The hottest critical care research in the Blue Journal: introduction to a special section

The extraordinary content of the special section in this issue reflects the most currently researched questions in critical care. Michael A. Matthay and Kathleen D. Liu have been working for years on mesenchymal stem cells (MSCs) as a possible treatment for the acute respiratory distress syndrome (ARDS) with the hope that the multiple potential benefits (anti-inflammatory, anti-apoptotic, anti-microbial and restorative properties for epithelial and endothelial functions) will improve outcomes. They conducted a phase 2b RCT in 120 ventilated patients with ARDS (PaO2/FiO2 < 250 mmHg [https://doi.org/10.1164/rccm.202411-2254OC]. It took place during the pandemic, and the majority of subjects had COVID-19 ARDS. A single dose of MSCs was given to the experimental arm, but the trial could not identify any physiologic or clinical benefit in terms of patient’s outcome; biomarkers identified subgroups of patients with potential differential treatment responses. An editorial discusses how this research on stem cells could continue in ARDS [https://doi.org/10.1164/rccm.202508-1925ED]. Xueyan Yuan and colleagues proposed an innovative approach for titrating PEEP in ARDS [https://doi.org/10.1093/ajrccm/aamaf125]. In their RCT, patients received a PEEP titration guided by electric impedance tomography (EIT-guided PEEP, indicating a compromise between collapse and distension) compared to the lower PEEP/FiO2 table. The trial was terminated for futility at 190 patients; at 28 days, mortality was 56% in the EIT-guided PEEP group and 53% in the lower PEEP/FiO2 table group (P = .821). Other secondary clinical and safety outcomes did not differ either between the 2 arms. Interestingly, a post hoc analysis suggested that EIT-guided PEEP assigned higher PEEP and decreased mortality in patients with higher lung recruitability, as assessed by the recruitment-inflation ratio, a hypothesis-generating positive finding. Two perspectives complement the frequently disappointing perception of RCTs in critical care, so often negative or neutral. First, Arthur S. Slutsky and colleagues make a plea against the idea of abandoning the extracorporeal CO2 removal techniques after several RCTs failed to demonstrate any benefit, explaining why the technique may have not been ready for such clinical evaluation [https://doi.org/10.1093/ajrccm/aamaf117]. Second, Ary Serpa Neto and colleagues discuss the new statistical approaches that could usefully help to find benefits despite neutral results of the primary endpoint [https://doi.org/10.1093/ajrccm/aamaf114]. They use precise examples of reanalysis of published studies. Having a target or a biomarker for ventilator-induced lung injury is still to come. Takashi Maezawa and colleagues propose a novel approach to visualize, detect, and quantify the potentially harmful regional lung stress induced by mechanical ventilation that cannot be detected at a global level [https://doi.org/10.1093/ajrccm/aamaf146]. They combined esophageal pressure (as a proxy for the dependent pleural pressure) and CT scan density analysis to calculate the regional superimposed pressure for each pixel and therefore map the lungs for regional stress. They use multiple models and data from patients to validate their promising new technique. A research letter by Björn Jonson and colleagues questions the utility of mechanical power as a marker of ventilator-induced lung injury, discussing the fact that the dissipated energy is the real part at risk for the lung [https://doi.org/10.1093/ajrccm/aamaf108]. Based on a small study, the results suggest that driving pressure much better correlates with this dissipated energy than the global mechanical power. Many trials assessed high versus low targets for oxygenation, one concern being the long-term effects, even if the short-term effects do not differ. Elena Crescioli and colleagues assessed the effects at 1 year after survival of being randomized to a partial pressure of arterial oxygen (PaO2) of 60 vs 90 mmHg in patients with hypoxemic respiratory failure, in terms of both cognitive and pulmonary functions [https://doi.org/10.1164/rccm.202412-2499OC]. From 2 trials, 1244 randomized patients were eligible for this follow-up. Cognitive impairment did not differ at 1 year depending on oxygenation target, but pulmonary diffusion capacity was lower in patients assigned to the lower oxygenation target. These results suggest a different impact on lung function. Along the same line, Alexandra B. Flemington and colleagues wondered whether the baseline hemoglobin level could modify the impact of oxygen saturation on outcomes and concluded a lack of impact [https://doi.org/10.1093/ajrccm/aamaf121]. Pulmonary embolism with severe circulatory failure could potentially benefit from early reperfusion. David Levy and colleagues report the impact of early mechanical reperfusion in a cohort study of 492 patients treated for severe pulmonary embolism and receiving ECMO in 39 ECMO centers internationally [https://doi.org/10.1093/ajrccm/aamaf116]. Although the clinical benefit of early reperfusion may have occurred in some patients, overall, they could not demonstrate a reduction in 90-day mortality or ECMO duration with this approach. Treatment with sepsis is now often guided by precise recommendations. Using a large multi-hospital database, Hallie C. Prescott and colleagues showed that the CDC’s Hospital Sepsis Program Core Elements are associated with improved management and outcomes of sepsis, providing preliminary validation of this program [https://doi.org/10.1093/ajrccm/aamaf113]. Mortality remains extremely high in cardiogenic shock, and many patients die despite a normalized cardiac output. Hamid Merdji and colleagues stress the fact that assessment of microcirculation may be an essential part of the management and describe the different techniques to be used [https://doi.org/10.1093/ajrccm/aamaf112]. Three studies assessed the physiological effects and the clinical impact of spontaneous breathing during assisted ventilation. In a multicenter observational study of patients with hypoxemic respiratory failure ventilated with assist-control and monitored with esophageal pressure, Irene Telias and colleagues studied the physiological consequences of breathing effort ­according to the mode of ventilation [https://doi.org/10.1164/rccm.202411-2155OC]. They showed that high effort was associated with higher stress during pressure-controlled ventilation but more negative alveolar pressure during volume control ventilation, indicating a different response with the 2 modes. In addition, higher efforts induced drop in saturation and worsening in compliance during follow-up, illustrating the risks of excessive effort under assisted ventilation. Carmen A. T. Reep and colleagues confirmed previously published findings showing that early switching from controlled to assisted ventilation is associated with improved outcomes, including shorter duration of mechanical ventilation [https://doi.org/10.1093/ajrccm/aamaf110]. Their new study suggests that the results are not driven by site-level differences in weaning practices. A study in preterm lambs sheds some light on the role of spontaneous effort on the preterm lung, whereas most of the studies in this field have been performed in adults [https://doi.org/10.1164/rccm.202506-1386OC]. Fully synchronized spontaneous breathing with positive pressure ventilation was compared to nonsynchronized or apneic positive pressure ventilation and had different effects on lung proteomes. Synchronous and apneic ventilation resulted in similar morphology and minimal acute injury. This can help to design lung-protective ventilation strategies in the newborn. Lastly, the benefits versus the risks of early mobilization are still highly debated since several trials have suggested risks of harm with early mobilization. Using a target trial emulation from adult ICU patients under invasive ventilation and included in the TEAM RCT, Ary Serpa Neto, and colleagues simulated different thresholds of duration of mobilization and of ICU mobility scale to determine which patients were more at risk [https://doi.org/10.1093/ajrccm/aamaf109]. Their results suggested that prolonged mobilization was harmful when patients had low ICU mobility scale. Inhaled sedation has gained interest in the ICU. Herminia R. Torrado and colleagues report on the occupational risk theoretically associated with inhaled sedation and remind us of important precautions to be taken [https://doi.org/10.1093/ajrccm/aamaf111]. Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online. Please see the ICMJE disclosure forms, which have been provided as supplementary material. No artificial intelligence tools were used in writing this manuscript.