Acute respiratory distress syndrome (ARDS) refers to a condition of acute lung injury and inflammation that leads to hypoxic respiratory failure. Although there is general agreement that ARDS can affect people of all ages [1], the original and revised definitions of ARDS (i.e., the American-European Consensus Conference definition in 1994 [2] and the Berlin definition in 2012 [3]) did not include pediatric considerations. As the pediatric population exhibits a distinctive epidemiology and prognosis [4], as well as intrinsic differences in respiratory physiology [5], the Pediatric Acute Lung Injury Consensus Conference (PALICC) established new definitions for pediatric ARDS (PARDS) in 2015 [6]. The key differences included in these PALICC criteria are the use of an oxygenation index (OI) for severity stratification instead of the ratio of the arterial partial oxygen pressure to the fraction of inspired oxygen (PaO₂/FiO₂), allowance for pulse oximetry-based metrics (e.g., oxygenation saturation index [OSI]) when PaO₂ is not available, less stringent chest radiograph standards, and a broader scope by including subjects with chronic lung disease and cyanotic heart disease [6].

The incidence of PARDS is reported as 1%–4% of pediatric intensive care unit (ICU) admissions [7,8]. Despite improvements in the quality of intensive care, PARDS still is a major challenge in the pediatric ICU due to mortality as high as 30% [7,9]. As most treatment strategies for PARDS have been extrapolated from evidence gathered in adult studies, there is a growing need for interventional trials focused on pediatric populations. Likewise, risk stratification and identification of high-risk cases of PARDS have been attempted to better understand patient populations and optimize the quality of care.

Although the above definitions use oxygenation metrics as a primary indicator for lung injury, there remains a lack of guidance regarding when clinicians should acquire the metrics for PARDS risk stratification. With regard to PaO₂/FiO₂, OI and OSI are influenced by ventilator settings [10-12] and vary according to the disease progression; thus, the timing of measuring these metrics should be considered during risk stratification. Notably, several recent reports [8,13,14] have shown that mortality discrimination in PARDS is improved with the use of oxygenation metrics within the first 24 hours after onset relative to using initial metrics.

In this study, we aimed to determine whether reclassification using oxygenation metrics 24 hours after diagnosis of PARDS would have prognostic ability in an Asian cohort. Respiratory variables to be used as early prediction factors for risk stratification in PARDS were also investigated.

In this study, PARDS severity changed frequently in the first 24 hours after diagnosis. Reclassification 24 hours after diagnosis provided similar effectiveness in outcome stratification of PARDS subjects compared with classification by using the initial metrics. Notably, progress within the first 24 hours was significantly associated with mortality and VFDs. Among a variety of clinical variables in this early timeframe, changes in oxygenation provided the most discernible predictor for outcomes in PARDS.

Several groups have demonstrated the discriminative ability of oxygenation metrics 24 hours after onset for outcomes in ARDS compared with those of metrics at onset [8,13,14]. Yehya et al. [13] reported that PaO2/FiO2 and OI, measured 24 hours after meeting ARDS criteria, accurately stratified the severity of lung injury. Parvathaneni et al. [14] reported up to 50% mortality in children who were categorized with severe ARDS at 24 hours. Although there was no difference in the discriminative power for mortality between PALICC criteria at diagnosis and 24 hours afterward, our findings revealed a significant association between initial progress within 24 hours and outcomes in PARDS. Subjects who showed identical or worsening severity within the first 24 hours exhibited an approximately three to four times higher risk for mortality and fewer VFDs. Moreover, those who were placed in the severe group at 24 hours demonstrated nearly 90% mortality, which implies a benefit for reclassification at 24 hours after PARDS diagnosis.

Although the cross-sectional nature of this study did not allow for determination of causality, the significant association of early progress in PARDS with final outcomes has critical implications. A possible hypothesis for this association is that differing responses to early phase resuscitation, including lung recruitment and subsequent improvement in ventilation/perfusion mismatches, might lead to different disease progression after onset. Indeed, the severity of PARDS changed widely in the first 24 hours, such that nearly two-thirds of patients were reclassified into categories of different severity. As there were no differences in these category changes in terms of the initial severity of PARDS, our results also highlight the importance of early interventions in the management of PARDS. Future prospective trials with larger cohorts are required to establish evidence-based interventions regarding populations who are most likely to benefit from changes in treatment within the first 24 hours.

Interestingly, we have shown that improvement in oxygenation was the most discernable predictor for outcomes in PARDS. Although changes in PIP, driving pressure, and PEEP also discriminated outcomes, ΔPaO₂/FiO₂ demonstrated superior prognostic ability for mortality compared with the other variables. This finding is consistent with a recent report by Yehya and Thomas [19] that verified that PaO₂/FiO₂ at 24 hours and ΔPaO₂/FiO₂ were exclusively associated with mortality, while pressure variables, including ΔPIP, Δdriving pressure, and ΔPEEP, were not. This distinguishing association between oxygenation response and survival indicates that oxygenation is a more appropriate surrogate metric for outcomes in PARDS compared with PIP or driving pressure. This finding raises questions regarding the beneficial effects of existing ventilation strategies in children that strictly limit TV and PIP [15,20]. Considering that the evidence for the effectiveness of low-TV ventilation in children has not been consistent [21], and that children exhibit a different respiratory physiology [5] that might result in dissimilar susceptibility to ventilator-induced lung injury compared to adults, detailed prospective trials are needed in children to identify the proper upper limits of TV, PIP, and driving pressure to achieve appropriate oxygenation.

In this study, PARDS occurred in approximately 26.2% of all ICU admissions of children. This prevalence was much higher than in previous reports [7]. Moreover, the overall mortality rate of 38.9% was higher than the rates of previous studies performed in North America [13,14,22] and Europe [8,23,24]. These discrepancies may result from differences in resources, socioeconomic circumstances, and patient characteristics. In our center, pediatric patients shared an ICU with adult patients until the year 2016, when the pediatric ICU was first established. For countries with limited resources, the indications for ICU admission are relatively more stringent than in more developed countries, which might lead to this increased incidence of PARDS in the ICU. Indeed, a recent meta-analysis demonstrated that studies performed in Asia had higher overall mortality than studies performed in Western countries [7]; the mortality result in our study is within the range of reported mortality in Asia [25-27]. In addition, postsurgical, cardiac, and neonatal cases are treated in separate specialized units in our center. As we have a large number of patients in the hematologyoncology and epilepsy centers, an increased incidence of these comorbidities might contribute to the increased mortality. In this study, logistic regression analysis demonstrated that mortality was significantly higher in subjects with those comorbidities (data not shown). Finally, subjects included in this study were confined to those who underwent at least one arterial blood-gas study; thus, mild cases could have been excluded. In this context, our findings demonstrate that PARDS remains a common cause of death in the field of pediatric critical care.

We acknowledge several limitations to this study. First, our study was conducted using a limited number of patients, since this was a single-center study. Second, treatment protocols regarding ventilator management might have varied over time. Third, our study results are limited to relatively short-term outcomes. In addition, since this study was retrospectively designed, we cannot exclude any possible bias regarding patient identification. Further prospective validations are needed to overcome the inherent limitations of this study design.

In conclusion, we demonstrated that the implementation of reclassification based on oxygenation metrics 24 hours after the initial diagnosis appropriately stratified outcomes in PARDS. Progress within the first 24 hours was significantly associated with mortality and ventilator free days in PARDS. Among the variables evaluated during this early phase, oxygenation response was the most discernable surrogate metric for mortality. These results may provide a framework to design future interventional trials in PARDS and to optimize clinical practices.