Vitamin D Status and Clinical Outcomes in Acute Respiratory Distress Syndrome: A Secondary Analysis From the Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury (ALVEOLI) Trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a highly morbid condition that has limited therapeutic options. Optimal vitamin D status has been linked to immunological effects that may benefit critically ill patients. Therefore, we investigated whether admission 25-hydroxyvitamin D levels (25OHD) are associated with clinical outcomes in ARDS patients. METHODS: We performed a secondary analysis of data from a randomized, controlled trial comparing oxygenation strategies in 549 patients with ARDS (NCT00000579). Baseline 25OHD was measured in stored plasma samples. We investigated the relationship between vitamin D status and ventilator-free days (VFD) as well as 90-day survival, using linear regression and Cox proportional hazard models, respectively. Analyses were adjusted for age, race, and Acute Physiology and Chronic Health Evaluation III score. RESULTS: Baseline 25OHD was measured in 476 patients. 90% of these individuals had 25OHD <20 ng/ml and 40% had 25OHD <10 ng/ml. Patients with 25OHD <20 ng/ml were likely to be ventilated for 3 days longer than patients with levels ≥20 ng/ml (ß 3.41; 95%CI 0.42-6.39: P = 0.02). Patients with 25OHD <10 ng/ml were likely to be ventilated for 9 days longer (ß 9.27; 95%CI 7.24-11.02: P < 0.001) and to have a 34% higher risk of 90-day mortality (HR 1.34; 95% CI 1.06-1.71: P = 0.02) compared to patients with levels >10 ng/ml. CONCLUSIONS: In patients with ARDS, vitamin D status is associated with duration of mechanical ventilation and 90-day mortality. Randomized, controlled trials are warranted to determine whether vitamin D supplementation improves clinical outcomes in ARDS patients.

Plasma Soluble Suppression of Tumorigenicity-2 Associates with Ventilator Liberation in Acute Hypoxemic Respiratory Failure.

Rationale: Standard physiologic assessments of extubation readiness in patients with acute hypoxemic respiratory failure (AHRF) may not reflect lung injury resolution and could adversely affect clinical decision-making and patient outcomes. Objectives: We hypothesized that elevations in inflammatory plasma biomarkers sST2 (soluble suppression of tumorigenicity-2) and IL-6 indicate ongoing lung injury in AHRF and better inform patient outcomes compared with standard clinical assessments. Methods: We measured daily plasma biomarkers and physiologic variables in 200 patients with AHRF for up to 9 days after intubation. We tested the associations of baseline values with the primary outcome of unassisted breathing at Day 29. We analyzed the ability of serial biomarker measurements to inform successful ventilator liberation. Measurements and Main Results: Baseline sST2 concentrations were higher in patients dead or mechanically ventilated versus breathing unassisted at Day 29 (491.7 ng/ml [interquartile range (IQR), 294.5-670.1 ng/ml] vs. 314.4 ng/ml [IQR, 127.5-550.1 ng/ml]; P = 0.0003). Higher sST2 concentrations over time were associated with a decreased probability of ventilator liberation (hazard ratio, 0.80 per log-unit increase; 95% confidence interval [CI], 0.75-0.83; P = 0.03). Patients with higher sST2 concentrations on the day of liberation were more likely to fail liberation compared with patients who remained successfully liberated (320.9 ng/ml [IQR, 181.1- 495.6 ng/ml] vs. 161.6 ng/ml [IQR, 95.8-292.5 ng/ml]; P = 0.002). Elevated sST2 concentrations on the day of liberation decreased the odds of successful liberation when adjusted for standard physiologic parameters (odds ratio, 0.325; 95% CI, 0.119-0.885; P = 0.03). IL-6 concentrations did not associate with outcomes. Conclusions: Using sST2 concentrations to guide ventilator management may more accurately reflect underlying lung injury and outperform traditional measures of readiness for ventilator liberation.

Medication use by US patients with pulmonary hypertension associated with chronic obstructive pulmonary disease: a retrospective study of administrative data.

BACKGROUND: Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). While clinical guidelines recommend specific drug therapies for pulmonary arterial hypertension (PAH), these drug therapies are not recommended for PH due to lung disease. METHODS: This was a retrospective cohort study using the Optum® Clinformatics® Data Mart from January 2009-September 2019. An algorithm was designed to identify adults with ≥ 2 ICD-9-CM or ICD-10-CM diagnosis codes for PH and with ≥ 2 diagnosis codes for COPD. Sensitivity analyses were conducted among subgroups of patients with evidence of a right heart catheterization (RHC) or pulmonary function test (PFT). Patient characteristics, medications used, and durations of use of PAH and COPD medications were analyzed. RESULTS: A total of 25,975 patients met the study inclusion criteria. Their mean age was 73.5 (SD 10.0) years and 63.8% were female. Medications targeting PAH were prescribed to 643 (2.5%) patients, most frequently a phosphodiesterase-5 inhibitor (2.1%) or an endothelin receptor antagonist (0.75%). Medications for COPD were prescribed to 17,765 (68.4%) patients, most frequently an inhaled corticosteroid (57.4%) or short-acting beta agonist (50.4%). The median durations of use ranged from 4.9 to 12.8 months for PAH medications, and from 0.4 to 5.9 months for COPD medications. Of the subgroup of patients with RHC (N = 2325), 257 (11.1%) were prescribed a PAH medication and 1670 (71.8%) used a COPD medication. Of the subgroup with a PFT (N = 2995), 58 (1.9%) were prescribed a PAH medication and 2100 (70.1%) a COPD medication. CONCLUSIONS: Patients with PH associated with COPD were identified in a US administrative claims database. Very few of these patients received any of the medications recommended for PAH, and only about two thirds received medications for COPD.

Use of Phenobarbital in Alcohol Withdrawal Management - A Retrospective Comparison Study of Phenobarbital and Benzodiazepines for Acute Alcohol Withdrawal Management in General Medical Patients.

BACKGROUND: Benzodiazepine-based protocols offer a standard of care for management of alcohol withdrawal, though they may not be safe or appropriate for all patients. Phenobarbital, a long-acting barbiturate, presents an alternative to conventional benzodiazepine treatment, though existing research offers only modest guidance to the safety and effectiveness of phenobarbital in managing alcohol withdrawal syndrome (AWS) in general hospital settings. METHODS: To compare clinical effectiveness of phenobarbital versus benzodiazepines in managing symptoms of alcohol withdrawal, we conducted a retrospective chart review of 562 patients admitted over a 2-year period to a general hospital and treated for AWS. The development of AWS-related complications (seizures, alcoholic hallucinosis, and alcohol withdrawal delirium) post-treatment initiation was the primary outcome examined in both treatment groups. Additional outcomes measured included hospital length of stay, intensive care unit (ICU) admission rates/length of stay, medication-related adverse events, and discharge against medical advice. RESULTS: Despite being significantly more likely to have a history of prior complications related to AWS (including seizures and delirium), patients initiated on phenobarbital (n = 143) had overall similar primary and secondary treatment outcomes to those in the benzodiazepine treatment protocol (n = 419). Additionally, a subset of patients (n = 16) initially treated with benzodiazepines displayed signs of treatment nonresponse, including significantly higher rates of AWS-related delirium and ICU admission rates, but were well-managed following transition to the phenobarbital protocol. CONCLUSION: The data from this retrospective chart review lend further support to effectiveness and safety of phenobarbital for the treatment and management of AWS. Further randomized controlled trials are warranted.

Deterioration of Regional Lung Strain and Inflammation during Early Lung Injury.

RATIONALE: The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown. OBJECTIVES: To test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24 hours of ventilation of initially normal lungs exposed to mild systemic endotoxemia in supine versus prone position, and that local neutrophilic inflammation is associated with local strain and blood volume at global strains below a proposed injurious threshold. METHODS: Voxel-level aeration and tidal strain were assessed by computed tomography in sheep ventilated with low Vt and positive end-expiratory pressure while receiving intravenous endotoxin. Regional inflammation and blood volume were estimated from 2-deoxy-2-[(18)F]fluoro-d-glucose (18F-FDG) positron emission tomography. MEASUREMENTS AND MAIN RESULTS: Spatial heterogeneity of aeration and strain increased only in supine lungs (P < 0.001), with higher strains and atelectasis than prone at 24 hours. Absolute strains were lower than those considered globally injurious. Strains redistributed to higher aeration areas as lung injury progressed in supine lungs. At 24 hours, tissue-normalized 18F-FDG uptake increased more in atelectatic and moderately high-aeration regions (>70%) than in normally aerated regions (P < 0.01), with differential mechanistically relevant regional gene expression. 18F-FDG phosphorylation rate was associated with strain and blood volume. Imaging findings were confirmed in ventilated patients with sepsis. CONCLUSIONS: Mechanical ventilation consistent with clinical practice did not generate excessive regional strain in heterogeneously aerated supine lungs. However, it allowed worsening of spatial strain distribution in these lungs, associated with increased inflammation. Our results support the implementation of early aeration homogenization in normal lungs.

Elevated Red Cell Distribution Width Is Associated With Decreased Ventilator-Free Days in Critically Ill Patients.

INTRODUCTION: Elevated red cell distribution width (RDW) is associated with mortality in a variety of respiratory conditions. Recent data also suggest that RDW is associated with mortality in intensive care unit (ICU) patients. Although respiratory failure is common in the ICU, the relationship between RDW and pulmonary outcomes in the ICU has not been previously explored. Therefore, our goal was to investigate the association of admission RDW with 30-day ventilator-free days (VFDs) in ICU patients. METHODS: We performed a retrospective analysis from an ongoing prospective, observational study. Patients were recruited from medical and surgical ICUs of a large teaching hospital in Boston, Massachusetts. The RDW was assessed within 1 hour of ICU admission. Poisson regression analysis was used to investigate the association of RDW (normal: 11.5%-14.5% vs elevated: >14.5%) with 30-day VFD, while controlling for age, sex, race, body mass index, Nutrition Risk in the Critically Ill score, the presence of chronic lung disease, Pao2/Fio2 ratio, and admission levels of hemoglobin, mean corpuscular volume, phosphate, albumin, C-reactive protein, and creatinine. RESULTS: A total of 637 patients comprised the analytic cohort. Mean RDW was 15 (standard deviation 4%), with 53% of patients in the normal range and 47% with elevated levels. Median VFD was 16 (interquartile range: 6-25) days. Poisson regression analysis demonstrated that ICU patients with elevated admission RDW were likely to have 32% lower 30-day VFDs compared to their counterparts with RDW in the normal range (incidence rate ratio: 0.68; 95% confidence interval: 0.55-0.83: P < .001). CONCLUSIONS: We observed an inverse association of RDW and 30-day VFD, despite controlling for demographics, nutritional factors, and severity of illness. This supports the need for future studies to validate our findings, understand the physiologic processes that lead to elevated RDW in patients with respiratory failure, and determine whether changes in RDW may be used to support clinical decision-making.

A Missense Genetic Variant in LRRC16A/CARMIL1 Improves Acute Respiratory Distress Syndrome Survival by Attenuating Platelet Count Decline.

RATIONALE: Platelets are believed to contribute to acute respiratory distress syndrome (ARDS) pathogenesis through inflammatory coagulation pathways. We recently reported that leucine-rich repeat-containing 16A (LRRC16A) modulates baseline platelet counts to mediate ARDS risk. OBJECTIVES: To examine the role of LRRC16A in ARDS survival and its mediating effect through platelets. METHODS: A total of 414 cases with ARDS from intensive care units (ICUs) were recruited who had exome-wide genotyping data, detailed platelet counts, and follow-up data during ICU hospitalization. Association of LRRC16A single-nucleotide polymorphisms (SNPs) and ARDS prognosis, and the mediating effect of SNPs through platelet counts were analyzed. LRRC16A mRNA expression levels for 39 cases with ARDS were also evaluated. MEASUREMENTS AND MAIN RESULTS: Missense SNP rs9358856G>A within LRRC16A was associated with favorable survival within 28 days (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.38-0.87; P = 0.0084) and 60 days (P = 0.0021) after ICU admission. Patients with ARDS who carried the variant genotype versus the wild-type genotype showed an attenuated platelet count decline (∆PLT) within 28 days (difference of ∆PLT, -27.8; P = 0.025) after ICU admission. Patients with ∆PLT were associated with favorable ARDS outcomes. Mediation analysis indicated that the SNP prognostic effect was mediated through ∆PLT within 28 days (28-day survival: HRIndirect, 0.937; 95% CI, 0.918-0.957; P = 0.0009, 11.53% effects mediated; 60-day survival: HRIndirect, 0.919; 95% CI, 0.901-0.936; P = 0.0001, 14.35% effects mediated). Functional exploration suggested that this SNP reduced LRRC16A expression at ICU admission, which was associated with a lesser ∆PLT during ICU hospitalization. CONCLUSIONS: LRRC16A appears to mediate ∆PLT after ICU admission to affect the prognosis in patients with ARDS.

High-flow oxygen therapy and other inhaled therapies in intensive care units.

In this Series paper, we review the current evidence for the use of high-flow oxygen therapy, inhaled gases, and aerosols in the care of critically ill patients. The available evidence supports the use of high-flow nasal cannulae for selected patients with acute hypoxaemic respiratory failure. Heliox might prevent intubation or improve gas flow in mechanically ventilated patients with severe asthma. Additionally, it might improve the delivery of aerosolised bronchodilators in obstructive lung disease in general. Inhaled nitric oxide might improve outcomes in a subset of patients with postoperative pulmonary hypertension who had cardiac surgery; however, it has not been shown to provide long-term benefit in patients with acute respiratory distress syndrome (ARDS). Inhaled prostacyclins, similar to inhaled nitric oxide, are not recommended for routine use in patients with ARDS, but can be used to improve oxygenation in patients who are not adequately stabilised with traditional therapies. Aerosolised bronchodilators are useful in mechanically ventilated patients with asthma and chronic obstructive pulmonary disease, but are not recommended for those with ARDS. Use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis shows promise, but the delivered dose can be highly variable if proper attention is not paid to the delivery method.

Patient-Specific Classification of ICU Sedation Levels From Heart Rate Variability.

OBJECTIVE: To develop a personalizable algorithm to discriminate between sedation levels in ICU patients based on heart rate variability. DESIGN: Multicenter, pilot study. SETTING: Several ICUs at Massachusetts General Hospital, Boston, MA. PATIENTS: We gathered 21,912 hours of routine electrocardiogram recordings from a heterogenous group of 70 adult ICU patients. All patients included in the study were mechanically ventilated and were receiving sedatives. MEASUREMENTS AND MAIN RESULTS: As "ground truth" for developing our method, we used Richmond Agitation Sedation Scale scores grouped into four levels denoted "comatose" (-5), "deeply sedated" (-4 to -3), "lightly sedated" (-2 to 0), and "agitated" (+1 to +4). We trained a support vector machine learning algorithm to calculate the probability of each sedation level from heart rate variability measures derived from the electrocardiogram. To estimate algorithm performance, we calculated leave-one-subject out cross-validated accuracy. The patient-independent version of the proposed system discriminated between the four sedation levels with an overall accuracy of 59%. Upon personalizing the system supplementing the training data with patient-specific calibration data, consisting of an individual's labeled heart rate variability epochs from the preceding 24 hours, accuracy improved to 67%. The personalized system discriminated between light- and deep-sedation states with an average accuracy of 75%. CONCLUSIONS: With further refinement, the methodology reported herein could lead to a fully automated system for depth of sedation monitoring. By enabling monitoring to be continuous, such technology may help clinical staff to monitor sedation levels more effectively and to reduce complications related to over- and under sedation.

Cost and Utility of Microbiological Cultures Early After Intensive Care Unit Admission for Intracerebral Hemorrhage.

BACKGROUND: Fever is common among intensive care unit (ICU) patients. Clinicians may use microbiological cultures to differentiate infectious and aseptic fever. However, their utility depends on the prevalence of infection; and false-positive results might adversely affect patient care. We sought to quantify the cost and utility of microbiological cultures in a cohort of ICU patients with spontaneous intracerebral hemorrhage (ICH). METHODS: We performed a secondary analysis of a cohort with spontaneous ICH requiring mechanical ventilation. We collected baseline data, measures of systemic inflammation, microbiological culture results for the first 48 h, and daily antibiotic usage. Two physicians adjudicated true-positive and false-positive culture results using standard criteria. We calculated the cost per true-positive result and used logistic regression to test the association between false-positive results with subsequent antibiotic exposure. RESULTS: Overall, 697 subjects were included. A total of 233 subjects had 432 blood cultures obtained, with one true-positive (diagnostic yield 0.1 %, $22,200 per true-positive) and 11 false-positives. True-positive urine cultures (5 %) and sputum cultures (13 %) were more common but so were false-positives (6 and 17 %, respectively). In adjusted analysis, false-positive blood and sputum results were associated with increased antibiotic exposure. CONCLUSIONS: The yield of blood cultures early after spontaneous ICH was very low. False-positive results significantly increased the odds of antibiotic exposure. Our results support limiting the use of blood cultures in the first two days after ICU admission for spontaneous ICH.

Plasma Concentrations of Soluble Suppression of Tumorigenicity-2 and Interleukin-6 Are Predictive of Successful Liberation From Mechanical Ventilation in Patients With the Acute Respiratory Distress Syndrome.

OBJECTIVES: Soluble suppression of tumorigenicity-2 and interleukin-6 concentrations have been associated with the inflammatory cascade of acute respiratory distress syndrome. We determined whether soluble suppression of tumorigenicity-2 and interleukin-6 levels can be used as prognostic biomarkers to guide weaning from mechanical ventilation and predict the need for reintubation. DESIGN, SETTING, AND PATIENTS: We assayed plasma soluble suppression of tumorigenicity-2 (n = 826) concentrations and interleukin-6 (n = 755) concentrations in the Fluid and Catheter Treatment Trial, a multicenter randomized controlled trial of conservative fluid management in acute respiratory distress syndrome. We tested whether soluble suppression of tumorigenicity-2 and interleukin-6 levels were associated with duration of mechanical ventilation, the probability of passing a weaning assessment, and the need for reintubation. MEASUREMENTS AND MAIN RESULTS: In models adjusted for Acute Physiology and Chronic Health Evaluation score and other relevant variables, patients with higher day 0 and day 3 median soluble suppression of tumorigenicity-2 and interleukin-6 concentrations had decreased probability of extubation over time (day 0 soluble suppression of tumorigenicity-2: hazard ratio, 0.85; 95% CI, 0.72-1.00; p = 0.05; day 0 interleukin-6: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; day 3 soluble suppression of tumorigenicity-2: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; and day 3 interleukin-6: hazard ratio, 0.73; 95% CI, 0.62-0.85; p = 0.0001). Higher biomarker concentrations were also predictive of decreased odds of passing day 3 weaning assessments (soluble suppression of tumorigenicity-2: odds ratio, 0.62: 95% CI, 0.44-0.87; p = 0.006 and interleukin-6: odds ratio, 0.61; 95% CI, 0.43-0.85; p = 0.004) and decreased odds of passing a spontaneous breathing trial (soluble suppression of tumorigenicity-2: odds ratio, 0.45; 95% CI, 0.28-0.71; p = 0.0007 and interleukin-6 univariate analysis only: odds ratio, 0.55; 95% CI, 0.36-0.83; p = 0.005). Finally, higher biomarker levels were significant predictors of the need for reintubation for soluble suppression of tumorigenicity-2 (odds ratio, 3.23; 95% CI, 1.04-10.07; p = 0.04) and for interleukin-6 (odds ratio, 2.58; 95% CI, 1.14-5.84; p = 0.02). CONCLUSIONS: Higher soluble suppression of tumorigenicity-2 and interleukin-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with acute respiratory distress syndrome. Biomarker-directed ventilator management may lead to improved outcomes in weaning of mechanical ventilation in patients with acute respiratory distress syndrome.

Predictors of Circulating Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-Binding Protein-3 in Critical Illness.

OBJECTIVE: To characterize predictors of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 in acute critical illness with the hypothesis that acute factors associated with critical illness will more strongly predict circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 than chronic clinical or genetic factors. DESIGN: Observational study nested within a large prospective study using multivariable linear regression to model circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 with acute and chronic clinical variables, and genotype from five polymorphisms in insulin-like growth factor pathway genes. SETTING: ICUs from two large academic medical centers. PATIENTS: Five hundred forty-three Caucasian patients with risk factors for acute respiratory distress syndrome and available plasma from early in critical illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 were measured in plasma using IMMULITE assays (Siemens, Malvern, PA). We examined age, gender, body mass index, cirrhosis, and diabetes, as well as Acute Physiology, Age, and Chronic Health Evaluation III score, acute hepatic dysfunction, pneumonia and aspiration, sepsis/septic shock, acute respiratory distress syndrome, and receipt of corticosteroids. Body mass index, cirrhosis, and acute respiratory distress syndrome were strongly associated with insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 levels; Acute Physiology, Age, and Chronic Health Evaluation III was strongly associated with insulin-like growth factor-1 levels; and age was strongly associated with insulin-like growth factor-binding protein-3. Five polymorphisms (IGF1: rs1520220, rs35767, rs2946834; IGFBP1: rs4619; IGFBP3: rs2854746) were analyzed for associations with plasma levels. When genotypes were added to models, rs2854746 was significantly associated with plasma insulin-like growth factor-binding protein-3. Genotype explained an additional 2% of variability with an overall adjusted R-square of 0.18. CONCLUSIONS: Despite the acute derangements of critical illness, both acute and chronic health factors significantly influence circulating levels of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 early in critical illness. rs2854746 is also significantly associated with insulin-like growth factor-binding protein-3 levels in this ICU cohort. Overall, phenotypic and genotypic factors explained only a modest amount of variability in insulin-like growth factor-1 and insulin-like growth factor-binding protein-3. Further research is needed to understand how to apply these findings to patient care.

Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial.

OBJECTIVES: To compare changes in vitamin D status and cathelicidin (LL-37) levels in septic ICU patients treated with placebo versus cholecalciferol. DESIGN: Randomized, placebo-controlled, trial. SETTING: Medical and surgical ICUs of a single teaching hospital in Boston, MA. PATIENTS: Thirty adult ICU patients. INTERVENTIONS: Placebo (n = 10) versus 200,000 IU cholecalciferol (n = 10) versus 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained at baseline (day 1) and on days 3, 5, and 7, to assess total 25-hydroxyvitamin D, as well as vitamin D-binding protein and albumin to calculate bioavailable 25-hydroxyvitamin D. Plasma LL-37 and high-sensitivity C-reactive protein levels were also measured. At baseline, median (interquartile range) plasma 25-hydroxyvitamin D was 17 ng/mL (13-22 ng/mL) and peaked by day 5 in both intervention groups. Groups were compared using Kruskal-Wallis tests. Relative to baseline, on day 5, median change in biomarkers for placebo, 200,000 IU cholecalciferol, and 400,000 IU cholecalciferol groups, respectively, were as follows: 1) total 25-hydroxyvitamin D, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25-hydroxyvitamin D, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37: -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity C-reactive protein levels did not differ between groups. A positive correlation was observed between bioavailable 25-hydroxyvitamin D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25-hydroxyvitamin D and LL-37. CONCLUSIONS: High-dose cholecalciferol supplementation rapidly and safely improves 25-hydroxyvitamin D and bioavailable 25-hydroxyvitamin D levels in patients with severe sepsis or septic shock. Changes in bioavailable 25-hydroxyvitamin D are associated with concomitant increases in circulating LL-37 levels. Larger trials are needed to verify these findings and to assess whether optimizing vitamin D status improves sepsis-related clinical outcomes.

Perspectives of continuous renal replacement therapy in the intensive care unit: a paired survey study of patient, physician, and nurse views.

BACKGROUND: Recent studies suggest discrepancies between patients and providers around perceptions of hemodialysis prognosis. Such data are lacking for continuous renal replacement therapy (CRRT). We aim to assess patient and provider understanding of outcomes around CRRT. METHODS: From February 1 to August 31, 2013, a triad of (1) a patient on CRRT (or health care proxy [HCP]), (2) physician and (3) primary nurse from the intensive care unit (ICU) team were surveyed. Univariate chi-square and qualitative analysis techniques were used. RESULTS: Ninety-six total participants (32 survey triads) were completed. Ninety one percent of patients/HCPs correctly identified that CRRT replaced the function of the kidneys. Six percent of patients/HCPs, 44 % of physicians, and 44 % of nurses identified rates of survival to hospital discharge that were consistent with published literature. Both physicians and nurses were more likely than patients/HCPs to assess survival consistently with published data (p = 0.001). Patients/HCPs were more likely to overestimate survival rates than physicians and nurses (p < 0.001). Thirty eight percent of patients/HCPs, 38 % of physicians, and 28 % of nurses identified rates of lifelong dialysis-dependence among surviving patients that were consistent with published literature. CONCLUSIONS: There is mismatch between patients, HCPs, and providers around prognosis of CRRT. Patients/HCPs are more likely to overestimate chances of survival than physicians or nurses. Further intervention is needed to improve this knowledge gap.

Predicting risk of postoperative lung injury in high-risk surgical patients: a multicenter cohort study.

BACKGROUND: Acute respiratory distress syndrome (ARDS) remains a serious postoperative complication. Although ARDS prevention is a priority, the inability to identify patients at risk for ARDS remains a barrier to progress. The authors tested and refined the previously reported surgical lung injury prediction (SLIP) model in a multicenter cohort of at-risk surgical patients. METHODS: This is a secondary analysis of a multicenter, prospective cohort investigation evaluating high-risk patients undergoing surgery. Preoperative ARDS risk factors and risk modifiers were evaluated for inclusion in a parsimonious risk-prediction model. Multiple imputation and domain analysis were used to facilitate development of a refined model, designated SLIP-2. Area under the receiver operating characteristic curve and the Hosmer-Lemeshow goodness-of-fit test were used to assess model performance. RESULTS: Among 1,562 at-risk patients, ARDS developed in 117 (7.5%). Nine independent predictors of ARDS were identified: sepsis, high-risk aortic vascular surgery, high-risk cardiac surgery, emergency surgery, cirrhosis, admission location other than home, increased respiratory rate (20 to 29 and ≥30 breaths/min), FIO2 greater than 35%, and SpO2 less than 95%. The original SLIP score performed poorly in this heterogeneous cohort with baseline risk factors for ARDS (area under the receiver operating characteristic curve [95% CI], 0.56 [0.50 to 0.62]). In contrast, SLIP-2 score performed well (area under the receiver operating characteristic curve [95% CI], 0.84 [0.81 to 0.88]). Internal validation indicated similar discrimination, with an area under the receiver operating characteristic curve of 0.84. CONCLUSIONS: In this multicenter cohort of patients at risk for ARDS, the SLIP-2 score outperformed the original SLIP score. If validated in an independent sample, this tool may help identify surgical patients at high risk for ARDS.

Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease.

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Methods: Eligible participants were 40-80 years old with COPD (FEV1/FVC <0.7; FEV1 >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Results: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%. Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

Role of diabetes in the development of acute respiratory distress syndrome.

OBJECTIVES: Diabetes has been associated with decreased development of acute respiratory distress syndrome in some, but not all, previous studies. Therefore, we examined the relationship between diabetes and development of acute respiratory distress syndrome and whether this association was modified by type of diabetes, etiology of acute respiratory distress syndrome, diabetes medications, or other potential confounders. DESIGN: Observational prospective multicenter study. SETTING: Four adult ICUs at two tertiary academic medical centers. PATIENTS: Three thousand eight hundred sixty critically ill patients at risk for acute respiratory distress syndrome from sepsis, pneumonia, trauma, aspiration, or massive transfusion. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Diabetes history was present in 25.8% of patients. Diabetes was associated with lower rates of developing acute respiratory distress syndrome on univariate (odds ratio, 0.79; 95% CI, 0.66-0.94) and multivariate analysis (adjusted odds ratio, 0.76; 95% CI, 0.61-0.95). After including diabetes medications into the model, diabetes remained protective (adjusted odds ratio, 0.75; 95% CI, 0.59-0.94). Diabetes was associated with decreased development of acute respiratory distress syndrome both in the subgroup of patients with sepsis (adjusted odds ratio, 0.77; 95% CI, 0.61-0.97) and patients with noninfectious etiologies (adjusted odds ratio, 0.30; 95% CI, 0.10-0.90). The protective effect of diabetes on acute respiratory distress syndrome development is not clearly restricted to either type 1 (adjusted odds ratio, 0.50; 95% CI, 0.26-0.99; p = 0.046) or type 2 (adjusted odds ratio, 0.77; 95% CI, 0.60-1.00; p = 0.050) diabetes. Among patients in whom acute respiratory distress syndrome developed, diabetes was not associated with 60-day mortality on univariate (odds ratio, 1.11; 95% CI, 0.80-1.52) or multivariate analysis (adjusted odds ratio, 0.81; 95% CI, 0.56-1.18). CONCLUSIONS: Diabetes is associated with a lower rate of acute respiratory distress syndrome development, and this relationship remained after adjusting for clinical differences between diabetics and nondiabetics, such as obesity, acute hyperglycemia, and diabetes-associated medications. In addition, this association was present for type 1 and 2 diabetics and in all subgroups of at-risk patients.

Prognostic and diagnostic value of plasma soluble suppression of tumorigenicity-2 concentrations in acute respiratory distress syndrome.

OBJECTIVES: Soluble suppression of tumorigenicity-2 is a biomarker of myocardial strain and inflammation. The characteristics of acute respiratory distress syndrome include inflammation and cardiovascular dysfunction. We sought to determine whether plasma soluble suppression of tumorigenicity-2 concentration is associated with outcome and response to conservative fluid management and whether soluble suppression of tumorigenicity-2 concentration discriminates acute respiratory distress syndrome from decompensated heart failure. DESIGN: A retrospective analysis of the Fluid and Catheter Treatment Trial, a multi-center randomized controlled trial of conservative fluid management in the acute respiratory distress syndrome, as well as of a cohort of patients with decompensated heart failure. SETTING: Twenty acute care hospitals. PATIENTS: Eight hundred twenty-six patients with acute respiratory distress syndrome and 209 patients with acutely decompensated heart failure. MEASUREMENTS AND MAIN RESULTS: Nonsurvivors had higher day 0 (p < 0.0001) and day 3 (p < 0.0001) soluble suppression of tumorigenicity-2 concentrations. After adjustment for severity of illness, higher soluble suppression of tumorigenicity-2 concentration was associated with mortality, with odds ratioadj 1.47 (95% CI, 0.99-2.20; p = 0.06) at day 0, 2.94 (95% CI, 2.00-4.33; p < 0.0001) at day 3, and 3.63 (95% CI, 2.38-5.53; p < 0.0001) if soluble suppression of tumorigenicity-2 increased between days. Cumulative fluid balance was more positive among patients with higher day 0 (median, 5,212 mL [interquartile range, 200-12,284 mL] vs median, 2,020 mL [interquartile range, -2,034 to 7,091 mL]; p < 0.0001) and day 3 soluble suppression of tumorigenicity-2 (median, 7,678 mL [interquartile range, 2,217-14,278 mL] vs median, 1,492 mL [interquartile range, -2,384 to 6,239 mL]; p < 0.0001). Soluble suppression of tumorigenicity-2 showed excellent discriminative ability between the Fluid and Catheter Treatment Trial and heart failure populations (area under receiver-operating characteristic curve = 0.98; p < 0.0001). CONCLUSIONS: Higher soluble suppression of tumorigenicity-2 concentrations are associated with worse outcome in acute respiratory distress syndrome and may have value for discriminating acute respiratory distress syndrome from heart failure.