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Rationale: The epidemiology, management, and outcomes of acute respiratory distress syndrome (ARDS) differ between children and adults, with lower mortality rates in children despite comparable severity of hypoxemia. However, the relationship between age and mortality is unclear.Objective: We aimed to define the association between age and mortality in ARDS, hypothesizing that it would be nonlinear.Methods: We performed a retrospective cohort study using data from two pediatric ARDS observational cohorts (n = 1,236), multiple adult ARDS trials (n = 5,547), and an adult observational ARDS cohort (n = 1,079). We aligned all datasets to meet Berlin criteria. We performed unadjusted and adjusted logistic regression using fractional polynomials to assess the potentially nonlinear relationship between age and 90-day mortality, adjusting for sex, PaO2/FiO2, immunosuppressed status, year of study, and observational versus randomized controlled trial, treating each individual study as a fixed effect.Measurements and Main Results: There were 7,862 subjects with median ages of 4 years in the pediatric cohorts, 52 years in the adult trials, and 61 years in the adult observational cohort. Most subjects (43%) had moderate ARDS by Berlin criteria. Ninety-day mortality was 19% in the pediatric cohorts, 33% in the adult trials, and 67% in the adult observational cohort. We found a nonlinear relationship between age and mortality, with mortality risk increasing at an accelerating rate between 11 and 65 years of age, after which mortality risk increased more slowly.Conclusions: There was a nonlinear relationship between age and mortality in pediatric and adult ARDS.

Approximately 25% of all pediatric consultations are due to respiratory conditions, 10% of which are for asthma. Regarding prevalence, bronchiolitis, acute bronchitis, and respiratory infections are other leading pediatric respiratory illnesses. Compared to the aforementioned diseases, pediatric acute respiratory distress syndrome (PARDS) is rare but lethal in the Intensive Care Unit patients. According to global studies, the mortality in PARDS ranges from 13.3% to 60.7%. Before the Pediatric Acute Lung Injury Consensus Conference (PALICC), adult acute respiratory distress syndrome (ARDS) management guidelines were used for PARDS. The PALICC set new criteria to identify PARDS with a different treatment and management approach. Steroids have been used to treat ARDS in some cases, although their effectiveness in treating pediatric patients is highly debated in the scientific community. This review examines steroid use in treating PARDS, emphasizes current developments in the field, and gives a broad overview of PARDS management.

Hypoxemia is used to stratify severity in acute respiratory failure (ARF) but is less useful in cyanotic congenital heart disease (CCHD) due to an inability to differentiate hypoxemia from lung injury versus cardiac shunting. Therefore, we aimed to determine whether variables related to respiratory mechanics were associated with outcomes to assist in stratifying ARF severity in pediatric CCHD. We performed a retrospective cohort study from a single cardiac intensive care unit enrolling children with CCHD with ARF requiring mechanical ventilation between 2011 and 2019. Time-averaged ventilator settings and oxygenation data in the first 24 h of ARF were screened for association with the primary outcome of 28-day mortality. Of 344 eligible patients, peak inspiratory pressure (PIP) and driving pressure (ΔP) were selected as candidate variables to stratify ARF severity. PIP (OR 1.10, 95% CI 1.02-1.19) and ΔP (1.11, 95% CI 1.01-1.24) were associated with higher mortality and fewer ventilator-free days (VFDs) at 28 days after adjusting for age, severity of cardiac history, and FiO2. A three-level (mild, moderate, severe) severity stratification was established for both PIP (≤ 20, 21-29, ≥ 30) and ΔP (≤ 16, 17-24, ≥ 25), showing increasing mortality (both P < 0.01), decreasing VFDs and increasing ventilator days in survivors (all P < 0.05) across increasing pressures. Overall, we found that higher PIP and ΔP were associated with mortality and duration of ventilation across a three-level severity stratification system in pediatric CCHD with ARF, providing a practical method to prognosticate in subjects with multifactorial etiologies for hypoxemia.

High mobility group box 1 (HMGB1) protein is one of the main risk factors for pediatric acute respiratory distress syndrome (PARDS) after living donor liver transplantation (LDLT). However, studies of the relationship between HMGB1 and PARDS are lacking. We evaluated the link between anomalies of intraoperative serum HMGB1 and PARDS in pediatric LDLT recipients with biliary atresia during the first week after transplant.
Data for 210 pediatric patients with biliary atresia who underwent LDLT between January 2018 and December 2021 were reviewed retrospectively. The main measure was serum HMGB1 levels 30 min after reperfusion, while the outcome was early PARDS after LDLT. Data including pretransplant conditions, laboratory indexes, variables of intraoperation, clinical complications, and outcomes after LDLT were analyzed for each patient. Univariate analysis of PARDS and multivariate logistic regression analyses of serum HMGB1 levels at 30 min in the neohepatic phase in the presence of PARDS were conducted to examine the potential associations. Subgroup interaction analyses and linear relationships between intraoperative serum HMGB1 levels and PARDS were also performed.
Among the participants, 55 had PARDS during 7 days after LDLT, including four in the first HMGB1 tertile (4.3-8.1 pg/mL), 18 in the second tertile (8.2-10.6 pg/mL), and 33 in the third tertile (10.6-18.8 pg/mL). The nonadjusted association between intraoperative HMGB1 levels and PARDS was positive (odds ratio 1.41, 95% confidence intervals 1.24-1.61, P < 0.0001). The association remained unchanged after adjustment for age, weight, pretransplant total bilirubin, albumin, graft cold ischemia time, and intraoperative blood loss volume (odds ratio 1.28, 95% confidence interval 1.10-1.49, P = 0.0017). After controlling for potential confounders, the association between intraoperative HMGB1 levels and PARDS remained positive, as well as in the subgroup analyses.
Serum HMGB1 levels at 30 min after reperfusion were positively associated with early PARDS among pediatric patients with biliary atresia who had undergone LDLT. Identifying such patients early may increase the efficacy of perioperative respiratory management.

Pediatric acute respiratory distress syndrome (PARDS) is a severe form of respiratory failure associated with high mortality among children. The objective of this study is reported to explore the clinical function and molecular roles of microRNA-101-3p (miR-101-3p) in PARDS. The levels of miR-101-3p and mRNA levels of SRY-related high-mobility group box 9 (Sox9) were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Additionally, the diagnostic role of miR-101-3p was identified by using the Receiver operating characteristic (ROC) curve. The cell proliferation and apoptosis were examined through Cell Counting Kit-8 (CCK-8) assay and flow cytometry. To detect inflammation in cells, enzyme-linked immunosorbent assays (ELISA) were performed. The target gene of miR-101-3p was confirmed through data obtained from the luciferase activity. In patients with PARDS, miR-101-3p expression was decreased. Moderate and severe PARDS patients had lower levels of miR-101-3p than mild PARDS patients. The inflammatory progression was related to the aberrant expression of miR-101-3p in all PARDS children. MiR-101-3p was highly predictive for the detection of children with PARDS. In addition, miR-101-3p might protect A549 cells from abnormal proliferation, apoptosis, and inflammation caused by lipopolysaccharide (LPS). Sox9 might be a target gene of miR-101-3p and increased mRNA expression of Sox9 in LPS-treated A549 cells was inhibited by overexpression of miR-101-3p. Ultimately, this study suggested that reduced expression of miR-101-3p plays a role in PARDS, providing a novel angle to study the disease.

UNASSIGNED: Extracorporeal membrane oxygenation (ECMO) has been increasingly used as rescue therapy for severe pediatric acute respiratory distress syndrome (PARDS) over the past decade. However, a contemporary comparison of venovenous (VV) and venoarterial (VA) ECMO in PARDS has yet to be well described. Therefore, the objective of our study was to assess the difference between VV and VA ECMO in efficacy and safety for infection-associated severe PARDS patients.
UNASSIGNED: This prospective multicenter cohort study included patients with infection-associated severe PARDS who received VV or VA ECMO in pediatric intensive care units (PICUs) of eight university hospitals in China between December 2018 to June 2021. The primary outcome was in-hospital mortality. Secondary outcomes included ECMO weaning rate, duration of ECMO and mechanical ventilation (MV), ECMO-related complications, and hospitalization costs.
UNASSIGNED: A total of 94 patients with 26 (27.66%) VV ECMO and 68 (72.34%) VA ECMO were enrolled. Compared to the VA ECMO patients, VV ECMO patients displayed a significantly lower in-hospital mortality (50 vs. 26.92%, p = 0.044) and proportion of neurologic complications, shorter duration of ECMO and MV, but the rate of successfully weaned from ECMO, bleeding, bloodstream infection complications and pump failure were similar. By contrast, oxygenator failure was more frequent in patients receiving VV ECMO. No significant intergroup difference was observed for the hospitalization costs.
UNASSIGNED: These positive findings showed the conferred survival advantage and safety of VV ECMO compared with VA ECMO, suggesting that VV ECMO may be an effective initial treatment for patients with infection-associated severe PARDS.

Pediatric acute respiratory distress syndrome (PARDS) remains a significant cause of morbidity and mortality, with mortality rates as high as 50% in children with severe PARDS. Despite this, pediatric lung injury and mechanical ventilation has been poorly studied, with the majority of investigations being observational or retrospective and with only a few randomized controlled trials to guide intensivists. The most recent and universally accepted guidelines for pediatric lung injury are based on consensus opinion rather than objective data. Therefore, most neonatal and pediatric mechanical ventilation practices have been arbitrarily adapted from adult protocols, neglecting the differences in lung pathophysiology, response to injury, and co-morbidities among the three groups. Low tidal volume ventilation has been generally accepted for pediatric patients, even in the absence of supporting evidence. No target tidal volume range has consistently been associated with outcomes, and compliance with delivering specific tidal volume ranges has been poor. Similarly, optimal PEEP has not been well-studied, with a general acceptance of higher levels of F i O2 and less aggressive PEEP titration as compared with adults. Other modes of ventilation including airway pressure release ventilation and high frequency ventilation have not been studied in a systematic fashion and there is too little evidence to recommend supporting or refraining from their use. There have been no consistent outcomes among studies in determining optimal modes or methods of setting them. In this review, the studies performed to date on mechanical ventilation strategies in neonatal and pediatric populations will be analyzed. There may not be a single optimal mechanical ventilation approach, where the best method may simply be one that allows for a personalized approach with settings adapted to the individual patient and disease pathophysiology. The challenges and barriers to conducting well-powered and robust multi-institutional studies will also be addressed, as well as reconsidering outcome measures and study design.

Both sepsis and acute respiratory distress syndrome (ARDS) rely on imprecise clinical definitions leading to heterogeneity, which has contributed to negative trials. Because circulating protein/DNA complexes have been implicated in sepsis and ARDS, we aimed to develop a proteomic signature of DNA-bound proteins to discriminate between children with sepsis with and without ARDS. We performed a prospective case-control study in 12 children with sepsis with ARDS matched to 12 children with sepsis without ARDS on age, severity of illness score, and source of infection. We performed co-immunoprecipitation and downstream proteomics in plasma collected ≤ 24 h of intensive care unit admission. Expression profiles were generated, and a random forest classifier was used on differentially expressed proteins to develop a signature which discriminated ARDS. The classifier was tested in six independent blinded samples. Neutrophil and nucleosome proteins were over-represented in ARDS, including two S100A proteins, superoxide dismutase (SOD), and three histones. Random forest produced a 10-protein signature that accurately discriminated between children with sepsis with and without ARDS. This classifier perfectly assigned six independent blinded samples as having ARDS or not. We validated higher expression of the most informative discriminating protein, galectin-3-binding protein, in children with ARDS. Our methodology has applicability to isolation of DNA-bound proteins from plasma. Our results support the premise of a molecular definition of ARDS, and give preliminary insight into why some children with sepsis, but not others, develop ARDS.

Acute Kidney Injury (AKI) is an independent risk factor for mortality in hospitalized patients. AKI syndrome leads to fluid overload, electrolyte and acid-base disturbances, immunoparalysis, and propagates multiple organ dysfunction through organ \"crosstalk\". Preclinical models suggest AKI causes acute lung injury (ALI), and conversely, mechanical ventilation and ALI cause AKI. In the clinical setting, respiratory complications are a key driver of increased mortality in patients with AKI, highlighting the bidirectional relationship. This article highlights the challenging and complex interactions between the lung and kidney in critically ill patients with AKI and acute respiratory distress syndrome (ARDS) and global implications of AKI. We discuss disease-specific molecular mediators and inflammatory pathways involved in organ crosstalk in the AKI-ARDS construct, and highlight the reciprocal hemodynamic effects of elevated pulmonary vascular resistance and central venous pressure (CVP) leading to renal hypoperfusion and pulmonary edema associated with fluid overload and increased right ventricular afterload. Finally, we discuss the notion of different ARDS \"phenotypes\" and the response to fluid overload, suggesting differential organ crosstalk in specific pathological states. While the directionality of effect remains challenging to distinguish at the bedside due to lag in diagnosis with conventional renal function markers and lack of tangible damage markers, this review provides a paradigm for understanding kidney-lung interactions in the critically ill patient.