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Background: There is a demand for a non-invasive bedside method to diagnose Acute Respiratory Distress Syndrome (ARDS). Octane was discovered and validated as the most important breath biomarker for diagnosis of ARDS using gas-chromatography and mass-spectrometry (GC-MS). However, GC-MS is unsuitable as a point-of-care (POC) test in the intensive care unit (ICU). Therefore, we determined if a newly developed POC breath test can reliably detect octane in exhaled breath of invasively ventilated ICU patients. Methods: Two developmental steps were taken to design a POC breath test that relies on gas-chromatography using air as carrier gas with a photoionization detector. Calibration measurements were performed with a laboratory prototype in healthy subjects. Subsequently, invasively ventilated patients were included for validation and assessment of repeatability. After evolving to a POC breath test, this device was validated in a second group of invasively ventilated patients. Octane concentration was based on the area under the curve, which was extracted from the chromatogram and compared to known values from calibration measurements. Results: Five healthy subjects and 53 invasively ventilated patients were included. Calibration showed a linear relation (R2 = 1.0) between the octane concentration and the quantified octane peak in the low parts per billion (ppb) range. For the POC breath test the repeatability was excellent (R2 = 0.98, ICC = 0.97 (95% CI 0.94–0.99)). Conclusion: This is the first study to show that a POC breath test can rapidly and reliably detect octane, with excellent repeatability, at clinically relevant levels of low ppb in exhaled breath of ventilated ICU patients. This opens possibilities for targeted exhaled breath analysis to be used as a bedside test and makes it a potential diagnostic tool for the early detection of ARDS.

Background Dysregulation of coagulation occurs commonly in sepsis, ranging from mild coagulopathy with decreased platelets to disseminated intravascular coagulation (DIC). We investigated the effect of induced normothermia on coagulation during lipopolysaccharide (LPS)-induced endotoxaemia in healthy volunteers. Methods Twelve volunteers received an infusion of bacterial lipopolysaccharide (Escherichia coli; 2 ng kg−1) and were assigned to either induced normothermia or control. Induced normothermia to maintain core temperature at 37°C consisted of external surface cooling, cold i.v. fluids, and medication to reduce shivering (buspirone, clonidine, and magnesium sulphate). The primary outcome was the DIC score (International Society on Thrombosis and Haemostasis guideline). Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, plasma von Willebrand factor (vWf), and rotational thromboelastometry (ROTEM) were measured before and 1, 3, 6, and 8 h after LPS infusion. Differences between groups were tested with a mixed effects model. Results In control subjects, lipopolysaccharide caused a fever, transiently decreased platelet levels and lowered activated partial thromboplastin time, while prolonging prothrombin time and increasing D-Dimer and vWf levels. Normothermia prevented the DIC-score exceeding 4, which occurred in 50% of control subjects. Normothermia also reduced the fall in platelet count by 67x109 L−1([95%CI:27-107]; p=0.002), aPTT (mean difference:3s [95%CI:1-5]; p=0.005) and lowered vWf levels by 89% ([95%CI:6-172]; p=0.03), compared to the fever group. ROTEM measurements were unaffected by lipopolysaccharide. Conclusion In human endotoxaemia, induced normothermia decreases markers of endothelial activation and DIC. Maintaining normothermia may reduce coagulopathy in hyperinflammatory states.

Background: Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak. Methods: PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342). Findings: Between March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6·3 mL/kg predicted bodyweight (IQR 5·7–7·1), PEEP was 14·0 cm H2O (IQR 11·0–15·0), and driving pressure was 14·0 cm H2O (11·2–16·0). Median respiratory system compliance was 31·9 mL/cm H2O (26·0–39·9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0–15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation. Interpretation: In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19. Funding: Amsterdam University Medical Centers, location Academic Medical Center.

Rationale Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS. Methods Medline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising. Results Forty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72–0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population. Conclusion This systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed., Accuracy of diagnosis of acute respiratory distress syndrome (ARDS) is associated with risk of bias. There is a lack of validated diagnostic tests in an unbiased setting, emphasising the need for quality driven diagnostic research in ARDS. https://bit.ly/2GfPAvf

International guidelines do not recommend a specific probe for assessment of lung aeration using lung ultrasound (LUS). The aim of this study was to assess the concordance between linear and sector array probes of a handheld ultrasound device in assessment of lung aeration in invasively ventilated intensive care unit patients. This study included intensive care unit patients who were expected to be ventilated for longer than 24 h. A 12-region LUS exam was performed with a linear and a sector array probe. In each image, the LUS aeration score and number of B-lines were determined. Adding the LUS aeration scores of all regions resulted in a global LUS aeration score. Agreement between the two probes was calculated using intra-class correlation coefficients (ICCs). A total of 30 LUS exams were performed in 19 patients, resulting in a total of 328 pairs of images. Twenty-nine pairs of images were excluded from analysis because the images from the linear probe could not be scored. ICCs calculated for the remaining images revealed good concordance the LUS aeration scores for individual images (ICC = 0.73, 95% confidence interval 0.67-0.78), number of B-lines (ICC = 0.79, 95% confidence interval 0.72-0.83) and global LUS aeration score (ICC = 0.74, 95% confidence interval 0.52-0.87). In conclusion, there is good concordance between linear and sector array probes of a handheld ultrasound device in assessment of lung aeration patterns in mechanically ventilated intensive care unit patients. However, in roughly 10% of the images acquired using the linear probe, the aeration pattern could not be scored. (E-mail: m.r. smit@amsterdamumc.nl) (C) 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved.