylprednisolone’s dose, duration, and administration from onset of symptoms and association with 60 days in hospital survival of coronavirus disease 2019 pneumonia. DESIGN: Cohort study. SETTING: Thirteen hospitals in New Jersey, United States during March to June 2020. PATIENTS: Seven-hundred fifty-nine hospitalized coronavirus disease 2019 patients. INTERVENTIONS: We performed a propensity matched cohort study between patients who received methylprednisolone and no methylprednisolone. Patients in the methylprednisolone group were further differentiated into dose (high dose and low dose), duration, and administration from onset of symptoms. MEASUREMENTS AND MAIN RESULTS: In the propensity matched sample, 99 out of 380 (26%) in no methylprednisolone, 69 out of 215 (31.9%) in low-dose methylprednisolone, and 74 out of 164 (55.2%) high-dose methylprednisolone expired. Overall median survival for no methylprednisolone (25.0 d), low-dose methylprednisolone (39.0 d), high-dose methylprednisolone (20.0 d), less than or equal to 7 days duration (19.0 d), 7–14 days duration (30.0 d), greater than 14 days duration (44.0 d), onset of symptoms less than or equal to 7 days (20.0 d), and onset of symptoms 7–14 days (27.0 d) were statistically significant (log-rank p ≤ 0.001). Multivariate Cox regression showed nursing home residents, coronary artery disease, and invasive mechanical ventilation were independently associated with mortality. Methylprednisolone was associated with reduced mortality compared with no methylprednisolone (hazard ratio, 0.40; 95% CI, 0.27–0.59; p < 0.001) but no added benefit with high dose. Low-dose methylprednisolone for 7–14 days was associated with reduced mortality compared with less than or equal to 7 days (hazard ratio, 0.45; 95% CI, 0.22–0.91; p = 0.0273), and no additional benefit if greater than 14 days (hazard ratio, 1.27; 95% CI, 0.60–2.69; p = 0.5434). Combination therapy with tocilizumab was associated with reduced mortality over monotherapy (p < 0.0116). CONCLUSIONS: Low-dose methylprednisolone was associated with reduced mortality if given greater than 7 days from onset of symptoms, and no additional benefit greater than 14 days. High dose was associated with higher mortality.

Survivors of sepsis hospitalization are at high risk for postsepsis morbidity, readmission, and death, but these negative outcomes can be mitigated by receipt of recommended care practices. We sought to assess factors associated with the receipt of recommended recovery-oriented care practices during hospitalization for sepsis. We hypothesized that patients treated in the ICU may be more likely than ward-treated patients to receive recommended care practices given the increasing focus on survivorship in the critical care field. DESIGN: Observational cohort study. SETTING: Michigan Medicine, a tertiary academic medical center. PATIENTS: Adult patients discharged alive from a hospitalization with a primary diagnosis of sepsis or septic shock in 2019. We further limited our cohort to patients receiving longitudinal care viewable in the Michigan Medicine electronic health record to ensure ability to capture posthospital care and outcomes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three-hundred sixty-five sepsis hospitalizations met study inclusion criteria. Using structured chart review, we determined receipt of the following recovery-based care practices during hospitalization: medication optimization, functional status evaluation at discharge, sepsis education, and scheduled follow-up within 2 weeks. The cohort was 46.6% female, 81.1% White, with a median age of 64 years. 51.2% were treated in the ICU. Medication optimization occurred in 93.7%, functional status evaluation in 82.7%, sepsis education in 20.0%, and scheduled follow-up within 2 weeks in 54.5%. ICU-treated patients had lower receipt of medication optimization and follow-up scheduling but greater receipt of functional and mental health status evaluations. In multivariable models, ICU treatment was associated with lower odds of receiving medication optimization (adjusted odds ratio, 0.72; 95% CI, 0.03–0.69) and not associated with receipt of other care practices. CONCLUSIONS: Our study shows incomplete receipt of recommended recovery-based care practices during sepsis hospitalization in both ward and ICU-treated patients. Sepsis education and mental health evaluation were particularly uncommon.

Supplemental Digital Content is available in the text., OBJECTIVES: Clinicians have little guidance on the time needed before assessing the effect of a mean airway pressure change during high-frequency oscillatory ventilation. We aimed to determine: 1) time to stable lung volume after a mean airway pressure change during high-frequency oscillatory ventilation and 2) the relationship between time to volume stability and the volume state of the lung. DESIGN: Prospective observational study. SETTING: Regional quaternary teaching hospital neonatal ICU. PATIENTS: Thirteen term or near-term infants receiving high-frequency oscillatory ventilation and muscle relaxants. INTERVENTIONS: One to two cm H2O mean airway pressure changes every 10 minutes as part of an open lung strategy based on oxygen response. MEASUREMENTS AND MAIN RESULTS: Continuous lung volume measurements (respiratory inductive plethysmography) were made during the mean airway pressure changes. Volume signals were analyzed with a biexponential model to calculate the time to stable lung volume if the model R2 was greater than 0.6. If volume stability did not occur within 10 minutes, the model was extrapolated to maximum 3,600 s. One-hundred ninety-six mean airway pressure changes were made, with no volume change in 33 occurrences (17%). One-hundred twenty-five volume signals met modeling criteria for inclusion; median (interquartile range) R2, 0.96 (0.91–0.98). The time to stable lung volume was 1,131 seconds (718–1,959 s) (mean airway pressure increases) and 647 seconds (439–1,309 s) (mean airway pressure decreases), with only 17 (14%) occurring within 10 minutes and time to stability being longer when the lung was atelectatic. CONCLUSIONS: During high-frequency oscillatory ventilation, the time to stable lung volume after a mean airway pressure change is variable, often requires more than 10 minutes, and is dependent on the preceding volume state.

Supplemental Digital Content is available in the text., OBJECTIVES: To investigate the association between plasma sodium concentrations and 6-month neurologic outcome in critically ill patients with aneurysmal subarachnoid hemorrhage. DESIGN: Prospective cohort study. SETTING: Eleven ICUs in Australia and New Zealand. PARTICIPANTS: Three-hundred fifty-six aneurysmal subarachnoid hemorrhage patients admitted to ICU between March 2016 and June 2018. The exposure variable was daily measured plasma sodium. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six-month neurologic outcome as measured by the modified Rankin Scale. A poor outcome was defined as a modified Rankin Scale greater than or equal to 4. The mean age was 57 years (± 12.6 yr), 68% were female, and 32% (n = 113) had a poor outcome. In multivariable analysis, including age, illness severity, and process of care measures as covariates, higher mean sodium concentrations (odds ratio, 1.17; 95% CI, 1.05–1.29), and greater overall variability—as measured by the sd (odds ratio, 1.53; 95% CI, 1.17–1.99)—were associated with a greater likelihood of a poor outcome. Multivariable generalized additive modeling demonstrated, specifically, that a high initial sodium concentration, followed by a gradual decline from day 3 onwards, was also associated with a poor outcome. Finally, greater variability in sodium concentrations was associated with a longer ICU and hospital length of stay: mean ICU length of stay ratio (1.13; 95% CI, 1.07–1.20) and mean hospital length of stay ratio (1.08; 95% CI, 1.01–1.15). CONCLUSIONS: In critically ill aneurysmal subarachnoid hemorrhage patients, higher mean sodium concentrations and greater variability were associated with worse neurologic outcomes at 6 months, despite adjustment for known confounders. Interventional studies would be required to demonstrate a causal relationship.

Supplemental Digital Content is available in the text., Objectives: To compare patient management and outcome during the first and second waves of the coronavirus 2019 pandemic. Design: Single-center prospective cohort study. Setting: Tertiary-care University Hospital. Patients: All adult patients admitted in either the first (from March 15 to May 15, 2020) or second (from October 1 to November 30, 2020) wave of coronavirus disease 2019. Interventions: None. Measurements and Main Results: Primary outcome was 30-day mortality. During the second wave of the coronavirus disease 2019 pandemic, 33 patients (4.8%) were transferred due to overcrowding and excluded from analysis. There were 341 (first wave of the coronavirus disease 2019 pandemic) and 695 (second wave of the coronavirus disease 2019 pandemic) coronavirus disease 2019 patients admitted to the hospital, with median age first wave of the coronavirus disease 2019 pandemic as 68 (57–80) and second wave of the coronavirus disease 2019 pandemic as 71 (60–80) (p = 0.15), and similar admission severity. For the first wave of the coronavirus disease 2019 pandemic versus second wave of the coronavirus disease 2019 pandemic, 30-day mortality was 74/341 (22%) and 98/662 (15%) (p = 0.007). In the ward, 11/341 (3.2%) and 404/662 (61%) received dexamethasone (p < 0.001); 6/341 (2%) and 79/662 (12%) received high-flow nasal oxygen (p < 0.0001); 2/341 (0.6%) and 88/662 (13.3%) received remdesivir (p < 0.0001); 249/341 (73%) and 0/662 (0%) received hydroxychloroquine (p < 0.0001); and 87/341 (26%) and 128/662 (19%) (p = 0.024) patients were transferred to ICU. On ICU admission, median Sequential Organ Failure Assessment was 6 (3–7) and 4 (3–6) (p = 0.02). High-flow nasal oxygen was given to 16/87 (18%) and 102/128 (80%) (p < 0.001); 69/87 (79%) and 56/128 (44%) received mechanical ventilation (p < 0.001) with durations 17 days (10–26 d) and 10 days (5–17 d) (p = 0.01). Median ICU length of stay was 14 days (5–27 d) and 6 days (3–11 d) (p < 0.001). Finally, 16/87 (18%) and 8/128 (6%) received renal replacement therapy (p = 0.0055); and 64/87 (74%) and 51/128 (40%) needed vasopressor support (p < 0.001). Conclusions: The main therapeutic changes between the first wave of the coronavirus disease 2019 pandemic and the second wave of the coronavirus disease 2019 pandemic were use of steroids, unrestrictive use of high-flow nasal oxygen for hypoxemic patients, and transfer of patients to other geographic areas in the case of ICU overcrowding. These changes were associated with a decrease in 30-day mortality, ICU admission, and organ support.

Supplemental Digital Content is available in the text., Objectives: Leukocytes are first responders to infection. Their activation state can reveal information about specific host immune response and identify dysregulation in sepsis. This study aims to use the Raman spectroscopic fingerprints of blood-derived leukocytes to differentiate inflammation, infection, and sepsis in hospitalized patients. Diagnostic sensitivity and specificity shall demonstrate the added value of the direct characterization of leukocyte’s phenotype. Design: Prospective nonrandomized, single-center, observational phase-II study (DRKS00006265). Setting: Jena University Hospital, Germany. Patients: Sixty-one hospitalized patients (19 with sterile inflammation, 23 with infection without organ dysfunction, 18 with sepsis according to Sepsis-3 definition). Interventions: None (blood withdrawal). Measurements AND MAIN RESULTS: Individual peripheral blood leukocytes were characterized by Raman spectroscopy. Reference diagnostics included established clinical scores, blood count, and biomarkers (C-reactive protein, procalcitonin and interleukin-6). Binary classification models using Raman data were able to distinguish patients with infection from patients without infection, as well as sepsis patients from patients without sepsis, with accuracies achieved with established biomarkers. Compared with biomarker information alone, an increase of 10% (to 93%) accuracy for the detection of infection and an increase of 18% (to 92%) for detection of sepsis were reached by adding the Raman information. Leukocytes from sepsis patients showed different Raman spectral features in comparison to the patients with infection that point to the special immune phenotype of sepsis patients. Conclusions: Raman spectroscopy can extract information on leukocyte’s activation state in a nondestructive, label-free manner to differentiate sterile inflammation, infection, and sepsis.

Supplemental Digital Content is available in the text., Objectives: There has been controversy about the timing and indications for intubation and mechanical ventilation in novel coronavirus disease 2019. This study assessed the effect of early intubation and mechanical ventilation on all-cause, inhospital mortality for coronavirus disease 2019 patients. Design: Multicenter retrospective cohort study. Setting: Eleven municipal hospitals in New York City from March 1, 2020, to December 1, 2020. Patients: Adult patients who tested positive for coronavirus disease 2019 in the emergency department were subsequently admitted. Patients with do-not-intubate orders at admission were excluded. Interventions: Intubation within 48 hours of triage and intubation at any point during hospital stay. Measurements and Main Results: Data from 7,597 coronavirus disease 2019 patients were included; of these, 1,628 (21%) were intubated overall and 807 (11%) were intubated within 48 hours of triage. After controlling for available confounders, intubation rates for coronavirus disease 2019 patients varied significantly across hospitals and decreased steadily as the pandemic progressed. After nearest neighbor propensity score matching, intubation within 48 hours of triage was associated with higher all-cause mortality (hazard ratio, 1.30 [1.15–1.48]; p < 0.0001), as was intubation at any time point (hazard ratio, 1.62 [1.45–1.80]; p < 0.0001). Among intubated patients, intubation within 48 hours of triage was not significantly associated with differences in mortality (hazard ratio, 1.09 [0.94–1.26]; p = 0.26). These results remained robust to multiple sensitivity analyses. CONCLUSIONS: Intubation within 48 hours of triage, as well as at any time point in the hospital course, was associated with increased mortality in coronavirus disease 2019 patients in this observational study.

Supplemental Digital Content is available in the text., OBJECTIVES: To characterize prearrest hemodynamic trajectories of children suffering inhospital cardiac arrest. DESIGN: Exploratory retrospective analysis of arterial blood pressure and electrocardiogram waveforms. SETTING: PICU and cardiac critical care unit in a tertiary-care children’s hospital. PATIENTS: Twenty-seven children with invasive blood pressure monitoring who suffered a total of 31 inhospital cardiac arrest events between June 2017 and June 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed changes in cardiac output, systemic vascular resistance, stroke volume, and heart rate derived from arterial blood pressure waveforms using three previously described estimation methods. We observed substantial prearrest drops in cardiac output (population median declines of 65–84% depending on estimation method) in all patients in the 10 minutes preceding inhospital cardiac arrest. Most patients’ mean arterial blood pressure also decreased, but this was not universal. We identified three hemodynamic patterns preceding inhospital cardiac arrest: subacute pulseless arrest (n = 18), acute pulseless arrest (n = 7), and bradycardic arrest (n = 6). Acute pulseless arrest events decompensated within seconds, whereas bradycardic and subacute pulseless arrest events deteriorated over several minutes. In the subacute and acute pulseless arrest groups, decreases in cardiac output were primarily due to declines in stroke volume, whereas in the bradycardic group, the decreases were primarily due to declines in heart rate. CONCLUSIONS: Critically ill children exhibit distinct physiologic behaviors prior to inhospital cardiac arrest. All events showed substantial declines in cardiac output shortly before inhospital cardiac arrest. We describe three distinct prearrest patterns with varying rates of decline and varying contributions of heart rate and stroke volume changes to the fall in cardiac output. Our findings suggest that monitoring changes in arterial blood pressure waveform-derived heart rate, pulse pressure, cardiac output, and systemic vascular resistance estimates could improve early detection of inhospital cardiac arrest by up to several minutes. Further study is necessary to verify the patterns witnessed in our cohort as a step toward patient rather than provider-centered definitions of inhospital cardiac arrest.

Supplemental Digital Content is available in the text., OBJECTIVES: With percutaneous left ventricular mechanical circulatory support devices becoming increasingly available for patients with cardiogenic shock due to acute myocardial infarction and the lack of a clear mortality benefit to date, identifying optimal candidates for this technology is crucial. We studied the effectiveness of Impella Cardiac Pow (Abiomed, Danvers, MA) in various stages of cardiogenic shock and elderly cohorts. DESIGN: Retrospective review. SETTING: Data were collected for patients at a single community hospital between January 1, 2018, and December 31, 2019. SUBJECTS: Thirty-one consecutive adult patients with cardiogenic shock due to acute myocardial infarction who received Impella Cardiac Pow support. Shock stages were defined by the Society for Cardiovascular Angiography and Intervention (Stages A–E). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital death across Society for Cardiovascular Angiography and Intervention cardiogenic shock stages and in patients greater than or equal to 80 and less than 80 years old. Secondary outcomes were Valve Academic Research Consortium-2 vascular and bleeding complications, stroke, and renal failure requiring dialysis. The median age of the study population was 64 years, with seven patients (23%) being greater than or equal to 80 years old. No patients were in Society for Cardiovascular Angiography and Intervention Stage A, whereas there were seven in B, eight in C, six in D, and 10 (32%) in E. Overall in-hospital mortality occurred in 61% of patients. All 10 patients in Stage E died before hospital discharge. Mortality occurred in 54% of patients (13/24) age less than 80 years compared with 86% of those 80 years or older (6/7). A total of 38.7% of patients (12/31) and 32.3% of patients (10/31) experienced Valve Academic Research Consortium-2 bleeding and vascular events, which were evenly distributed across Society for Cardiovascular Angiography and Intervention cardiogenic shock Stages. CONCLUSIONS: In conclusion, patients with shock in extremis and those 80 years old and older may have a prohibitively high mortality despite Impella use. These findings merit further prospective investigation in a larger number of patients to evaluate the effectiveness of Impella (and other left ventricular mechanical circulatory devices) and the inherent resource utilization in advanced cardiogenic shock and the elderly.

Supplemental Digital Content is available in the text., OBJECTIVES: To evaluate whether different approaches in note text preparation (known as preprocessing) can impact machine learning model performance in the case of mortality prediction ICU. DESIGN: Clinical note text was used to build machine learning models for adults admitted to the ICU. Preprocessing strategies studied were none (raw text), cleaning text, stemming, term frequency-inverse document frequency vectorization, and creation of n-grams. Model performance was assessed by the area under the receiver operating characteristic curve. Models were trained and internally validated on University of California San Francisco data using 10-fold cross validation. These models were then externally validated on Beth Israel Deaconess Medical Center data. SETTING: ICUs at University of California San Francisco and Beth Israel Deaconess Medical Center. SUBJECTS: Ten thousand patients in the University of California San Francisco training and internal testing dataset and 27,058 patients in the external validation dataset, Beth Israel Deaconess Medical Center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mortality rate at Beth Israel Deaconess Medical Center and University of California San Francisco was 10.9% and 7.4%, respectively. Data are presented as area under the receiver operating characteristic curve (95% CI) for models validated at University of California San Francisco and area under the receiver operating characteristic curve for models validated at Beth Israel Deaconess Medical Center. Models built and trained on University of California San Francisco data for the prediction of inhospital mortality improved from the raw note text model (AUROC, 0.84; CI, 0.80–0.89) to the term frequency-inverse document frequency model (AUROC, 0.89; CI, 0.85–0.94). When applying the models developed at University of California San Francisco to Beth Israel Deaconess Medical Center data, there was a similar increase in model performance from raw note text (area under the receiver operating characteristic curve at Beth Israel Deaconess Medical Center: 0.72) to the term frequency-inverse document frequency model (area under the receiver operating characteristic curve at Beth Israel Deaconess Medical Center: 0.83). CONCLUSIONS: Differences in preprocessing strategies for note text impacted model discrimination. Completing a preprocessing pathway including cleaning, stemming, and term frequency-inverse document frequency vectorization resulted in the preprocessing strategy with the greatest improvement in model performance. Further study is needed, with particular emphasis on how to manage author implicit bias present in note text, before natural language processing algorithms are implemented in the clinical setting.

Supplemental Digital Content is available in the text., OBJECTIVES: Hyperoxia is common among critically ill patients and may increase morbidity and mortality. However, limited evidence exists for critically injured patients. The objective of this study was to determine the association between hyperoxia and in-hospital mortality in adult trauma patients requiring ICU admission. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, retrospective cohort study was conducted at two level I trauma centers and one level II trauma center in CO between October 2015 and June 2018. All adult trauma patients requiring ICU admission within 24 hours of emergency department arrival were eligible. The primary exposure was oxygenation during the first 7 days of hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was in-hospital mortality. Secondary outcomes were hospital-free days and ventilator-free days. We included 3,464 critically injured patients with a mean age of 52.6 years. Sixty-five percent were male, and 66% had blunt trauma mechanism of injury. The primary outcome of in-hospital mortality occurred in 264 patients (7.6%). Of 226,057 patient-hours, 46% were spent in hyperoxia (oxygen saturation > 96%) and 52% in normoxia (oxygen saturation 90–96%). During periods of hyperoxia, the adjusted risk for mortality was higher with greater oxygen administration. At oxygen saturation of 100%, the adjusted risk scores for mortality (95% CI) at Fio2 of 100%, 80%, 60%, and 50% were 6.4 (3.5–11.8), 5.4 (3.4–8.6), 2.7 (1.7–4.1), and 1.5 (1.1–2.2), respectively. At oxygen saturation of 98%, the adjusted risk scores for mortality (95% CI) at Fio2 of 100%, 80%, 60%, and 50% were 7.7 (4.3–13.5), 6.3 (4.1–9.7), 3.2 (2.2–4.8), and 1.9 (1.4–2.7), respectively. CONCLUSIONS: During hyperoxia, higher oxygen administration was independently associated with a greater risk of mortality among critically injured patients. Level of evidence: Cohort study, level III.

Supplemental Digital Content is available in the text., Objectives: Treatment of hypoxemic respiratory failure and acute respiratory distress syndrome is complex. Evidence-based therapies that can improve survival and guidelines advocating their use exist; however, implementation is inconsistent. Our objective was to develop and validate an evidence-based, stakeholder-informed standardized management pathway for hypoxemic respiratory failure and acute respiratory distress syndrome to improve adherence to best practice. Design: A standardized management pathway was developed using a modified Delphi consensus process with a multidisciplinary group of ICU clinicians. The proposed pathway was externally validated with a survey involving multidisciplinary stakeholders and clinicians. Setting: In-person meeting and web-based surveys of ICU clinicians from 17 adult ICUs in the province of Alberta, Canada. Intervention: Not applicable. Measurements and Main Results: The consensus panel was comprised of 30 ICU clinicians (4 nurses, 10 respiratory therapists, 15 intensivists, 1 nurse practitioner; median years of practice 17 [interquartile range, 13–21]). Ninety-one components were serially rated and revised over two rounds of online and one in-person review. The final pathway included 46 elements. For the validation survey, 692 responses (including 59% nurses, 33% respiratory therapists, 7% intensivists and 1% nurse practitioners) were received. Agreement of greater than 75% was achieved on 43 of 46 pathway elements. Conclusions: A 46-element evidence-informed hypoxemic respiratory failure and acute respiratory distress syndrome standardized management pathway was developed and demonstrated to have content validity.

Supplemental Digital Content is available in the text., Objectives: ICU treatments frequently result in long-term psychologic impairments, negatively affecting quality of life. An effective treatment strategy is still lacking. The aim of this study was to describe and evaluate the safety and immersiveness of a newly designed ICU-specific virtual reality module. Design: A randomized controlled healthy volunteer trial. Setting: ICU of the Franciscus Gasthuis & Vlietland Hospital (Rotterdam, the Netherlands), a large teaching hospital. Participants: Forty-five virtual reality–naive healthy volunteers. Interventions: Volunteers were randomized to three arms: the head-mounted display virtual reality group (n = 15), the 2D group (n = 15), and the crossover group (n = 15). Safety was assessed by changes in vital signs and the occurrence of simulator sickness (Simulator Sickness Questionnaire). Immersiveness was assessed using the Igroup Presence Questionnaire. Measurements and Main Results: Volunteers in the head-mounted display virtual reality group experienced more mild symptoms of simulator sickness, expressed as symptoms of dizziness (p = 0.04) and stomach awareness (p = 0.04), than the 2D group. Nevertheless, none of the individual Simulator Sickness Questionnaire items were scored as being severe, no changes in vital signs were observed, and no sessions were prematurely stopped. Volunteers in the crossover group experienced a higher total presence (p < 0.001) when using head-mounted display virtual reality, expressed as a higher sense of presence (p < 0.001), more involvement (p < 0.01), and more experienced realism (p < 0.001). Conclusions: ICU-specific virtual reality appears safe and more immersive than 2D, implicating that ICU-specific virtual reality is feasible for clinical use. One should however be aware of simulator sickness-related symptoms. Future research is needed to confirm these findings in survivors of critical illness.

Supplemental Digital Content is available in the text., OBJECTIVES: To investigate patients’ experience of ICU diaries 6 months after ICU discharge among survivors. This study was designed to add insight into a large randomized study, which found no benefit of the ICU diary to post-traumatic stress disorder among critically ill patients having received mechanical ventilation. DESIGN: A preplanned qualitative substudy of patients receiving an ICU diary written by ICU caregivers and families. Six months after ICU discharge, survivors were contacted by a psychologist for a telephone interview using a semi-directive guide. SETTING: Thirty-five French ICUs. PATIENTS: All ICU survivors having received an ICU diary. INTERVENTION: An ICU diary written by both ICU staff and families. MEASUREMENTS AND MAIN RESULTS: Among the 332 patients randomized in the intervention group (having had an ICU diary filled by both ICU staff and families), 191 (57.7%) were alive at 6 months and 101 of 191 (52.9%) participated in a telephone interview. They were (median [interquartile range]) 64 years old (53–70 yr old); 65 (64.4%) were men, and 79 (78.2%) were medical patients. Duration of ICU stay was 13 days (8–21 d). Three themes were derived from the thematic analysis: 1) reading the diary: between emotion and pain, 2) how the diary helped, and 3) the bittersweet representation of the diary. For half of the patients, the diary is a good memory of difficult times (55/101, 54.5%), others seem to be more ambivalent about it (28/101, 27.8%), and 37 of 101, 36.6% see it as a painful representation of a time to be forgotten. CONCLUSIONS: When reading their ICU diaries, ICU survivors experienced mixed emotions, related to family messages, medical caregiving, and to the severity of their illness. Patients described diaries as a help or a hindrance to recovery, depending on their wish to remember the period or move on from it.

Supplemental Digital Content is available in the text., OBJECTIVES: The purpose of this study is to evaluate the overall occurrence of inhospital mortality in trauma patients who were placed on extracorporeal membrane oxygenation following the complication of the acute respiratory distress syndrome. DESIGN: Observational cohort study. SETTING: The data of all patients who were traumatically injured and developed the complication of acute respiratory distress syndrome were accessed from the Trauma Quality Improvement Program database from the calendar years of 2013 to 2016. PATIENTS: Patients 16 years old and less than 90 years old were included in the study. Variables included patient demography, Injury Severity Score, Glasgow Coma Scale score, Abbreviated Injury Scale score, and outcomes. INTERVENTIONS: Extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Propensity-matched analysis was performed between two groups: patients placed on extracorporeal membrane oxygenation and patients placed on conventional mode of ventilation. The primary outcome was inhospital mortality. Out of 6,121 patients who developed acute respiratory distress syndrome, 118 patients (1.93%) were placed on extracorporeal membrane oxygenation. The pair matched analysis showed significant difference between the two groups (extracorporeal membrane oxygenation vs conventional mode of ventilation) for overall inhospital mortality (35.6% vs 14.4%; p < 0.001). There were significant differences found between the two groups for the median hospital length of stay (41 [35–49] vs 27 [24–33]), ICU days (35 [30–41] vs 19 [17–24]), and ventilator days (30 [27–34] vs 15 [13–18]). All p values are less than 0.001. CONCLUSIONS: Approximately 2% of acute respiratory distress syndrome patients were placed on extracorporeal membrane oxygenation. The overall inhospital mortality remained high despite patients being placed on extracorporeal membrane oxygenation.

Supplemental Digital Content is available in the text., Objectives: The plasma level of N-terminal pro-brain natriuretic peptide is regulated by sex hormones. It has been controversial whether N-terminal pro-brain natriuretic peptide is a prognosis marker for sepsis. The aim of this study is to examine the sex-dependent association of plasma N-terminal pro-brain natriuretic peptide with organ dysfunction and mortality of sepsis patients. Design: In this retrospective study, the association between plasma N-terminal pro-brain natriuretic peptide concentration on the day of sepsis diagnosis and the degree of organ dysfunction, occurrence of septic shock, or 30-day mortality in both male and female patients was analyzed. Setting: This study was conducted in the Sepsis Laboratory at the Huaihe Hospital of Henan University in China. Patients: Diagnoses of sepsis, and septic shock, were based on the recently revised criteria (Sepsis 3.0). All sepsis patients (517) hospitalized in the respiratory ICU of the Huaihe Hospital from June 2016 to December 2019 were enrolled in this study. Interventions: None. Measurements and Main Results: No significant difference was found in the age, occurrence rate of septic shock, 30-day mortality, or degree of organ dysfunction between male and female patients. Median concentration of plasma N-terminal pro-brain Natriuretic peptide was higher by 93.48% in female than male patients. A significant association was found between N-terminal pro-brain natriuretic peptide and septic shock or 30-day mortality in female, but not in male patients of community- or hospital-acquired sepsis. N-terminal pro-brain natriuretic peptide levels correlated to functional deficiencies of the cardiac and nervous systems, only in female patients. Conclusions: The plasma N-terminal pro-brain natriuretic peptide level is a female-specific prognosis indicator of septic shock and mortality.

Supplemental Digital Content is available in the text., Objectives: To use latent class growth analysis to identify posttraumatic stress disorder symptom trajectories in ICU family caregivers. Design: Prospective cohort study. Setting: The medical ICU at a tertiary-care center in the United States. Participants: Adult patients experiencing acute cardiorespiratory failure (defined as requiring at least one of the following: 1) vasopressors, 2) noninvasive positive pressure ventilation, 3) high-flow nasal cannula, or 4) mechanical ventilation) were enrolled in a pair with their primary family caregivers. Measurements and Main Results: Participants were enrolled within the first 48 hours of ICU admission. Family caregiver posttraumatic stress disorder symptoms were measured using the Impact of Events Scale-Revised at four time points: at enrollment, shortly after ICU discharge, and at 3 and 6 months after ICU discharge. The data were examined using latent class growth analysis to identify posttraumatic stress disorder symptom trajectories. Two distinct symptom trajectories were identified: a persistently high trajectory, characterized by high posttraumatic stress disorder symptoms at initial assessment, which remained elevated over time, and a persistently low trajectory, characterized by low posttraumatic stress disorder symptoms at initial assessment, which remained low over time. Approximately two-thirds of caregivers belonged to the persistently high trajectory, and one-third of caregivers belonged to the persistently low trajectory. Conclusions: Using latent class growth analysis to measure 6-month ICU family caregiver posttraumatic stress disorder symptom trajectories, we identified two distinct trajectories (persistently low and persistently high). A larger cohort study is warranted to further delineate posttraumatic stress disorder trajectories in this population, with the ultimate goal of targeting high-risk caregivers for interventions to reduce psychologic distress and improve long-term caregiver outcomes.

Objectives:. To assess differences in cognitive outcomes and sleep in adult survivors of critical illness, managed with venovenous extracorporeal membrane oxygenation as compared to conventional mechanical ventilation only. Design:. Retrospective cohort study linked with data from the COGnitive outcomes and WELLness study. Setting:. A multisite study from five adult medical/surgical ICUs in Toronto. Patients:. Thirty-three ICU survivors including adult patients who received venovenous extracorporeal membrane oxygenation (n = 11) matched with patients who received mechanical ventilation only (n = 22) using specified covariates (e.g., age). Interventions:. None. Measurements and Main Results:. Baseline demographics and admission diagnoses were collected at enrollment. Cognitive outcome was evaluated using the Repeatable Battery for the Assessment of Neuropsychologic Status (global cognitive function) and Trail Making Test B (executive function), and sleep variables were estimated using actigraphy. Assessments occurred at 7 days post ICU discharge and again at 6- and 12-month follow-up. No statistically significant difference was seen between patients treated with or without venovenous extracorporeal membrane oxygenation in the mean daily Riker Sedation Agitation Score; however, patients in the venovenous extracorporeal membrane oxygenation group received greater amounts of fentanyl over their ICU stay as compared to patients receiving conventional mechanical ventilation only (p < 0.001). No significant differences were found in performance on either of the cognitive assessment tools, between survivors treated or not with venovenous extracorporeal membrane oxygenation at any of the time points assessed. Total sleep time estimated by actigraphy increased from approximately 6.5 hours in hospital to 7.5 hours at 6-month follow-up in all patients, regardless of treatment type. Total sleep time remained consistent in both groups from 6 to 12 months post ICU discharge. Conclusions:. In this small retrospective case series, no significant differences were found in sleep or cognitive outcomes between extracorporeal life support and non–extracorporeal life support survivors. Further, in this hypothesis-generating study, differences in administered sedative doses during the ICU stay seen between the two groups did not impact 6- or 12-month cognitive performance or actigraphy-estimated sleep time.

Objectives:. To identify the most efficacious timing for tocilizumab administration in critically ill patients infected with severe acute respiratory syndrome coronavirus-2. Design:. Observational multicenter cohort study. Setting:. A total of 23 acute care hospitals in four states. Patients:. One-hundred eighteen patients admitted between March 13, 2020, and April 16, 2020. Eighty-one patients received tocilizumab, and 37 were untreated and served as a control group. Measurements and Main Results:. The main outcome was mortality and was analyzed by timing of tocilizumab dosing. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered greater than 1 day after intubation. A control group that was treated only with standard of care, and without tocilizumab, was used for comparison. Early tocilizumab therapy was associated with a statistically significant decrease in mortality as compared to patients who were untreated (p = 0.003). Dosing tocilizumab late was associated with an increased mortality compared with the untreated group (p = 0.006). Conclusions:. Early tocilizumab administration was associated with decreased mortality in critically ill severe acute respiratory syndrome coronavirus-2 patients, but a potential detriment was suggested by dosing later in a patient’s course.

Objectives:. To determine how several existing crisis standards of care triage protocols would have distinguished between patients with coronavirus disease 2019 requiring intensive care. Design:. Retrospective cohort study. Setting:. Single urban academic medical center. Patients:. One-hundred twenty patients with coronavirus disease 2019 who required intensive care and mechanical ventilation. Interventions:. None. Measurements and Main Results:. The characteristics of each patient at the time of ICU triage were used to determine how patients would have been prioritized using four crisis standards of care protocols. The vast majority of patients in the cohort would have been in the highest priority group using a triage protocol focusing on Sequential Organ Failure Assessment alone. Prioritization based on Sequential Organ Failure Assessment and 1-year life expectancy would have resulted in only slightly more differentiation between patients. Prioritization based on Sequential Organ Failure Assessment and 5-year life expectancy would have added significant additional differentiation depending on how priority groups were defined. Conclusions:. There is considerable controversy regarding the use of criteria other than prognosis for short-term survival in initial allocation of critical care resources under crisis standards of care triage protocols. To the extent that initial triage protocols would not create sufficient differentiation between patients, effectively resulting in a first-come, first-served initial allocation of resources, it is important to focus on how resources would be reallocated in the event of ongoing scarcity.

Objectives:. Critical care teams are encouraged to follow best practice protocols to help wean mechanically ventilated patients from the ventilator to reduce ventilator-associated events including ventilator-associated conditions, probable ventilator-associated pneumonias, and infection-related ventilator-associated conditions. Providers monitor for alerts suggestive of possible ventilator-associated events and advise when patients should undergo spontaneous breathing trials. Compliance with protocols in most units is suboptimal. Design:. Retrospective review of clinical data over 24 months. Setting:. St. Joseph Mercy Hospital Candler Hospital Medical-Surgical ICU. Patients:. All mechanically ventilated patients. Interventions:. The Respiratory Knowledge Portal was implemented in our ICU. For 13 months, Respiratory Knowledge Portal data were ported to ICU workstations (control). For the following 11 months, Respiratory Knowledge Portal data were also presented on tablet computers (intervention) for use during multidisciplinary rounds. We performed a retrospective review of Respiratory Knowledge Portal data from before and after the implementation of the tablet computers. Measurements and Main Results:. Data were collected from 337 patients (187 control group, 150 intervention group). A decrease in the occurrence of ventilator-associated events was observed during the intervention group compared with the control group. Only 2.0% of patients in the intervention group experienced any category of ventilator-associated event, while 11.2% of patients in the control group experienced one event (p = 0.003). Intervention patients experienced less ventilator-associated conditions (p = 0.002), infection-related ventilator-associated conditions (p = 0.026), and probable ventilator-associated pneumonias (p = 0.036) than control patients. Twenty-one of the 24 patients with any ventilator-associated events were in the control group. There was no significant difference between the days spent on ventilation nor hospital length of stay in the control compared with intervention group patients. Conclusions:. Fewer ventilator-associated events, ventilator-associated conditions, infection-related ventilator-associated conditions, and probable ventilator-associated pneumonias were seen during the period when Respiratory Knowledge Portal monitoring data was presented on tablet computers. There was no difference in time on ventilator nor overall length of stay.

Supplemental Digital Content is available in the text., Objectives: To comprehensively classify interventions performed by emergency medicine clinical pharmacists and quantify cost avoidance generated through their accepted interventions. Design: A multicenter, prospective, observational study was performed between August 2018 and January 2019. Setting: Community and academic hospitals in the United States. Participants: Emergency medicine clinical pharmacists. Interventions: Recommendations classified into one of 38 intervention categories associated with cost avoidance. Measurements and Main Results: Eighty-eight emergency medicine pharmacists at 49 centers performed 13,984 interventions during 917 shifts that were accepted on 8,602 patients and generated $7,531,862 of cost avoidance. The quantity of accepted interventions and cost avoidance generated in six established categories were as follows: adverse drug event prevention (1,631 interventions; $2,225,049 cost avoidance), resource utilization (628; $310,582), individualization of patient care (6,122; $1,787,170), prophylaxis (24; $22,804), hands-on care (3,533; $2,836,811), and administrative/supportive tasks (2,046; $342,881). Mean cost avoidance was $538.61 per intervention, $875.60 per patient, and $8,213.59 per emergency medicine pharmacist shift. The annualized cost avoidance from an emergency medicine pharmacist was $1,971,262. The monetary cost avoidance to pharmacist salary ratio was between $1.4:1 and $10.6:1. Conclusions: Pharmacist involvement in the care of patients presenting to the emergency department results in significant avoidance of healthcare costs, particularly in the areas of hands-on care and adverse drug event prevention. The potential monetary benefit-to-cost ratio for emergency medicine pharmacists is between $1.4:1 and $10.6:1.