Assessment of Symptom, Disability, and Financial Trajectories in Patients Hospitalized for COVID-19 at 6 Months.

Importance: Individuals who survived COVID-19 often report persistent symptoms, disabilities, and financial consequences. However, national longitudinal estimates of symptom burden remain limited. Objective: To measure the incidence and changes over time in symptoms, disability, and financial status after COVID-19-related hospitalization. Design, Setting, and Participants: A national US multicenter prospective cohort study with 1-, 3-, and 6-month postdischarge visits was conducted at 44 sites participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network's Biology and Longitudinal Epidemiology: COVID-19 Observational (BLUE CORAL) study. Participants included hospitalized English- or Spanish-speaking adults without severe prehospitalization disabilities or cognitive impairment. Participants were enrolled between August 24, 2020, and July 20, 2021, with follow-up occurring through March 30, 2022. Exposure: Hospitalization for COVID-19 as identified with a positive SARS-CoV-2 molecular test. Main Outcomes and Measures: New or worsened cardiopulmonary symptoms, financial problems, functional impairments, perceived return to baseline health, and quality of life. Logistic regression was used to identify factors associated with new cardiopulmonary symptoms or financial problems at 6 months. Results: A total of 825 adults (444 [54.0%] were male, and 379 [46.0%] were female) met eligibility criteria and completed at least 1 follow-up survey. Median age was 56 (IQR, 43-66) years; 253 (30.7%) participants were Hispanic, 145 (17.6%) were non-Hispanic Black, and 360 (43.6%) were non-Hispanic White. Symptoms, disabilities, and financial problems remained highly prevalent among hospitalization survivors at month 6. Rates increased between months 1 and 6 for cardiopulmonary symptoms (from 67.3% to 75.4%; P = .001) and fatigue (from 40.7% to 50.8%; P < .001). Decreases were noted over the same interval for prevalent financial problems (from 66.1% to 56.4%; P < .001) and functional limitations (from 55.3% to 47.3%; P = .004). Participants not reporting problems at month 1 often reported new symptoms (60.0%), financial problems (23.7%), disabilities (23.8%), or fatigue (41.4%) at month 6. Conclusions and Relevance: The findings of this cohort study of people discharged after COVID-19 hospitalization suggest that recovery in symptoms, functional status, and fatigue was limited at 6 months, and some participants reported new problems 6 months after hospital discharge.

Eradication of early MRSA infection in cystic fibrosis: a novel study design for the STAR-ter trial.

Introduction: Early eradication of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis is desirable. Prospective studies are challenging owing to the feasibility of recruiting patients with a rare event in an orphan disease. Our prior randomised study (Staph Aureus Resistance-Treat Or Observe (STAR-too)) showed improved clearance and outcomes with aggressive therapy compared to no treatment. We present a novel trial design to guide treatment for eradicating incident infection with a focus on feasibility. Methods: Subjects with cystic fibrosis with incident MRSA infection were enrolled into the Staph Aureus Resistance-Treat Early And Repeat (STAR-ter) protocol and treated with a combination of an oral antibiotic and topical (nare and throat) decolonisation. The primary outcome was MRSA-negative respiratory culture at Day 28, i.e. 14 days after completion of oral antibiotics. What was novel about this study design was that the control/comparator group was the untreated group of the STAR-too trial. This design was developed because having a "no treatment" group would be unethical given prior findings and a superiority design would delay the time to results based on small numbers of eligible subjects. Both studies used the same inclusion and exclusion criteria and drew subjects from the same geographic regions. The main difference between the studies was the use of a single oral antibiotic, trimethoprim-sulfamethoxazole, rather than the combination with oral rifampin used in STAR-too. Discussion: An innovative approach to address a clinical question for a rare event in an orphan disease, cystic fibrosis, is presented to enhance current clinical evidence to guide cystic fibrosis care in relation to new MRSA infection.

Functional, imaging, and respiratory evaluation (FIRE) of patients post-hospitalization for COVID-19: protocol for a pilot observational study.

INTRODUCTION: We describe a protocol for FIRE CORAL, an observational cohort study that examines the recovery from COVID-19 disease following acute hospitalization with an emphasis on functional, imaging, and respiratory evaluation. METHODS AND ANALYSIS: FIRE CORAL is a multicenter prospective cohort study of participants recovering from COVID-19 disease with in-person follow-up for functional and pulmonary phenotyping conducted by the National Heart, Lung and Blood Institute (NHLBI) Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. FIRE CORAL will include a subset of participants enrolled in Biology and Longitudinal Epidemiology of PETAL COVID-19 Observational Study (BLUE CORAL), an NHLBI-funded prospective cohort study describing the clinical characteristics, treatments, biology, and outcomes of hospitalized patients with COVID-19 across the PETAL Network. FIRE CORAL consists of a battery of in-person assessments objectively measuring pulmonary function, abnormalities on lung imaging, physical functional status, and biospecimen analyses. Participants will attend and perform initial in-person testing at 3 to 9 months after hospitalization. The primary objective of the study is to determine the feasibility of longitudinal assessments investigating multiple domains of recovery from COVID-19. Secondarily, we will perform descriptive statistics, including the prevalence and characterization of abnormalities on pulmonary function, chest imaging, and functional status. We will also identify potential clinical and biologic factors that predict recovery or the occurrence of persistent impairment of pulmonary function, chest imaging, and functional status. ETHICS AND DISSEMINATION: FIRE CORAL is approved via the Vanderbilt University central institutional review board (IRB) and via reliance agreement with the site IRBs. Results will be disseminated via the writing group for the protocol committee and reviewed by the PETAL Network publications committee prior to publication. Data obtained via the study will subsequently be made publicly available via NHLBI's biorepository. STRENGTHS AND LIMITATIONS OF THE STUDY: Strengths: First US-based multicenter cohort of pulmonary and functional outcomes in patients previously hospitalized for COVID-19 infection Longitudinal biospecimen measurement allowing for biologic phenotyping of abnormalities Geographically diverse cohort allowing for a more generalizable understanding of post-COVID pulmonary sequela Limitations: Selected cohort given proximity to a participating center Small cohort which may be underpowered to identify small changes in pulmonary function.

Characteristics and Outcomes of US Patients Hospitalized With COVID-19.

BACKGROUND: Understanding COVID-19 epidemiology is crucial to clinical care and to clinical trial design and interpretation. OBJECTIVE: To describe characteristics, treatment, and outcomes among patients hospitalized with COVID-19 early in the pandemic. METHODS: A retrospective cohort study of consecutive adult patients with laboratory-confirmed, symptomatic SARS-CoV-2 infection admitted to 57 US hospitals from March 1 to April 1, 2020. RESULTS: Of 1480 inpatients with COVID-19, median (IQR) age was 62.0 (49.4-72.9) years, 649 (43.9%) were female, and 822 of 1338 (61.4%) were non-White or Hispanic/Latino. Intensive care unit admission occurred in 575 patients (38.9%), mostly within 4 days of hospital presentation. Respiratory failure affected 583 patients (39.4%), including 284 (19.2%) within 24 hours of hospital presentation and 413 (27.9%) who received invasive mechanical ventilation. Median (IQR) hospital stay was 8 (5-15) days overall and 15 (9-24) days among intensive care unit patients. Hospital mortality was 17.7% (n = 262). Risk factors for hospital death identified by penalized multivariable regression included older age; male sex; comorbidity burden; symptoms-to-admission interval; hypotension; hypoxemia; and higher white blood cell count, creatinine level, respiratory rate, and heart rate. Of 1218 survivors, 221 (18.1%) required new respiratory support at discharge and 259 of 1153 (22.5%) admitted from home required new health care services. CONCLUSIONS: In a geographically diverse early-pandemic COVID-19 cohort with complete hospital folllow-up, hospital mortality was associated with older age, comorbidity burden, and male sex. Intensive care unit admissions occurred early and were associated with protracted hospital stays. Survivors often required new health care services or respiratory support at discharge.

Continuing Cardiopulmonary Symptoms, Disability, and Financial Toxicity 1 Month After Hospitalization for Third-Wave COVID-19: Early Results From a US Nationwide Cohort.

BACKGROUND: Patients discharged after COVID-19 report ongoing needs. OBJECTIVES: To measure incident symptoms after COVID-19 hospitalization. DESIGN, SETTING, AND PARTICIPANTS: Preplanned early look at 1-month follow-up surveys from patients hospitalized August 2020 to January 2021 in NHLBI PETAL Network's Biology and Longitudinal Epidemiology: COVID-19 Observational (BLUE CORAL) study. English- or Spanish-speaking hospitalized adults without substantial pre-COVID-19 disability with a positive molecular test for SARS-CoV-2. RESULTS: Overall, 253 patients were hospitalized for a median of 5 days (interquartile range [IQR], 3-8), and had a median age of 60 years (IQR, 45-68). By race/ethnicity, 136 (53.8%) were non-Hispanic White, 23 (9.1%) were non-Hispanic Black, and 83 (32.8%) were Hispanic. Most (139 [54.9%]) reported a new or worsened cardiopulmonary symptom, and 16% (n = 39) reported new or increased oxygen use; 213 (84.2%) patients reported not feeling fully back to their pre-COVID-19 level of functioning. New limitations in activities of daily living were present in 130 (52.8%) patients. Financial toxicities, including job loss or change (49 [19.8%]), having a loved one take time off (93 [37.8%]), and using up one's savings (58 [23.2%]), were common. Longer lengths of hospital stay were associated with greater odds of 1-month cardiopulmonary symptoms (adjusted odds ratio [aOR], 1.82 per additional week in the hospital; 95% CI, 1.11-2.98) and new disability (aOR, 2.06; 95% CI, 1.21-3.53). There were not uniform demographic patterns of association. LIMITATIONS: We prioritized patients' reports of their own incident problems over objective testing. CONCLUSION: Patients who survived COVID-19 in the United States during late 2020/early 2021 still faced new burdens 1 month after hospital discharge.

Provider-Documented Anxiety in the ICU: Prevalence, Risk Factors, and Associated Patient Outcomes.

PURPOSE: To determine the prevalence of provider-documented anxiety in critically ill patients, associated risk factors, and related patient outcomes. METHOD: Chart review of 100 randomly sampled, adult patients, with a length of stay ≥48 hours in a medical or trauma/surgical intensive care unit (ICU). Provider-documented anxiety was identified based on a comprehensive retrospective chart review of the ICU stay, searching for any acute episode of anxiety (e.g., documented words related to anxiety, panic, and/or distress). RESULTS: Of 100 patients, 45% (95% confidence interval: 35%-55%) had documented anxiety, with similar prevalence in medical vs. trauma/surgical ICU. Patients with documented anxiety more frequently had history of anxiety (22% vs. 4%, p = .004) and substance abuse (40% vs. 22%, p = .048). In the ICU, they had greater severity of illness (median (IQR) Acute Physiology Score 16(13,21) vs. 13(8,19), p = .018), screened positive for delirium at least once during ICU stay, (62% vs. 31%, p = .002), benzodiazepines and antipsychotics use (87% vs. 58%, p = .002; 33% vs. 13%, p = .013, respectively), and mental health consultation (31% vs. 18%, p = .132). These patients also had longer ICU and hospital lengths of stay (6(4,11) vs. 4(3,6), p<.001 and 18(10,30) vs. 10(6,16) days, p<.001, respectively) and less frequent discharge back to home (27% vs. 44%, p = .079). CONCLUSIONS: Documented anxiety, occurring in almost half of ICU patients with length of stay ≥48 hours, was associated with a history of anxiety and/or substance abuse, and greater ICU severity of illness, delirium, psychiatric medications, and length of stay. Increased awareness along with more standardized protocols for assessment of anxiety in the ICU, as well as greater evaluation of non-pharmacological treatments for anxiety symptoms in the ICU are warranted.

Fluid management in ARDS: an evaluation of current practice and the association between early diuretic use and hospital mortality.

BACKGROUND: Acute respiratory distress syndrome (ARDS) and volume overload are associated with increased hospital mortality. Evidence supports conservative fluid management in ARDS, but whether current practice reflects the implementation of that evidence has not been described. This study reports the variability in contemporary fluid management for ICU patients with ARDS. We compared routine care to trial protocols and analyzed whether more conservative management with diuretic medications in contemporary, usual care is associated with outcomes. METHODS: We performed a retrospective cohort study in nine ICUs at two academic hospitals during 2016 and 2017. We included 234 adult patients with ARDS in an ICU at least 3 days after meeting moderate-severe ARDS criteria (PaO2:FIO2 ≤ 150). The primary exposure was any diuretic use in 48 to 72 h after meeting ARDS criteria. The primary outcome was hospital mortality. Unadjusted statistical analyses and multivariable logistic regression were used. RESULTS: In 48-72 h after meeting ARDS criteria, 116 patients (50%) received a diuretic. In-hospital mortality was lower in the group that received diuretics than in the group that did not (14% vs 25%; p = 0.025). At ARDS onset, both groups had similar Sequential Organ Failure Assessment scores and ICU fluid balances. During the first 48 h after ARDS, the diuretic group received less crystalloid fluid than the no diuretic group (median [inter-quartile range]: 1.2 L [0.2-2.8] vs 2.4 L [1.2-5.0]; p < 0.001), but both groups received more fluid from medications and nutrition than from crystalloid. At 48 h, the prevalence of volume overload (ICU fluid balance >10% of body weight) in each group was 16% and 25%(p = 0.09), respectively. During 48-72 h after ARDS, the overall prevalence of shock was 44% and similar across both groups. Central venous pressure was recorded in only 18% of patients. Adjusting for confounders, early diuretic use was independently associated with lower hospital mortality (AOR 0.46, 95%CI [0.22, 0.96]). CONCLUSIONS: In this sample of ARDS patients, volume overload was common, and early diuretic use was independently associated with lower hospital mortality. These findings support the importance of fluid management in ARDS and suggest opportunities for further study and implementation of conservative fluid strategies into usual care.

Direct Lung Sampling Indicates That Established Pathogens Dominate Early Infections in Children with Cystic Fibrosis.

Culture and sequencing have produced divergent hypotheses about cystic fibrosis (CF) lung infections. Culturing suggests that CF lungs are uninfected before colonization by a limited group of CF pathogens. Sequencing suggests diverse communities of mostly oral bacteria inhabit lungs early on and diversity decreases as disease progresses. We studied the lung microbiota of CF children using bronchoscopy and sequencing, with measures to reduce contamination. We found no evidence for oral bacterial communities in lung lavages that lacked CF pathogens. Lavage microbial diversity varied widely, but decreases in diversity appeared to be driven by increased CF pathogen abundance, which reduced the signal from contaminants. Streptococcus, Prevotella, and Veillonella DNA was detected in some lavages containing CF pathogens, but DNA from these organisms was vastly exceeded by CF pathogen DNA and was not associated with inflammation. These findings support the hypothesis that established CF pathogens are primarily responsible for CF lung infections.

Bronchoalveolar fluid and plasma inflammatory biomarkers in contemporary ARDS patients.

Purpose: Bronchoalveolar fluid (BALF) and plasma biomarkers are often endpoints in early phase randomized trials (RCTs) in acute respiratory distress syndrome (ARDS). With ARDS mortality decreasing, we analyzed baseline biomarkers in samples from contemporary ARDS patients participating in a prior RCT and compared these to historical controls. Materials and methods: Ninety ARDS adult patients enrolled in the parent trial. BALF and blood were collected at baseline, day 4 ± 1, and day 8 ± 1. Interleukins-8/-6/-1ß/-1 receptor antagonist/-10; granulocyte colony stimulating factor; monocyte chemotactic protein-1; tumour necrosis factor-α; surfactant protein-D; von Willebrand factor; leukotriene B4; receptor for advanced glycosylation end products; soluble Fas ligand; and neutrophil counts were measured. Results: Compared to historical measurements, our values were generally substantially lower, despite our participants being similar to historical controls. For example, our BALF IL-8 and plasma IL-6 were notably lower than in a 1999 RCT of low tidal volume ventilation and a 2007 biomarker study, respectively. Conclusions: Baseline biomarker levels in current ARDS patients are substantially lower than 6-20 years before collection of these samples. These findings, whether from ICU care changes resulting in less inflammation or from variation in assay techniques over time, have important implications for design of future RCTs with biomarkers as endpoints.

The acute respiratory distress syndrome after out-of-hospital cardiac arrest: Incidence, risk factors, and outcomes.

OBJECTIVE: To define the incidence of the acute respiratory distress syndrome (ARDS) following out-of-hospital cardiac arrest (OHCA) and characterize its impact on outcome. METHODS: This was a retrospective cohort study conducted at two urban, tertiary, academic hospitals from 2007 to 2014. We included adults with non-traumatic OHCA and survived for ≥48 h. Patients who received mechanical ventilation for ≥24 h, had 2 consecutive arterial blood gases with a ratio of the partial pressure of oxygen to the fraction of inspired oxygen ≤300, and bilateral radiographic opacities within 48 h of hospital admission were defined as having ARDS. We examined the associations between ARDS and outcome using multivariable analyses and performed sensitivity analyses excluding patients with evidence of cardiac dysfunction. RESULTS: Of 978 OHCA patients transported to the study hospitals, 600 were mechanically ventilated and survived ≥48 h. A total of 287 (48%, 95% CI 44-52%) met criteria for ARDS within 48 h of admission. There were no differences in demographics, OHCA etiology, or cardiac rhythm according to ARDS status. Patients with ARDS had higher hospital mortality, longer ICU stays, more ventilator days, and were less likely to survive with full neurologic recovery. Upon excluding patients with cardiac dysfunction, the incidence of ARDS was unchanged. CONCLUSION: Nearly half of initial OHCA survivors develop ARDS within 48 h of hospital admission. ARDS was associated with poor outcome and increased resource utilization. OHCA should be considered among the traditional ARDS risk factors.

Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections.

The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infections. Our results show that micromolar concentrations of gallium inhibited P. aeruginosa growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic P. aeruginosa lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens.

Changing Rates of Chronic Pseudomonas aeruginosa Infections in Cystic Fibrosis: A Population-Based Cohort Study.

Background: Chronic Pseudomonas aeruginosa lung infection is associated with significant morbidity and mortality in cystic fibrosis (CF). It is not known whether recent advances in care have affected the rates of chronic infection. We aimed to determine if the rates of developing new chronic P. aeruginosa infection among adolescents and adults with CF significantly changed over time. Methods: The cohort consisted of individuals with CF followed in the Cystic Fibrosis Foundation Patient Registry aged ≥13 years without chronic P. aeruginosa at baseline. Multivariable regression models accounting for within-patient correlation were used to assess the change in rate of developing chronic P. aeruginosa infection between 2003 and 2012. Results: A total of 15504 individuals were followed for a median of 5 (interquartile range, 2-9) years. The annual rates of developing new chronic P. aeruginosa decreased from 14.3% in 2003 to 6.4% in 2012. After adjusting for potential confounders, relative risk (RR) of developing chronic P. aeruginosa infection decreased significantly over time compared to 2003 (P value test of trend < .001). Compared with 2003, the RR of developing chronic P. aeruginosa infection in 2012 was 0.33 (95% confidence interval, 0.30-0.37). No significant increases in risk of chronic infections with other major CF bacterial pathogens relative to 2003 were identified. Conclusions: Among individuals with CF, a significant decrease in the risk and rates of developing chronic P. aeruginosa infection between 2003 and 2012 was observed. Whether this decline results in changes in clinical outcomes warrants further exploration.

Low tidal volume ventilation use remains low in patients with acute respiratory distress syndrome at a single center.

PURPOSE: Low tidal volume ventilation (LTVV) reduces mortality in acute respiratory distress syndrome (ARDS) patients. Understanding local barriers to LTVV use at a former ARDS Network hospital may provide new insight to improve LTVV implementation. METHODS: A cohort of 214 randomly selected adults met the Berlin definition of ARDS at Harborview Medical Center between 2008 and 2012. The primary outcome was the receipt of LTVV (tidal volume of ≤6.5mL/kg predicted body weight) within 48h of ARDS onset. We constructed a multivariable logistic regression model to identify factors associated with the outcome. RESULTS: Only 27% of patients received tidal volumes of ≤6.5mL/kg PBW within 48h of ARDS onset. Increasing plateau pressure (OR 1.11; 95% CI 1.03 to 1.19; p-value<0.01) was positively associated with LTVV use while increasing PaO2:FIO2 ratio was negatively associated (OR 0.75; 95% CI 0.57 to 0.98; p-value 0.03). Physicians documented an ARDS diagnosis in only 21% of the cohort. Neither patient height nor gender was associated with LTVV use. CONCLUSIONS: Most ARDS patients did not receive LTVV despite implementation of a protocol. ARDS was also recognized in a minority of patients, suggesting an opportunity for improvement of care.

Point Prevalence Study of Mobilization Practices for Acute Respiratory Failure Patients in the United States.

OBJECTIVE: Early mobility in mechanically ventilated patients is safe, feasible, and may improve functional outcomes. We sought to determine the prevalence and character of mobility for ICU patients with acute respiratory failure in U.S. ICUs. DESIGN: Two-day cross-sectional point prevalence study. SETTING: Forty-two ICUs across 17 Acute Respiratory Distress Syndrome Network hospitals. PATIENTS: Adult patients (≥ 18 yr old) with acute respiratory failure requiring mechanical ventilation. INTERVENTIONS: We defined therapist-provided mobility as the proportion of patient-days with any physical or occupational therapy-provided mobility event. Hierarchical regression models were used to identify predictors of out-of-bed mobility. MEASUREMENTS AND MAIN RESULTS: Hospitals contributed 770 patient-days of data. Patients received mechanical ventilation on 73% of the patient-days mostly (n = 432; 56%) ventilated via an endotracheal tube. The prevalence of physical therapy/occupational therapy-provided mobility was 32% (247/770), with a significantly higher proportion of nonmechanically ventilated patients receiving physical therapy/occupational therapy (48% vs 26%; p ≤ 0.001). Patients on mechanical ventilation achieved out-of-bed mobility on 16% (n = 90) of the total patient-days. Physical therapy/occupational therapy involvement in mobility events was strongly associated with progression to out-of-bed mobility (odds ratio, 29.1; CI, 15.1-56.3; p ≤ 0.001). Presence of an endotracheal tube and delirium were negatively associated with out-of-bed mobility. CONCLUSIONS: In a cohort of hospitals caring for acute respiratory failure patients, physical therapy/occupational therapy-provided mobility was infrequent. Physical therapy/occupational therapy involvement in mobility was strongly predictive of achieving greater mobility levels in patients with respiratory failure. Mechanical ventilation via an endotracheal tube and delirium are important predictors of mobility progression.

Change in Pseudomonas aeruginosa prevalence in cystic fibrosis adults over time.

BACKGROUND: Little is known about risk factors for chronic and mucoid Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) adults, and whether the prevalence is changing. METHODS: We employed a retrospective cohort to analyze data from a single adult CF center (2002 to 2012). Regression models were used to assess independent predictors and change in prevalence of chronic and mucoid Pa infection over time. RESULTS: The odds ratio of mucoid Pa infection was significantly less in individuals with better baseline lung function (OR 0.84,95%CI:0.77-0.92) and those diagnosed after the age of 25 (OR 0.21, 95%CI:0.05-0.95). The prevalence of chronic Pa and mucoid Pa decreased during the time interval. After adjusting for confounders, the observed decrease in chronic and mucoid Pa between 2002 and 2012 was no longer significant. CONCLUSIONS: The prevalence of chronic and mucoid Pa is decreasing. Larger studies are needed to confirm these regional trends and their significance.

Development and validation of a prehospital prediction model for acute traumatic coagulopathy.

BACKGROUND: Acute traumatic coagulopathy (ATC) is a syndrome of early, endogenous clotting dysfunction that afflicts up to 30% of severely injured patients, signaling an increased likelihood of all-cause and hemorrhage-associated mortality. To aid identification of patients within the likely therapeutic window for ATC and facilitate study of its mechanisms and targeted treatment, we developed and validated a prehospital ATC prediction model. METHODS: Construction of a parsimonious multivariable logistic regression model predicting ATC - defined as an admission international normalized ratio >1.5 - employed data from 1963 severely injured patients admitted to an Oregon trauma system hospital between 2008 and 2012 who received prehospital care but did not have isolated head injury. The prediction model was validated using data from 285 severely injured patients admitted to a level 1 trauma center in Seattle, WA, USA between 2009 and 2013. RESULTS: The final Prediction of Acute Coagulopathy of Trauma (PACT) score incorporated age, injury mechanism, prehospital shock index and Glasgow Coma Score values, and prehospital cardiopulmonary resuscitation and endotracheal intubation. In the validation cohort, the PACT score demonstrated better discrimination (area under the receiver operating characteristic curve 0.80 vs. 0.70, p = 0.032) and likely improved calibration compared to a previously published prehospital ATC prediction score. Designating PACT scores ≥196 as positive resulted in sensitivity and specificity for ATC of 73% and 74%, respectively. CONCLUSIONS: Our prediction model uses routinely available and objective prehospital data to identify patients at increased risk of ATC. The PACT score could facilitate subject selection for studies of targeted treatment of ATC.

Volume Overload: Prevalence, Risk Factors, and Functional Outcome in Survivors of Septic Shock.

RATIONALE: Survivors of septic shock have impaired functional status. Volume overload is associated with poor outcomes in patients with septic shock, but the impact of volume overload on functional outcome and discharge destination of survivors is unknown. OBJECTIVES: This study describes patterns of fluid management both during and after septic shock. We examined factors associated with volume overload upon intensive care unit (ICU) discharge. We then examined associations between volume overload upon ICU discharge, mobility limitation, and discharge to a healthcare facility in septic shock survivors, with the hypothesis that volume overload is associated with increased odds of these outcomes. METHODS: We retrospectively reviewed the medical records of 247 patients admitted with septic shock to an academic county hospital between June 2009 and April 2012 who survived to ICU discharge. We defined volume overload as a fluid balance expected to increase the subject's admission weight by 10%. Statistical methods included unadjusted analyses and multivariable logistic regression. MEASUREMENTS AND MAIN RESULTS: Eighty-six percent of patients had a positive fluid balance, and 35% had volume overload upon ICU discharge. Factors associated with volume overload in unadjusted analyses included more severe illness, cirrhosis, blood transfusion during shock, and higher volumes of fluid administration both during and after shock. Blood transfusion during shock was independently associated with increased odds of volume overload (odds ratio [OR], 2.65; 95% confidence interval [CI], 1.33-5.27; P = 0.01) after adjusting for preexisting conditions and severity of illness. Only 42% of patients received at least one dose of a diuretic during their hospitalization. Volume overload upon ICU discharge was independently associated with inability to ambulate upon hospital discharge (OR, 2.29; 95% CI, 1.24-4.25; P = 0.01) and, in patients admitted from home, upon discharge to a healthcare facility (OR, 2.34; 95% CI, 1.1-4.98; P = 0.03). CONCLUSIONS: Volume overload is independently associated with impaired mobility and discharge to a healthcare facility in survivors of septic shock. Prevention and treatment of volume overload in patients with septic shock warrants further investigation.

Development and Validation of a Mortality Prediction Model for Patients Receiving 14 Days of Mechanical Ventilation.

OBJECTIVES: The existing risk prediction model for patients requiring prolonged mechanical ventilation is not applicable until after 21 days of mechanical ventilation. We sought to develop and validate a mortality prediction model for patients earlier in the ICU course using data from day 14 of mechanical ventilation. DESIGN: Multicenter retrospective cohort study. SETTING: Forty medical centers across the United States. PATIENTS: Adult patients receiving at least 14 days of mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Predictor variables were measured on day 14 of mechanical ventilation in the development cohort and included in a logistic regression model with 1-year mortality as the outcome. Variables were sequentially eliminated to develop the ProVent 14 model. This model was then generated in the validation cohort. A simplified prognostic scoring rule (ProVent 14 Score) using categorical variables was created in the development cohort and then tested in the validation cohort. Model discrimination was assessed by the area under the receiver operator characteristic curve. Four hundred ninety-one patients and 245 patients were included in the development and validation cohorts, respectively. The most parsimonious model included age, platelet count, requirement for vasopressors, requirement for hemodialysis, and nontrauma admission. The area under the receiver operator characteristic curve for the ProVent 14 model using continuous variables was 0.80 (95% CI, 0.76-0.83) in the development cohort and 0.78 (95% CI, 0.72-0.83) in the validation cohort. The ProVent 14 Score categorized age at 50 and 65 years old and platelet count at 100×10(9)/L and had similar discrimination as the ProVent 14 model in both cohorts. CONCLUSION: Using clinical variables available on day 14 of mechanical ventilation, the ProVent 14 model can identify patients receiving prolonged mechanical ventilation with a high risk of mortality within 1 year.

The Epidemiology of Transfusion-related Acute Lung Injury Varies According to the Applied Definition of Lung Injury Onset Time.

RATIONALE: Research that applies an unreliable definition for transfusion-related acute lung injury (TRALI) may draw false conclusions about its risk factors and biology. The effectiveness of preventive strategies may decrease as a consequence. However, the reliability of the consensus TRALI definition is unknown. OBJECTIVES: To prospectively study the effect of applying two plausible definitions of acute respiratory distress syndrome onset time on TRALI epidemiology. METHODS: We studied 316 adults admitted to the intensive care unit and transfused red blood cells within 24 hours of blunt trauma. We identified patients with acute respiratory distress syndrome, and defined acute respiratory distress syndrome onset time two ways: (1) the time at which the first radiographic or oxygenation criterion was met, and (2) the time both criteria were met. We categorized two corresponding groups of TRALI cases transfused in the 6 hours before acute respiratory distress syndrome onset. We used Cohen's kappa to measure agreement between the TRALI cases and implicated blood components identified by the two acute respiratory distress syndrome onset time definitions. In a nested case-control study, we examined potential risk factors for each group of TRALI cases, including demographics, injury severity, and characteristics of blood components transfused in the 6 hours before acute respiratory distress syndrome onset. MEASUREMENTS AND MAIN RESULTS: Forty-two of 113 patients with acute respiratory distress syndrome were TRALI cases per the first acute respiratory distress syndrome onset time definition and 63 per the second definition. There was slight agreement between the two groups of TRALI cases (κ = 0.16; 95% confidence interval, -0.01 to 0.33) and between the implicated blood components (κ = 0.15, 95% confidence interval, 0.11-0.20). Age, Injury Severity Score, high plasma-volume components, and transfused plasma volume were risk factors for TRALI when applying the second acute respiratory distress syndrome onset time definition but not when applying the first definition. CONCLUSIONS: The epidemiology of TRALI varies when applying two plausible definitions of acute respiratory distress syndrome onset time to severely injured trauma patients. A TRALI definition that standardizes acute respiratory distress syndrome onset time might improve reliability and align efforts to understand epidemiology, biology, and prevention.