Mortality In ARDS Research Articles

Risk factors for in-hospital mortality in recipients of allogeneic hematopoietic stem cell transplantation with acute respiratory distress syndrome: a retrospective study based on the 2023 new definition of acute respiratory distress syndrome

IntroductionARDS (acute respiratory distress syndrome) is the most severe form of acute hypoxic respiratory failure. Most studies related to ARDS have excluded patients with hematologic diseases, let alone allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Numerous patients experiencing severe hypoxic respiratory failure do not meet the Berlin definition due to the limitations of diagnosis and treatment. A new definition of ARDS, remove some diagnosis restrictions, was proposed in 2023. Based on the 2023 new definition of ARDS, we investigated the clinical features of ARDS in allo-HSCT recipients and reported risk factors for in-hospital mortality in allo-HSCT recipients defined by the Berlin definition and the new definition of ARDS respectively.MethodsFrom Jan 2016 to Dec 2020, 135 allo-HSCT recipients identified with the new definition and 87 identified with the Berlin definition at three teaching hospitals were retrospectively included in this study. Variables (demographic information, characteristics of hematologic disease and ARDS episode, laboratory tests and SOFA score) with P < 0.05 in univariate logistic regression analysis were included in multivariate stepwise logistic regression analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported.ResultsUnder the new definition, SOFA score (OR = 1.351, 95% CI: 1.146–1.593, P < 0.01) were found as an independent risk factor for in-hospital mortality in ARDS after allo-HSCT, while SpO2/FiO2 (OR = 0.984, 95% CI: 0.972–0.996, P < 0.01) was a protective factor. The infusion of peripheral-derived stem cells was found to be a protective factor against in-hospital mortality in post-transplantation ARDS compared with the infusion of bone marrow-derived stem cells (OR = 0.726, 95% CI: 0.164–3.221, P = 0.04). Under the Berlin definition, PaO2/FiO2 (OR = 0.977, 95% CI: 0.961–0.993, P = 0.01, lactate (OR = 7.337, 95% CI: 1.313–40.989, P < 0.01) and AST (OR = 1.165, 95% CI: 1.072–1.265, P < 0.01) were independently associated with in-hospital mortality.ConclusionThese prognostic risk factors we found in allo-HSCT recipients may contribute to closer monitoring and ARDS prevention strategies. These findings require confirmation in prospective, large sample size studies.

ECMO is associated with decreased hospital mortality in COVID-19 ARDS

This study determined whether compared to conventional mechanical ventilation (MV), extracorporeal membrane oxygenation (ECMO) is associated with decreased hospital mortality or fibrotic changes in patients with COVID-19 acute respiratory distress syndrome. A cohort of 72 patients treated with ECMO and 390 with conventional MV were analyzed (February 2020–December 2021). A target trial was emulated comparing the treatment strategies of initiating ECMO vs no ECMO within 7 days of MV in patients with a PaO2/FiO2 < 80 or a PaCO2 ≥ 60 mmHg. A total of 222 patients met the eligibility criteria for the emulated trial, among whom 42 initiated ECMO. ECMO was associated with a lower risk of hospital mortality (hazard ratio [HR], 0.56; 95% confidence interval [CI] 0.36–0.96). The risk was lower in patients who were younger (age < 70 years), had less comorbidities (Charlson comorbidity index < 2), underwent prone positioning before ECMO, and had driving pressures ≥ 15 cmH2O at inclusion. Furthermore, ECMO was associated with a lower risk of fibrotic changes (HR, 0.30; 95% CI 0.11–0.70). However, the finding was limited due to relatively small number of patients and differences in observability between the ECMO and conventional MV groups.

Administration of Δ8-tetrahydrocannabinol enhances lung function and attenuates neutrophiles infiltration in a preclinical model of acute respiratory distress syndrome

Abstract Acute respiratory distress syndrome ARDS, characterized by severe hypoxemia, is an inflammatory response leads to high mortality rate. Patients with ARDS, such as some COVID-19 patients, suffer from pulmonary alveolar damage and major oedema due to diffuse infiltration of immune cells. Neutrophils are predominantly elevated in the bronchoalveolar lavage fluids of ARDS patients. Our laboratory already reported that Δ9-tetrahydrocannabinol (THC) administration effectively attenuated lung inflammation, cytokine storm, and prevents mortality in ARDS. In current study, we tested the effect of Δ8-THC, a cannabinoid which is less psychoactive than Δ9-THC, in lipopolysaccharide-endotoxin (LPS)-induced model of ARDS. Our data showed that Δ8-THC exhibited improvement of pulmonary function tests and decreased bronchoconstriction index in freely conscious-tested animals accompanied with significant decreasing in immune cells infiltration, specifically neutrophiles, and decreasing of serum tumor necrosis factor alpha (TNFα) level. Interestingly, Single cell RNA sequencing analysis of pulmonary cell tSNE clusters showed that Δ8-THC dramatically reduced neutrophils clusters and dysregulates certain genes involved in movement of neutrophils and chemokines production such as CCl6, CCl9, Cxcl3, Cxcl10, and CCl5. Together, these findings suggest that Δ8-THC mitigates ARDS by preventing neutrophiles trafficking into the lungs, and thus, may serve as a therapeutic agent to treat ARDS. This work was supported in parts by NIH grants R01ES030144, P01AT003961, P20GM103641, and R01AI123947, R01AI160896

The prognostic value of early measures of the ventilatory ratio in the ARDS ROSE trial

BackgroundThe ventilatory ratio (VR, [minute ventilation × PaCO2]/[predicted body weight × 100 × 37.5]) is associated with mortality in ARDS. The aims of this study were to test whether baseline disease severity or neuromuscular blockade (NMB) modified the relationship between VR and mortality.MethodsThis was a post hoc analysis of the PETAL-ROSE trial, which randomized moderate-to-severe ARDS patients to NMB or control. Survival among patients with different VR trajectories or VR cutoff above and below the median was assessed by Kaplan–Meier analysis. The relationships between single-day or 48-h VR trajectories with 28- or 90-day mortality were tested by logistic regression. Randomization allocation to NMB and markers of disease severity were tested as confounders by multivariable regression and interaction term analyses.ResultsPatients with worsening VR trajectories had significantly lower survival compared to those with improving VR (n = 602, p < 0.05). Patients with VR > 2 (median) at day 1 had a significantly lower 90-day survival compared to patients with VR ≤ 2 (HR 1.36, 95% CI 1.10–1.69). VR at day 1 was significantly associated with 28-day mortality (OR = 1.40, 95% CI 1.15–1.72). There was no interaction between NMB and VR for 28-day mortality. APACHE-III had a significant interaction with VR at baseline for the outcome of 28-day mortality, such that the relationship between VR and mortality was stronger among patients with lower APACHE-III. There was a significant association between rising VR trajectory and mortality that was independent of NMB, baseline PaO2/FiO2 ratio and generalized markers of disease severity (Adjusted OR 1.81, 95% CI 1.28–2.84 for 28-day and OR 2.07 95% CI 1.41–3.10 for 90-day mortality). APACHE-III and NMB were not effect modifiers in the relationship between VR trajectory and mortality.ConclusionsElevated baseline and day 1 VR were associated with higher 28-day mortality. The relationship between baseline VR and mortality was stronger among patients with lower APACHE-III. APACHE-III was not an effect modifier for the relationship between VR trajectory and mortality, so that the VR trajectory may be optimally suited for prognostication and predictive enrichment. VR was not different between patients randomized to NMB or control, indicating that VR can be utilized without correcting for NMB.

Prognostic value of neutrophils to lymphocytes and platelets ratio for 28-day mortality in patients with acute respiratory distress syndrome: a retrospective study

BackgroundAcute respiratory distress syndrome (ARDS) is a rapidly progressive and fatal respiratory failure disease that often occurs in critically ill patients. Since ARDS is associated with immune dysregulation and coagulation abnormalities, it is necessary to identify an appropriate predictor that can accurately predict ARDS mortality based on its pathophysiology. Therefore, this study aimed to evaluate the clinical value of neutrophils to lymphocytes and platelets ratio (N/LPR) in predicting 28-day mortality in ARDS patients.MethodsFrom July 2018 to October 2021, the medical records of ARDS patients were retrospective reviewed. Neutrophil count, lymphocyte count, and platelet count were collected, and the neutrophil-to-lymphocyte ratio (NLR) and N/LPR were calculated. Multivariate logistic regression analyses were performed to identify independent predictors of 28-day mortality in ARDS. Receiver operating characteristic (ROC) curve with the area under curve (AUC) was used to evaluate optimal cut-off values for 28-day mortality in ARDS. Kaplan–Meier analysis was used to estimate the 28-day survival probabilities stratified by optimal cut-off values of N/LPR and NLR.ResultsA total of 136 ARDS patients were included in this study and were further divided into survivors (n = 69) and non-survivors (n = 67) groups according to their survival status on day 28. There were no significant differences between the two groups in age, sex, history of smoking and drinking, comorbidities, and reasons of admission (P > 0.05). Non-survivors had significantly higher neutrophil counts, NLR and N/LPR and had significantly lower platelet counts than survivors (P < 0.05). Multivariate regression analysis revealed that N/LPR, NLR and platelet counts were independent predictors for 28-day mortality in ARDS (P < 0.05). The ROC analyses showed that N/LPR with optimal cut-off value of 10.57 (sensitivity: 74.6%; specificity: 72.5%) is a more reliable predictor for 28-day mortality in ARDS than NLR and platelet count (AUC: 0.785 vs. 0.679 vs. 0.326). Further subgroup analysis confirmed that ARDS patients with N/LPR < 10.57 had significantly lower 28-day mortality than patients with N/LPR ≥ 10.57 (P < 0.001). Kaplan–Meier analysis also confirmed that ARDS patients with N/LPR < 10.57 had significantly longer survival.ConclusionN/LPR is an independent risk factor associated with 28-day mortality in ARDS patients and shows better performance in predicting mortality rate than NLR.

The relationship between immature granulocyte count and mortality in ARDS Due to COVID-19.

Acute phase reactants and inflammation biomarkers such as ferritin, procalcitonin, C-reactive protein (CRP), and complete blood count parameters (White blood cell, platelet count) are usually used to evaluate and monitor the disease severity and treatment response of systemic inflammatory diseases. In addition to these parameters, Immature granulocytes (IG) that increase during systemic infection, hematological malignancy, and drug treatments (such as chemotherapy and glucocorticoids) are important parameters for evaluating systemic inflammation. The sensitivity and specificity of IG are as high as the abovementioned inflammatory biomarkers for monitoring disease severity and treatment response. The aim of the study is to evaluate the relationship between IG count and the need for mechanical ventilation and mortality in patients hospitalized in the intensive care unit (ICU) due to coronavirus disease 2019 (COVID-19). The medical records of the 401 patients who were followed up in the ICU due to COVID-19-related acute respiratory distress syndrome between October 2020 and February 2021 were retrospectively reviewed. On the day of admission to the ICU complete blood count (CBC), arterial blood gas analysis, coagulation parameters (fibrinogen, D-dimer) are recorded. CRP, procalcitonin, and ferritin levels are also recorded at the day of admission. During the follow-up period, the survival status and mechanical ventilation status of the patients were recorded and the relation between IG count and these parameters was evaluated. The mean IG at the admission was 0.2 ± 0.4 109/L. The IG level of the intubated patients at the time of intubation was 0.3 ± 0.5 109/L. There was a significant positive correlation between mortality and IG levels at admission and at the time of intubation (IG admission; P = 0.001, r = 0.347 and IG at intubation; P = 0.001, r = 0.228). IG levels in CBC data could be a potential practical biomarker. This issue requires further research and the development of therapies targeting IG cells is needed.

4DPRR- Index for predicting mortality in COVID-19 ARDS

Abstract Background Mortality in ARDS was reduced significantly after the introduction of the low tidal volume ventilation strategy. It has been recently shown that lung-protective ventilation strategies should primarily target driving pressure rather than Vt and that ventilator induced lung injury is not just dependent on tidal volume but also other factors like respiratory rate and driving pressure. Ventilator induced lung injury is also thought to be dependent on the amount of energy transferred by the ventilator to the patient which in turn is dependent on tidal volume size (VT), plateau pressure (Pplat), respiratory rate (RR). Mechanical power can be calculated accurately through power equations which can increase their applicability in clinical practice. One simple composite equation (driving pressure multiplied by four plus respiratory rate [4DPRR]) has been recently suggested as a simple surrogate for the power equation. This equation also doesn’t include PEEP as it has been theorized that it is the only elastic dynamic component of driving energy which affects the outcome and not the elastic static component (i.e., PEEP) and the resistive power (related to flow and airway resistance). Objectives To assess the mechanical power as measured by 4DPRR in mechanically ventilated patients who have moderate to severe COVID-19 ARDS. Methods: We obtained data on ventilatory variables and mechanical power from the patients who were admitted with moderate to severe COVID ARDS in our hospital from March 2021 to June 2021. Results We included 34 patients (28% women; mean age, 57 ± 17 yrs.). The average ΔP was 21.44 ± 3.98 cmH2O, the RR was 23.8 ± 3.84 breaths/min, and the mean driving pressure was 21.4 cmH2O. 28% (n = 10) of patients expired. There was no significant association of 4DPRR (P 0.72), Pplat (P 0.79).and RR (P 0.21) with mortality as predicted by area under ROC curves. Conclusions Driving power and plateau pressure were associated with mortality during controlled mechanical ventilation in COVID ARDS, but a simpler model of mechanical power using only the driving pressure and respiratory rate was found to be a poor predictor of mortality. Keywords: COVID-19, ARDS, Mechanical power, Driving pressure, Plateau pressure

Outcomes of hospitalizations with acute respiratory distress syndrome with and without atrial fibrillation - Analyses from the National Inpatient Sample (2004-2014)

BackgroundAcute respiratory distress syndrome (ARDS) is associated with high mortality. Atrial fibrillation (AF) is a common arrhythmia seen in critically ill patients. The impact of AF on the outcomes in patients with ARDS is less understood. In this analysis we attempt to evaluate the association of concurrent AF and various clinical outcomes in patients with ARDS. MethodsWe conducted a retrospective analysis of adult discharges from the National Inpatient Sample (NIS) between 2004 and 2014. International Classification of Disease codes were used to identify those with ARDS and AF. ResultsWe found 1,200,737 hospitalizations with ARDS, out of which 238,455 had concomitant diagnosis of AF. Hospitalizations with AF had higher prevalence of comorbidities including chronic pulmonary disease, diabetes mellitus, hypertension, obesity, congestive heart failure and renal failure. On adjusted analysis, AF was associated with increased odds of acute myocardial infarction, cardiogenic shock, pressor use, acute kidney injury, permanent pacemaker implantation, cardiac arrest, mechanical circulatory support use and higher length of stay and inflation-adjusted cost in hospitalizations with ARDS. However, there was no significant difference in adjusted all-cause mortality in ARDS with and without AF (25.42% vs 20.23%, p=0.53). ConclusionsAF is associated with worse clinical outcomes, higher length of stay and cost in ARDS hospitalizations as compared to those without AF.

Effect of Trendelenburg position during prone ventilation in fifteen COVID-19 patients. Observational study

Background Prone position ventilation has shown to improve oxygenation and mortality in severe ARDS. The data of prone position ventilation during severe ARDS secondary to COVID-19 have shown similar benefit in oxygenation and mortality. Usually, patient placed in prone position are placed flat or in reverse Trendelenburg positioning to decrease risk of aspiration and abdominal girth compressing the chest. To date, no studies are available to compare the effects of positioning the bed in different angles during the prone position ventilation. Methods An observational study in fifteen patients with severe ARDS secondary to COVID-19 who were placed in the prone position for the first time. All the patients were sedated and chemically paralyzed with no spontaneous effort. All patients were ventilated with the pressure-controlled mode with set PEEP according to the pressure-volume curves. Five patients had esophageal balloon manometry to estimate pleural pressures and trans-pulmonary pressures. Patients were initially placed in reverse Trendelenburg position and later in Trendelenburg position. Tidal volume and respiratory compliance were observed for 30 minutes after bed positioning has been achieved. Tidal volume and total respiratory compliance in both Trendelenburg and reverse Trendelenburg position were compared. Ventilator settings were not changed during the observation. No patients were suspected of increased intra-cranial or intra-ocular pressures. T-test was done to compare the values. Results Tidal volume significantly increased by 80.26 ± 23.4 ml/breath (95% CI 37.7 - 122.9) from 391.3 ± 52.7 to 471.6 ± 60.9 (20.5%) P 0.001. The respiratory system compliance significantly increased by 4.9 ml/cmH2O (95% CI 1.4 - 8.4) from 34.6 ± 4.7 to 39.5 ± 4.6 (14%) P 0.001. Of the five patients with esophageal balloon, the lung compliance significantly increased by 16.7 ml/cmH2O (95% CI 12.8 – 20.6) from 66.6 ± 1.7 to 83.3 ± 3.3 (25%) P 0.001. The chest wall compliance had small but non-significant increase by 1.5 ml/cmH2O (95% CI -1.3 – 4.3) from 65 ± 1.4 to 66.5 ± 2.3 (2%) P 0.085. Conclusion In this study, statistically significant increase in tidal volume, lung and respiratory system compliance were observed in patients placed in the Trendelenburg position during prone position ventilation. The results reflect the effect of body positioning during prone position ventilation. These effects may be the reflection of altered ventilation distribution throughout the lungs and change in pleural pressure as well as trans-pulmonary pressure during body positioning. More studies need to be done to confirm and examine this phenomenon. Precautions should be taken as this maneuver can increase the intra-cranial and intra-ocular pressures. Keywords: COVID-19, Trendelenburg, Reverse Trendelenburg, ARDS

Adverse Events of Prone Positioning in Mechanically Ventilated Adults With ARDS.

Prone positioning is a therapy utilized globally to improve gas exchange, minimize ventilator-induced lung injury, and reduce mortality in ARDS, particularly during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Whereas the respiratory benefits of prone positioning in ARDS have been accepted, the concurrent complications could be undervalued. Therefore, this study aimed to identify the adverse events (AEs) related to prone positioning in ARDS and, secondarily, to collect strategies and recommendations to mitigate these AEs. In this scoping review, we searched recommendation documents and original studies published between June 2013 and November 2020 from 6 relevant electronic databases and the websites of intensive care societies. We selected 41 documents from 121 eligible documents, comprising 13 recommendation documents and 28 original studies (involving 1,578 subjects and 994 prone maneuvers). We identified > 40 individual AEs, and the highest-pooled occurrence rates were those of severe desaturation (37.9%), barotrauma (30.5%), pressure sores (29.7%), ventilation-associated pneumonia (28.2%), facial edema (16.7%), arrhythmia (15.4%), hypotension (10.2%), and peripheral nerve injuries (8.1%). The reported mitigation strategies during prone positioning included alternate face rotation (18 [43.9%]), repositioning every 2 h (17 [41.5%]), and the use of pillows under the chest and pelvis (14 [34.1%]). The reported mitigation strategies for performing the prone maneuver comprised one person being at the headboard (23 [56.1%]), the use of a pre-maneuver safety checklist (18 [43.9%]), vital sign monitoring (15 [36.6%]), and ensuring appropriate ventilator settings (12 [29.3%]). We identified > 40 AEs reported in prone positioning ARDS studies, including additional AEs not yet reported by previous systematic reviews. The pooled AE proportions collected in this review could guide research and clinical practice decisions, and the strategies to mitigate AEs could promote future consensus-based recommendations.

Role of Sildenafil in Management of Pediatric Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) has high mortality and multiple therapeutic strategies have been used to improve the outcome. Inhaled nitric oxide (INO), a pulmonary vasodilator, is used to improve oxygenation. This study was conducted to determine the role of sildenafil, an oral vasodilator, to improve oxygenation and mortality in pediatric ARDS (PARDS). The prevalence of pulmonary hypertension in PARDS was studied as well. Inclusion criteria included children (1-18 years) with ARDS requiring invasive ventilation admitted to the pediatric intensive care unit of a teaching hospital in Northern India over a 1-year period of time. Thirty-five patients met the inclusion criteria. Pulmonary arterial pressure (PAP) was determined by echocardiogram. Patients with persistent hypoxemia were started on oral sildenafil. The majority of patients (77%) had a primary pulmonary etiology of PARDS. Elevated PAP (>25 mm Hg) was detected in 54.3% patients at admission. Sildenafil was given to 20 patients who had severe and persistent hypoxemia. Oxygenation improved in most patients after the first dose with statistically significant improvement in PaO 2 /FiO 2 ratios at both 12 and 24 hours following initiation of therapeutic dosing of sildenafil. Improvement in oxygenation occurred irrespective of initial PAP. Outcomes included a total of 57.1% patients discharged, 28.6% discharged against medical advice (DAMA), and a 14.3% mortality rate. Mortality was related to the severity of PARDS and not the use of sildenafil. This is the first study to determine the effect of sildenafil in PARDS. Sildenafil led to improvement in oxygenation in nearly all the cases without affecting mortality. Due to unavailability of INO in most centers of developing countries, sildenafil may be considered as an inexpensive alternative in cases of persistent hypoxemia in PARDS. We recommend additional randomized controlled trials to confirm the effect of sildenafil in PARDS as determined in this study.

Prognostic Factors to Predict ICU Mortality in Patients with Severe ARDS Who Received Early and Prolonged Prone Positioning Therapy.

Early and prolonged prone positioning (PP) therapy improve survival in advanced ARDS; however, the predictors of mortality remain unclear. The study aims to identify predictive factors correlated with mortality and build-up the prognostic score in patients with severe ARDS who received early and prolonged PP therapy. A total of 116 patients were enrolled in this retrospective cohort study. Univariate and multivariate regression models were used to estimate the odds ratio (OR) of mortality. Factors associated with mortality were assessed by Cox regression analysis and presented as the hazard ratio (HR) and 95% CI. In the multivariate regression model, renal replacement therapy (RRT; OR: 4.05, 1.54–10.67), malignant comorbidity (OR: 8.86, 2.22–35.41), and non-influenza-related ARDS (OR: 5.17, 1.16–23.16) were significantly associated with ICU mortality. Age, RRT, non-influenza-related ARDS, malignant comorbidity, and APACHE II score were included in a composite prone score, which demonstrated an area under the curve of 0.816 for predicting mortality risk. In multivariable Cox proportional hazard model, prone score more than 3 points was significantly associated with ICU mortality (HR: 2.13, 1.12–4.07, p = 0.021). We suggest prone score ≥3 points could be a good predictor for mortality in severe ARDS received PP therapy.

Dead space estimates may not be independently associated with 28-day mortality in COVID-19 ARDS

BackgroundEstimates for dead space ventilation have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19-related ARDS.MethodsSecondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicenter, retrospective observational study done at 22 intensive care units 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 aim was to quantify the dynamics and determine the prognostic value of surrogate markers of wasted ventilation in patients with COVID-19-related ARDS.ResultsA total of 927 consecutive patients admitted with COVID-19-related ARDS were included in this study. Estimations of wasted ventilation such as the estimated dead space fraction (by Harris–Benedict and direct method) and ventilatory ratio were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p < 0.001). The end-tidal-to-arterial PCO2 ratio was lower in non-survivors than in survivors (p < 0.001). As ARDS severity increased, mortality increased with successive tertiles of dead space fraction by Harris–Benedict and by direct estimation, and with an increase in the VR. The same trend was observed with decreased levels in the tertiles for the end-tidal-to-arterial PCO2 ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the dead space estimates measured at the start of ventilation or the following days were significantly associated with 28-day mortality.ConclusionsThere is significant impairment of ventilation in the early course of COVID-19-related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk model.Trial registration: ISRCTN04346342. Registered 15 April 2020. Retrospectively registered.

Cardiac biomarkers in acute respiratory distress syndrome: a systematic review and meta-analysis

BackgroundAcute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in the intensive care unit. Biochemical markers of cardiac dysfunction are associated with high mortality in many respiratory conditions. The aim of this systematic review is to examine the link between elevated biomarkers of cardiac dysfunction in ARDS and mortality.MethodsA systematic review of MEDLINE, EMBASE, Web of Science and CENTRAL databases was performed. We included studies of adult intensive care patients with ARDS that reported the risk of death in relation to a measured biomarker of cardiac dysfunction. The primary outcome of interest was mortality up to 60 days. A random-effects model was used for pooled estimates. Funnel-plot inspection was done to evaluate publication bias; Cochrane chi-square tests and I2 tests were used to assess heterogeneity.ResultsTwenty-two studies were included in the systematic review and 18 in the meta-analysis. Biomarkers of cardiac stretch included NT-ProBNP (nine studies) and BNP (six studies). Biomarkers of cardiac injury included Troponin-T (two studies), Troponin-I (one study) and High-Sensitivity-Troponin-I (three studies). Three studies assessed multiple cardiac biomarkers. High levels of NT-proBNP and BNP were associated with a higher risk of death up to 60 days (unadjusted OR 8.98; CI 4.15-19.43; p<0.00001). This association persisted after adjustment for age and illness severity. Biomarkers of cardiac injury were also associated with higher mortality, but this association was not statistically significant (unadjusted OR 2.21; CI 0.94-5.16; p= 0.07).ConclusionBiomarkers of cardiac stretch are associated with increased mortality in ARDS.

Effectiveness of Glucocorticoids in Acute Respiratory Distress Syndrome: An Umbrella Review

Objectives. Acute respiratory distress syndrome is a very challenging condition that is associated with high morbidity and mortality. This review was intended to evaluate evidence on the effectiveness of glucocorticoid treatment for acute respiratory distress syndrome. Method. A comprehensive search strategy was conducted on PubMed/Medline, Cochrane Library, Science Direct, and LILACS. Data extraction was carried out by two independent reviewers using a customized checklist. The quality of each systematic review was assessed by two independent reviewers using an AMSTAR tool, and the overall quality of evidence was generated with online GRADEpro GDT software for primary and secondary outcomes. Results. The umbrella review included nine systematic reviews and meta-analysis and one narrative review with 8491 participants. The methodological quality of the included studies was moderate-to-high quality. The overall quality of evidence and recommendations varied form high to very low. Conclusion. There is high-to-moderate quality evidence that early low-dose prolonged glucocorticoid therapy reduces mortality in ARDS. However, randomized controlled trials with large sample sizes to address ventilator-free days, the incidence of infection, and other glucocorticoid-associated adverse events are required as the quality of evidence for these secondary outcomes which were low to very low. Registration. This umbrella review was registered in PROSPERO, the International Prospective Register of Systematic Reviews (CRD42019130539).

Effectiveness and Safety of MSC Cell Therapies for Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

Background: Covid-19 has contributed to high mortality and morbidity among hospitalized patients. One of the main pathophysiological processes of the disease is an exuberant immune response leading to respiratory failure. MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies have shown promise in modulating responses in inflammatory diseases and trend in decreasing mortality in ARDS. Controlled clinical trials with limited sample size assessing the effectiveness of MSC in patients hospitalized for COVID-19 suggest safety and potential to improve outcomes. We performed a meta-analysis of published trials assessing the clinical effectiveness and adverse events of MSC cell therapy in individuals hospitalized for COVID-19.Methods: Systematic searches were performed in multiple databases through April 8 th , 2021. Reports in all languages were included. Randomized clinical trials, comparative observational studies, and case series/case reports that evaluated safety and/or efficacy of MSC cell therapy in hospitalized patients with COVID-19.Independent reviewers selected studies and extracted data. Random effects model was used to pool outcomes from RCTs and comparative observational studies. Outcome measures included all-cause mortality, serious adverse events (SAEs), mild adverse events (AEs), pulmonary function, laboratory and imaging findings. Findings: A total of 413 patients were identified from 25 studies, which included 8 controlled trials (3 RCTs), 5 comparative observational studies, n=300) and 17 case-series/case reports (n=113). The patients age was 60.5 years (mean) and 33.7% were women. When compared with the control group receiving institutionally defined standard of care, MSC cell therapy was associated with reduction in all-cause mortality (RR=0.31, 95% CI: 0.12 to 0.75, I 2 =0.0%; 3 RCTs and 5 comparative observational studies, 300 patients), and reduction in SAEs (IRR=0.36, 95% CI: 0.14 to 0.90, I 2 =0.0%; 3 RCTs and 2 comparative studies, n=219). There was no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC cell therapy. Interpretation: Together these findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function in patients hospitalized for COVID-19 compared to conventional care. Large scale double-blinded, well-powered randomized controlled trials should be conducted to further explore these results. Funding: None to declare. Declaration of Interest: W. Q., J. M. H., J. K., C. R. reported roles as principal investigators of MSC trials. J. M. H. reported having a patent for cardiac cell-based therapy, holds equity in Vestion, Inc., and maintains a professional relationship with Vestion, Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board; J. M. H. is also the Chief Scientific Officer, a compensated consultant and advisory board member, for Longeveron and holds equity in Longeveron; J. M. H. is the coinventor of intellectual property licensed to Longeveron. J. M. H. declared inventor or patent holder and research funding from Longeveron, Heart Genomics; advisory role and research funding with Vestion; research funding from NHLBI. J. K. declare Intellectual property rights with IDF, hCT-MSC for treatment of ASD, HIE, which were licensed to CryoCell Int’l by Duke University; NMDP Scientific Advisor; Celularity SAB; research funding from the Marcus Foundation, NIH, HRSA; leadership position with Istari—CMO (spouse). G. B. consults for SciNeuro and Vida Ventures, had consulted for AbbVie, E-Scape, and Eisai, and receives funding from NIH and Cure Alzheimer’s Fund. He serves as a Co-Editor-in-Chief for Molecular Neurodegeneration. The other authors indicated no potential conflicts of interest. K.M. is a consultant in RESTEM.

Corrected Minute Ventilation Is Associated With Mortality in ARDS Caused by COVID-19.

The ratio of dead space to tidal volume (VD/VT) is associated with mortality in patients with ARDS. Corrected minute ventilation ([Formula: see text]) is a simple surrogate of dead space, but, despite its increasing use, its association with mortality has not been proven. The aim of our study was to assess the association between [Formula: see text] and hospital mortality. We also compared the strength of this association with that of estimated VD/VT and ventilatory ratio. We performed a retrospective study with prospectively collected data. We evaluated 187 consecutive mechanically ventilated subjects with ARDS caused by novel coronavirus disease (COVID-19). The association between [Formula: see text] and hospital mortality was assessed in multivariable logistic models. The same was done for estimated VD/VT and ventilatory ratio. Mean ± SD [Formula: see text] was 11.8 ± 3.3 L/min in survivors and 14.5 ± 3.9 L/min in nonsurvivors (P < .001) and was independently associated with mortality (adjusted odds ratio 1.15, P = .01). The strength of association of [Formula: see text] with mortality was similar to that of VD/VT and ventilatory ratio. [Formula: see text] was independently associated with hospital mortality in subjects with ARDS caused by COVID-19. [Formula: see text] could be used at the patient's bedside for outcome prediction and severity stratification, due to the simplicity of its calculation. These findings need to be confirmed in subjects with ARDS without viral pneumonia and when lung-protective mechanical ventilation is not rigorously applied.

Plasma Insulin-like Growth Factor Binding Protein 7 Contributes Causally to ARDS 28-Day Mortality: Evidence From Multistage Mendelian Randomization

ARDS is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified. Would multistage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality? Three hundred moderate to severe ARDS patients were selected randomly from the Molecular Epidemiology of ARDS cohort for proteomics analysis. Orthogonal projections to latent structures discriminant analysis was applied to detect the association between proteins and ARDS 28-day mortality. Candidate proteins were analyzed using generalized summary data-based Mendelian randomization (GSMR). Protein quantitative trait summary statistics were retrieved from the Efficiency and safety of varying the frequency of whole blood donation (INTERVAL) study (n= 2,504), and a genome-wide association study for ARDS was conducted from the Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR) consortium study (n= 534). Causal mediation analysis detected the role of platelet count in mediating the effect of protein on ARDS prognosis. Plasma insulin-like growth factor binding protein 7 (IGFBP7) moderately increased ARDS 28-day mortality (OR, 1.11; 95%CI, 1.04-1.19; P= .002) per log2 increase. GSMR analysis coupled with four other Mendelian randomization methods revealed IGFBP7 as a causal biomarker for ARDS 28-day mortality (OR, 2.61; 95%CI, 1.33-5.13; P= .005). Causal mediation analysis indicated that the association between IGFBP7 and ARDS 28-day mortality is mediated by platelet count (OR, 1.03; 95%CI, 1.02-1.04; P= .01). We identified plasma IGFBP7 as a novel causal protein involved in the pathogenesis of ARDS 28-day mortality and platelet function in ARDS, a topic for further experimental and clinical investigation.

Dynamic Airway Driving Pressure and Outcomes in Children With Acute Hypoxemic Respiratory Failure.

Limited adult data suggest that airway driving pressure might better reflect the potential risk for lung injury than tidal volume based on ideal body weight, and the parameter correlates with mortality in ARDS. There is a lack of data about the effect of driving pressure on mortality in pediatric ARDS. This study aimed to evaluate the effect of driving pressure on morbidity and mortality of children with acute hypoxemic respiratory failure. This retrospective cohort study was performed in a tertiary level pediatric ICU. Children who received invasive mechanical ventilation for acute hypoxemic respiratory failure (defined as [Formula: see text] < 300 within 24 h after intubation), in a 2-y period were included. The cohort was divided into 2 groups based on the highest dynamic driving pressure (ΔP, calculated as the difference between peak inspiratory pressure and PEEP) in the first 24 h, with a cutoff value of 15 cm H2O. Of the 380 children who were mechanically ventilated during the study period, 101 children who met eligibility criteria were enrolled. Common diagnoses were pneumonia (n = 51), severe sepsis (n = 24), severe dengue (n = 10), and aspiration pneumonia (n = 7). In comparison to the group with high ΔP (ie, ≥ 15 cm H2O), children in the group with low ΔP (ie, < 15 cm H2O) had significantly lower median (interquartile range) duration of ventilation (5 [4-6] d vs 8 [6-11] d, P < .001], ICU length of stay (6 [5-8] d vs 12 [8-15] d, P < .001], and more ventilator-free days at day 28 (23 [20-24] vs 17 [0-22] d, P < .001). Logistic regression analysis also suggested driving pressure as an independent predictor of morbidity after adjusting for confounding variables. However, there was no statistically significant difference in mortality between the 2 groups (17% in low ΔP vs 24% in high ΔP, P = .38). Subgroup analysis of 65 subjects who fulfilled ARDS criteria yielded similar results with respect to mortality and morbidity. Below a threshold of 15 cm H2O, ΔP was associated with significantly decreased morbidity in children with acute hypoxemic respiratory failure.

Lessons to learn from epidemiologic studies in ARDS.

Recent advances in our understanding of the epidemiology of ARDS has generated key insights into the incidence, risk factors, demographics, management and outcomes from this devastating clinical syndrome. ARDS occurs in 10% of all ICU patients, in 23% of all mechanically ventilated patients, with 5.5 cases per ICU bed each year. Although some regional variation exists regarding ARDS incidence, this may be less than previously thought. Subphenotypes are increasingly identified within the ARDS cohort, with studies identifying a 'hyperinflammatory' or 'reactive' subgroup that has a higher mortality, and may respond differently to therapeutic interventions. Demographic factors, such as race, may also affect the therapeutic response. Although mortality in ARDS is decreasing in clinical trials, it remains unchanged at approximately 40% in major observational studies. Modifiable ventilatory management factors, including PEEP, airway pressures, and respiratory rate are associated with mortality in ARDS. Hospital and ICU organizational factors play a role in outcome, whereas socioeconomic status is independently associated with survival in patients with ARDS. The Kigali adaptation of the Berlin ARDS definition may provide useful insights into the burden of ARDS in the developing world. ARDS exerts a substantial disease burden, with 40% of patients dying in hospital. Diverse factors, including patient-related factors such as age and illness severity, country level socioeconomic status, and ventilator management and ICU organizational factors each contribute to outcome from ARDS. Addressing these issues provides opportunities to improve outcome in patients with ARDS.