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Background: It is unknown whether lung-protective ventilation is applied in burn patients and whether they benefit from it. This study aimed to determine ventilation practices in burn intensive care units (ICUs) and investigate the association between lung-protective ventilation and the number of ventilator-free days and alive at day 28 (VFD-28). Methods: This is an international prospective observational cohort study including adult burn patients requiring mechanical ventilation. Low tidal volume (V T) was defined as V T ≤ 8 mL/kg predicted body weight (PBW). Levels of positive end-expiratory pressure (PEEP) and maximum airway pressures were collected. The association between V T and VFD-28 was analyzed using a competing risk model. Ventilation settings were presented for all patients, focusing on the first day of ventilation. We also compared ventilation settings between patients with and without inhalation trauma. Results: A total of 160 patients from 28 ICUs in 16 countries were included. Low V T was used in 74% of patients, median V T size was 7.3 [interquartile range (IQR) 6.2-8.3] mL/kg PBW and did not differ between patients with and without inhalation trauma (p = 0.58). Median VFD-28 was 17 (IQR 0-26), without a difference between ventilation with low or high V T (p = 0.98). All patients were ventilated with PEEP levels ≥5 cmH2O; 80% of patients had maximum airway pressures

Detection of diaphragmatic muscle activity during invasive ventilation may provide valuable information about patient-ventilator interactions. Transesophageal electromyography of the diaphragm ([Formula: see text]) is used in neurally adjusted ventilatory assist. This technique is invasive and can only be applied with one specific ventilator. Surface electromyography of the diaphragm ([Formula: see text]) is noninvasive and can potentially be applied with all types of ventilators. The primary objective of our study was to compare the ability of diaphragm activity detection between [Formula: see text] and [Formula: see text].In this single-center pilot study, [Formula: see text] and [Formula: see text] recordings were obtained simultaneously for 15 min in adult subjects in the ICU who were invasively ventilated. The number of breathing efforts detected by [Formula: see text] and [Formula: see text] were determined. The percentage of detected breathing efforts by [Formula: see text] compared with [Formula: see text] was calculated. Temporal and signal strength relations on optimum recordings of 10 breaths per subject were also compared. The Spearman correlation coefficient was used to determine the correlation between [Formula: see text] and [Formula: see text]. Agreement was calculated by using Bland-Altman statistics.Fifteen subjects were included. The [Formula: see text] detected 3,675 breathing efforts, of which 3,162 (86.0%) were also detected by [Formula: see text]. A statistically significant temporal correlation (r = 0.95,Analysis of our results showed that [Formula: see text] was not reliable for breathing effort detection in subjects who were invasively ventilated compared with [Formula: see text]. In stable recordings, however, [Formula: see text] and [Formula: see text] had excellent temporal correlation and good agreement. With optimization of signal stability, [Formula: see text] may become a useful monitoring tool.

OBJECTIVE: Ventilation strategies aiming at prevention of ventilator-induced lung injury (VILI), including low tidal volumes (VT) and use of positive end-expiratory pressures (PEEP) are increasingly used in critically ill patients. It is uncertain whether ventilation practices changed in a similar way in burn patients. Our objective was to describe applied ventilator settings and their relation to development of VILI in burn patients. DATA SOURCES: Systematic search of the literature in PubMed and EMBASE using MeSH, EMTREE terms and keywords referring to burn or inhalation injury and mechanical ventilation. STUDY SELECTION: Studies reporting ventilator settings in adult or pediatric burn or inhalation injury patients receiving mechanical ventilation during the ICU stay. DATA EXTRACTION: Two authors independently screened abstracts of identified studies for eligibility and performed data extraction. DATA SYNTHESIS: The search identified 35 eligible studies. VT declined from 14 ml/kg in studies performed before to around 8 ml/kg predicted body weight in studies performed after 2006. Low-PEEP levels (

Rationale: Myocardial injury occurs frequently during sepsis and is independently associated with mortality. However, its etiology remains largely unknown. Objectives: To assess the relative contributions of hyperinflammation, activated coagulation, and endothelial dysfunction to myocardial injury in critically ill patients with sepsis. Methods: We included consecutive patients with sepsis presenting to two tertiary intensive care units in the Netherlands between 2011 and 2013. High-sensitivity cardiac troponin I as well as a wide range of plasma biomarkers related to inflammation, coagulation, and endothelial function were measured. Structural equation modeling was used to construct latent variables representing each of these pathophysiological constructs and to subsequently study their associations with troponin elevation while adjusting for confounders. Results: We analyzed 908 (88%) of 1,037 eligible patients, 553 (61%) of whom had raised high-sensitivity cardiac troponin I levels upon intensive care unit admission. The latent variables included interleukin (IL)-6, IL-8, and IL-1b for inflammation; platelet count, prothrombin time, and protein C for coagulation; and soluble E-selectin, intercellular adhesion molecule-1, and angiopoietin-2 for endothelial function. After adjustment for age and cardiovascular comorbidities, structural equation modeling analysis showed that activated coagulation was independently associated with elevated troponin during sepsis (standardized regression coefficient, 0.551; 95% confidence interval [CI], 0.257-0.845; P,0.001) whereas hyperinflammation and endothelial dysfunction were not (standardized regression coefficient, 20.161; 95% CI, 20.418 to 0.096 and 20.054; 95% CI, 20.168 to 0.060, respectively). Conclusions: Our findings suggest that myocardial injury during sepsis is mediated by systemic activation of coagulation rather than by circulating inflammatory mediators or activation of the endothelium. These findings may guide evaluation of strategies to protect the myocardium during sepsis. Clinical trial registered with clinicaltrials.gov (NCT01905033).

Rationale: Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment. Objectives: To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS. Methods: This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latentclass analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS. Measurements and Main Results: We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive"subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed"subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles. Conclusions: The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients.

Background: A prolonged prothrombin time (PT) is a common feature in sepsis indicating consumptive coagulopathy., Objectives: To determine the association between a prolonged PT and aberrations in other host response mechanisms in sepsis., Methods: Patients admitted to the intensive care unit with sepsis were divided in quartiles according to the highest PT value measured within 24 h after admission. The host response was evaluated by measuring 19 plasma biomarkers reflecting pathways implicated in sepsis pathogenesis and by blood leukocyte gene expression profiling., Measurements and main results: Of 1524 admissions for sepsis, 386 (25.3%) involved patients with a normal PT (≤12.7 s); the remaining quartiles entailed 379 (24.9%) patients with a slightly prolonged PT (12.8 ≤ PT ≤ 15.0 s), 383 (25.1%) with an intermediately prolonged PT (15.1 ≤ PT ≤ 17.2 s), and 376 (24.7%) with an extremely prolonged PT (≥17.3 s). While patients with an extremely prolonged PT showed an increased crude mortality up to 1 year after admission, none of the prolonged PT groups was independently associated with 30-day adjusted mortality. Comparison of the host response between patients with a normal PT or an extremely prolonged PT matched for baseline characteristics including severity of disease showed that an extremely prolonged PT was associated with impaired anticoagulant mechanisms, a more disturbed endothelial barrier integrity and increased systemic inflammation, and blood leukocyte transcriptomes indicating more prominent metabolic reprogramming and protein catabolism., Conclusion: A prolonged PT is associated with stronger anomalies in pathways implicated in the pathogenesis of sepsis, suggesting that activation of coagulation impacts other host response mechanisms., peer-reviewed

BACKGROUND: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin. METHODS: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility. RESULTS: The study was prematurely stopped after inclusion of 13 patients (heparin N = 7, placebo N = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations. CONCLUSION: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients. ispartof: Journal of Clinical Medicine vol:9 issue:4 ispartof: location:Switzerland status: published

Severe burn injury is associated with systemic coagulopathy. The changes in coagulation described in patients with severe burns resemble those found patients with sepsis or major trauma. Coagulopathy in patients with severe burns is characterized by procoagulant changes, and impaired fibrinolytic and natural anticoagulation systems. Both the timing of onset and the severity of hemostatic derangements are related to the severity of the burn. The exact pathophysiology and time course of coagulopathy are uncertain, but, at least in part, result from hemodilution and hypothermia. As the occurrence of coagulopathy in patients with severe burns is associated with increased comorbidity and mortality, coagulopathy could be seen as a potential therapeutic target. Clear guidelines for the treatment of coagulopathy in patients with severe burns are lacking, but supportive measures and targeted treatments have been proposed. Supportive measures are aimed at avoiding preventable triggers such as tissue hypoperfusion caused by shock, or hemodilution and hypothermia following the usually aggressive fluid resuscitation in these patients. Suggested targeted treatments that could benefit patients with severe burns include systemic treatment with anticoagulants, but sufficient randomized controlled trial evidence is lacking.

Rationale: Myocardial injury, as reflected by elevated cardiac troponin levels in plasma, is common in patients with community-acquired pneumonia (CAP), but its temporal dynamics and etiology remain unknown. Objectives: Our aim was to determine the incidence of troponin release in patients with CAP and identify risk factors that may point to underlying etiologic mechanisms. Methods: We included consecutive patients admitted with severe CAP to two intensive care units in the Netherlands between 2011 and 2015. High-sensitivity cardiac troponin I was measured daily during the first week. We used multivariable linear regression to identify variables associated with troponin release on admission, and we used mixed-effects regression to model the daily rise and fall of troponin levels over time. Results: Of 200 eligible patients, 179 were included, yielding 792 observation days. A total of 152 (85%) patients developed raised troponin levels greater than 26 ng/L. Baseline factors independently associated with troponin release included coronary artery disease (176% increase; 95% confidence interval [CI], 11–589), smoking (248% increase; 95% CI, 33–809), and higher Acute Physiology and Chronic Health Evaluation IV score (2% increase; 95% CI, 0.8–3.3), whereas Staphylococcus aureus as a causative pathogen was protective (70% reduction; 95% CI, 18–89). Time-dependent risk factors independently associated with daily increase in troponin concentrations included reduced platelet count (2.3% increase; 95% CI, 0.6–4), tachycardia (1.5% increase; 95% CI, 0.1–2.9), hypotension (6.2% increase; 95% CI, 2.1–10.6), dobutamine use (44% increase; 95% CI, 12–85), prothrombin time (8.2% increase; 95% CI, 0.2–16.9), white cell count (1.7% increase; 95% CI, 0–3.5), and fever (22.7% increase; 95% CI, 0.1–49.6). Conclusions: Cardiac injury develops in a majority of patients with severe CAP. Myocardial oxygen supply–demand mismatch and activated inflammation/coagulation are associated with this injury.

Summary Background Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. Methods This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. Findings The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1–4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0·022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1·86 [95% CI 1·21–2·86]; p=0·0045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0·64 [0·40–1·04]; p=0·061), 16 (23%) of 71 people with a Mars3 endotype (HR 0·71 [0·41–1·22]; p=0·19), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1·13 [0·63–2·04]; p=0·69). Analysis of the net reclassification improvement using a combined clinical and endotype model significantly improved risk prediction to 0·33 (0·09–0·58; p=0·008). A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. Only Mars1 was consistently significantly associated with 28-day mortality across the cohorts. To facilitate possible clinical use, a biomarker was derived for each endotype; BPGM and TAP2 reliably identified patients with a Mars1 endotype. Interpretation This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission. Detection of sepsis endotypes might assist in providing personalised patient management and in selection for trials. Funding Center for Translational Molecular Medicine, Netherlands.

Background: Sepsis is frequently complicated by the release of cardiac troponin, but the clinical significance of this myocardial injury remains unclear. We studied the associations between troponin release during sepsis and 1-year outcomes. Methods and Results: We enrolled consecutive patients with sepsis in 2 Dutch intensive care units between 2011 and 2013. Subjects with a clinically apparent cause of troponin release were excluded. High-sensitivity cardiac troponin I (hs-cTnI) concentration in plasma was measured daily during the first 4 intensive care unit days, and multivariable Cox regression analysis was used to model its association with 1-year mortality while adjusting for confounding. In addition, we studied cardiovascular morbidity occurring during the first year after hospital discharge. Among 1258 patients presenting with sepsis, 1124 (89%) were eligible for study inclusion. Hs-cTnI concentrations were elevated in 673 (60%) subjects on day 1, and 755 (67%) ever had elevated levels in the first 4 days. Cox regression analysis revealed that high hs-cTnI concentrations were associated with increased death rates during the first 14 days (adjusted hazard ratio, 1.72; 95% confidence interval, 1.14–2.59 and hazard ratio, 1.70; 95% confidence interval, 1.10–2.62 for hs-cTnI concentrations of 100–500 and >500 ng/L, respectively) but not thereafter. Furthermore, elevated hs-cTnI levels were associated with the development of cardiovascular disease among 200 hospital survivors who were analyzed for this end point (adjusted subdistribution hazard ratio, 1.25; 95% confidence interval, 1.04–1.50). Conclusions: Myocardial injury occurs in the majority of patients with sepsis and is independently associated with early—but not late—mortality, as well as postdischarge cardiovascular morbidity.

Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho-alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator-induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ARDS and pneumonia.

Pulmonary coagulopathy is a hallmark of lung injury following inhalation trauma. Locally applied heparin attenuates lung injury in animal models of smoke inhalation. Whether local treatment with heparin benefits patients with inhalation trauma is uncertain. The present trial aims at comparing a strategy using frequent nebulizations of heparin with standard care in intubated and ventilated burn patients with bronchoscopically confirmed inhalation trauma. The Randomized Controlled Trial Investigating the Efficacy and Safety of Nebulized HEParin versus Placebo in BURN Patients with Inhalation Trauma (HEPBURN) is an international multi-center, double-blind, placebo-controlled, two-arm study. One hundred and sixteen intubated and ventilated burn patients with confirmed inhalation trauma are randomized to nebulizations of heparin (the nebulized heparin strategy) or nebulizations of normal saline (the control strategy) every four hours for 14 days or until extubation, whichever comes first. The primary endpoint is the number of ventilator-free days, defined as days alive and breathing without assistance during the first 28 days, if the period of unassisted breathing lasts for at least 24 consecutive hours. As far as the authors know, HEPBURN is the first randomized, placebo-controlled trial, powered to investigate whether local treatment with heparin shortens duration of ventilation of intubated and ventilated burn patients with inhalation trauma. NCT01773083 ( http://www.clinicaltrials.gov ), registered on 16 January 2013. Recruiting. Randomisation commenced on 1 January 2014.

Mechanical ventilation has the potential to induce pulmonary coagulopathy. Local treatment by nebulization of heparin could be beneficial in ventilated patients. The aim of this data metaanalysis is to determine the association between nebulization of heparin and outcome of mechanically ventilated critically ill patients.

Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severeStreptococcus pneumoniaepneumonia. Rats were intra–tracheally challenged withS. pneumoniaeto induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56–2.59] and at 40 h 2.08 % [0.98–5.12], compared to 0.50 % [0.07–0.59] and 0.03 % [0.03–0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16–1.93] and at 40 h 2.38 % [0.54–4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severeS. pneumoniaepneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

Pulmonary coagulopathy is a characteristic feature of lung injury including ventilator-induced lung injury. The aim of this individual patient data meta-analysis is to assess the effects of nebulized anticoagulants on outcome of ventilated intensive care unit (ICU) patients. A systematic search of PubMed (1966–2014), Scopus, EMBASE, and Web of Science was conducted to identify relevant publications. Studies evaluating nebulization of anticoagulants in ventilated patients were screened for inclusion, and corresponding authors of included studies were contacted to provide individual patient data. The primary endpoint was the number of ventilator-free days and alive at day 28. Secondary endpoints included hospital mortality, ICU- and hospital-free days at day 28, and lung injury scores at day seven. We constructed a propensity score-matched cohort for comparisons between patients treated with nebulized anticoagulants and controls. Data from five studies (one randomized controlled trial, one open label study, and three studies using historical controls) were included in the meta-analysis, compassing 286 patients. In all studies unfractionated heparin was used as anticoagulant. The number of ventilator-free days and alive at day 28 was higher in patients treated with nebulized heparin compared to patients in the control group (14 [IQR 0–23] vs. 6 [IQR 0–22]), though the difference did not reach statistical significance (P = 0.459). The number of ICU-free days and alive at day 28 was significantly higher, and the lung injury scores at day seven were significantly lower in patients treated with nebulized heparin. In the propensity score-matched analysis, there were no differences in any of the endpoints. This individual patient data meta-analysis provides no convincing evidence for benefit of heparin nebulization in intubated and ventilated ICU patients. The small patient numbers and methodological shortcomings of included studies underline the need for high-quality well-powered randomized controlled trials. Electronic supplementary material The online version of this article (doi:10.1186/s13613-016-0138-4) contains supplementary material, which is available to authorized users.

While complement protein deficiencies are associated with severe and recurrent pulmonary infections, excessive complement activation plays a role in the pathogenesis of lung injury. We hypothesized that inhibition of the complement system by repetitive treatment with nebulized plasma-derived human C1-esterase inhibitor (C1-INH) reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation in a model of severe Streptococcus pneumoniae pneumonia.