Daily Ards Research Analysis
A large international Phase 3 RCT (PROTHOR) found that higher PEEP with recruitment during one-lung ventilation did not reduce postoperative pulmonary complications but increased intraoperative hypotension and arrhythmias. A clinical–translational study identified extracellular cyclophilin A (eCyPA) as a prognostic biomarker for 28-day mortality in ARDS, with improved discrimination when combined with platelet count and oxygenation index. A retrospective cohort in ARDS patients receiving inhaled
Summary
A large international Phase 3 RCT (PROTHOR) found that higher PEEP with recruitment during one-lung ventilation did not reduce postoperative pulmonary complications but increased intraoperative hypotension and arrhythmias. A clinical–translational study identified extracellular cyclophilin A (eCyPA) as a prognostic biomarker for 28-day mortality in ARDS, with improved discrimination when combined with platelet count and oxygenation index. A retrospective cohort in ARDS patients receiving inhaled nitric oxide (iNO) suggested longer iNO duration was associated with lower mortality, supporting phenotype-targeted trials.
Research Themes
- Perioperative lung-protective ventilation strategies
- Inflammation biomarkers for ARDS prognosis
- Phenotype-targeted vasomodulatory therapy in ARDS
Selected Articles
1. Effects of intraoperative higher versus lower positive end-expiratory pressure during one-lung ventilation for thoracic surgery on postoperative pulmonary complications (PROTHOR): a multicentre, international, randomised, controlled, phase 3 trial.
In a 74-site international Phase 3 RCT of 2200 thoracic surgery patients undergoing one-lung ventilation, higher PEEP with recruitment did not reduce postoperative pulmonary complications compared with lower PEEP without recruitment. High PEEP increased intraoperative hypotension and arrhythmias, while hypoxemia rescue maneuvers were more frequent in the low PEEP group.
Impact: This pragmatic, large-scale RCT provides definitive evidence against routine intraoperative lung expansion strategies during one-lung ventilation, directly informing anesthetic ventilation protocols.
Clinical Implications: Avoid routine use of higher PEEP with recruitment during one-lung ventilation in patients with BMI <35; prefer lower PEEP with permissive atelectasis and individualized rescue maneuvers, with vigilant hemodynamic monitoring if higher PEEP is considered.
Key Findings
- Primary outcome (postoperative pulmonary complications) did not differ: 53.6% (high PEEP) vs 56.4% (low PEEP); absolute risk difference -2.68 percentage points (95% CI -6.36 to 1.01); p=0.155.
- High PEEP increased intraoperative complications: hypotension 37.3% vs 14.3% and new arrhythmias 9.9% vs 3.9% compared with low PEEP.
- Extrapulmonary postoperative complications and total adverse events were similar between groups.
Methodological Strengths
- Multicentre, international, randomised, controlled Phase 3 design with large sample size (n=2200).
- Modified intention-to-treat analysis with prespecified outcomes and pragmatic perioperative setting.
Limitations
- Generalizability limited by exclusion of patients with BMI ≥35 kg/m².
- Hemodynamic instability with high PEEP may confound interpretation of net clinical benefit in some subgroups.
Future Directions: Define optimal individualized PEEP targets during one-lung ventilation, integrate real-time hemodynamic/oxygenation monitoring, and assess outcomes in obese populations and high-risk subgroups.
BACKGROUND: The effect of higher positive end-expiratory pressure (PEEP) and recruitment manoeuvres aimed at lung expansion as compared with lower PEEP without recruitment manoeuvres aimed at permissive atelectasis on postoperative pulmonary complications (PPCs) in patients undergoing one-lung ventilation (OLV) during thoracic surgery is unclear. We aimed to determine the contribution of an intraoperative lung expansion strategy to preventing PPCs. METHODS: In this multicentre, randomised, controlled, international phase 3 trial (PROTHOR) conducted at 74 sites in 28 countries, we enrolled adult patients (aged ≥18 years) with a BMI of less than 35 kg/m FINDINGS: Between Jan 3, 2017, and Feb 12, 2024, 2200 patients were randomly allocated: 1099 to the high PEEP group and 1101 to the low PEEP group. 43 patients in the high PEEP group and 33 in the low PEEP group were excluded from the modified intention-to-treat analysis after randomisation. The primary outcome occurred in 555 (53·6%) of 1036 patients in the high PEEP group and 592 (56·4%) of 1049 patients in the low PEEP group (absolute risk difference -2·68 percentage points [95% CI -6·36 to 1·01]; p=0·155). Intraoperative complications occurred in 484 (49·8%) of 972 patients in the high PEEP group and in 305 (31·3%) of 974 patients in the low PEEP group (absolute risk difference 18·09 percentage points [95% CI 14·41-21·77]), among which hypotension (360 [37·3%] of 966 patients in the high PEEP group vs 140 [14·3%] of 978 in the low PEEP group) and new arrhythmias (89 [9·9%] of 899 vs 37 [3·9%] of 956) were more frequent in the high PEEP group, while hypoxaemia rescue manoeuvres were more frequent in the low PEEP group (29 [3·3%] of 888 vs 86 [8·8%] of 982). The proportions of patients with extrapulmonary postoperative complications (110 [10·6%] of 1036 vs 107 [10·2%] of 1049 patients), and the numbers of adverse events (209 vs 204 events), did not differ between groups. INTERPRETATION: In patients with a BMI of less than 35 kg/m FUNDING: Clinical Trials Network of the European Society of Anaesthesiology and Intensive Care; Department of Anaesthesiology and Intensive Care, University Hospital Carl Gustav Carus, Technische Universität Dresden (Dresden, Germany); Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasília, Brazil); and the Association of Anaesthetists of GB and Ireland.
2. The role of eCyPA as an inflammatory biomarker for predicting 28-day mortality in ARDS patients.
In 50 ARDS patients, higher serum eCyPA levels were associated with 28-day mortality and showed fair discrimination (AUC 0.754), which improved to 0.887 when combined with platelet count and oxygenation index. In LPS-induced ARDS mice, eCyPA rose over 7 days in serum and BALF, paralleling inflammatory cytokines.
Impact: Identifies a mechanistically plausible biomarker that augments prognostic models for ARDS, bridging clinical observation with experimental validation.
Clinical Implications: eCyPA could support early risk stratification in ARDS and, when combined with routine indices, improve mortality prediction; prospective multicentre validation is needed before clinical adoption.
Key Findings
- Non-survivors had higher serum eCyPA than survivors (10.1 ng/ml [IQR 7.5–10.6] vs 7.2 ng/ml [IQR 5.9–8.2]; p=0.002).
- eCyPA predicted 28-day mortality with AUC 0.754; adding platelet count and oxygenation index improved AUC to 0.887 (P<0.001).
- In LPS-induced ARDS mice, eCyPA increased over 7 days in serum and BALF, mirroring cytokine dynamics.
Methodological Strengths
- Combined clinical cohort with experimental ARDS mouse model for translational insight.
- Robust statistical analyses including multivariable logistic regression, ROC, Kaplan–Meier, and incremental prognostic value assessment.
Limitations
- Single-centre retrospective cohort with small sample size (n=50), limiting generalizability.
- Lack of external validation and standardized clinical cutoffs for eCyPA.
Future Directions: Prospective multicentre validation of eCyPA thresholds, integration into risk scores, and mechanistic studies to evaluate eCyPA as a therapeutic target.
BACKGROUND: Acute respiratory distress syndrome (ARDS) is the primary manifestation of systemic inflammatory response syndrome in the lungs. Extracellular cyclophilin A (eCyPA) as a novel inflammatory marker, this study aims to investigate the expression of eCyPA in ARDS and its relationship with patient prognosis. METHODS: This retrospective study collected serum samples from adult patients diagnosed with acute respiratory distress syndrome (ARDS) upon their admission to ICU. Additionally, venous blood and bronchoalveolar lavage fluid were obtained from a lipopolysaccharide (LPS)-induced ARDS mouse model. The expression levels of extracellular cyclophilin A in serum and bronchoalveolar lavage fluid were quantified using enzyme-linked immunosorbent assay (ELISA). The data collection period extended from December 2021 to December 2023. Binary logistic regression analysis, ROC curve, Kaplan-Meier survival analysis were employed to evaluate the correlation with 28-day all-cause mortality in ARDS patients. An incremental prognostic value analysis was conducted to further investigate the enhancement in predictive value when combined with clinically significant indicators (platelet count and oxygenation index). Additionally, we assessed the dynamic trends of eCyPA and cytokines in serum and bronchoalveolar lavage fluid at 0, 1, 3, and 7 days in LPS-induced ARDS mouse models. RESULTS: A total of 50 patients were enrolled. The serum eCyPA expression level was significantly higher among non-survivors compared to survivors (7.2 ng/ml, interquartile range, IQR, 5.9-8.2 vs. 10.1 ng/ml, IQR 7.5-10.6; p = 0.002), and this finding remained consistent across various subgroups. eCyPA is an effective predictor of 28-day mortality in ARDS patients (AUC = 0.754). When combined with platelet count and oxygenation index, the prognostic value assessment improved the AUC to 0.887 (P < 0.001). In ARDS mice, eCyPA increased continuously over 7 days in serum and bronchoalveolar lavage fluid, the trend is similar to inflammatory cytokines in ARDS mice. CONCLUSIONS: The findings suggest that eCyPA may serve as a potential biomarker for predicting 28-day mortality in patients with acute respiratory distress syndrome.
3. Impact of inhaled nitric oxide on clinical outcomes in severe acute respiratory distress syndrome with associated right ventricular dysfunction.
In ARDS patients treated with iNO, mortality did not differ between those with RV dysfunction and normal RV function. However, each additional hour of iNO was associated with a 2.5% reduction in mortality hazard (HR 0.975), with no differences in renal replacement therapy, length of stay, or vasopressor use.
Impact: Addresses an ARDS subphenotype (RV dysfunction) and suggests a time-dependent survival association with iNO, informing design of phenotype-targeted interventional trials.
Clinical Implications: Consider echocardiographic assessment of RV function in ARDS and protocolized iNO use for refractory hypoxemia; findings support evaluating dose–duration strategies in prospective trials rather than routine prolonged use.
Key Findings
- No significant difference in in-hospital or 28-day mortality between ARDS patients with RV dysfunction and those with normal RV function treated with iNO.
- Each additional hour of iNO was associated with a 2.5% mortality hazard reduction (HR 0.975; 95% CI 0.957–0.993; p<0.01).
- No significant differences in renal replacement therapy initiation, hospital/ICU length of stay, or vasopressor requirements.
Methodological Strengths
- Focus on an ARDS subphenotype (RV dysfunction) with clinically relevant outcomes.
- Time-to-event modeling (Cox) adjusting for treatment duration.
Limitations
- Retrospective single-centre design with small sample size (n=52) and potential confounding by indication.
- All patients received iNO, limiting causal inference due to absence of an untreated control group.
Future Directions: Conduct prospective, randomized trials stratified by RV phenotype to test iNO dose and duration, with integrated echocardiography and hemodynamic endpoints.
A significant number of patients with acute respiratory distress syndrome (ARDS) develop right ventricular (RV) dysfunction, which is an independent poor prognostic marker in ARDS; currently there are no well-established treatment approaches directed at this ARDS subphenotype. This study aimed to determine whether inhaled nitric oxide (iNO), when used for refractory hypoxemia, was associated with differences in clinical outcomes among patients with ARDS-associated RV dysfunction as compared to patients with normal RV function. This was a retrospective single-center cohort analysis of 52 patients with ARDS with normal and dysfunctional RVs who were treated with iNO. The outcomes of interest were death during hospitalization, 28-day mortality, and initiation of renal replacement therapy. There was no significant mortality difference during hospitalization or 28 days between the RV dysfunction and normal RV group while hospitalized or 28-days post-admission. In a Cox proportional hazards model adjusting for length of iNO treatment, each additional hour of iNO showed a small yet significant mortality benefit of 2.5 % (HR = 0.975, 95 % CI: 0.957-0.993, p < 0.01) across both groups. There was no significant difference in need for renal replacement therapy, length of hospitalization or ICU stay, or vasopressor requirements between the groups. Although ARDS-associated RV dysfunction is frequently associated with poorer outcomes as compared to patients with ARDS and normal RV, the use of iNO may even the gap in mortality. Longer duration of treatment with iNO may improve survival. These data justify further investigation into the use of iNO for this subphenotype of ARDS.