Search

Background: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT)., Methods: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients., Results: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission., Conclusions: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission., (Copyright © 2021 by the American Society of Nephrology.)

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness., Objective: To test whether tocilizumab decreases mortality in this population., Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding., Exposures: Treatment with tocilizumab in the first 2 days of ICU admission., Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences., Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%)., Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.

Introduction: This study evaluates the utility of heart rate variability (HRV) for assessment of severity of illness and poor outcome in Emergency Department (ED) patients with sepsis. HRV measures evaluated included low frequency (LF) signal, high frequency (HF) signal, and deviations in LF and HF signal from age-adjusted reference values., Methods: This was a prospective, observational study. Seventy-two adult ED patients were assessed within 6 h of arrival., Results: Severity of illness as defined by sepsis subtype correlated with decreased LF signal (sepsis: 70.68 ± 22.95, severe sepsis: 54.00 ± 28.41, septic shock: 45.54 ± 23.31, p = 0.02), increased HF signal (sepsis: 27.87 ± 19.42, severe sepsis: 44.63 ± 27.29, septic shock: 47.66 ± 20.98, p = 0.01), increasingly negative deviations in LF signal (sepsis: 0.41 ± 24.53, severe sepsis: -21.43 ± 30.09, septic shock -30.39 ± 26.09, p = 0.005) and increasingly positive deviations in HF signal (sepsis: -1.86 ± 21.09, severe sepsis: 20.07 ± 29.03, septic shock: 23.6 ± 24.17, p = 0.004). Composite poor outcome correlated with decreased LF signal (p = 0.008), increased HF signal (p = 0.03), large negative deviations in LF signal (p = 0.004) and large positive deviations in HF signal (p = 0.02). Deviations in LF and HF signal from age-adjusted reference values correlated with individual measures of poor outcome with greater consistency than LF or HF signal., Discussion: Accounting for the influence of age on baseline HRV signal improves the predictive value of HRV measures in ED patients with sepsis., Competing Interests: Declaration of competing interest JEA reports no conflict of interest. JKL reports no conflict of interest. WJHF reports no conflict of interest. SC reports no conflict of interest. EF reports no conflict of interest. EJS reports no conflict of interest. RS reports no conflict of interest. PMH reports the following: 1.) Co-founder RVMetrics, LLC; 2) Sponsored research for Caretaker Medical., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19., Objectives: To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19., Design, Setting, and Participants: This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020., Exposures: Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds., Main Outcomes and Measures: The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes., Results: A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao2:Fio2<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2-4 vs 0: OR, 2.61; 95% CI, 1.30-5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46-4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies., Conclusions and Relevance: This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO 2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Severe acute respiratory coronavirus 2 (SARS-CoV-2) has caused a devastating worldwide pandemic. Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2, but clinical data supporting HCQ for coronavirus disease 2019 (COVID-19) are limited., Methods: This was a retrospective cohort study of hospitalized patients with COVID-19 who received ≥1 dose of HCQ at two New York City hospitals. We measured incident Grade 3 or 4 blood count and liver test abnormalities, ventricular arrhythmias, and vomiting and diarrhea within 10 days after HCQ initiation, and the proportion of patients who completed HCQ therapy. We also describe changes in Sequential Organ Failure Assessment hypoxia scores between baseline and day 10 after HCQ initiation and in-hospital mortality., Results: None of the 153 hospitalized patients with COVID-19 who received HCQ developed a sustained ventricular tachyarrhythmia. Incident blood count and liver test abnormalities occurred in <15% of patients and incident vomiting or diarrhea was rare. Eighty-nine percent of patients completed their HCQ course and three patients discontinued therapy because of QT prolongation. Fifty-two percent of patients had improved hypoxia scores 10 days after starting HCQ. Thirty-one percent of patients who were receiving mechanical ventilation at the time of HCQ initiation died during their hospitalization, compared to 18% of patients who were receiving supplemental oxygen but not requiring mechanical ventilation, and 8% of patients who were not requiring supplemental oxygen. Co-administration of azithromycin was not associated with improved outcomes., Conclusions: HCQ appears to be reasonably safe and tolerable in most hospitalized patients with COVID-19. However, nearly one-half of patients did not improve with this treatment, highlighting the need to evaluate HCQ and alternate therapies in randomized trials., Competing Interests: The authors have declared that no competing interests exist.

Importance: It is uncertain whether coronavirus disease 2019 (COVID-19) is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection., Objective: To compare the rate of ischemic stroke between patients with COVID-19 and patients with influenza, a respiratory viral illness previously associated with stroke., Design, Setting, and Participants: This retrospective cohort study was conducted at 2 academic hospitals in New York City, New York, and included adult patients with emergency department visits or hospitalizations with COVID-19 from March 4, 2020, through May 2, 2020. The comparison cohort included adults with emergency department visits or hospitalizations with influenza A/B from January 1, 2016, through May 31, 2018 (spanning moderate and severe influenza seasons)., Exposures: COVID-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 in the nasopharynx by polymerase chain reaction and laboratory-confirmed influenza A/B., Main Outcomes and Measures: A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, mechanisms, and outcomes. We used logistic regression to compare the proportion of patients with COVID-19 with ischemic stroke vs the proportion among patients with influenza., Results: Among 1916 patients with emergency department visits or hospitalizations with COVID-19, 31 (1.6%; 95% CI, 1.1%-2.3%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78 years); 18 (58%) were men. Stroke was the reason for hospital presentation in 8 cases (26%). In comparison, 3 of 1486 patients with influenza (0.2%; 95% CI, 0.0%-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was higher with COVID-19 infection than with influenza infection (odds ratio, 7.6; 95% CI, 2.3-25.2). The association persisted across sensitivity analyses adjusting for vascular risk factors, viral symptomatology, and intensive care unit admission., Conclusions and Relevance: In this retrospective cohort study from 2 New York City academic hospitals, approximately 1.6% of adults with COVID-19 who visited the emergency department or were hospitalized experienced ischemic stroke, a higher rate of stroke compared with a cohort of patients with influenza. Additional studies are needed to confirm these findings and to investigate possible thrombotic mechanisms associated with COVID-19.

Background: Acute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it., Methods: A secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS., Results: Of the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); p<0.001] and baseline severity of illness was higher in patients with versus without persistent severe ARDS. Mortality at 60 days [95/232 (41%) versus 233/1299 (18%); p<0.001] was higher, and ventilator-free (p<0.001), intensive care unit-free [0 (0-14) versus 19 (7-23); p<0.001] and non-pulmonary organ failure-free [3 (0-21) versus 20 (1-26); p<0.001] days were fewer in patients with versus without persistent severe ARDS. PaO2:FiO2, FiO2, hepatic failure and positive end-expiratory pressure at enrollment were useful predictive variables., Conclusions: Patients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials., Competing Interests: The corresponding author has read the journal’s policy and the authors of this manuscript have the following competing interests: AMC is a co-founder of Proterris and serving as a consultant for an advisory board meeting of Teva Pharmaceutical Industries, July 2018. None declared (ES, DRP, KPC, CO, EJS, IIS). This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Background: Despite numerous publications on mitochondrial DNA (mtDNA) in the last decade it remains to be seen whether mtDNA can be used clinically. We conducted a systematic review to assess circulating cell-free mtDNA as a biomarker of mortality in critically ill patients., Methods: This systematic review was registered with PROSPERO (CRD42016046670). PubMed, CINAHL, the Cochrane Library, Embase, Scopus, and Web of Science, and reference lists of retrieved articles were searched. Studies measuring circulating cell-free mtDNA and reporting on all-cause mortality in critically ill adult and pediatric patients were included. The primary and secondary outcomes were mortality and morbidity, respectively., Results: Of the 1,566 initially retrieved publications, 40 studies were included, accounting for 3,450 critically ill patients. Substantial differences between studies were noted in how mtDNA was isolated and measured. Sixteen of the 40 included studies (40%) explored the association between mtDNA levels and mortality; of those 16 studies, 11 (68.8%) reported a statistically significant association. The area under the receiver operating characteristic (AUROC) curve for mtDNA and mortality was calculated for 10 studies and ranged from 0.61 to 0.95., Conclusions: There is growing interest in mtDNA as a predictor of mortality in critically ill patients. Most studies are small, lack validation cohorts, and utilize different protocols to measure mtDNA. When reported, AUROC analysis usually suggests a statistically significant association between mtDNA and mortality. Standardization of mtDNA protocols and the completion of a large, prospective, multicenter trial may be warranted to firmly establish the clinical usefulness of mtDNA., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored the relationship between TRAIL and RIPK3., Methods: We performed an observational study of critically ill adults admitted to intensive care units at 3 academic medical centers across 2 continents, using 1 as derivation and the other 2 as validation cohorts. Levels of TRAIL were measured in the plasma of 570 subjects by ELISA., Results: In all cohorts, lower (<28.5 pg/ml) versus higher levels of TRAIL were associated with increased organ dysfunction (P ≤ 0.002) and septic shock (P ≤ 0.004). Lower TRAIL levels were associated with in-hospital mortality in 2 of 3 cohorts (Weill Cornell-Biobank of Critical Illness, P = 0.012; Brigham and Women's Hospital Registry of Critical Illness, P = 0.011; Asan Medical Center, P = 0.369). Lower TRAIL was also associated with increased RIPK3 (P ≤ 0.001)., Conclusion: Lower levels of TRAIL were associated with septic shock and organ dysfunction in 3 independent ICU cohorts. TRAIL was inversely associated with RIPK3 in all cohorts., Funding: NIH (R01-HL055330 and KL2-TR002385).

Background: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it., Methods: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a Pao 2 to Fio 2 ratio (Pao 2 :Fio 2 ) > 300 on the first study day following enrollment., Results: The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. Pao 2 :Fio 2 at screening, change in Pao 2 :Fio 2 from screening to enrollment, use of vasopressor agents, Fio 2 at enrollment, and serum bilirubin levels were useful predictive variables., Conclusions: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: We examined whether patients with acute respiratory distress syndrome (ARDS) lacking risk factors are enrolled in therapeutic trials and assessed their clinical characteristics and outcomes., Methods: We performed a secondary analysis of patient-level data pooled from the ARMA, ALVEOLI, FACTT, ALTA and EDEN ARDSNet randomized controlled trials obtained from the Biologic Specimen and Data Repository Information Coordinating Center of the National Heart, Lung and Blood Institute. We compared baseline characteristics and clinical outcomes (before and after adjustment using Poisson regression model) of ARDS patients with versus without risk factors., Results: Of 3733 patients with ARDS, 81 (2.2%) did not have an identifiable risk factor. Patients without risk factors were younger, had lower baseline severity of illness, were more likely to have the ARDS resolve rapidly (i.e., within 24 h) (p < 0.001) and they had more ventilator-free days (median 21; p = 0.003), more intensive care unit-free days (18; p = 0.010), and more non-pulmonary organ failure-free days (24; p < 0.001) than comparators (17, 14 and 18, respectively). Differences persisted after adjustment for potential confounders., Conclusions: Patients with ARDS without identifiable risk factors are enrolled in therapeutic trials and may have better outcomes, including a higher proportion of rapidly resolving ARDS, than those with risk factors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness., Methods: Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data., Results: In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure., Conclusions: Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure., Funding: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

In patients requiring ventilator support, mechanical ventilation (MV) may induce acute lung injury (ventilator-induced lung injury [VILI]). VILI is associated with substantial morbidity and mortality in mechanically ventilated patients with and without acute respiratory distress syndrome. At the cellular level, VILI induces necrotic cell death. However, the contribution of necroptosis, a programmed form of necrotic cell death regulated by receptor-interacting protein-3 kinase (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), to the development of VILI remains unexplored. Here, we show that plasma levels of RIPK3, but not MLKL, were higher in patients with MV (i.e., those prone to VILI) than in patients without MV (i.e., those less likely to have VILI) in two large intensive care unit cohorts. In mice, RIPK3 deficiency, but not MLKL deficiency, ameliorated VILI. In both humans and mice, VILI was associated with impaired fatty acid oxidation (FAO), but in mice this association was not observed under conditions of RIPK3 deficiency. These findings suggest that FAO-dependent RIPK3 mediates pathogenesis of acute lung injury.

Objectives: Sterile and infectious critical illnesses often result in vasoplegic shock and a robust systemic inflammatory response that are similar in presentation. The innate immune system is at the center of the response to both infectious and traumatic insults. Damage-associated molecular patterns are small molecules that are released from stressed or dying cells. Damage-associated molecular patterns activate pattern recognition receptors and coordinate the leading edge of the innate immune response. This review introduces the concept of damage-associated molecular patterns and how they activate a systemic inflammatory response, specifically in trauma, neurologic injury, and infection. It also explores how, when carried to extremes, damage-associated molecular patterns may even perpetuate multisystem organ failure., Data Sources: Basic and clinical studies were obtained from a PubMed search through August 2017., Study Selection: Articles considered include original articles, review articles, and conference proceedings., Data Extraction: An analysis of scientific, peer-reviewed data was performed. High quality preclinical and clinical studies adjudicated by the authors were included and summarized., Data Synthesis: Pattern recognition receptors respond to damage-associated molecular patterns and then activate inflammatory pathways. Damage-associated molecular patterns have been linked to the recruitment of sentinel leukocytes and the initiation of the inflammatory cascade. Damage-associated molecular patterns have been linked to many conditions in critical care illnesses. Preclinical models have added insight into how they may mediate distant organ dysfunction., Conclusions: Damage-associated molecular pattern activation and release is an important research for intensive care practitioners. It will add to our understanding of the phase and state of the innate immune response to an insult. Early work is encouraging. However, only with improved understanding of damage-associated molecular pattern activation and function, we can perhaps hope to target damage-associated molecular patterns as diagnostic and/or therapeutic modalities in the future.

Objective: Patients with pulmonary hypertension and right heart failure have a high risk of clinical deterioration and death during or soon after endotracheal intubation. The effects of sedation, hypoxia, hypoventilation, and changes in intrathoracic pressure can lead to severe hemodynamic instability. In search for safer approach to endotracheal intubation in this cohort of patients, we evaluate the safety and feasibility of an alternative intubation technique., Data Sources: Retrospective data analysis., Study Selection: Two medical ICUs in large university hospitals in the United States., Data Extraction: We report a case series of nine nonconsecutive patients with compromised right heart function, pulmonary hypertension, and severe acute hypoxemic respiratory failure who underwent endotracheal intubation with a novel technique combining awake bronchoscopic intubation supported with nasally delivered noninvasive positive pressure ventilation or high-flow nasal cannula., Data Synthesis: All patients were intubated in the first attempt without major complications and eight patients (88%) were alive 24 hours after intubation. Systemic hypotension was the most frequent complication following the procedure., Conclusions: Awake bronchoscopic intubation supported with a noninvasive positive pressure delivery systems may be feasible alternative to standard direct laryngoscopy approach. Further studies are needed to better assess its safety and applicability.

Purpose: American Society of Anesthesiologists guidelines recommend the use of bronchoscopic intubation as a rescue technique in critically ill patients. We sought to assess the safety and efficacy of bronchoscopic intubation as an initial approach in critically ill patients., Methods: We performed a retrospective cohort study of patients who underwent endotracheal intubation in the medical intensive care unit of a tertiary urban referral center over 1 academic year. The primary outcome was first-pass success rate., Measurements and Main Results: We identified 219 patients who underwent either bronchoscopic (n=52) or laryngoscopic guided (n=167) intubation as the initial attempt. There was a higher first-pass success rate in the bronchoscopic intubation group than in the laryngoscopic group (96% vs 78%; P=.003). The bronchoscopic intubation group had a higher body mass index (28.4 vs 25.9; P=.027) and higher preintubation fraction of inspired oxygen requirement (0.73±0.27 vs 0.63±0.30; P=.044) than the laryngoscopic group. There were no cases of right mainstem intubation, esophageal intubation, or pneumothorax with bronchoscopic intubation. Rates of postintubation hypotension and hypoxemia were similar in both groups. The association with first-pass success remained with multivariate and propensity matched analysis., Conclusions: Bronchoscopic intubation as an initial strategy in critically ill patients is associated with a higher first-pass success rate than laryngoscopic intubation, and is not associated with an increase in complications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Task Force recently introduced a new clinical score termed quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) for identification of patients at risk of sepsis outside the intensive care unit (ICU). We attempted to compare the discriminatory capacity of the qSOFA versus the Systemic Inflammatory Response Syndrome (SIRS) score for predicting mortality, ICU-free days, and organ dysfunction-free days in patients with suspicion of infection outside the ICU., Methods: The Weill Cornell Medicine Registry and Biobank of Critically Ill Patients is an ongoing cohort of critically ill patients, for whom biological samples and clinical information (including vital signs before and during ICU hospitalization) are prospectively collected. Using such information, qSOFA and SIRS scores outside the ICU (specifically, within 8 hours before ICU admission) were calculated. This study population was therefore comprised of patients in the emergency department or the hospital wards who had suspected infection, were subsequently admitted to the medical ICU and were included in the Registry and Biobank., Results: One hundred fifty-two patients (67% from the emergency department) were included in this study. Sixty-seven percent had positive cultures and 19% died in the hospital. Discrimination of in-hospital mortality using qSOFA [area under the receiver operating characteristic curve (AUC), 0.74; 95% confidence intervals (CI), 0.66-0.81] was significantly greater compared with SIRS criteria (AUC, 0.59; 95% CI, 0.51-0.67; p = 0.03). The qSOFA performed better than SIRS regarding discrimination for ICU-free days (p = 0.04), but not for ventilator-free days (p = 0.19), any organ dysfunction-free days (p = 0.13), or renal dysfunction-free days (p = 0.17)., Conclusions: In patients with suspected infection who eventually required admission to the ICU, qSOFA calculated before their ICU admission had greater accuracy than SIRS for predicting mortality and ICU-free days. However, it may be less clear whether qSOFA is also better than SIRS criteria for predicting ventilator free-days and organ dysfunction-free days. These findings may help clinicians gain further insight into the usefulness of qSOFA.

Purpose of Review: Point of care ultrasound continues to become more prevalent in the diagnosis and management of many disease states. In this review, we focus on the use of bedside lung ultrasound (LUS) in the diagnosis of pneumonia. We describe the sonographic findings associated with pneumonia and the recent literature exploring its use in different settings and patient populations., Recent Findings: The limited sensitivity of chest radiography in the diagnosis of pneumonia has been well described. Ultrasound is an attractive option because of its low cost, lack of ionizing radiation, portability, and repeatability. An alveolar or focal interstitial pattern has been described as the usual sonographic findings in pneumonia. Multiple studies have compared LUS with chest radiography in pneumonia, and have shown that LUS is at least equivalent, and in many instances superior, to chest radiography., Summary: Point of care LUS is an invaluable tool in the diagnosis of multiple pulmonary conditions, including pneumonia. Its use in real time with clinical correlation makes it an ideal tool for rapid diagnosis, especially in situations with unstable patients or in low-resource settings.

Objectives: We hypothesise that there is an association between an elevated pulmonary artery/aorta (PA/A) and World Trade Center-Lung Injury (WTC-LI). We assessed if serum vascular disease biomarkers were predictive of an elevated PA/A., Design: Retrospective case-cohort analysis of thoracic CT scans of WTC-exposed firefighters who were symptomatic between 9/12/2001 and 3/10/2008. Quantification of vascular-associated biomarkers from serum collected within 200 days of exposure., Setting: Urban tertiary care centre and occupational healthcare centre., Participants: Male never-smoking firefighters with accurate pre-9/11 forced expiratory volume in 1 s (FEV1)≥75%, serum sampled ≤200 days of exposure was the baseline cohort (n=801). A subcohort (n=97) with available CT scans and serum biomarkers was identified. WTC-LI was defined as FEV1≤77% at the subspecialty pulmonary evaluation (n=34) and compared with controls (n=63) to determine the associated PA/A ratio. The subcohort was restratified based on PA/A≥0.92 (n=38) and PA/A<0.92(n=59) to determine serum vascular biomarkers that were predictive of this vasculopathy., Outcome Measures: The primary outcome of this study was to identify a PA/A ratio in a cohort of individuals exposed to WTC dust that was associated with WTC-LI. The secondary outcome was to identify serum biomarkers predictive of the PA/A ratio using logistic regression., Results: PA/A≥0.92 was associated with WTC-LI, OR of 4.02 (95% CI 1.21 to 13.41; p=0.023) when adjusted for exposure, body mass index and age at CT. Elevated macrophage derived chemokine and soluble endothelial selectin were predictive of PA/A≥0.92, (OR, 95% CI 2.08, 1.05 to 4.11, p=0.036; 1.33, 1.06 to 1.68, p=0.016, respectively), while the increased total plasminogen activator inhibitor 1 was predictive of not having PA/A≥0.92 (OR 0.88, 0.79 to 0.98; p=0.024)., Conclusions: Elevated PA/A was associated with WTC-LI. Development of an elevated PA/A was predicted by biomarkers of vascular disease found in serum drawn within 6 months of WTC exposure. Increased PA/A is a potentially useful non-invasive biomarker of WTC-LI and warrants further study., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Rationale: Metabolic syndrome, inflammatory and vascular injury markers measured in serum after World Trade Center (WTC) exposures predict abnormal FEV1. We hypothesized that elevated LPA levels predict FEV₁ < LLN., Methods: Nested case-control study of WTC-exposed firefighters. Cases had FEV₁ < LLN. Controls derived from the baseline cohort. Demographics, pulmonary function, serum lipids, LPA and ApoA1 were measured., Results: LPA and ApoA1 levels were higher in cases than controls and predictive of case status. LPA increased the odds by 13% while ApoA1 increased the odds by 29% of an FEV₁ < LLN in a multivariable model., Conclusions: Elevated LPA and ApoA1 are predictive of a significantly increased risk of developing an FEV₁ < LLN.

Background: Firefighters exposed to World Trade Center (WTC) dust have developed chronic rhinosinusitis (CRS) and abnormal forced expiratory volume in 1 s (FEV1). Overlapping but distinct immune responses may be responsible for the clinical manifestations of upper and lower airway injury. We investigated whether a panel of inflammatory cytokines, either associated or not associated with WTC-LI, can predict future chronic rhinosinusitis disease and its severity., Methods: Serum obtained within six months of 9/11/2001 from 179 WTC exposed firefighters presenting for subspecialty evaluation prior to 3/2008 was assayed for 39 cytokines. The main outcomes were medically managed CRS (N = 62) and more severe CRS cases requiring sinus surgery (N = 14). We tested biomarker-CRS severity association using ordinal logistic regression analysis., Results: Increasing serum IL-6, IL-8, GRO and neutrophil concentration reduced the risk of CRS progression. Conversely, increasing TNF-α increased the risk of progression. In a multivariable model adjusted for exposure intensity, increasing IL-6, TNF-α and neutrophil concentration remained significant predictors of progression. Elevated IL-6 levels and neutrophil counts also reduced the risk of abnormal FEV1 but in contrast to CRS, increased TNF-α did not increase the risk of abnormal FEV1., Conclusions: Our study demonstrates both independent and overlapping biomarker associations with upper and lower respiratory injury, and suggests that the innate immune response may play a protective role against CRS and abnormal lung function in those with WTC exposure., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We describe the development of novel benzimidazoles as small molecule histamine H4 receptor (H4R) antagonists and their profiling in rat early toxicity studies. The discovery and optimisation of a second series of pyrimidine based antagonists is then described culminating in the identification of the clinical development candidate 13 (PF-3893787). The pre-clinical profile of 13 (PF-3893787) is presented including the development of a translatable biomarker. Our pragmatic approach to target selection, safety assessment, and testing for efficacy faced numerous challenges and we share a number of lessons which the team learned and which will assist us and others in future drug discovery projects., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The ability of mutant bovine growth hormones (bGH) to serve as either agonist or antagonist has been demonstrated in transgenic mice. We have prepared two transgenic strains of FVB/N mice, one expressing wild-type bGH and a second with a glutamic acid mutation at serine 84 in helix 2. Comparison of their phenotypes to those of nontransgenic littermates indicates that wild-type bGH induces a previously described phenotype for hyper-somatotrophic mice. In contrast, the replacement of the side chain hydroxyl at serine 84 with acetic acid produced a phenotype that expressed bGH at appreciable concentrations, but failed to elicit the phenotype observed with either an agonist or an antagonist of bGH. These results indicate that serine 84 is crucial for the activity of bGH despite this site being distal to the receptor binding surfaces.

The biological activity of bovine prolactin (PRL) is reduced by in vivo phosphorylation of serine 90 (S90) that is located within a putative N+4 salt bridge (R89 and D93). We substituted hydrophobic, polar, or acidic residues for S90 and/or replaced members of the putative R89/D93 salt bridge to determine if a functional relationship between the putative salt bridge and the phosphorylation could be observed. At position 90 the bulk of the residue was the most important factor in modulating biological activity in either the rat Nb2 cell bioassay or PRL receptor binding. Charge played a smaller role. Replacement of either partner of the salt bridge reduced both biological and binding activities indicating the presence of a salt bridge at this position. The combination of replacing a salt bridge member and substituting glutamic acid at S90 produced greater than additive changes in our experimental endpoints, indicating a functional coupling between the salt bridge and phosphorylation site. We interpret the data to indicate that either in vivo phosphorylation or specific mutations that destabilize the salt bridge impairs biological activity.