Association of Arterial Hyperoxia With Outcomes in Critically Ill Children: A Systematic Review and Meta-analysis

Importance: Oxygen supplementation is a cornerstone treatment in pediatric critical care. Accumulating evidence suggests that overzealous use of oxygen, leading to hyperoxia, is associated with worse outcomes compared with patients with normoxia. Objectives: To evaluate the association of arterial hyperoxia with clinical outcome in critically ill children among studies using varied definitions of hyperoxia. Data Sources: A systematic search of EMBASE, MEDLINE, Cochrane Library, and ClinicalTrials.gov from inception to February 1, 2021, was conducted. Study Selection: Clinical trials or observational studies of children admitted to the pediatric intensive care unit that examined hyperoxia, by any definition, and described at least 1 outcome of interest. No language restrictions were applied. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology guideline and Newcastle-Ottawa Scale for study quality assessment were used. The review process was performed independently by 2 reviewers. Data were pooled with a random-effects model. Main Outcomes and Measures: The primary outcome was 28-day mortality; this time was converted to mortality at the longest follow-up owing to insufficient studies reporting the initial primary outcome. Secondary outcomes included length of stay, ventilator-related outcomes, extracorporeal organ support, and functional performance. Results: In this systematic review, 16 studies (27 555 patients) were included. All, except 1 randomized clinical pilot trial, were observational cohort studies. Study populations included were post-cardiac arrest (n = 6), traumatic brain injury (n = 1), extracorporeal membrane oxygenation (n = 2), and general critical care (n = 7). Definitions and assessment of hyperoxia differed among included studies. Partial pressure of arterial oxygen was most frequently used to define hyperoxia and mainly by categorical cutoff. In total, 11 studies (23 204 patients) were pooled for meta-analysis. Hyperoxia, by any definition, showed an odds ratio of 1.59 (95% CI, 1.00-2.51; after Hartung-Knapp adjustment, 95% CI, 1.05-2.38) for mortality with substantial between-study heterogeneity (I2 = 92%). This association was also found in less heterogeneous subsets. A signal of harm was observed at higher thresholds of arterial oxygen levels when grouped by definition of hyperoxia. Secondary outcomes were inadequate for meta-analysis. Conclusions and Relevance: These results suggest that, despite methodologic limitations of the studies, hyperoxia is associated with mortality in critically ill children. This finding identifies the further need for prospective observational studies and importance to address the clinical implications of hyperoxia in critically ill children

Towards a biological definition of ARDS: are treatable traits the solution?

The pathophysiology of acute respiratory distress syndrome (ARDS) includes the accumulation of protein-rich pulmonary edema in the air spaces and interstitial areas of the lung, variable degrees of epithelial injury, variable degrees of endothelial barrier disruption, transmigration of leukocytes, alongside impaired fluid and ion clearance. These pathophysiological features are different between patients contributing to substantial biological heterogeneity. In this context, it is perhaps unsurprising that a wide range of pharmacological interventions targeting these pathophysiological processes have failed to improve patient outcomes. In this manuscript, our goal is to provide a narrative summary of the potential methods to capture the underlying biological heterogeneity of ARDS and discuss how this information could inform future ARDS redefinitions. We discuss what biological tests are available to identify patients with any of the following predominant biological patterns: (1) epithelial and/or endothelial injury, (2) protein rich pulmonary edema and (3) systemic or within lung inflammatory responses

Bedside breath tests in children with abdominal pain: a prospective pilot feasibility study

Background: There is no definitive method of accurately diagnosing appendicitis before surgery. We evaluated the feasibility of collecting breath samples in children with abdominal pain and gathered preliminary data on the accuracy of breath tests. Methods: We conducted a prospective pilot study at a large tertiary referral paediatric hospital in the UK. We recruited 50 participants with suspected appendicitis, aged between 5 and 15 years. Five had primary diagnosis of appendicitis. The primary outcome was the number of breath samples collected. We also measured the number of samples processed within 2 h and had CO2 ≥ 3.5%. Usability was assessed by patient-reported pain pre- and post-sampling and user-reported sampling difficulty. Logistic regression analysis was used to predict appendicitis and evaluated using the area under the receiver operator characteristic curve (AUROC). Results: Samples were collected from all participants. Of the 45 samples, 36 were processed within 2 h. Of the 49 samples, 19 had %CO2 ≥ 3.5%. No difference in patient-reported pain was observed (p = 0.24). Sampling difficulty was associated with patient age (p = 0.004). The logistic regression model had AUROC = 0.86. Conclusions: Breath tests are feasible and acceptable to patients presenting with abdominal pain in clinical settings. We demonstrated adequate data collection with no evidence of harm to patients. The AUROC was better than a random classifier; more specific sensors are likely to improve diagnostic performance. Trial registration: ClinicalTrials.gov, NCT03248102. Registered 14 Aug 2017

Assessment of the effect of recruitment maneuver on lung aeration through imaging analysis in invasively ventilated patients: a systematic review

Background: Recruitment maneuvers (RMs) have heterogeneous effects on lung aeration and have adverse side effects. We aimed to identify morphological, anatomical, and functional imaging characteristics that might be used to predict the RMs on lung aeration in invasively ventilated patients. Methods: We performed a systemic review. Studies included invasively ventilated patients who received an RM and in whom re-aeration was examined with chest computed tomography (CT), electrical impedance tomography (EIT), and lung ultrasound (LUS) were included. Results: Twenty studies were identified. Different types of RMs were applied. The amount of re-aerated lung tissue after an RM was highly variable between patients in all studies, irrespective of the used imaging technique and the type of patients (ARDS or non-ARDS). Imaging findings suggesting a non-focal morphology (i.e., radiologic findings consistent with attenuations with diffuse or patchy loss of aeration) were associated with higher likelihood of recruitment and lower chance of overdistention than a focal morphology (i.e., radiological findings suggestive of lobar or segmental loss of aeration). This was independent of the used imaging technique but only observed in patients with ARDS. In patients without ARDS, the results were inconclusive. Conclusions: ARDS patients with imaging findings suggestive of non-focal morphology show most re-aeration of previously consolidated lung tissue after RMs. The role of imaging techniques in predicting the effect of RMs on re-aeration in patients without ARDS remains uncertain

Lung ultrasound assessment of focal and non-focal lung morphology in patients with acute respiratory distress syndrome

Background: The identification of phenotypes based on lung morphology can be helpful to better target mechanical ventilation of individual patients with acute respiratory distress syndrome (ARDS). We aimed to assess the accuracy of lung ultrasound (LUS) methods for classification of lung morphology in critically ill ARDS patients under mechanical ventilation. Methods: This was a post hoc analysis on two prospective studies that performed LUS and chest computed tomography (CT) scanning at the same time. Expert panels from the two participating centers separately developed two LUS methods for classifying lung morphology based on LUS aeration scores from a 12-region exam (Amsterdam and Lombardy method). Moreover, a previously developed LUS method based on anterior LUS scores was tested (Piedmont method). Sensitivity and specificity of all three LUS methods was assessed in the cohort of the other center(s) by using CT as the gold standard for classification of lung morphology. Results: The Amsterdam and Lombardy cohorts consisted of 32 and 19 ARDS patients, respectively. From these patients, 23 (45%) had focal lung morphology while others had non-focal lung morphology. The Amsterdam method could classify focal lung morphology with a sensitivity of 77% and a specificity of 100%, while the Lombardy method had a sensitivity and specificity of 100 and 61%. The Piedmont method had a sensitivity and specificity of 91 and 75% when tested on both cohorts. With both the Amsterdam and Lombardy method, most patients could be classified based on the anterior regions alone. Conclusion: LUS-based methods can accurately classify lung morphology in invasively ventilated ARDS patients compared to gold standard chest CT. The anterior LUS regions showed to be the most discriminant between focal and non-focal lung morphology, although accuracy increased moderately when lateral and posterior LUS regions were integrated in the method

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

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

The prognostic capacity of the radiographic assessment for lung edema score in patients with COVID-19 acute respiratory distress syndrome—an international multicenter observational study

Background: The radiographic assessment for lung edema (RALE) score has an association with mortality in patients with acute respiratory distress syndrome (ARDS). It is uncertain whether the RALE scores at the start of invasive ventilation or changes thereof in the next days have prognostic capacities in patients with COVID-19 ARDS. Aims and Objectives: To determine the prognostic capacity of the RALE score for mortality and duration of invasive ventilation in patients with COVID-19 ARDS. Methods: An international multicenter observational study included consecutive patients from 6 ICUs. Trained observers scored the first available chest X-ray (CXR) obtained within 48 h after the start of invasive ventilation (“baseline CXR”) and each CXRs thereafter up to day 14 (“follow-up CXR”). The primary endpoint was mortality at day 90. The secondary endpoint was the number of days free from the ventilator and alive at day 28 (VFD-28). Results: A total of 350 CXRs were scored in 139 patients with COVID-19 ARDS. The RALE score of the baseline CXR was high and was not different between survivors and non-survivors (33 [24–38] vs. 30 [25–38], P = 0.602). The RALE score of the baseline CXR had no association with mortality (hazard ratio [HR], 1.24 [95% CI 0.88–1.76]; P = 0.222; area under the receiver operating characteristic curve (AUROC) 0.50 [0.40–0.60]). A change in the RALE score over the first 14 days of invasive ventilation, however, had an independent association with mortality (HR, 1.03 [95% CI 1.01–1.05]; P < 0.001). When the event of death was considered, there was no significant association between the RALE score of the baseline CXR and the probability of being liberated from the ventilator (HR 1.02 [95% CI 0.99–1.04]; P = 0.08). Conclusion: In this cohort of patients with COVID-19 ARDS, with high RALE scores of the baseline CXR, the RALE score of the baseline CXR had no prognostic capacity, but an increase in the RALE score in the next days had an association with higher mortality