Development and validation of a point-of-care breath test for octane detection

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.</p

Biological subphenotypes of acute respiratory distress syndrome may not reflect differences in alveolar inflammation

Biological subphenotypes have been identified in acute respiratory distress syndrome (ARDS) based on two parsimonious models: the “uninflamed” and “reactive” subphenotype (cluster-model) and “hypo-inflammatory” and “hyper-inflammatory” (latent class analysis (LCA) model). The distinction between the subphenotypes is mainly driven by inflammatory and coagulation markers in plasma. However, systemic inflammation is not specific for ARDS and it is unknown whether these subphenotypes also reflect differences in the alveolar compartment. Alveolar inflammation and dysbiosis of the lung microbiome have shown to be important mediators in the development of lung injury. This study aimed to determine whether the “reactive” or “hyper-inflammatory” biological subphenotype also had higher concentrations of inflammatory mediators and enrichment of gut-associated bacteria in the lung. Levels of alveolar inflammatory mediators myeloperoxidase (MPO), surfactant protein D (SPD), interleukin (IL)-1b, IL-6, IL-10, IL-8, interferon gamma (IFN-ƴ), and tumor necrosis factor-alpha (TNFα) were determined in the mini-BAL fluid. Key features of the lung microbiome were measured: bacterial burden (16S rRNA gene copies/ml), community diversity (Shannon Diversity Index), and community composition. No statistically significant differences between the “uninflamed” and “reactive” ARDS subphenotypes were found in a selected set of alveolar inflammatory mediators and key features of the lung microbiome. LCA-derived subphenotypes and stratification based on cause of ARDS (direct vs. indirect) showed similar profiles, suggesting that current subphenotypes may not reflect the alveolar host response. It is important for future research to elucidate the pulmonary biology within each subphenotype properly, which is arguably a target for intervention

Prevention of ventilator-associated pneumonia by oral decontamination - A prospective, randomized, double-blind, placebo-controlled study

Colonization of the intestinal tract has been assumed to be important in the pathogenesis of ventilator-associated pneumonia (VAP), but relative Impacts of oropharyngeal, gastric, or intestinal colonization have not been elucidated. Our aim was to prevent VAP by modulation of oropharyngeal colonization, without influencing gastric and Intestinal colonization and without systemic prophylaxis. In a prospective, randomized, placebo-controlled, double-blind study, 87 patients received topical antimicrobial prophylaxis (gentamicin/ colistin/vancomycin 2% in Orabase, every 6 h) in the oropharynx and 139 patients, divided over two control groups, received placebo (78 patients were studied in the presence of patients receiving topical prophylaxis [control group A] and 61 patients were studied In an intensive care unit where no topical prophylaxis was used [control group B]). Baseline characteristics were comparable in all three groups. Topical prophylaxis eradicated colonization present on admission in oropharynx (75% in study group versus 0% in control group A [p <0.00001] and 9% in control group B patients [p <0.00001]) and In trachea (52% versus 22% in A [p = 0.03] and 7% in 8 [p = 0.004]). Moreover, topical prophylaxis prevented acquired oropharyngeal colonization (10% versus 59% in A [p <0.00001] and 63% in B [p <0.00001]). Colonization rates In stomach and intestine were not affected. Incidences of VAP were 10% in study patients, 31% in Group A, and 23% in Group B patients (p = 0.001 and p = 0.04 respectively). This was not associated with shorter durations of ventilation or ICU stay or better survival. Oropharyngeal colonization is of paramount importance in the pathogenesis of VAP, and a targeted approach to prevent colonization at this site is a very effective method of infection prevention

Breath octane and acetaldehyde as markers for acute respiratory distress syndrome in invasively ventilated patients suspected to have ventilator-associated pneumonia

Rationale The concentration of octane and acetaldehyde in exhaled breath has good diagnostic accuracy for acute respiratory distress syndrome (ARDS). We aimed to determine whether breath octane and acetaldehyde are able to distinguish the presence and absence of ARDS in critically ill patients suspected to have ventilator-associated pneumonia (VAP). Methods This is a secondary analysis of a prospective observational study into exhaled breath analysis using gas chromatography–time-of-flight mass spectrometry. Difference in the relative abundance of octane and acetaldehyde in exhaled breath was compared between patients with and without ARDS using the Mann–Whitney U-test and the association was quantified using logistic regression. The discriminative accuracy of octane and acetaldehyde, alone or in combination, was calculated using the area under the receiver operating characteristic curve (AUROCC). Results We included 98 patients, of whom 32 had ARDS and 66 did not. The area under the acetaldehyde peak was higher in patients with ARDS (p=0.03), and associated with the presence of ARDS (OR 1.06 per 100 000 count change, 95% CI 1.02–1.13 per 100 000 count change; p=0.01). A combined model with octane and acetaldehyde showed a high specificity and low sensitivity (90% and 40.6%, respectively), with a low accuracy (AUROCC 0.65, 95% CI 0.53–0.78). Conclusion Patients suspected to have VAP with ARDS had a higher acetaldehyde concentration in exhaled breath than patients suspected to have VAP without ARDS. However, in this patient population, discrimination of these breath biomarkers for ARDS was poor, indicating the difficulty of translating diagnostic tests between clinical settings

Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies

Background Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. Methods We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. Findings Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20-29 and simplified acute physiology score [SAPS 2] 35-58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing ri Interpretation The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay