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Observational studies suggest obesity is associated with sepsis survival, but these studies are small, fail to adjust for key confounders, measure body mass index at inconsistent time points, and/or use administrative data to define sepsis. To estimate the relationship between body mass index and sepsis mortality using detailed clinical data for case detection and risk adjustment.Retrospective cohort analysis of a large clinical data repository.One-hundred thirty-nine hospitals in the United States.Adult inpatients with sepsis meeting Sepsis-3 criteria.Body mass index in six categories: underweight (body mass index18.5 kg/m), normal weight (body mass index = 18.5-24.9 kg/m), overweight (body mass index = 25.0-29.9 kg/m), obese class I (body mass index = 30.0-34.9 kg/m), obese class II (body mass index = 35.0-39.9 kg/m), and obese class III (body mass index ≥ 40 kg/m).Multivariate logistic regression with generalized estimating equations to estimate the effect of body mass index category on short-term mortality (in-hospital death or discharge to hospice) adjusting for patient, infection, and hospital-level factors. Sensitivity analyses were conducted in subgroups of age, gender, Elixhauser comorbidity index, Sequential Organ Failure Assessment quartiles, bacteremic sepsis, and ICU admission.From 2009 to 2015, we identified 55,038 adults with sepsis and assessable body mass index measurements: 6% underweight, 33% normal weight, 28% overweight, and 33% obese. Crude mortality was inversely proportional to body mass index category: underweight (31%), normal weight (24%), overweight (19%), obese class I (16%), obese class II (16%), and obese class III (14%). Compared with normal weight, the adjusted odds ratio (95% CI) of mortality was 1.62 (1.50-1.74) for underweight, 0.73 (0.70-0.77) for overweight, 0.61 (0.57-0.66) for obese class I, 0.61 (0.55-0.67) for obese class II, and 0.65 (0.59-0.71) for obese class III. Results were consistent in sensitivity analyses.In adults with clinically defined sepsis, we demonstrate lower short-term mortality in patients with higher body mass indices compared with those with normal body mass indices (both unadjusted and adjusted analyses) and higher short-term mortality in those with low body mass indices. Understanding how obesity improves survival in sepsis would inform prognostic and therapeutic strategies.

Objective Inhaled anticoagulation regimens are increasingly being used to manage smoke inhalation-associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruction, ventilation, oxygenation, pulmonary infections, bleeding complications, and survival. Data sources PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Relevant unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, MINDCULL.com, Current Controlled Trials, and Google. Study selection Inclusion criteria were any preclinical or clinical study in which 1) animals or subjects experienced smoke inhalation exposure, 2) they were treated with nebulized or aerosolized anticoagulation regimens, including heparin, heparinoids, antithrombins, or fibrinolytics (e.g., tissue plasminogen activator), 3) a control and/or sham group was described for preclinical studies, and 4) a concurrent or historical control group described for clinical studies. Exclusion criteria were 1) the absence of a group treated with a nebulized or aerosolized anticoagulation regimen, 2) the absence of a control or sham group, and 3) case reports. Data extraction Ninety-nine potentially relevant references were identified. Twenty-seven references met inclusion criteria including 19 preclinical references reporting 18 studies and eight clinical references reporting five clinical studies. Data synthesis A systematic review of the literature is provided. Both clinical and methodological diversity precluded combining these studies in a meta-analysis. Conclusions The high mortality associated with smoke inhalation-associated acute lung injury results from airway damage, mucosal dysfunction, neutrophil infiltration, airway coagulopathy with cast formation, ventilation-perfusion mismatching with shunt, and barotrauma. Inhaled anticoagulation regimens in both preclinical and clinical studies improve survival and decrease morbidity without altering systemic markers of clotting and anticoagulation. In some preclinical and clinical studies, inhaled anticoagulants were associated with a favorable effect on survival. This approach appears sufficiently promising to merit a well-designed prospective study to validate its use in patients with severe smoke inhalation-associated acute lung injury requiring mechanical ventilation.

Objective: Evaluate the effects of methylprednisolone on markers of inflammation, coagulation, and angiogenesis during early acute respiratory distress syndrome. Design: Retrospective analysis. Setting: Four intensive care units. Subjects: Seventy-nine of 91 patients with available samples enrolled in a randomized, blinded controlled trial. Interventions: Early methylprednisolone infusion (n = 55) compared with placebo (n = 24). Measurements and Main Results: Interleukin-6, tumor necrosis factor alpha, vascular endothelial growth factor, protein C, procalcitonin, and proadrenomedullin were measured in archived plasma. Changes from baseline to day 3 and day 7 were compared between groups and in subgroups based on the precipitating cause of acute respiratory distress syndrome. Methylprednisolone therapy was associated with greater improvement in Lung Injury Score (p = .003), shorter duration of mechanical ventilation (p = .005), and lower intensive care unit mortality (p = .05) than control subjects. On days 3 and 7, methylprednisolone decreased interleukin-6 and increased protein C levels (all p

Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia.Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ≤ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ≤ .05), consistent with adrenal suppression.In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.

Transcompartmental signaling during early inflammation may lead to propagation of disease to other organs. The time course and the mechanisms involved are still poorly understood. We aimed at comparing acute transcompartmental inflammatory responses in humans following lipopolysaccharide-induced pulmonary and systemic inflammation.Randomized, double-blind, placebo-controlled, crossover study.Healthy male volunteers.Fifteen volunteers (mean age, 23; SD, 2 yr) received Escherichia coli endotoxin (lipopolysaccharide, 4 ng/kg) IV or endobronchially on two different study days. Groups were evaluated by bronchoalveolar lavage at baseline (0 hr) and 2, 4, 6, 8, or 24 hours postchallenge. Cardiorespiratory variables were continuously recorded throughout the study day, and plasma and bronchoalveolar lavage fluid markers of inflammation were measured.IV endotoxin elicited a systemic inflammatory response with a time-dependent increase and peak in tumor necrosis factor-α, interleukin-6, and leukocyte counts (all p0.001). Furthermore, a delayed (6-8 hr) increase in bronchoalveolar lavage fluid interleukin-6 concentration (p0.001) and alveolar leukocyte count (p = 0.03) and a minor increase in bronchoalveolar lavage fluid tumor necrosis factor-α were observed (p = 0.06). Endobronchial endotoxin was followed by progressive alveolar neutrocytosis and increased bronchoalveolar lavage fluid tumor necrosis factor-α, interleukin-6, and albumin (all p0.001); a systemic inflammatory response was observed after 2-4 hours, with no change in plasma tumor necrosis factor-α.Acute lung or systemic inflammation in humans is followed by a transcompartmental proinflammatory response, the degree and differential kinetics of which suggests that the propagation of inflammation may depend on the primary site of injury.

Objective: Clinical trial designs that randomize patients to fixed treatment regimens may disrupt preexisting relationships between illness severity and level of therapy. The practice misalignments created by such designs may have unintended effects on trial results and safety. Methods: To illustrate this problem, the Transfusion Requirements in Critical Care (TRICC) trial and the Acute Respiratory Distress Syndrome Network low tidal volume (ARMA) trial were analyzed. Results: Publications before TRICC indicated that clinicians used higher transfusion thresholds in patients with ischemic heart disease compared with younger, healthier patients (p = .001). The trial, however, randomized patients (n = 838) to liberal (10 g/dL hemoglobin) or restrictive (7 g/dL) transfusion thresholds. Thirty-day mortality was different and opposite in the liberal compared with the restrictive arm depending on presence (21 vs. 26%) or absence (25 vs. 16%) of ischemic heart disease (p = .03). At baseline in ARMA, consistent with prior publications, physicians set ventilator volumes lower in patients with high airway pressures and poor compliance (8.4-10.6 mL/kg interquartile range) than patients with less severe abnormalities (9.6-12 mL/kg) (p = .0001). In the trial, however, patients (n = 861) were randomized to low (6 mL/kg) or high (12 mL/kg) tidal volumes. In patients with low compliance (

Objective To determine whether human endotoxemia is associated with a loss of the physiologic beat-to-beat variability of heart rate. Design Prospective, randomized, crossover, single-blind study. Setting Clinical research center in a federal, nonuniversity hospital. Subjects Healthy volunteers. Interventions Intravenous administration of reference (Escherichia coli) endotoxin or saline placebo, with or without previous administration of oral ibuprofen. Measurements and main results Electrocardiograms were continuously recorded and digitized using series of 1000 beat epochs of R-R intervals over 8 hrs. Analyses included measures in the time domain (standard deviation), frequency domain (power spectra), and a measure of regularity (approximate entropy). Endotoxin administration was associated with loss of variability by all measures. This loss of variability remained significant even with administration of ibuprofen, which blocked the development of fever and endotoxin-related symptoms. Conclusions Infusion of endotoxin into human volunteers causes loss of heart rate variability, as measured by standard deviation and power spectra, as well as an increase in heart rate regularity, as measured by approximate entropy. Changes in approximate entropy occurred earlier than changes in other heart rate variability measures and may be a useful means of detecting early sepsis. This reduction in regularity is consistent with a model in which the pathogenesis of multiple organ system dysfunction syndrome involves the physiologic uncoupling of vital organ systems.

Care bundles or protocols that combine several medical practices have been proposed as tools to promote rapid adoption of proven therapies, benchmark performance, and improve patient outcomes (1). Reports that several practices instituted together could reduce the prevalence of catheter-related infection or mortality in mechanically ventilated patients supported this approach (2, 3). Care bundles have also been proposed based on the holistic principle that the whole is greater than the sum of its parts (4). Based on this therapeutic approach, the Institute for Healthcare Improvement and the Centers for Medicare and Medicaid Services recently proposed instituting “all or none” performance measures (5, 6). Hospital performance, and possibly re-imbursement in the future, may be based on the frequency with which all elements of a care bundle were administered together (7, 8). The Joint Commission and Institute for Healthcare Improvement have recommended that components of a bundle should individually have proven benefit and wide acceptance, and together have even greater benefit (1, 9, 10). Importantly, bundle proponents encourage determination that individual components add to aggregate beneficial effects on outcome (6). However, there is currently no consensus on methods and standards for the development and testing of valid care bundles. Although promising, care bundles pose challenges. Several care bundles posted on the Internet have not undergone rigorous peer review (11, 12). Some bundles addressing the same problem—sepsis—differ in content and compliance rates (13). Many bundles lack strong evidence for the efficacy of one or more of their individual components (14). Importantly, adoption of all bundle elements as a single intervention limits the ability to test the interdependent and independent efficacy of individual components (15). Therefore, the introduction of care bundles may mandate changes in standard care without the ability to fully monitor the impact of component parts. Resolving these issues has become critical as care bundles have evolved from preventing complications (e.g., catheter-related infections) to treating life-threatening conditions (e.g., sepsis). As bundle development and application lack clear standards but are increasing in frequency, we examined this approach for the treatment of sepsis. We performed a meta-analysis of clinical trials, testing the impact of sepsis bundles compared with nonprotocolized care. Component therapies of interest were adopted from two widely instituted sepsis bundles, i.e., a 6-hr acute bundle and a 24-hr management bundle (Table 1) that were based on guidelines originally developed by the Surviving Sepsis Campaign and available at the time of these clinical trials (12, 16). Our goals were to examine the effect of bundle institution on survival and the application of individual bundle components. Table 1 Components in two sepsis bundles formulated by the Surviving Sepsis Campaign (12, 16)

Objective: Discuss the research needs of the critical illness and injury communities in the United States. Data Sources: Workshop session held during the 5 th National Institutes of Health Symposium on the Functional Genomics of Critical Illness and Injury (November 15, 2007). Study Selection: The current clinical research infrastructure misses opportunities for synergy and does not address many important needs. In addition, it remains challenging to rapidly and properly implement system-wide changes based upon reproducible evidence from clinical research. Data Extraction: Author presentations, panel discussion, attendee feedback. Data Synthesis: The critical illness and injury research communities seek better communication and interaction, both of which will improve the breadth and quality of acute care research. Success in meeting these needs should come from cooperative and strategic actions that favor collaboration, standardization of protocols, and strong leadership. An alliance framed on common goals will foster collaboration among experts to better promote clinical trials within the critically ill or injured patient population. Conclusions: The U.S. Critical Illness and Injury Trials Group was funded to create a clinical research framework that can reduce the barriers to investigation using an investigator-initiated, evidence-driven, inclusive approach that has proven successful elsewhere. This alliance will provide an annual venue for systematic review and strategic planning that will include framing the research agenda, raising awareness for the value of acute care research, gathering and promoting best practices, and bolstering the critical care workforce.

Recent strides in computational biology and high-throughput technologies have generated considerable interest in understanding complex biological systems. The application of these technologies to critical illness and injury offers the potential to define adaptive and maladaptive programs of gene expression induced by infection, shock, trauma, or other inflammatory triggers, and to detect biomarkers and genetic polymorphisms linked to these responses and outcome. A systems biology approach is timely because despite substantial effort, treatment approaches directed at a single mediator or inflammatory pathway have met with little success in altering outcomes of critically ill or injured patients. Highlights from the Fourth National Institute of Health Functional Genomics of Critical Illness and Injury Symposium are described herein, in addition to deliverables for the field identified during panel discussions. Next steps for the community and suggestions for future research are presented.

To measure the effect of experimental endotoxemia and anti-inflammatory therapy on plasma dehydroepiandrosterone (DHEA) levels in humans.Controlled, randomized, single-blind, prospective clinical study.Monitored unit in research hospital.Twelve healthy volunteers served as their own controls and were randomized to receive intravenous endotoxin (Escherichia coli) or saline separated by 1 wk. Six were randomized to receive ibuprofen, a cyclooxygenase inhibitor, and six were given placebo.Measurement of vital signs and hormones during a 24-hr period.All subjects given endotoxin had a significant increase in plasma DHEA, cortisol, and adrenocorticotropic hormone (ACTH) levels (all p = .02). DHEA levels were maximum at 2 hrs and returned to baseline values by 6 hrs. Ibuprofen administration significantly blunted the endotoxin-induced increase in DHEA secretion (p = .001), whereas the increase in cortisol and ACTH was not affected.Acute endotoxemia leads to a rise in plasma DHEA levels in humans. Maximum levels of DHEA but not cortisol or ACTH were blunted by ibuprofen, suggesting a different regulation of these synthetic pathways in the adrenal cortex inner zone during acute inflammation.

The clinical, radiographic, and pathologic correlates of acute respiratory failure due to Pneumocystis carinii pneumonia were studied in 12 renal transplant patients treated with cyclosporin (CS) and prednisone. Six patients required only supplemental oxygen, while the other six patients developed the adult respiratory distress syndrome (ARDS) requiring prolonged mechanical ventilation despite similar predisposing factors and prompt initiation of therapy. Ten (83%) patients survived. Increased frequency of human leukocyte antigen (HLA) DR6 was noted in six of the 11 patients tested. The resolution of radiographic infiltrates was significantly slower in ARDS patients; however, there was no apparent difference in the severity of early alveolar damage between the two groups. There was also no association between the development of ARDS due to P. carinii pneumonia and the mean daily dose of CS and prednisone, the presence of cytomegalovirus infection or pneumonia, HLA-DR6 antigen, or initial hypoxemia.