What Is the New Research in Pediatric Acute Respiratory Distress Syndrome Since the 2023 Consensus Conference?

The February 2023 guidance from the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) changes the way we now think about Pediatric Acute Respiratory Distress Syndrome (PARDS) (1). Publications through to April 2022 were used by 52 content and four methodology experts (from multiple disciplines and 15 countries) to generate 146 recommendations and statements. There were 34 clinical practice recommendations and another 112 consensus-based statements, of which 32 were focused on a proposed research agenda. These research statements outlined seven broad areas of investigation, including: 1) screening, diagnosis, and monitoring (2,3); 2) mechanical ventilation and cardiovascular system support and monitoring (4–6); 3) therapeutic drugs (7,8); 4) extracorporeal life support (9); 5) pain, agitation, and neuromuscular blockade, as well as delirium and early mobilization (8); 6) fluids, nutrition, and blood use (8); and 7) follow-up after PICU admission (10). So, given this road map, what is the tangible progress in PARDS research for our Pediatric Critical Care Medicine (PCCM) community? In this second item of the 2025 Editor’s Notes series (11) we can reflect on four areas of clinical research development in PARDS since the 2023 PALICC-2 guidance. Each of these is supported by a significant amount of work and warrants discussion on management with invasive mechanical ventilation (IMV) and noninvasive ventilation (NIV), biomarkers of pathobiology, and follow-up outcomes in survivors. IMV AND MONITORING IN PARDS The 2023 PALICC-2 guidance on IMV and monitoring in PARDS highlighted certain areas that needed more research (1,4,6). For example, “use of protocols and definitions in studies measuring tidal volume (VT), peak inspiratory pressure (PIP), plateau pressure (PPlat), positive end-expiratory pressure (PEEP), mean airway pressure; use of mechanical power calculations; use of monitoring pulmonary resistance and strain-stress relationships.” Since the PALICC-2 publication, two large multicenter international collaboratives have reported data meeting the requirements of the research agenda. First, the Pediatric Acute & Critical Care Medicine Asian Network (PACCMAN) reported an observational study with historical controls in 21 PICUs (2017−2023) (12). The before versus after design (408 vs 285 PARDS patients) focused on outcomes associated with introducing a lung-protective IMV protocol that emphasized limiting PIP, delta/driving pressure (DP), VT, and PEEP to fraction of inspired oxygen (FiO2) combinations, while also targeting permissive hypercarbia and conservative pulse oximetry (SpO2) values. The network found that adherence to PIP, DP, and PEEP/FiO2 targets during the first week of IMV for PARDS was associated with lower adjusted hazard of 60-day mortality. The second international study came from 12 PICUs in Colombia (2018−2022) that reported the time course of IMV parameters in 184 intubated children with moderate to severe PARDS (13). The collaborative found that a DP > 15 cm H2O at 72 hours after starting IMV was associated with greater odds of 28-day mortality and longer duration of IMV. In conjunction, these international datasets add weight to the PALICC-2 guidance on IMV practice in PARDS patients, as well as stressing the importance of monitoring respiratory parameters. Regarding the further integration of respiratory monitoring in our practice, other reports since PALICC-2 have focused on the physiology of PPlat and DP during IMV for PARDS (14,15); the impact of PEEP on mechanical power and DP in mild or moderate PARDS (16); and the relationship between normalized mechanical power and the severity of PARDS (17). NIV IN PARDS The 2023 PALICC-2 guidance also raised research questions regarding mode of respiratory support, including research about NIV (1,5). On this matter, there are two publications that used the 2016/2017 multicenter, international PARDS Incidence and Epidemiology (PARDIE) dataset. The first report was a planned PARDIE ancillary study of 160 of 708 PARDS patients who had received NIV at PARDS diagnosis (18). The analysis showed that early use of NIV in children with mild to moderate hypoxemia was associated with shorter exposure to subsequent IMV, but there was high risk of NIV failure in some children. The accompanying editorial noted that this timely and important work updates the position of the PALICC-2 recommendation on NIV in PARDS; that is, the new PARDIE data characterized a time-limited role for NIV, and the PCCM editorialists wrote “…another dogma bites the dust” (19). In the second publication using the PARDIE dataset, the investigators proposed an entity called immunocompromised-associated PARDS (I-PARDS) and contrasted these patients with those suffering other causes of PARDS (20). Of note, I-PARDS versus PARDS was associated with more NIV-failure and need for IMV. Furthermore, I-PARDS was associated with greater severity of illness-adjusted hazard of mortality in the PICU. In summary, these two analyses of the 2016/2017 PARDIE dataset have important clinical ramifications for the care of PARDS patients (18–20). That said, at PCCM we would also like to know more about how NIV is implemented in contemporary practice. There are survey data published in 2024 from the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) network, based on likely professionals’ practice in certain clinical scenarios (21), but we do not have actual practice on a large-scale across a country or internationally–hopefully more reports will come in 2025. PLASMA BIOMARKERS AND SEVERITY OF PARDS Another area for clinical research that was highlighted by the 2023 PALICC-2 guidance is the exploratory field of plasma biomarkers of severity of lung tissue disease and molecular phenotype and endotype (1,2). Since 2023, there have been a number of informative clinical studies, and three main datasets about PARDS patients managed between 2009 and 2020. There are studies that give details of different trajectories of serial cytokines, and markers of endothelial and alveolar epithelial injury, and DAMPs (damage-associated molecular patterns), all by outcome (22–25). There are also studies of these trajectories along with clinical information showing that hypoinflammatory versus hyperinflammatory subphenotypes differ by outcome, with mortality markers overlapping the markers indicating persistent multiple organ dysfunction syndrome rather than persistent PARDS (23,26,27). Finally, there are studies that compare PARDS-associated plasma biomarkers with lung injury severity, and prognosis (28,29). Considering everything we now know about biomarkers of pathobiology in PARDS, we must conclude that this area of clinical research is a promising work in progress. Even though the prognostic utility of such testing requires enrichment (29), our PCCM editorialist in this area has written perceptively “…we must revolutionize our consideration of biomarkers in our quest to bring precision medicine to bear on critically ill children with complex, heterogeneous syndromes such as PARDS” (30). POST-PICU FOLLOW-UP AND OUTCOME OF PARDS The fourth area of work that extends the 2023 PALICC-2 research agenda focuses on topics such as follow-up outcomes in relation to pre-PICU baseline state, and later post-PICU endpoints (1,10). There are two reports to know about. First, a single-center retrospective cohort of PARDS patients managed in the United States, 2011−2017 (31). These investigators had enrolled 41 PARDS patients into the hospital’s outcome assessment program, which included collection of preadmission baseline and median 6-week postdischarge information about health-related quality of life (HRQL). The results showed that decline in HRQL was common, and the risk of decline was associated with PARDS severity. The second report describes a post hoc analysis of a multicenter Collaborative Pediatric Critical Care Research Network (CPCCRN) study carried out in 2019−2020 (32). Out of 109 PARDS patients, follow-up survey information was available for 74 and 63 patients at 3- and 9-month post-PICU, respectively. Overall, the families described high rates of healthcare burden and use of health resources. In the multivariable analysis, preillness functional state and chronic conditions were associated with these healthcare endpoints. Combining these observations, we must conclude that outcomes in post-PARDS patients and support for families are most definitely concerning, and our community will need to address these issues in future family-centered care and research (33). Therefore, in answer to the question “What is the new research in PARDS since the 2023 PALICC-2 guidance?,” we can say that at the level of observations and associations we know much about IMV (PACCMAN, 2017−2023; Colombia, 2018−2022), NIV (PARDIE, 2016/2027), plasma biomarkers (three groups, 2009−2020), and post-PICU outcomes (single center in US, 2011−2017; CPCCRN, 2019−2020). However, what is missing is contemporary, prospective, and ongoing clinical PARDS research using datasets starting after 2023. As a community, we have some data from randomized controlled trials (RCTs) that may be useful, and PCCM welcomes post hoc analyses using these datasets. For example, the 2020−2022 multicenter RCT of conservative versus liberal oxygenation targets in 2,040 critically ill children (34) has led to interesting discussions in PCCM (35,36). In this issue of the Journal, this RCT dataset has been used to look at SpO2 and FiO2 in children undergoing IMV with severely impaired oxygenation–likely those with severe lung injury (37). PCCM seeks more work using a priori, research-curated data that has the potential to inform contemporary practice. PCCM also looks forward to more information about PARDS-related RCTs. At present, the Journal has one protocol in moderate to severe PARDS patients: the Prone and Oscillation Pediatric Clinical Trial (PROSpect), which started recruitment in 2019 and hopes to complete in 2026 (38). And, finally, look out for the PARDS research that will be published throughout 2025–this material has been selected because it aligns with the 2023 PALICC-2 research agenda (1).