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Background: Transfusion guidelines regarding platelet-count thresholds before the placement of a central venous catheter (CVC) offer conflicting recommendations because of a lack of good-quality evidence. The routine use of ultrasound guidance has decreased CVC-related bleeding complications., Methods: In a multicenter, randomized, controlled, noninferiority trial, we randomly assigned patients with severe thrombocytopenia (platelet count, 10,000 to 50,000 per cubic millimeter) who were being treated on the hematology ward or in the intensive care unit to receive either one unit of prophylactic platelet transfusion or no platelet transfusion before ultrasound-guided CVC placement. The primary outcome was catheter-related bleeding of grade 2 to 4; a key secondary outcome was grade 3 or 4 bleeding. The noninferiority margin was an upper boundary of the 90% confidence interval of 3.5 for the relative risk., Results: We included 373 episodes of CVC placement involving 338 patients in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval [CI], 1.27 to 4.70). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI, 0.75 to 7.93). A total of 15 adverse events were observed; of these events, 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement., Conclusions: The withholding of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter did not meet the predefined margin for noninferiority and resulted in more CVC-related bleeding events than prophylactic platelet transfusion. (Funded by ZonMw; PACER Dutch Trial Register number, NL5534.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Carriership with methicillin resistant Staphylococcus aureus (MRSA) is a risk for the development of secondary infections in critically ill patients. Previous studies suggest that enteral vancomycin is able to eliminate enteral carriership with MRSA. Data on individual effects of this treatment are lacking., Methods: Retrospective analysis of a database containing 15 year data of consecutive patients from a mixed medical-(cardio)surgical 18 bedded intensive care unit was conducted. All consecutive critically ill patients with enteral MRSA carriership detected in throat and/or rectal samples were collected. We analyzed those with follow-up cultures to determine the success rate of enteral vancomycin. Topical application of 2% vancomycin in a sticky oral paste was performed combined with a vancomycin solution of 500 mg four times daily in the nasogastric tube. This treatment was added to a regimen of selective digestive tract decontamination (SDD) to prevent ICU acquired infection., Results: Thirteen patients were included. The mean age was 65 years and the median APACHE II score was 21. MRSA was present in the throat in 8 patients and in both throat and rectum in 5 patients. In all patients MRSA was successfully eliminated from both throat and rectum, which took 2-11 days with a median duration until decontamination of 4 days. Secondary infections with MRSA did not occur., Conclusions: Topical treatment with vancomycin in a 2% sticky oral paste four times daily in the nasogastric tube was effective in all patients in the elimination of MRSA and prevented secondary MRSA infections.

Background: Mechanical ventilation with low tidal volumes has the potential to mitigate ventilation-induced lung injury, yet the clinical effect of tidal volume size on myocardial function has not been clarified. This cross-sectional study investigated whether low tidal volume ventilation has beneficial effects on myocardial systolic and diastolic function compared to intermediate tidal volume ventilation., Methods: Forty-two mechanically ventilated patients without acute respiratory distress syndrome (ARDS) underwent transthoracic echocardiography after more than 24 h of mechanical ventilation according to the Protective Ventilation in Patients without ARDS (PReVENT) trial comparing a low versus intermediate tidal volume strategy. The primary outcome was left ventricular and right ventricular myocardial performance index as measure for combined systolic and diastolic function, with lower values indicating better myocardial function and a right ventricular myocardial performance index greater than 0.54 regarded as the abnormality threshold. Secondary outcomes included specific systolic and diastolic parameters., Results: One patient was excluded due to insufficient acoustic windows, leaving 21 patients receiving low tidal volumes with a tidal volume size (mean ± SD) of 6.5 ± 1.8 ml/kg predicted body weight, while 20 patients were subjected to intermediate tidal volumes receiving a tidal volume size of 9.5 ± 1.6 ml/kg predicted body weight (mean difference, -3.0 ml/kg; 95% CI, -4.1 to -2.0; P < 0.001). Right ventricular dysfunction was reduced in the low tidal volume group compared to the intermediate tidal volume group (myocardial performance index, 0.41 ± 0.13 vs. 0.64 ± 0.15; mean difference, -0.23; 95% CI, -0.32 to -0.14; P < 0.001) as was left ventricular dysfunction (myocardial performance index, 0.50 ± 0.17 vs. 0.63 ± 0.19; mean difference, -0.13; 95% CI, -0.24 to -0.01; P = 0.030). Similarly, most systolic parameters were superior in the low tidal volume group compared to the intermediate tidal volume group, yet diastolic parameters did not differ between both groups., Conclusions: In patients without ARDS, intermediate tidal volume ventilation decreased left ventricular and right ventricular systolic function compared to low tidal volume ventilation, although without an effect on diastolic function.

Importance: It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS)., Objective: To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy., Design, Setting, and Participants: A randomized clinical trial, conducted from September 1, 2014, through August 20, 2017, including patients without ARDS expected to not be extubated within 24 hours after start of ventilation from 6 intensive care units in the Netherlands., Interventions: Invasive ventilation using low tidal volumes (n = 477) or intermediate tidal volumes (n = 484)., Main Outcomes and Measures: The primary outcome was the number of ventilator-free days and alive at day 28. Secondary outcomes included length of ICU and hospital stay; ICU, hospital, and 28- and 90-day mortality; and development of ARDS, pneumonia, severe atelectasis, or pneumothorax., Results: In total, 961 patients (65% male), with a median age of 68 years (interquartile range [IQR], 59-76), were enrolled. At day 28, 475 patients in the low tidal volume group had a median of 21 ventilator-free days (IQR, 0-26), and 480 patients in the intermediate tidal volume group had a median of 21 ventilator-free days (IQR, 0-26) (mean difference, -0.27 [95% CI, -1.74 to 1.19]; P = .71). There was no significant difference in ICU (median, 6 vs 6 days; 0.39 [-1.09 to 1.89]; P = .58) and hospital (median, 14 vs 15 days; -0.60 [-3.52 to 2.31]; P = .68) length of stay or 28-day (34.9% vs 32.1%; hazard ratio [HR], 1.12 [0.90 to 1.40]; P = .30) and 90-day (39.1% vs 37.8%; HR, 1.07 [0.87 to 1.31]; P = .54) mortality. There was no significant difference in the percentage of patients developing the following adverse events: ARDS (3.8% vs 5.0%; risk ratio [RR], 0.86 [0.59 to 1.24]; P = .38), pneumonia (4.2% vs 3.7%; RR, 1.07 [0.78 to 1.47]; P = .67), severe atelectasis (11.4% vs 11.2%; RR, 1.00 [0.81 to 1.23]; P = .94), and pneumothorax (1.8% vs 1.3%; RR, 1.16 [0.73 to 1.84]; P = .55)., Conclusions and Relevance: In patients in the ICU without ARDS who were expected not to be extubated within 24 hours of randomization, a low tidal volume strategy did not result in a greater number of ventilator-free days than an intermediate tidal volume strategy., Trial Registration: ClinicalTrials.gov Identifier: NCT02153294.

Purpose: The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury., Methods: We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume., Results: Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01-1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02-1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07-3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher V T ., Conclusions: Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).

Background: Evidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs. We hypothesize that ventilation with low PEEP is noninferior to ventilation with high PEEP with regard to the number of ventilator-free days and being alive at day 28 in this population.  METHODS/DESIGN: The "REstricted versus Liberal positive end-expiratory pressure in patients without ARDS" trial (RELAx) is a national, multicenter, randomized controlled, noninferiority trial in adult intensive care unit (ICU) patients with uninjured lungs who are expected not to be extubated within 24 h. RELAx will run in 13 ICUs in the Netherlands to enroll 980 patients under invasive ventilation. In all patients, low tidal volumes are used. Patients assigned to ventilation with low PEEP will receive the lowest possible PEEP between 0 and 5 cm H 2 O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H 2 O. The primary endpoint is the number of ventilator-free days and being alive at day 28, a composite endpoint for liberation from the ventilator and mortality until day 28, with a noninferiority margin for a difference between groups of 0.5 days. Secondary endpoints are length of stay (LOS), mortality, and occurrence of pulmonary complications, including severe hypoxemia, major atelectasis, need for rescue therapies, pneumonia, pneumothorax, and development of acute respiratory distress syndrome (ARDS). Hemodynamic support and sedation needs will be collected and compared., Discussion: RELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP., Trial Registration: ClinicalTrials.gov , ID: NCT03167580 . Registered on 23 May 2017.

Background: The majority of critically ill patients do not suffer from acute respiratory distress syndrome (ARDS). To improve the treatment of these patients, we aimed to identify potentially modifiable factors associated with outcome of these patients., Methods: The PRoVENT was an international, multicenter, prospective cohort study of consecutive patients under invasive mechanical ventilatory support. A predefined secondary analysis was to examine factors associated with mortality. The primary endpoint was all-cause in-hospital mortality., Results: 935 Patients were included. In-hospital mortality was 21%. Compared to patients who died, patients who survived had a lower risk of ARDS according to the 'Lung Injury Prediction Score' and received lower maximum airway pressure (P max ), driving pressure (ΔP), positive end-expiratory pressure, and FiO 2 levels. Tidal volume size was similar between the groups. Higher P max was a potentially modifiable ventilatory variable associated with in-hospital mortality in multivariable analyses. ΔP was not independently associated with in-hospital mortality, but reliable values for ΔP were available for 343 patients only. Non-modifiable factors associated with in-hospital mortality were older age, presence of immunosuppression, higher non-pulmonary sequential organ failure assessment scores, lower pulse oximetry readings, higher heart rates, and functional dependence., Conclusions: Higher P max was independently associated with higher in-hospital mortality in mechanically ventilated critically ill patients under mechanical ventilatory support for reasons other than ARDS. Trial Registration ClinicalTrials.gov (NCT01868321).

Background: Scant information exists about the epidemiological characteristics and outcome of patients in the intensive care unit (ICU) at risk of acute respiratory distress syndrome (ARDS) and how ventilation is managed in these individuals. We aimed to establish the epidemiological characteristics of patients at risk of ARDS, describe ventilation management in this population, and assess outcomes compared with people at no risk of ARDS., Methods: PRoVENT (PRactice of VENTilation in critically ill patients without ARDS at onset of ventilation) is an international, multicentre, prospective study undertaken at 119 ICUs in 16 countries worldwide. All patients aged 18 years or older who were receiving mechanical ventilation in participating ICUs during a 1-week period between January, 2014, and January, 2015, were enrolled into the study. The Lung Injury Prediction Score (LIPS) was used to stratify risk of ARDS, with a score of 4 or higher defining those at risk of ARDS. The primary outcome was the proportion of patients at risk of ARDS. Secondary outcomes included ventilatory management (including tidal volume [V T ] expressed as mL/kg predicted bodyweight [PBW], and positive end-expiratory pressure [PEEP] expressed as cm H 2 O), development of pulmonary complications, and clinical outcomes. The PRoVENT study is registered at ClinicalTrials.gov, NCT01868321. The study has been completed., Findings: Of 3023 patients screened for the study, 935 individuals fulfilled the inclusion criteria. Of these critically ill patients, 282 were at risk of ARDS (30%, 95% CI 27-33), representing 0·14 cases per ICU bed over a 1-week period. V T was similar for patients at risk and not at risk of ARDS (median 7·6 mL/kg PBW [IQR 6·7-9·1] vs 7·9 mL/kg PBW [6·8-9·1]; p=0·346). PEEP was higher in patients at risk of ARDS compared with those not at risk (median 6·0 cm H 2 O [IQR 5·0-8·0] vs 5·0 cm H 2 O [5·0-7·0]; p<0·0001). The prevalence of ARDS in patients at risk of ARDS was higher than in individuals not at risk of ARDS (19/260 [7%] vs 17/556 [3%]; p=0·004). Compared with individuals not at risk of ARDS, patients at risk of ARDS had higher in-hospital mortality (86/543 [16%] vs 74/232 [32%]; p<0·0001), ICU mortality (62/533 [12%] vs 66/227 [29%]; p<0·0001), and 90-day mortality (109/653 [17%] vs 88/282 [31%]; p<0·0001). V T did not differ between patients who did and did not develop ARDS (p=0·471 for those at risk of ARDS; p=0·323 for those not at risk)., Interpretation: Around a third of patients receiving mechanical ventilation in the ICU were at risk of ARDS. Pulmonary complications occur frequently in patients at risk of ARDS and their clinical outcome is worse compared with those not at risk of ARDS. There is potential for improvement in the management of patients without ARDS. Further refinements are needed for prediction of ARDS., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Protective mechanical ventilation with low tidal volumes is standard of care for patients with acute respiratory distress syndrome. The aim of this individual patient data analysis was to determine the association between tidal volume and the occurrence of pulmonary complications in ICU patients without acute respiratory distress syndrome and the association between occurrence of pulmonary complications and outcome in these patients., Design: Individual patient data analysis., Patients: ICU patients not fulfilling the consensus criteria for acute respiratory distress syndrome at the onset of ventilation., Interventions: Mechanical ventilation with low tidal volume., Measurements and Main Results: The primary endpoint was development of a composite of acute respiratory distress syndrome and pneumonia during hospital stay. Based on the tertiles of tidal volume size in the first 2 days of ventilation, patients were assigned to a "low tidal volume group" (tidal volumes ≤ 7 mL/kg predicted body weight), an "intermediate tidal volume group" (> 7 and < 10 mL/kg predicted body weight), and a "high tidal volume group" (≥ 10 mL/kg predicted body weight). Seven investigations (2,184 patients) were included. Acute respiratory distress syndrome or pneumonia occurred in 23% of patients in the low tidal volume group, in 28% of patients in the intermediate tidal volume group, and in 31% of the patients in the high tidal volume group (adjusted odds ratio [low vs high tidal volume group], 0.72; 95% CI, 0.52-0.98; p = 0.042). Occurrence of pulmonary complications was associated with a lower number of ICU-free and hospital-free days and alive at day 28 (10.0 ± 10.9 vs 13.8 ± 11.6 d; p < 0.01 and 6.1 ± 8.1 vs 8.9 ± 9.4 d; p < 0.01) and an increased hospital mortality (49.5% vs 35.6%; p < 0.01)., Conclusions: Ventilation with low tidal volumes is associated with a lower risk of development of pulmonary complications in patients without acute respiratory distress syndrome.

Purpose: To evaluate the predictive value of 6 different biomarkers in the development of multiple-organ failure (MOF) and mortality in a contemporary prospective cohort of acute respiratory distress syndrome (ARDS)., Methods: Patients with ARDS admitted to a tertiary referral center during an 8-month period were included. Plasma sample collection of 6 different biomarkers on days 1, 3, and 5 after ARDS onset was performed (von Willebrand factor, thrombin-antithrombin III complex, plasminogen activator inhibitor 1, interleukin 8, receptor for advanced glycation end-products, and club cell secretory protein). Main outcomes included hospital mortality and development of MOF. Logistic regression models for MOF and mortality prediction were created including biomarkers levels and clinical predictors., Results: One hundred patients were included in the study. Do-not-resuscitate status and McCabe score were independently associated with increased mortality. None of the 6 biomarkers measured at the time of ARDS diagnosis predicted hospital mortality. After adjustment for important clinical characteristics, elevated day-1 interleukin 8 levels were associated with the development of MOF., Conclusions: Addition of biomarkers did not improve mortality prediction in this cohort of ARDS. Association between elevated interleukin 8 levels and progression of organ failures suggests an important role of exaggerated inflammatory response in the development of MOF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Mechanical ventilation with lower tidal volumes (≤6 ml/kg of predicted body weight, PBW) could benefit patients without acute respiratory distress syndrome (ARDS). However, tidal volume reduction could be associated with increased patient discomfort and sedation needs, and consequent longer duration of ventilation. The aim of this individual patient data meta-analysis was to assess the associations between tidal volume size, duration of mechanical ventilation, and sedation needs in patients without ARDS., Methods: Studies comparing ventilation with different tidal volume sizes in patients without ARDS were screened for inclusion. Corresponding authors were asked to provide individual participant data. Patients were assigned to three groups based on tidal volume size (≤6 ml/kg PBW, 6-10 ml/kg PBW, or ≥10 ml/kg PBW). Ventilator-free days, alive at day 28, and dose and duration of sedation (propofol and midazolam), analgesia (fentanyl and morphine), and neuromuscular blockade (NMB) were compared., Results: Seven investigations (2,184 patients) were included in the analysis. The number of patients breathing without assistance by day 28 was higher in the group ventilated with tidal volume ≤6 ml/kg PBW compared to those ventilated with tidal volume ≥10 ml/kg PBW (93.1 vs. 88.6%; p = 0.027, respectively). Only two investigations (187 patients) could be included in the meta-analysis of sedation needs. There were neither differences in the percentage of study days that patients received sedatives, opioids, or NMBA nor in the total dose of benzodiazepines, propofol, opioids, and NMBA., Conclusions: This meta-analysis suggests that use of lower tidal volumes in patients without ARDS at the onset of mechanical ventilation could be associated with shorter duration of ventilation. Use of lower tidal volumes seems not to affect sedation or analgesia needs, but this must be confirmed in a robust, well-powered randomized controlled trial.

Background: Serum levels of N-terminal proB-type natriuretic peptide (NT-proBNP) are elevated in patients acute respiratory distress syndrome (ARDS). Recent studies showed a lower incidence of acute cor pulmonale in ARDS patients ventilated with lower tidal volumes. Consequently, serum levels of NT-proBNP may be lower in these patients. We investigated the relation between serum levels of NT-proBNP and tidal volumes in critically ill patients without ARDS at the onset of mechanical ventilation., Methods: Secondary analysis of a randomized controlled trial of lower versus conventional tidal volumes in patients without ARDS. NT-pro BNP were measured in stored serum samples. Serial serum levels of NT-pro BNP were analyzed controlling for acute kidney injury, cumulative fluid balance and presence of brain injury. The primary outcome was the effect of tidal volume size on serum levels of NT-proBNP. Secondary outcome was the association with development of ARDS., Results: Samples from 150 patients were analyzed. No relation was found between serum levels of NT-pro BNP and tidal volume size. However, NT-proBNP levels were increasing in patients who developed ARDS. In addition, higher levels were observed in patients with acute kidney injury, and in patients with a more positive cumulative fluid balance., Conclusion: Serum levels of NT-proBNP are independent of tidal volume size, but are increasing in patients who develop ARDS.

Introduction: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies., Objective: To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI., Design, Setting, and Patients: Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (V(T), 10 mL/kg) with low tidal volume (V(T), 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase-associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4., Results: Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P = .88.) The courses of neutrophil gelatinase-associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups., Conclusion: In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objective. Bronchoalveolar coagulopathy is a characteristic feature of pulmonary inflammation. We compared bronchoalveolar and systemic levels of coagulation in patients who did and patients who did not develop ventilator-associated lung injury (VALI). Methods. Secondary analysis of a randomized controlled trial evaluating the effect of lower tidal volumes versus conventional tidal volumes in patients without acute lung injury or acute respiratory distress syndrome at the onset of mechanical ventilation. Results. Ten patients with VALI and 10 random control patients without lung injury during the course of mechanical ventilation, but all ventilated with conventional tidal volumes, were compared. Patients who developed VALI showed both bronchoalveolar activation of coagulation (increase in thrombin-antithrombin complex levels P < 0.001 versus baseline) and inhibition of fibrinolysis (decline in plasminogen activator activity P < 0.001 versus baseline). The later seemed to be dependent on higher levels of plasminogen activator inhibitor type 1 (P = 0.001 versus baseline). Patients who developed VALI also showed elevated systemic thrombin-antithrombin complex levels and decreased systemic plasminogen activator activity levels. Conclusions. VALI is characterized by bronchoalveolar coagulopathy. Systemic and bronchoalveolar coagulopathy at the onset of mechanical ventilation may be a risk factor for developing VALI in patients ventilated with conventional tidal volumes.

Background: Pulmonary coagulopathy is intrinsic to pneumonia and other forms of acute lung injury. We hypothesized patients with burn injuries and inhalation trauma to have similar alterations in pulmonary coagulation and fibrinolysis., Methods: We performed a prospective study on changes in pulmonary and systemic thrombin generation and fibrinolytic activity in patients with burn injuries and inhalation trauma requiring mechanical ventilation. Nondirected bronchial lavage was performed on alternate days. Patients requiring mechanical ventilation for nonpulmonary reasons who did not meet the North American European Consensus Conference criteria for acute lung injury functioned as control patients., Results: We studied 13 patients with burn injuries and inhalation trauma and 15 control patients. On admission, patients with burn injuries and inhalation trauma showed a significant increase in thrombin generation in the airways compared with control patients, as reflected by increased lavage fluid levels of thrombin-antithrombin complexes and fibrin degradation products, and decreased lavage fluid levels of activated protein C and antithrombin. Simultaneously, burn patients showed a significant decrease in fibrinolytic activity, as reflected by decreased lavage fluid levels of plasminogen activator activity. Pulmonary coagulopathy persisted throughout the period of mechanical ventilation and was accompanied by similar changes in systemic coagulation and fibrinolysis. There was no significant correlation between changes in coagulation and fibrinolysis and the extent of burn injury., Conclusions: Patients with burn injuries and inhalation trauma requiring mechanical ventilation show a distinct and sustained procoagulant and antifibrinolytic shift in the pulmonary compartment. Pulmonary coagulopathy could be an important therapeutic target in these patients.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Both antibodies and bioactive lipids that have accumulated during storage of blood have been implicated in TRALI pathogenesis. In a single-center, nested, case-control study, patients were prospectively observed for onset of TRALI according to the consensus definition. Of 668 patients, 16 patients (2.4%) developed TRALI. Patient-related risk factors for onset of TRALI were age and time on the cardiopulmonary bypass. Transfusion-related risk factors were total amount of blood products (odds ratio [OR] = 1.2; 95% confidence interval [CI], 1.03-1.44), number of red blood cells stored more than 14 days (OR = 1.6; 95% CI, 1.04-2.37), total amount of plasma (OR = 1.2; 95% CI, 1.03-1.44), presence of antibodies in donor plasma (OR = 8.8; 95% CI, 1.8-44), and total amount of transfused bioactive lipids (OR = 1.0; 95% CI, 1.00-1.07). When adjusted for patient risk factors, only the presence of antibodies in the associated blood products remained a risk factor for TRALI (OR = 14.2; 95% CI, 1.5-132). In-hospital mortality of TRALI was 13% compared with 0% and 3% in transfused and nontransfused patients, respectively (P < .05). In conclusion, the incidence of TRALI is high in cardiac surgery patients and associated with adverse outcome. Our results suggest that cardiac surgery patients may benefit from exclusion of blood products containing HLA/HNA antibodies.

Introduction: Soluble urokinase-type plasminogen activator receptor (suPAR) has been proposed as a biologic marker of fibrinolysis and inflammation. The aim of this study was to investigate the diagnostic and prognostic value of systemic and pulmonary levels of suPAR in burn patients with inhalation trauma who need mechanical ventilation., Methods: suPAR was measured in plasma and nondirected lung-lavage fluid of mechanically ventilated burn patients with inhalation trauma. The samples were obtained on the day of inhalation trauma and on alternate days thereafter until patients were completely weaned from the mechanical ventilator. Mechanically ventilated patients without burns and without pulmonary disease served as controls., Results: Systemic levels of suPAR in burn patients with inhalation trauma were not different from those in control patients. On admission and follow up, pulmonary levels of suPAR in patients with inhalation trauma were significantly higher compared with controls. Pulmonary levels of suPAR highly correlated with pulmonary levels of interleukin 6, a marker of inflammation, and thrombin-antithrombin complexes, markers of coagulation, but not plasminogen activator activity, a marker of fibrinolysis. Systemic levels of suPAR were predictive of the duration of mechanical ventilation and length of intensive care unit (ICU) stay. Duration of mechanical ventilation and length of ICU stay were significantly longer in burn-injury patients with systemic suPAR levels > 9.5 ng/ml., Conclusions: Pulmonary levels of suPAR are elevated in burn patients with inhalation trauma, and they correlate with pulmonary inflammation and coagulation. Although pulmonary levels of suPAR may have diagnostic value in burn-injury patients, systemic levels of suPAR have prognostic value.

Background: Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation., Methods: Plasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation., Results: Plasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed., Conclusion: Plasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.

Background and Objective: Conventional methods to establish pleural infection are time-consuming and sometimes inadequate. Biomarkers may aid in making rapid diagnosis of infection. In an observational study we evaluated and compared the diagnostic value of pleural fluid levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), C-reactive protein and procalcitonin in intensive care patients with pleural effusions., Methods: Thirty-six patients with de novo pleural effusions were included and 20 patients with pleural effusions after cardiothoracic surgery and 20 patients with pleural effusions after esophagus surgery acted as controls. Levels of sTREM-1, C-reactive protein and procalcitonin were measured in pleural effusions., Results: Levels of sTREM-1 were highest in empyemas, followed by infectious exudates. Levels of sTREM-1 were low in transudates and non-infectious exudates. C-reactive protein levels were highest in exudates and empyemas, while procalcitonin levels were highest in exudates. Pleural fluid with positive culture results contained higher sTREM-1 and C-reactive protein levels as compared to samples with negative culture results. A cut-off level of 50pg/mlsTREM-1 yielded a sensitivity of 93% and a specificity of 86%, while these were 87% and 67% respectively for a cut-off value of 7.5microg/ml C-reactive protein, and 60% and 64% respectively for a cut-off value of 0.15 ng/ml procalcitonin., Conclusion: sTREM-1 is superior to C-reactive protein and procalcitonin in detecting infection.

Introduction: Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation., Methods: We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality., Results: One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury., Conclusions: Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation., Trial Registration: ISRCTN82533884.

Background: Despite consensus criteria, diagnosing acute lung injury, or its more severe form acute respiratory distress syndrome (ALI/ARDS) remains challenging. Adding objective measures, such as plasma levels of biological markers could facilitate recognition of ALI/ARDS. This study was designed to assess and compare the diagnostic accuracy of biological markers for ALI/ARDS with ventilator-associated pneumonia (VAP)., Methods: We performed serial measurements of Clara cell protein (CC16), soluble receptor for advanced glycation end products (sRAGE), surfactant protein D (SP-D) and Krebs von den Lungen (KL-6) in plasma of patients with VAP and mechanically ventilated control patients without VAP. ALI/ARDS was diagnosed using the criteria of the North-American European consensus conference., Results: Thirty-seven patients were enrolled - 22 patients with VAP and 15 control patients. Ten patients with pneumonia met the ALI/ARDS consensus criteria. Control patients never met these criteria. Plasma CC16 had a good diagnostic capacity for ALI/ARDS as shown by the receiver operating characteristic curve with an area under the curve of 0.91 (95% confidence interval (CI) 0.79 - 1.00; p < 0.001). Identification of ALI/ARDS patients by sudden increases in plasma CC16 of 30% or more yielded a sensitivity of 90% and a specificity of 92%. Of note, levels of CC16 increased 2 days before ALI/ARDS diagnosis. A cut-off level of 50 ng/ml SP-D yielded a specificity of 100% while the sensitivity was 70%. The area under the curve for SP-D was 0.80 (95% CI 0.58 - 1.00; p = 0.02). The diagnostic accuracies of KL-6 and sRAGE were low., Conclusion: Plasma CC16 seems a potential biological marker for ALI/ARDS in patients with VAP. Plasma levels of sRAGE, SP-D and KL-6 have limited discriminative power for diagnosing ALI/ARDS in VAP.

Identification of patients with ongoing abdominal infection after emergency surgery for abdominal sepsis is difficult. The purpose of this study was to evaluate whether plasma and abdominal fluid sTREM-1 levels can adequately select patients with ongoing abdominal infection. In a single center retrospective observational study, plasma and abdominal fluid samples were collected every 24 h for 4 days in patients who underwent an emergency laparotomy for severe secondary peritonitis. Patients after elective esophagus surgery served as controls. sTREM-1 levels were measured with an ELISA. Plasma sTREM-1 levels were not elevated compared to controls. Abdominal fluid sTREM-1 levels were initially high (median (246 [IQR 121-455] pg/ml), and declined 24 h after surgery (P=0.01). On day 2 and 3, patients with ongoing infection had significantly higher abdominal fluid sTREM-1 levels (319 [180-671] and 245 [173-541] pg/ml, respectively) compared to patients without infection (85 [49-306] and 121 [20-196] pg/ml, respectively). sTREM-1 levels were moderately predictive for persistent infection but had a high negative predictive value (0.86 (95% CI 0.69-0.94) below a cut-off level of 160 pg/ml. In clinical practice, abdominal fluid sTREM-1 levels may be useful for exclusion but not detection of ongoing abdominal infection after surgery for secondary peritonitis.

Critically ill patients frequently suffer from sepsis or localized infections. Diagnosing sepsis can be a challenge since several of its signs overlap with those found with other inflammatory states. Recognition of localized infections can at times be difficult too. While microbiological cultures of blood or other specimens are frequently used to distinguish infection from non-infectious conditions, this diagnostic technique lacks sensitivity and specificity. In addition, there is often a considerable time delay since bacterial cultures may require 24-48 h for analysis, which may be too long for a treatment decision in critically ill patients. Also, the reliability of microbiological cultures decreases in case of prior antimicrobial therapy. Use of biologic markers such as procalcitonin (PCT) or soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been suggested to improve recognition of patients with true infection and facilitate decisions of whether or not to treat. Unfortunately, neither PCT nor sTREM-1 fulfill all expectations. Data on the diagnostic value, in particular of sTREM-1, are contradicting. The combination of systemic PCT and local and/or systemic sTREM-1 could be useful in distinguishing patients with infection from those with non-infectious illness, though. Results from several randomized intervention studies on PCT-guided antimicrobial therapy in sepsis or lower respiratory tract infections show the superiority of PCT in clinical decision making. At present, randomized intervention studies on the potential antimicrobial stewardship of sTREM-1 are lacking.

Clara cell protein levels are elevated in plasma of individuals with mild or subclinical lung injury. We studied the influence of two mechanical ventilation strategies on local and systemic levels of Clara cell protein (CC16) and compared them with levels of soluble receptor for advanced glycation end products (sRAGE) and surfactant proteins (SP)-A and -D in patients undergoing elective surgery. Saved samples from a previously reported investigation were used for the study. Forty patients planned for elective surgery were randomized to mechanical ventilation with either a conventional tidal volume (V(T)) of 12 ml/kg without positive end-expiratory pressure (PEEP) or low V(T) of 6 ml/kg and 10 cmH(2)O PEEP. Plasma and bronchoalveolar lavage fluid (BALF) was collected directly after intubation and after 5 h of mechanical ventilation. While systemic levels of SP-A and SP-D remained unchanged, systemic levels of CC16 and sRAGE increased significantly in both groups after 5 h (P < 0.001 for both). BALF levels of SP-A, SP-D, CC16, and sRAGE remained unaffected. No differences were found between the two mechanical ventilation strategies regarding any of the measured biological markers. In conclusion, systemic levels of CC16 and sRAGE rise after 5 h in patients receiving mechanical ventilation for elective surgery. Mechanical ventilation with lower tidal volumes and PEEP did not have a different effect on levels of biomarkers of lung epithelial injury compared with conventional mechanical ventilation.

Objective: To determine whether feedback and education improve adoption of lung-protective mechanical ventilation (ie, with lower tidal volume [V(T)])., Methods: We conducted a retrospective study of ventilator settings; we used data from 3 consecutive studies of patients with acute lung injury and/or acute respiratory distress syndrome, in the intensive care units of 2 university hospitals in the Netherlands. At site 1 we conducted a time series study of before and after education and feedback about lung-protective mechanical ventilation, and we compared the results from site 1 to the ventilation strategies used at site 2, which did not undergo the education and feedback intervention. Feedback and education consisted of presentations of actual ventilator settings, advised ventilator settings, and discussions on potential reasons for not using lower V(T)., Results: Two studies were performed at site 1, in 1999-2000 (Study 1, n = 22) and in 2002 (Study 2, n = 12). In 2003-2004, Study 3 was performed simultaneously at site 1 (n = 8) and site 2 (n = 17). At site 1, the mean +/- SD V(T) was 10.9 mL/kg predicted body weight (PBW) (95% CI 10.3-11.6) in Study 1 and 9.9 mL/kg PBW (95% CI 9.0-10.8) in Study 2 (difference not significant). After the feedback and education intervention at site 1, V(T) declined to 7.6 mL/kg PBW (95% CI 6.5-8.7) in Study 3 (p = 0.003). At site 2, where no feedback or education were given, V(T) was 10.3 mL/kg PBW (95% CI 9.5-11.0) in Study 3 (p < 0.001 vs Site 1)., Conclusions: Adoption of a lower-V(T) ventilation strategy in patients with acute lung injury or acute respiratory distress syndrome is far from complete in the Netherlands. Adoption of a lower-V(T) strategy improves after feedback and education.

Objectives: This study investigated levels of coagulation and fibrinolysis factors in cerebrospinal fluid (CSF) from adults with bacterial meningitis in relation to development of brain infarction., Methods: CSF was collected from 92 adults with community-acquired bacterial meningitis, who participated in the prospective Dutch Meningitis Cohort Study; 8 patients with viral meningitis and 9 healthy control subjects. Levels of proteins involved in the coagulation cascade were determined by means of immunoassays., Results: Bacterial meningitis was accompanied by local activation of coagulation, as shown by significantly higher CSF soluble tissue factor (P<0.001) and prothrombin fragment F1+2 concentrations (P<0.001) as compared to viral meningitis patients and controls. This was accompanied by a significantly higher D-dimer formation (P<0.001). In addition, in bacterial meningitis fibrinolysis was attenuated, since CSF plasminogen activator inhibitor (PAI)-1 levels were significantly higher as compared to the controls (P=0.02). In patients with bacterial meningitis who developed brain infarction, CSF PAI-1 levels were higher than in those without infarction (P=0.04)., Conclusions: Activation of coagulation and attenuation of fibrinolysis in the CSF are important features of bacterial meningitis; the net effect on fibrin turnover may contribute to the development of brain infarction.

Introduction: We compared the effects of mechanical ventilation with a lower tidal volume (V(T)) strategy versus those of greater V(T) in patients with or without acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) on the use of opioids and sedatives., Methods: This is a secondary analysis of a previously conducted before/after intervention study, which consisting of feedback and education on lung protective mechanical ventilation using lower V(T). We evaluated the effects of this intervention on medication prescriptions from days 0 to 28 after admission to our multidisciplinary intensive care unit., Results: Medication prescriptions in 23 patients before and 38 patients after intervention were studied. Of these patients, 10 (44%) and 15 (40%) suffered from ALI/ARDS. The V(T) of ALI/ARDS patients declined from 9.7 ml/kg predicted body weight (PBW) before to 7.8 ml/kg PBW after the intervention (P = 0.007). For patients who did not have ALI/ARDS there was a trend toward a decline from 10.2 ml/kg PBW to 8.6 ml/kg PBW (P = 0.073). Arterial carbon dioxide tension was significantly greater after the intervention in ALI/ARDS patients. Neither the proportion of patients receiving opioids or sedatives, or prescriptions at individual time points differed between pre-intervention and post-intervention. Also, there were no statistically significant differences in doses of sedatives and opioids. Findings were no different between non-ALI/ARDS patients and ALI/ARDS patients., Conclusion: Concerns regarding sedation requirements with use of lower V(T) are unfounded and should not preclude its use in patients with ALI/ARDS.

Objective: To evaluate whether soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in CSF can serve as a biomarker for the presence of bacterial meningitis and outcome in patients with this disease., Design: Retrospective study of diagnostic accuracy., Setting and Patients: CSF was collected from 92 adults with community-acquired bacterial meningitis who participated in the prospective Dutch Meningitis Cohort Study; 8 patients with viral meningitis and 9 healthy control subjects., Results: CSF sTREM-1 levels were higher in patients with bacterial meningitis (median 82 pg/ml, range 0-988) than in those with viral meningitis (0 pg/ml, 0-48) and controls (0 pg/ml, 0-36). The diagnostic accuracy of sTREM-1 in discriminating between patients with and without bacterial meningitis, expressed as the area under the receiver operating characteristic curve, was 0.82. At a cutoff level of 20 pg/ml the sensitivity was 0.73 and specificity 0.77. In patients with bacterial meningitis CSF sTREM-1 levels were associated with mortality (survivors, median 73 pg/ml, range 0-449 pg/ml; nonsurvivors, 15 pg/ml, 0-988)., Conclusions: Measuring sTREM-1 in CSF may be a valuable new additional approach to accurately diagnose bacterial meningitis and identify patients at high risk for adverse outcome. Therefore a prospective study of sTREM-1 as a biomarker in bacterial meningitis is needed.

Objective: To determine the diagnostic role of soluble triggering receptor expressed on myeloid cells (sTREM)-1 in non-directed bronchial lavage fluid in ventilator-associated pneumonia (VAP)., Design: Non-directed bronchial lavage fluid and plasma were collected on alternate days in critically ill mechanically ventilated patients from the start of ventilatory support until complete weaning from the ventilator. Soluble TREM-1 levels were measured by an enzyme-linked immunosorbent assay., Setting: A general adult medical and surgical university hospital intensive care unit., Patients: Nine patients who developed VAP and 19 patients who did not develop VAP (controls)., Results: Plasma levels of sTREM-1 did not change significantly in either patient group. While in controls concentrations of sTREM-1 in non-directed bronchial lavage fluid did not change significantly over time, in patients who developed VAP levels of sTREM-1 in non-directed bronchial lavage fluid increased towards the diagnosis of VAP. A cut-off value for non-directed bronchial lavage fluid sTREM-1 levels of 200 pg/ml on the day of VAP had a diagnostic sensitivity of 75% and a specificity of 84%. Sensitivity increased when taking into account all sTREM-1 levels higher than 200 pg/ml from the 6-day period before the day of diagnosis that were preceded by an increase of at least 100 pg/ml (sensitivity 88%, specificity 84%)., Conclusions: Soluble TREM-1 is a potential biomarker of VAP.

Purpose: To investigate the sensitivity and specificity of polyp detection and the image quality of computed tomographic (CT) colonography at different radiation dose levels and to study effective doses reported in literature on CT colonography., Materials and Methods: CT colonography and colonoscopy were performed with 100 mAs in 50 consecutive patients at high risk for colorectal cancer; 50- and 30-mAs CT colonographic examinations were simulated with controlled addition of noise to raw transmission measurements. One radiologist randomly evaluated all original and simulated images for the presence of polyps and scored image quality. Differences in image quality were assessed with the Wilcoxon rank test. Scan protocols from the literature and recent (unpublished) updates were collected., Results: In nine of 10 patients with polyps 5 mm in diameter or larger (sensitivity, 90%) and in seven of 17 patients with polyps smaller than 5 mm, polyps were correctly identified with CT colonography at all dose levels. Specificity for patients without polyps 5 mm or larger was 53%-60% at all dose levels and for patients without any polyps was 26% (at 100 and 50 mAs) and 48% (at 30 mAs). Image quality decreased significantly as the dose level decreased. The median effective doses (supine and prone positions) calculated from protocols reported in the literature and updates were 7.8 and 8.8 mSv, respectively., Conclusion: Although image quality decreases significantly at 30 mAs (3.6 mSv), polyp detection remains unimpaired. The median dose for CT colonography at institutions that perform CT colonographic research is currently 8.8 mSv.