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Acute liver failure (ALF) is a rare syndrome resulting from an acute insult to the liver in patients without known underlying chronic liver disease. It is characterized by loss of synthetic function in the form of jaundice and coagulopathy and development of hepatic encephalopathy. Multiorgan failure (MOF) eventually develops, leading to death. Many different etiologies have been identified, with acetaminophen (APAP) overdose and viral hepatitis being the most common causes worldwide. The pathophysiology of ALF can be divided into cause-specific liver injury pathophysiologies and pathophysiology related to occurrence of secondary MOF. In terms of liver injury pathophysiology, APAP toxicity is the most well known. Secondary MOF is often a result of the initial massive proinflammatory response generating a systemic inflammatory response syndrome followed by a compensatory anti-inflammatory response leading to immune cell dysfunction and sepsis. As the liver is a tremendously important metabolic organ involved in energy metabolism, protein synthesis, fat metabolism, and glycemic control, multiple aspects of nutrition also need to be considered as part of the overall pathophysiology of ALF., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Purpose: Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are associated with significant mortality and morbidity. Extracorporeal liver support (ECLS) devices have been used as a bridge to liver transplant; however, the efficacy and safety of ECLS are unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the efficacy and safety of ECLS in liver failure., Methods: We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through March 13, 2019. RCTs comparing ECLS to usual care in ALF or ACLF were included. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence., Results: We identified 25 RCTs (1796 patients). ECLS use was associated with reduction in mortality (RR 0.84; 95% CI 0.74, 0.96, moderate certainty) and improvement in hepatic encephalopathy (HE) (RR 0.71; 95% CI 0.60, 0.84, low certainty) in patients with ALF or ACLF. The effect of ECLS on hypotension (RR 1.46; 95% CI 0.98, 2.2, low certainty), bleeding (RR 1.21; 95% CI 0.88, 1.66, moderate certainty), thrombocytopenia (RR 1.62; 95% CI 1.0, 2.64, very low certainty) and line infection (RR 1.92; 95% CI 0.11, 33.44, low certainty) was uncertain., Conclusions: ECLS may reduce mortality and improve HE in patients with ALF and ACLF. The effect on other outcomes is uncertain. However, the evidence is limited by risk of bias and imprecision, and larger trials are needed to better determine the effect of ECLS on patient-important outcomes.

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS)., Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS., Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018., Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours., Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours., Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours., Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS., Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

Background: There is a lack of consensus regarding the yield and safety of transbronchial cryobiopsies for diagnosing diffuse parenchymal lung diseases (DPLD). The purpose of this study was to perform a systematic review and meta-analysis assessing the diagnostic yield and safety profile of transbronchial cryobiopsies in DPLD., Methods: A literature search of MEDLINE, EMBASE databases, and Google Scholar was performed in August 2017. The quality of included studies was assessed using Quality Assessment, Data Abstraction and Synthesis-2 tool. Meta-analysis was performed using MedCalc (version 17.2). Inverse variance weighting was used to aggregate diagnostic yield proportions across studies, with the number of subjects in each study representing its weight. Random effects model was used when significant heterogeneity was observed (I>40%)., Results: A total of 31 studies were included in the review. Of these, 27 studies with 1443 patients reported data on the performance of cryobiopsies for diagnosing DPLD. The diagnostic yield was 72.9% [95% confidence interval (CI), 67.9%-77.7%]. The pooled mean specimen size obtained by cryobiopsies was 23.4 mm (95% CI, 9.6-37.3 mm). The overall complication rate was 23.1% with bleeding and pneumothoraces being the most commonly reported complications. The incidence of significant bleeding was 14.2% (95% CI, 7.9%-21.9%), whereas pneumothorax was seen in 9.4% (95% CI, 6.7%-12.5%) of patients. Overall reported mortality was 0.3%., Conclusion: Our meta-analysis shows that cryobiopsies have a good diagnostic yield but a significant risk for complications. Cryobiopsy outcomes vary markedly among different centers. Further research is needed to standardize the procedure and improve its safety profile.

We report a higher prevalence of bla KPC in patient room sink drains located next to toilets (87.0%) when compared with sink drains located farther away from toilets (21.7%) using direct polymerase chain reaction assay. However, culture methods were only able to recover bla KPC -positive isolates from 16% of polymerase chain reaction-positive drains., (Copyright © 2018 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Extra-esophageal reflux is suspected to cause a wide range of clinical symptoms in the upper airways. Diagnosis and treatment has focused on acid, but realization of the role of nonacid reflux has resulted in research investigating the use of pepsin as a biomarker for gastric reflux and aspiration. Pepsin analysis can complement the use of questionnaires and office-based diagnosis and lessen the dependency on invasive and expensive diagnostic tests. Furthermore, pepsin as a first-line diagnostic biomarker has been shown to improve the accuracy of reflux diagnosis. In addition to its use as a diagnostic biomarker, pepsin has been shown to cause inflammation independent of the pH of the refluxate and thus despite acid suppression therapy. Research is ongoing to develop new therapies for airway reflux that specifically target pepsin., (© 2018 New York Academy of Sciences.)

Background: Acute kidney injury (AKI) is a common complication of critical illness and is associated with worse outcomes. However, the influence of deterioration or improvement in renal function on clinical outcomes is unclear. Using a large international database, we evaluated the prevalence and evolution of AKI over a 7-day period and its effects on clinical outcomes in septic and non-septic critically ill patients worldwide., Methods: From the 10,069 adult intensive care unit (ICU) patients in the Intensive Care Over Nations database, all those with creatinine and urine output data were included in this substudy. Patients who developed sepsis during the ICU stay (≥ 2 days after admission) were excluded. AKI was evaluated within 72 hours after admission and before discharge/death up to day 7 according to the Acute Kidney Injury Network (AKIN) criteria., Results: A total of 7970 patients were included, 59% of whom met AKIN criteria for AKI within the first 72 hours of the ICU stay. Twenty-four per cent of patients had sepsis on admission, of whom 68% had AKI, compared to 57% of those without sepsis on admission (p < 0.001). AKIN stage 3 (40% vs 24%, p < 0.001) and use of renal replacement therapy (20% vs 5%, p < 0.0001) were more prevalent in patients with sepsis. Patients with sepsis and AKIN stage 3 were less likely to improve to a lower stage during the 7-day follow-up period than non-septic patients with AKIN stage 3 (21% vs 32%, p < 0.0001). In-hospital mortality was related to severity of AKI and was reduced in patients in whom AKI improved compared to those who remained stable or deteriorated, but remained higher than in patients without AKI, even if there was apparent full recovery at day 7., Conclusion: These findings illustrate the different kinetics of AKI in septic and non-septic ICU patients and emphasize the important impact of AKI on mortality rates even when there is apparent full renal recovery at day 7.

Purpose: To evaluate differences in the characteristics and outcomes of intensive care unit (ICU) patients over time., Methods: We reviewed all epidemiological data, including comorbidities, types and severity of organ failure, interventions, lengths of stay and outcome, for patients from the Sepsis Occurrence in Acutely ill Patients (SOAP) study, an observational study conducted in European intensive care units in 2002, and the Intensive Care Over Nations (ICON) audit, a survey of intensive care unit patients conducted in 2012., Results: We compared the 3147 patients from the SOAP study with the 4852 patients from the ICON audit admitted to intensive care units in the same countries as those in the SOAP study. The ICON patients were older (62.5 ± 17.0 vs. 60.6 ± 17.4 years) and had higher severity scores than the SOAP patients. The proportion of patients with sepsis at any time during the intensive care unit stay was slightly higher in the ICON study (31.9 vs. 29.6%, p = 0.03). In multilevel analysis, the adjusted odds of ICU mortality were significantly lower for ICON patients than for SOAP patients, particularly in patients with sepsis [OR 0.45 (0.35-0.59), p < 0.001]., Conclusions: Over the 10-year period between 2002 and 2012, the proportion of patients with sepsis admitted to European ICUs remained relatively stable, but the severity of disease increased. In multilevel analysis, the odds of ICU mortality were lower in our 2012 cohort compared to our 2002 cohort, particularly in patients with sepsis.

Purpose: The optimal timing of endotracheal intubation in critically ill patients requiring invasive mechanical ventilation remains undefined., Material and Methods: In a secondary analysis of the large, prospective ICON database, we used a piecewise proportional hazards model to compare outcomes in patients who underwent intubation early (within two days after intensive care unit [ICU] admission) or later., Results: After excluding 5340 patients already intubated on admission or with therapeutic limitation, 4729 patients were analyzed, of whom 4074 never underwent intubation. Of the remaining 655 patients, 449 underwent intubation early and 206 later. Despite similar severity scores on ICU admission, unadjusted ICU (27.6 vs. 18.2%) and hospital (33.3 vs. 23.4%) mortality rates were higher in patients intubated later than in those intubated earlier, as were ICU (9 [5-16] vs. 4 [2-9] days) and hospital (24 [9-35] vs. 13 [7-24] days) lengths-of-stay (all p<0.001). After adjustment, the hazard for ICU and hospital death was significantly greater >10days after ICU admission for patients intubated late., Conclusions: In this large cohort of critically ill patients requiring intubation, intubation >2days after admission was associated with increased mortality later in the hospital course., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Poor sign-out or handover of care may lead to preventable patient harm. Critically ill patients in intensive care units (ICU) are complex and prone to rapid clinical deterioration. If clinical deterioration occurs, timeliness of appropriate interventions is essential to prevent or reduce adverse outcomes. Therefore sign-outs need to efficiently transmit key information and provide anticipatory guidance. Interventions to improve resident-to-resident ICU sign-outs have not been well described. We conducted a controlled trial to test the effectiveness of a standardised ICU sign-out process to the usual ICU sign-out., Design: Prospective controlled trial., Setting: A 26-bed medical intensive care unit (MICU) in an urban tertiary academic medical centre., Subjects: Residents rotating through the MICU., Interventions: ICU-specific written sign-out template., Methods: Residents completed postcall surveys assessing satisfaction with verbal and written sign-outs and incidence of non-routine events. Our main outcome of interest was the occurrence of non-routine events., Main Results: Compared with the intervention group, on significantly more nights, night float residents in the control group encountered patients who were sicker than sign-out would have suggested (15.94% vs 43.75%; p<0.0001). On significantly fewer nights, night float residents in the intervention group indicated that either something happened to patients that was unexpected (18.84% vs 36.51%; p=0.023) or they were insufficiently prepared for (4.35% vs 35.94%; p<0.0001). Similarly, on fewer nights, residents in the intervention group indicated that they had to perform interventions that were unplanned or unanticipated (15.9% vs 37.7%; p=0.005)., Conclusion: A structured sign-out process compared with usual sign-out significantly reduced the occurrence of non-routine events in an academic MICU., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: Hand-offs are vulnerable times for hospitalized patients. Nurses and physicians routinely engage in hand-off communication but their communications remains siloed. Our objectives were to identify key information from each profession that would be of use to the other's hand-off process, and to identify facilitators and barriers to obtaining that input., Materials and Methods: We conducted this qualitative study in a medical intensive care unit. Subjects included 8 physicians, 2 advanced practice providers, and 6 nurses. We conducted observations of hand-offs and afternoon rounds as well as semistructured interviews. We analyzed the transcribed interviews and field note observations\ to identify themes of interest using a grounded theory approach., Results: Physicians were interested in patient data in context, family dynamics, and changing patient condition. Nurses were interested in details about the plan of care and anticipatory guidance. Facilitators of communication included proximity, face-to-face communication, and the electronic medical record. Barriers were busy schedules, inaccurate data, and negative attitudes., Conclusions: There are key areas of content that both physicians and nurses would like from the other profession to enhance intensive care unit hand-off communication. Interventions designed to increase interdisciplinary communication should focus on these key areas of content., (Published by Elsevier Inc.)

Objectives: Excessive fluid therapy in patients with sepsis may be associated with risks that outweigh any benefit. We investigated the possible influence of early fluid balance on outcome in a large international database of ICU patients with sepsis., Design: Observational cohort study., Setting: Seven hundred and thirty ICUs in 84 countries., Patients: All adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance. For this analysis, we included only the 1,808 patients with an admission diagnosis of sepsis. Patients were stratified according to quartiles of cumulative fluid balance 24 hours and 3 days after ICU admission., Measurements and Main Results: ICU and hospital mortality rates were 27.6% and 37.3%, respectively. The cumulative fluid balance increased from 1,217 mL (-90 to 2,783 mL) in the first 24 hours after ICU admission to 1,794 mL (-951 to 5,108 mL) on day 3 and decreased thereafter. The cumulative fluid intake was similar in survivors and nonsurvivors, but fluid balance was less positive in survivors because of higher fluid output in these patients. Fluid balances became negative after the third ICU day in survivors but remained positive in nonsurvivors. After adjustment for possible confounders in multivariable analysis, the 24-hour cumulative fluid balance was not associated with an increased hazard of 28-day in-hospital death. However, there was a stepwise increase in the hazard of death with higher quartiles of 3-day cumulative fluid balance in the whole population and after stratification according to the presence of septic shock., Conclusions: In this large cohort of patients with sepsis, higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.

Background: This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society and the American College of Chest Physicians., Methods: A multidisciplinary panel posed six clinical questions in a Population, Intervention, Comparator, and Outcomes format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, the confidence in the evidence, the certainty about how much the public values the main outcomes, the magnitude and balance of desirable and undesirable outcomes, the resources and costs associated with the intervention, the impact on health disparities, and the acceptability and feasibility of the intervention., Results: Evidence-based recommendations were formulated and graded initially by subcommittees and then modified after full-panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation., Conclusions: The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and Chest.

Background: Interventions that lead to earlier liberation from mechanical ventilation can improve patient outcomes. This guideline, a collaborative effort between the American Thoracic Society and the American College of Chest Physicians, provides evidence-based recommendations to optimize liberation from mechanical ventilation in critically ill adults., Methods: Two methodologists performed evidence syntheses to summarize available evidence relevant to key questions about liberation from mechanical ventilation. The methodologists appraised the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach and summarized the results in evidence profiles. The guideline panel then formulated recommendations after considering the balance of desirable consequences (benefits) versus undesirable consequences (burdens, adverse effects, and costs), the certainty in the evidence, and the feasibility and acceptability of various interventions. Recommendations were rated as strong or conditional., Results: The guideline panel made four conditional recommendations related to rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. The recommendations were for acutely hospitalized adults mechanically ventilated for more than 24 hours to receive protocolized rehabilitation directed toward early mobilization, be managed with a ventilator liberation protocol, be assessed with a cuff leak test if they meet extubation criteria but are deemed high risk for postextubation stridor, and be administered systemic steroids for at least 4 hours before extubation if they fail the cuff leak test., Conclusions: The American Thoracic Society/American College of Chest Physicians recommendations are intended to support healthcare professionals in their decisions related to liberating critically ill adults from mechanical ventilation.

Background: This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society (ATS) and the American College of Chest Physicians (CHEST)., Methods: A multidisciplinary panel posed six clinical questions in a population, intervention, comparator, outcomes (PICO) format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, confidence in the evidence, certainty about how much the public values the main outcomes, magnitude and balance of desirable and undesirable outcomes, resources and costs associated with the intervention, impact on health disparities, and acceptability and feasibility of the intervention., Results: Evidence-based recommendations were formulated and graded initially by subcommittees and then modified following full panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation., Conclusions: The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and CHEST., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: An update of evidence-based guidelines concerning liberation from mechanical ventilation is needed as new evidence has become available. The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have collaborated to provide recommendations to clinicians concerning liberation from the ventilator., Methods: Comprehensive evidence syntheses, including meta-analyses, were performed to summarize all available evidence relevant to the guideline panel's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, and the results were summarized in evidence profiles. The evidence syntheses were discussed and recommendations developed and approved by a multidisciplinary committee of experts in mechanical ventilation., Results: Recommendations for three population, intervention, comparator, outcome (PICO) questions concerning ventilator liberation are presented in this document. The guideline panel considered the balance of desirable (benefits) and undesirable (burdens, adverse effects, costs) consequences, quality of evidence, feasibility, and acceptability of various interventions with respect to the selected questions. Conditional (weak) recommendations were made to use inspiratory pressure augmentation in the initial spontaneous breathing trial (SBT) and to use protocols to minimize sedation for patients ventilated for more than 24 h. A strong recommendation was made to use preventive noninvasive ventilation (NIV) for high-risk patients ventilated for more than 24 h immediately after extubation to improve selected outcomes. The recommendations were limited by the quality of the available evidence., Conclusions: The guideline panel provided recommendations for inspiratory pressure augmentation during an initial SBT, protocols minimizing sedation, and preventative NIV, in relation to ventilator liberation., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate which factors influence time to death in hospital in critically ill patients worldwide, including the possible impact of gross national income (GNI)., Methods: This was a pre-defined post hoc analysis of the Intensive Care Over Nations (ICON) database, which included 10,069 patients. For this sub-analysis, we included only the 2062 60-day in-hospital non-survivors (22.3 %) among the 9258 patients with available hospital mortality and length-of-stay data. We categorized these non-survivors into three groups according to the time of death after ICU admission: early (<5 days), intermediate (6-28 days) or late (>28 days)., Results: Time to death in hospital was early in 1068 of the 2062 non-survivors (52 %), intermediate in 808 (39 %), and late in 186 (9 %). Patients who died early had higher severity scores and were more likely to require mechanical ventilation on ICU admission, whereas those who died late were more likely to be older and to have had infection on ICU admission or during the ICU stay. Multilevel analysis indicated a stepwise increase in the risk of late or intermediate deaths according to increasing GNI. Patients admitted to ICUs in countries with high or upper-middle GNI were more likely to die late than those admitted to countries with low/lower-middle GNI [odds ratio (95 % confidence interval) 4.78 (1.94-11.76), p < 0.001, and 1.64 (1.10-2.45), p = 0.02, respectively]., Conclusions: Duration of hospital stay prior to death in critically ill patients is longer in older patients, surgical patients, and patients with infection. GNI is a major determinant of time to death in hospital in these patients. These observations may have important organizational and ethical implications.

Purpose: Current guidelines provide weak recommendations for starting enteral nutrition (EN) in patients with septic shock (on vasopressor support). Outcomes of patients receiving EN in septic shock on vasopressor support have not been well studied. We hypothesize that early trophic EN in mechanically ventilated patients with septic shock is associated with improved outcomes., Methods: Single-center retrospective study of mechanically ventilated patients admitted with septic shock to identify patients receiving (1) no EN, (2) <600 kcal/d within 48 hours, and (3) ≥600 kcal/d within 48 hours. Outcomes studied included in-hospital mortality, length of intensive care unit stay (LOS), duration of mechanical ventilation (DOMV), and complications of feeding intolerance., Results: Sixty-six patients were identified. In all, 15 received no EN, 37 received <600 kcal/d, and 14 received ≥600 kcal/d EN daily. Median LOS was 12, 5, and 13 days, respectively. The LOS was lower in patients receiving <600 kcal/d when compared to either no EN (P < .001) or those receiving ≥600 kcal/d (P < .001). Median DOMV was lower in patients receiving <600 kcal/d (median 3, P < .001) as compared to no EN (median 7, P < .001) or those receiving ≥600 kcal/d (median 7.5, P < .001). Mortality was not different. There were no significant complications among groups., Conclusion: In patients with septic shock, those receiving <600 kcal/d EN within 48 hours had lower DOMV and LOS when compared to those who did not receive EN or those who received ≥600 kcal/d. These observations provide strong justification for prospective evaluation of the effect of early trophic EN in patients with septic shock., (© The Author(s) 2014.)

Objective: To assess the effect of body mass index on ICU outcome and on the development of ICU-acquired infection., Design: A substudy of the Intensive Care Over Nations audit., Setting: Seven hundred thirty ICUs in 84 countries., Patients: All adult ICU patients admitted between May 8 and 18, 2012, except those admitted for less than 24 hours for routine postoperative monitoring (n = 10,069). In this subanalysis, only patients with complete data on height and weight (measured or estimated) on ICU admission in order to calculate the body mass index were included (n = 8,829)., Interventions: None., Measurements and Main Results: Underweight was defined as body mass index less than 18.5 kg/m, normal weight as body mass index 18.5-24.9 kg/m, overweight as body mass index 25-29.9 kg/m, obese as body mass index 30-39.9 kg/m, and morbidly obese as body mass index greater than or equal to 40 kg/m. The mean body mass index was 26.4 ± 6.5 kg/m. The ICU length of stay was similar among categories, but overweight and obese patients had longer hospital lengths of stay than patients with normal body mass index (10 [interquartile range, 5-21] and 11 [5-21] vs 9 [4-19] d; p < 0.01 pairwise). ICU mortality was lower in morbidly obese than in normal body mass index patients (11.2% vs 16.6%; p = 0.015). In-hospital mortality was lower in morbidly obese and overweight patients and higher in underweight patients than in those with normal body mass index. In a multilevel Cox proportional hazard analysis, underweight was independently associated with a higher hazard of 60-day in-hospital death (hazard ratio, 1.32; 95% CI, 1.05-1.65; p = 0.018), whereas overweight was associated with a lower hazard (hazard ratio, 0.79; 95% CI, 0.71-0.89; p < 0.001). No body mass index category was associated with an increased hazard of ICU-acquired infection., Conclusions: In this large cohort of critically ill patients, underweight was independently associated with a higher hazard of 60-day in-hospital death and overweight with a lower hazard. None of the body mass index categories as independently associated with an increased hazard of infection during the ICU stay.

Objective: Severe sepsis requires timely management and has high mortality if care is delayed. Hematopoietic stem cell transplant recipients are more likely to be immunocompromised and are predisposed to serious infections. Reports of outcomes of severe sepsis in this population are limited to data from single, tertiary care centers, and national outcomes data are missing., Design: Retrospective analysis of an administrative database., Setting: Twenty percent of community hospitals in United States, excluding federal hospitals., Subject: Patients with severe sepsis., Intervention: None., Measurements and Main Results: We used International Classification of Diseases, 9th Edition, Clinical Modification codes indicating the presence of sepsis and organ system failure to identify hospitalizations for severe sepsis between 2000 and 2008. We also used International Classification of Diseases, 9th Edition, Clinical Modification codes to identify hematopoietic stem cell transplant recipients. We compared outcomes of hematopoietic stem cell transplant recipients with severe sepsis during engraftment and subsequent admissions with a non-hematopoietic stem cell transplant cohort and excluded solid-organ transplantation from this cohort. We used mixed effect, multivariate logistic regression modeling with propensity score adjustment to examine factors associated with mortality of severe sepsis in hematopoietic stem cell transplant recipients. A total of 21,898 hematopoietic stem cell transplant recipients with severe sepsis were identified. The frequency of severe sepsis in hematopoietic stem cell transplant recipients was five times higher when compared with the non-hematopoietic stem cell transplant cohort. The unadjusted mortality was 32.9% in non-hematopoietic stem cell transplant cohort, which was similar to autologous hematopoietic stem cell transplant recipients (30.1%) and those who did not develop graft-versus-host disease (35%). Mortality was significantly higher in allogeneic transplants (55.1%, p < 0.001) and in those who developed graft-versus-host disease (47.9%, p < 0.001). After adjustment, during engraftment admission, the odds of in-hospital mortality in allogeneic hematopoietic stem cell transplant (odds ratio, 3.81; 95% CI, 2.39-6.07) and autologous hematopoietic stem cell transplant (odds ratio, 1.28; 95% CI, 1.06-1.53) recipients was significantly higher than non-hematopoietic stem cell transplant patients. Similarly, in subsequent admissions, hematopoietic stem cell transplant recipients with graft-versus-host disease (odds ratio, 2.14; 95% CI, 1.88-2.45) and without graft-versus-host disease (odds ratio, 1.35; 95% CI, 1.19-1.54) had significantly higher odds of mortality than non-hematopoietic stem cell transplant patients. Among patients with hematopoietic stem cell transplant, persons with autologous hematopoietic stem cell transplant and those without graft-versus-host disease fared better as compared with their allogeneic and graft-versus-host disease counterparts., Conclusions: Hematopoietic stem cell transplant recipients are more likely to develop severe sepsis and die following a severe sepsis episode than nontransplant patients. Autologous hematopoietic stem cell transplant recipients and those who do not develop graft-versus-host disease have significantly better outcomes than allogeneic and graft-versus-host disease patients.

Purpose: Admission serum bilirubin levels have been incorporated into severity of illness scoring systems in critical illness as a marker of liver dysfunction. The purpose of our study is to determine the independent association of serum bilirubin with mortality in severe sepsis and septic shock., Methods: We conducted a retrospective study of adult patients admitted with severe sepsis and septic shock. We excluded patients with a prior history of liver disease. We identified the highest serum bilirubin within 72 hours of admission and stratified bilirubin levels into ≤1 mg/dL (normal), 1.1 to 2 mg/dL (abnormal up to 2 mg/dL), and >2 mg/dL. We sought to determine the independent association of hyperbilirubinemia with mortality and length of intensive care unit stay in persons with severe sepsis and septic shock., Results: A total of 251 patients met criteria for severe sepsis. In all, 200 patients had a bilirubin of <1 mg/dL, and 51 had a bilirubin of >1 mg/dL. Of these 51, 12 had a bilirubin >2 mg/dL. Mortality was 12%, 24%, and 42% in persons with a bilirubin ≤1, 1.1 to 2, and >2 mg/dL, respectively. Compared to those with a bilirubin ≤ 1 mg/dL, adjusted odds of mortality in patients were 3.85 (95% confidence interval [CI] 1.21-12.2) and 9.85 (95% CI 1.92-50.5) times higher in persons with bilirubin levels between 1.1 and 2 and >2 mg/dL, respectively., Conclusion: After multivariable adjustment for potential confounding factors, elevated serum bilirubin levels within 72 hours of admission are associated with an increased risk of mortality in patients with severe sepsis and septic shock. Prospective studies are warranted to further validate our findings., (© The Author(s) 2013.)

Background: The current frequency of noninvasive (NIV) and invasive mechanical ventilation use in asthma exacerbations (AEs) and the relationship to outcomes are unknown., Methods: We used the Healthcare Cost and Utilization Project Nationwide Inpatient Sample to identify patients discharged with a principal diagnosis of AE. For each discharge, we determined whether NIV or invasive mechanical ventilation was initiated during the first 2 hospital days. Using multivariate logistic regression to adjust for potential confounders, we determined whether use of mechanical ventilation and in-hospital mortality changed between 2000 and 2008., Results: The number of AEs increased by 15.8% from 2000 to 2008. The proportion of admissions for which invasive mechanical ventilation was used during the first 2 days decreased from 1.4% in 2000 to 0.73% in 2008, whereas NIV use increased from 0.34% to 1.9%. The adjusted mortality from AEs requiring NIV or invasive mechanical ventilation was unchanged from 2000 to 2008. The hospital stay was also unchanged., Conclusions: There was a substantial increase in the use of mechanical ventilation, accompanied by a shift from invasive mechanical ventilation to NIV. Although we could not determine the clinical reasons for this increase, hospital stay and mortality were unchanged. A randomized trial is needed to determine whether NIV can improve outcomes in AEs before widespread adoption makes it impossible to conduct such a trial.

Objective: Patients with severe sepsis have high mortality that is improved by timely, often expensive, treatments. Patients without insurance are more likely to delay seeking care; they may also receive less intense care., Design: We performed a retrospective analysis of administrative database-Healthcare Costs and Utilization Project's Nationwide Inpatient Sample-to test whether mortality is more likely among uninsured patients hospitalized for severe sepsis., Patients: None., Interventions: We used International Classification of Diseases-9th Revision, Clinical Modification, codes indicating sepsis and organ system failure to identify hospitalizations for severe sepsis among patients aged 18-64 between 2000 and 2008. We excluded patients with end-stage renal disease or solid organ transplants because very few are uninsured. We performed multivariate logistic regression modeling to examine the association of insurance status and in-hospital mortality, adjusted for patient and hospital characteristics. We performed subgroup analysis to examine whether the impact of insurance status varied by geographical region; by patient age, sex, or race; or by hospital characteristics such as teaching status, size, or ownership. We used similar methods to examine the impact of insurance status on the use of certain procedures, length of stay, and discharge destination., Measurements and Main Results: There were 1,600,269 discharges with severe sepsis from 2000 through 2008 in the age group 18-64 years. Uninsured people, who accounted for 7.5% of admissions with severe sepsis, had higher adjusted odds of mortality (odds ratio, 1.43; 95% CI, 1.37-1.47) than privately insured people. The higher mortality in uninsured was present in all subgroups and was similar in each year from 2000 to 2008. After adjustment, uninsured individuals had a slightly shorter length of stay than insured people and were less likely to receive five of the six interventions we examined. They were also less likely to be discharged to skilled nursing facilities or with home healthcare after discharge., Conclusions: Uninsured are more likely to die following admission for severe sepsis than patients with insurance, even after adjusting for potential confounders. This was not due to a hospital effect or demographic or clinical factors available in our administrative database. Further research should examine the mechanisms that lead to this association., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Background: Endothelium-derived microparticles (EMPs) are submicron vesicles released from the plasma membrane of endothelial cells in response to injury, apoptosis or activation. We have previously demonstrated EMP-induced acute lung injury (ALI) in animal models and endothelial barrier dysfunction in vitro. Current treatment options for ALI are limited and consist of supportive therapies. We hypothesize that standard clinical continuous venovenous hemofiltration (CVVH) reduces serum EMP levels and may be adapted as a potential therapeutic intervention., Materials and Methods: EMPs were generated from plasminogen activation inhibitor-1 (PAI-1)-stimulated human umbilical vein endothelial cells (HUVECs). Flow cytometric analysis was used to characterize EMPs as CD31- and annexin V-positive events in a submicron size gate. Enumeration was completed against a known concentration of latex beads. Ultimately, a concentration of ~650,000 EMP/mL perfusate fluid (total 470 mL) was circulated through a standard CVVH filter (pore size 200 μm, flow rate 250 mL/hr) for a period of 70 minutes. 0.5 mL aliquots were removed at 5- to 10-minute intervals for flow cytometric analysis. EMP concentration in the dialysate was measured at the end of 4 hours to better understand the fate of EMPs., Results: A progressive decrease in circulating EMP concentration was noted using standard CVVH at 250 mL/hr (a clinical standard rate) from a 470 mL volume modelling a patient's circulation. A 50% reduction was noted within the first 30 minutes. EMPs entering the dialysate after 4 hours were 5.7% of the EMP original concentration., Conclusion: These data demonstrate that standard CVVH can remove EMPs from circulation in a circuit modelling a patient. An animal model of hemofiltration with induction of EMP release is required to test the therapeutic potential of this finding and potential of application in early treatment of ALI.

Abstract Pulmonary or systemic infections and hypoxemic respiratory failure are among the leading causes of admission to intensive care units, and these conditions frequently exist in sequence or in tandem. Inflammatory responses to infections are reproduced by lipopolysaccharide (LPS) engaging Toll-like receptor 4 (TLR4). Apoptosis is a hallmark of lung injury in sepsis. This study was conducted to determine whether preexposure to LPS or hypoxia modulated the survival of pulmonary artery endothelial cells (PAECs). We also investigated the role TLR4 receptor expression plays in apoptosis due to these conditions. Bovine PAECs were cultured in hypoxic or normoxic environments and treated with LPS. TLR4 antagonist TAK-242 was used to probe the role played by TLR4 receptors in cell survival. Cell apoptosis and survival were measured by caspase 3 activity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) incorporation. TLR4 expression and tumor necrosis factor α (TNF-α) production were also determined. LPS increased caspase 3 activity in a TAK-242-sensitive manner and decreased MTT incorporation. Apoptosis was decreased in PAECs preconditioned with hypoxia prior to LPS exposure. LPS increased TNF-α production, and hypoxic preconditioning blunted it. Hypoxic preconditioning reduced LPS-induced TLR4 messenger RNA and TLR4 protein. TAK-242 decreased to baseline the LPS-stimulated expression of TLR4 messenger RNA regardless of environmental conditions. In contrast, LPS followed by hypoxia substantially increased apoptosis and cell death. In conclusion, protection from LPS-stimulated PAEC apoptosis by hypoxic preconditioning is attributable in part to reduction in TLR4 expression. If these signaling pathways apply to septic patients, they may account for differing sensitivities of individuals to acute lung injury depending on oxygen tensions in PAECs in vivo.

Background: Critically ill, morbidly obese patients (BMI≥40 kg/m2) are at high risk of respiratory failure requiring invasive mechanical ventilation (IMV). It is not clear if outcomes of critically ill, obese patients are affected by obesity. Due to limited cardiopulmonary reserve, they may have poor outcomes. However, literature to this effect is limited and conflicted., Methods: We used the Nationwide Inpatient Sample from 2004 to 2008 to examine the outcomes of morbidly obese people receiving IMV and compared them to nonobese people. We identified hospitalizations requiring IMV and morbid obesity using International Classification of Diseases, 9th Revision, Clinical Modification codes. Primary outcomes studied were inhospital mortality, rates of prolonged mechanical ventilation (≥96 h), and tracheostomy. Multivariable logistic regression was used to adjust for potential confounding variables. We also examined outcomes stratified by number of organs failing., Results: Of all hospitalized, morbidly obese people, 2.9% underwent IMV. Mean age, comorbidity score, and severity of illness were lower in morbidly obese people. The adjusted mortality was not significantly different in morbidly obese people (OR 0.89; 95% CI, 0.74-1.06). When stratified by severity of disease, there was a stepwise increase in risk for mortality among morbidly obese people relative to nonobese people (range: OR, 0.77; 95% CI, 0.58-1.01 for only respiratory failure, to OR, 4.14; 95% CI, 1.11-15.3 for four or more organs failing). Rates of prolonged mechanical ventilation were similar, but rate of tracheostomy (OR 2.19; 95% CI, 1.77-2.69) was significantly higher in patients who were morbidly obese., Conclusions: Morbidly obese people undergoing IMV have a similar risk for death as nonobese people if only respiratory failure is present. When more organs fail, morbidly obese people have increased risk for mortality compared with nonobese people.

Background and Objectives: CKD and ESRD are growing burdens. It is unclear whether these conditions affect pulmonary embolism (PE) risk, given that they affect both procoagulant and anticoagulant factors. This study examined the frequency and associated outcomes of PE in CKD and ESRD., Design, Setting, Participants, & Measurements: The Healthcare Cost and Utilization Project's Nationwide Inpatient Sample was used to estimate the frequency and outcomes of PE in adults with CKD and ESRD. Hospitalizations for the principal diagnosis of PE and presence of CKD or ESRD were identified using International Classification of Diseases, Ninth Revision codes. Data from the annual US Census and US Renal Data System reports were used to calculate the number of adults with CKD, ESRD, and normal kidney function (NKF) as well as the annual incidence of PE in each group. Logistic regression modeling was used to compare in-hospital mortality among persons admitted for PE who had ESRD or CKD to those without these conditions., Results: The annual frequency of PE was 527 per 100,000, 204 per 100,000, and 66 per 100,000 persons with ESRD, CKD, and NKF, respectively. In-hospital mortality was higher for persons with ESRD and CKD (P<0.001) compared with persons with NKF. Median length of stay was longer by 1 day in CKD and 2 days in ESRD than among those with NKF., Conclusions: Persons with CKD and ESRD are more likely to have PE than persons with NKF. Once they have PE, they are more likely to die in the hospital.

Background: The outcome of gastrointestinal bleeding in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients is difficult to discern from the literature. Many publications are small, single-center series or are from an era prior to advanced interventional endoscopy, widespread use of proton pump inhibitors or treatment for Helicobacter pylori infections. In this study, we quantify the role of CKD and ESRD as independent predictors of mortality in patients admitted to the hospital with a principal diagnosis of primary upper gastrointestinal bleeding (UGIB)., Methods: We used the Nationwide Inpatient Sample that contains data on approximately 8 million admissions in 1,000 hospitals chosen to approximate a 20% stratified sample of all US facilities. Patients discharged with the principal diagnosis of primary UGIB, CKD or ESRD were identified through the ninth revision of the International Classification of Diseases, clinical modification (ICD-9-CM) codes. The outcome variables included frequency and in-hospital mortality of UGIB in CKD and ESRD patients as compared to non-CKD patients and were analyzed using logistic regression modeling., Results: In 2007, out of a total of 398,213 admissions with a diagnosis of primary UGIB, 35,985 were in CKD, 14,983 in ESRD, and 347,245 in non-renal disease groups. The OR for primary UGIB hospitalization in CKD and ESRD was 1.30 (95% CI 1.17-1.46) and 1.84 (95% CI 1.61-2.09), respectively. The corresponding all-cause mortality OR was 1.47 (95% CI 1.21-1.78) and 3.02 (95% CI 2.23-4.1), respectively., Conclusion: Patients with CKD or ESRD admitted with primary UGIB have up to three times higher risk of all-cause in-hospital mortality, warranting heightened vigilance by their clinicians., (Copyright © 2012 S. Karger AG, Basel.)

Background: Severe sepsis is common and often fatal. The expanding armamentarium of evidence-based therapies has improved the outcomes of persons with this disease. However, the existing national estimates of the frequency and outcomes of severe sepsis were made before many of the recent therapeutic advances. Therefore, it is important to study the outcomes of this disease in an aging US population with rising comorbidities., Methods: We used the Healthcare Costs and Utilization Project's Nationwide Inpatient Sample (NIS) to estimate the frequency and outcomes of severe sepsis hospitalizations between 2000 and 2007. We identified hospitalizations for severe sepsis using International Classification of Diseases, Ninth Revision, Clinical Modification codes indicating the presence of sepsis and organ system failure. Using weights from NIS, we estimated the number of hospitalizations for severe sepsis in each year. We combined these with census data to determine the number of severe sepsis hospitalizations per 100,000 persons. We used discharge status to identify in-hospital mortality and compared mortality rates in 2000 with those in 2007 after adjusting for demographics, number of organ systems failing, and presence of comorbid conditions., Results: The number of severe sepsis hospitalizations per 100,000 persons increased from 143 in 2000 to 343 in 2007. The mean number of organ system failures during admission increased from 1.6 to 1.9 (P < .001). The mean length of hospital stay decreased from 17.3 to 14.9 days. The mortality rate decreased from 39% to 27%. However, more admissions ended with discharge to a long-term care facility in 2007 than in 2000 (35% vs 27%, P < .001)., Conclusions: An increasing number of admissions for severe sepsis combined with declining mortality rates contribute to more individuals surviving to hospital discharge. Importantly, this leads to more survivors being discharged to skilled nursing facilities and home with in-home care. Increased attention to this phenomenon is warranted.

Purpose: To characterize structural and functional injuries following a single dose of whole-thorax irradiation that might be survivable after a nuclear attack/accident., Methods: Rats were exposed to 5 or 10 Gy of X-rays to the whole thorax with other organs shielded. Non-invasive measurements of breathing rate and arterial oxygen saturation, and invasive evaluations of bronchoalveolar lavage fluid, (for total protein, Clara cell secretory protein), vascular reactivity and histology were conducted for at least 6 time points up to 52 weeks after irradiation., Results: Irradiation with 10 Gy resulted in increased breathing rate, a reduction in oxygen saturation, an increase in bronchoalveolar lavage fluid protein and attenuation of vascular reactivity between 4-12 weeks after irradiation. These changes were not observed with the lower dose of 5 Gy. Histological examination revealed perivascular edema at 4-8 weeks after exposure to both doses, and mild fibrosis beyond 20 weeks after 10 Gy., Conclusions: Single-dose exposure of rat thorax to 10 but not 5 Gy X-irradiation resulted in a decrease in oxygen uptake and vasoreactivity and an increase in respiratory rate, which paralleled early pulmonary vascular pathology. Vascular edema resolved and was replaced by mild fibrosis beyond 20 weeks after exposure, while lung function recovered.

The snr1 gene of Drosophila melanogaster encodes a conserved component of the multiprotein Brahma (Brm) complex, a counterpart to the SWI/SNF complexes that participate in ATP-dependent chromatin remodeling. Loss-of-function and null mutations in the snr1 gene reveal its essential role in Drosophila development. We identified new mutant alleles and ectopically expressed deleted forms to dissect the specific functions of SNR1. Somatic and germ cell clone analyses confirmed its requirement in a continuous and widespread fashion for proper cell fate determination and oogenesis. Expression of SNR1 transgenes revealed unexpected roles in wing patterning, abdomen development, oogenesis, and sustained adult viability. A widespread distribution of SNR1 and BRM on the salivary gland polytene chromosomes showed that the Brm complex associated with many genes, but not always at transcribed loci, consistent with genetic data suggesting roles in both gene activation and repression. Despite essential Brm complex functions in leg development, genetic and protein localization studies revealed that snr1 was not required or expressed in all tissues dependent on Brm complex activities. Thus, SNR1 is essential for some, but not all Brm functions, and it likely serves as an optional subunit, directing Brm complex activity to specific gene loci or cellular processes.