The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis.

Zinc is a structural component of proteins, functions as a catalytic co-factor in DNA synthesis and transcription of hundreds of enzymes, and has a regulatory role in protein-DNA interactions of zinc-finger proteins. For many years, zinc has been acknowledged for its anti-oxidative and anti-inflammatory functions. Furthermore, zinc is a potent inhibitor of caspases-3, -7, and -8, modulating the caspase-controlled apoptosis and necroptosis. In recent years, the immunomodulatory role of zinc in sepsis and COVID-19 has been investigated. Both sepsis and COVID-19 are related to various regulated cell death (RCD) pathways, including apoptosis and necroptosis. Lack of zinc may have a negative effect on many immune functions, such as oxidative burst, cytokine production, chemotaxis, degranulation, phagocytosis, and RCD. While plasma zinc concentrations decline swiftly during both sepsis and COVID-19, this reduction is primarily attributed to a redistribution process associated with the inflammatory response. In this response, hepatic metallothionein production increases in reaction to cytokine release, which is linked to inflammation, and this protein effectively captures and stores zinc in the liver. Multiple regulatory mechanisms come into play, influencing the uptake of zinc, the binding of zinc to blood albumin and red blood cells, as well as the buffering and modulation of cytosolic zinc levels. Decreased zinc levels are associated with increasing severity of organ dysfunction, prolonged hospital stay and increased mortality in septic and COVID-19 patients. Results of recent studies focusing on these topics are summarized and discussed in this narrative review. Existing evidence currently does not support pharmacological zinc supplementation in patients with sepsis or COVID-19. Complementation and repletion should follow current guidelines for micronutrients in critically ill patients. Further research investigating the pharmacological mechanism of zinc in programmed cell death caused by invasive infections and its therapeutic potential in sepsis and COVID-19 could be worthwhile.

The Impact of Estimated Energy and Protein Balances on Extrauterine Growth in Preterm Infants.

BACKGROUND: Nutritional support of preterm infants remains a field of debate in the literature and clinical practice varies significantly. Adequate nutrition should promote growth and aim for optimal later neurodevelopment. However, it is often impaired by prematurity-associated morbidity and the physiologic immaturity of preterm infants. This study assessed the impact of energy and macronutrient provision on growth velocity and outcome and explored differences attributed to the heterogeneity of the preterm population. METHODS: We retrospectively collected clinical and nutritional data from neonates hospitalized in two separate Neonatal Intensive Care Units (NICUs). Estimated energy and protein balance were calculated based on the ESPGHAN guidelines and their association with the growth outcome was explored. Growth assessment was based on somatometry Delta (Δ) z-scores at discharge. RESULTS: In total, 174 neonates were included in the study. By day 14, most preterm infants were exclusively enterally fed, whereas there were infants in the <28 and 28-31+6 subgroups fed exclusively parenterally. Energy balance was positive for all gestational age (GA) subgroups except for those born <28 weeks. Protein balance was consistently positive for extremely premature but negative for late preterms. Cumulative substrates provisions were strong predictors of a positive energy or protein balance in the <34 weeks GA preterms on days 14 (ROC analyses, p < 0.001) and 7 (p < 0.05). A higher GA (p = 0.013) and enteral nutrition (p = 0.005) were additional predictors of a positive energy balance. All GA subgroups had a negative Δ z-score of weight at discharge. In the <34 GA subcohorts, a positive protein balance on day 14 (p = 0.009) and a short time to regain birth weight (exp(B) 3.1 (p = 0.004)) were independently associated with a positive Δ z-score of weight at discharge. CONCLUSIONS: Early achievement of a positive energy and protein balance, based on the ESPGHAN guidelines, is crucial to ensure optimal postnatal growth and prevent extrauterine growth restriction, a relatively common occurrence in preterm infants.

Suicidality Prevalence in a Pediatric Psychiatric Clinic: Relation to Social and Environmental Risk Factors.

Suicidality is a growing public health problem in children and adolescents. The aim of this retrospective data analysis study was to estimate the prevalence of suicidality in pediatric patients admitted to an academic Pediatric Psychiatric Clinic (PPC) and to analyze social and environmental risk factors associated with suicide. Suicidal ideation was assessed by the Self-Injurious Thoughts and Behaviors Interview. Using established psychometric scales, social and stressful events were analyzed. During the four-year study, 249 episodes of care were experienced by 152 individuals (mean age 15.2 ± 2 years, girls/boys 107/45). Twenty-eight patients (11.2%) were admitted from the Pediatric Intensive Care Unit and the Department of Pediatrics, 162 (65.1%) from the Pediatric Emergency Department, and 59 (23.7%) from other Hospitals (p = 0.003). A significant longitudinal increase in admissions to PPC, with increasing trends of suicidal ideation, suicide attempts, and suicidality, was recorded. Suicidal behavior, bullying, internet addiction, friends quarreling, and family problems were risk factors for suicide attempts and suicidality. Our results have implications for prevention programs, highlighting an increasing need for care for suicide attempts and suicidal ideation, related to specific stressful events and contextual socio-environmental status.

Ex Vivo Evaluation of Glutamine Treatment in Sepsis and Trauma in a Human Peripheral Blood Mononuclear Cells Model.

We aimed to assess the lipopolysaccharide (LPS), or heat shock (HS) induction, and glutamine-modulating effects on heat shock protein-90α (HSP90α) and cytokines in an ex vivo model using peripheral blood mononuclear cells (PBMCs). The PBMCs of patients with septic shock, trauma-related systemic inflammatory response syndrome (SIRS), and healthy subjects were incubated with 1 µg/mL LPS at 43 °C (HS). Glutamine 10 mM was added 1 hour before or after induction or not at all. We measured mRNA HSP90α, monocyte (m) and lymphocyte (l) HSP90α proteins, interleukin (IL)-1b, -6, -8, -10, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) supernatant levels. Heat shock increased the HSP90α mRNA and mHSP90α in all groups (10-fold in sepsis, p < 0.001 and p = 0.047, respectively). LPS induced the mHSP90α and lHSP90α in healthy (p < 0.001) and mHSP90α in SIRS (p = 0.004) but not in sepsis. LPS induced the cytokines at 24 and 48 h in all groups, especially in trauma (p < 0.001); HS only induced the IL-8 in healthy (p = 0.003) and septic subjects (p = 0.05). Glutamine at 10 mM before or after stimulation did not alter any induction effect of LPS or HS on HSP90α mRNA and mHSP90α protein in sepsis. In SIRS, glutamine before LPS decreased the mHSP90α but increased it when given after HS (p = 0.018). Before or after LPS (p = 0.049) and before HS (p = 0.018), glutamine decreased the lHSP90α expression in sepsis but increased it in SIRS when given after HS (p = 0.003). Regarding cytokines, glutamine enhanced the LPS-induced MCP-1 at 48 h in healthy (p = 0.011), SIRS (p < 0.001), and sepsis (p = 0.006). In conclusion, glutamine at 10 mM, before or after LPS and HS, modulates mHSP90α and lHSP90α in sepsis and SIRS differently and unpredictably. Although it does not alter the stimulation effect on interleukins, glutamine enhances the LPS induction effect on supernatant MCP-1 in all groups. Future research should seek to elucidate better the impact of glutamine and temperature modulation on HSP90α and MCP-1 pathways in sepsis and trauma.

Pediatric tumefactive multiple sclerosis case (with baló-like lesions), diagnostic and treatment challenges.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, rare during childhood. MS variations, like tumefactive MS and Balo concentric sclerosis, constitute puzzling to treat diagnostic dilemmas for pediatric patients. Differential diagnosis, mainly from brain tumors, is an absolute necessity. In addition, apart from treating acute attacks, immunomodulatory alternatives are limited. CASE: We present a 12.5-year-old boy diagnosed, 5 years ago, with tumefactive relapsing-remitting MS, with severe recurrent clinical attacks. Definite diagnosis of demyelination was achieved via combined brain imaging including magnetic resonance (MR) imaging, MR spectroscopy and computed tomography, avoiding brain biopsy. Acute attacks showed satisfactory response to aggressive treatment choices, like plasmapheresis and cyclophosphamide, but age-appropriate immunomodulating treatment was available, only 2 years later. Finally, after a last radiological relapse, when he was 10 years old, fingolimod was initiated. He has been clinically and radiologically stable since, presenting an excellent treatment tolerance.

External Validation of Equations to Estimate Resting Energy Expenditure in Critically Ill Children and Adolescents with and without Malnutrition: A Cross-Sectional Study.

We evaluated the validity of sixteen predictive energy expenditure equations for resting energy expenditure estimation (eREE) against measured resting energy expenditure using indirect calorimetry (REEIC) in 153 critically ill children. Predictive equations were included based on weight, height, sex, and age. The agreement between eREE and REEIC was analyzed using the Bland−Altman method. Precision was defined by the 95% limits of the agreement; differences > ±10% from REEIC were considered clinically unacceptable. The reliability was assessed by the intraclass correlation coefficient (Cronbach's alpha). The influence of anthropometric, nutritional, and clinical variables on REEIC was also assessed. Thirty (19.6%) of the 153 enrolled patients were malnourished (19.6%), and fifty-four were overweight (10.5%) or obese (24.8%). All patients received sedation and analgesia. Mortality was 3.9%. The calculated eREE either underestimated (median 606, IQR 512; 784 kcal/day) or overestimated (1126.6, 929; 1340 kcal/day) REEIC compared with indirect calorimetry (928.3, 651; 1239 kcal/day). These differences resulted in significant biases of −342 to 592 kcal (95% limits of agreement (precision)−1107 to 1380 kcal/day) and high coefficients of variation (up to 1242%). Although predicted equations exhibited moderate reliability, the clinically acceptable ±10% accuracy rate ranged from only 6.5% to a maximum of 24.2%, with the inaccuracy varying from −31% to +71.5% of the measured patient's energy needs. REEIC (p = 0.017) and eREE (p < 0.001) were higher in the underweight compared to overweight and obese patients. Apart from a younger age, malnutrition, clinical characteristics, temperature, vasoactive drugs, neuromuscular blockade, and energy intake did not affect REEIC and thereby predictive equations' accuracy. Commonly used predictive equations for calculating energy needs are inaccurate for individual patients, either underestimating or overestimating REEIC compared with indirect calorimetry. Altogether these findings underscore the urgency for measuring REEIC in clinical situations where accurate knowledge of energy needs is vital.

External Validation with Accuracy Confounders of VCO2-Derived Predicted Energy Expenditure Compared to Resting Energy Expenditure Measured by Indirect Calorimetry in Mechanically Ventilated Children.

Optimal energy provision, guided by measured resting energy expenditure (REE) and determined by indirect calorimetry (IC), is fundamental in Intensive Care Units (ICU). Because IC availability is limited, methods to predict REE based on carbon dioxide production (VCO2) measurements (REEVCO2) alone have been proposed as a surrogate for REE measured by IC (REEIC). The study aimed at externally and internally validating the accuracy of the REEVCO2 as an alternative to REEIC in mechanically ventilated children. A ventilator's integrated gas exchange module (E-COVX) was used to prospectively measure REEIC and predict REEVCO2 on 107 mechanically ventilated children during the first 24 h of admission. The accuracy of the REEVCO2 compared to REEIC was assessed through the calculation of bias and precision, paired median differences, linear regression, and ROC analysis. Accuracy within ±10% of the REEIC was deemed acceptable for the REEVCO2 equation. The calculated REEVCO2 based on respiratory quotient (RQ) 0.89 resulted in a mean bias of −72.7 kcal/day (95% limits of agreement −321.7 to 176.3 kcal/day) and a high coefficient of variation (174.7%), while 51.4% of the calculations fell outside the ±10% accuracy rate. REEVCO2 derived from RQ 0.80 or 0.85 did not improve accuracy. Only measured RQ (Beta 0.73, p < 0.001) and no-recorded neuromuscular blocking agents (Beta −0.13, p = 0.044) were independently associated with the REEVCO2−REEIC difference. Among the recorded anthropometric, metabolic, nutrition, or clinical variables, only measured RQ was a strong predictor of REEVCO2 inaccuracy (p < 0.001). Cutoffs of RQ = 0.80 predicted 89% of underestimated REEIC (sensitivity 0.99; specificity 0.89) and RQ = 0.82 predicted 56% of overestimated REEIC (sensitivity of 0.99; specificity 0.56). REEVCO2 cannot be recommended as an alternative to REEIC in mechanically ventilated children, regardless of the metabolic, anthropometric, or clinical status at the time of the evaluation.

Impact of Intracranial Hypertension on Outcome of Severe Traumatic Brain Injury Pediatric Patients: A 15-Year Single Center Experience.

Background: Intracranial hypertension (IC-HTN) is significantly associated with higher risk for an unfavorable outcome in pediatric trauma. Intracranial pressure (ICP) monitoring is widely becoming a standard of neurocritical care for children. Methods: The present study was designed to evaluate influences of IC-HTN on clinical outcomes of pediatric TBI patients. Demographic, injury severity, radiologic characteristics were used as possible predictors of IC-HTN or of functional outcome. Results: A total of 118 pediatric intensive care unit (PICU) patients with severe TBI (sTBI) were included. Among sTBI cases, patients with GCS < 5 had significantly higher risk for IC-HTN and for mortality. Moreover, there was a statistically significant positive correlation between IC-HTN and severity scoring systems. Kaplan−Meier analysis determined a significant difference for good recovery among patients who had no ICP elevations, compared to those who had at least one episode of IC-HTN (log-rank chi-square = 11.16, p = 0.001). A multivariable predictive logistic regression analysis distinguished the ICP-monitored patients at risk for developing IC-HTN. The model finally revealed that higher ISS and Helsinki CT score increased the odds for developing IC-HTN (p < 0.05). Conclusion: The present study highlights the importance of ICP-guided clinical practices, which may lead to increasing percentages of good recovery for children.

Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations.

Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93-0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.

Specific characteristics and current diagnostic and treatment modalities performance of super refractory status epilepticus in children: A comparative study.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is associated with significant morbidity and mortality in children. We explored the clinical spectrum, specific characteristics, and outcome in SRSE patients admitted in a pediatric intensive care unit (PICU) and investigated how well current diagnostic or treatment modalities perform compared to Status Epilepticus (SE) and Refractory SE (RSE) patients. METHODS: Retrospective analysis of PICU patients admitted with convulsive SE during 2009-2019. Eighty-six patients were classified as SE, RSE, and SRSE. New-onset RSE (NORSE) and febrile infection-related epilepsy syndrome (FIRES) were also identified. Functional outcome was evaluated by the modified Rankin scale. RESULTS: Patients with SRSE (n = 20) had longer weaning off anesthetics (p = 0.014), length of stay, mechanical ventilation duration, higher illness severity scores, and poorer outcome compared to SE (n = 13) or RSE (n = 53) patients (all p < 0.001). Diagnosis, mainly expressed by high prevalence of NORSE (n = 13) and FIRES (n = 9), was independently associated with SRSE (p = 0.024). Abnormal MRI findings (p = 0.005), and epilepsy-related pathogenic variants identified by whole-exome sequencing (WES) were mostly found in SRSE patients. Compared to intravenous immunoglobulins and steroid pulses, plasmapheresis and ketogenic diet, more often used in SRSE (p < 0.01), contributed better to seizure control. Only SRSE (AUROC > 0.80, 95% CI = 0.68-0.94, p < 0.001) and diagnosis (AUROC > 0.70, 95% CI = 0.55-0.83, p = 0.02) could predict a poor outcome. CONCLUSION: The majority of SRSE patients are characterized by considerable functional decline and morbidity. WES analysis may reveal epilepsy-related pathogenic variants while early aggressive immunotherapy and/or ketogenic diet might prove beneficial. Multicenter studies for prediction models of outcome are needed.

Epidemiology and Outcomes of Critically Ill Children at Risk for Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: Interventional trials aimed at pediatric acute respiratory distress syndrome prevention require accurate identification of high-risk patients. In this study, we aimed to characterize the frequency and outcomes of children meeting "at risk for pediatric acute respiratory distress syndrome" criteria as defined by the Pediatric Acute Lung Injury Consensus Conference. DESIGN: Planned substudy of the prospective multicenter, international Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study conducted during 10 nonconsecutive weeks (May 2016-June 2017). SETTING: Thirty-seven international PICUs. PATIENTS: Three-hundred ten critically ill children meeting Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency of children at risk for pediatric acute respiratory distress syndrome and rate of subsequent pediatric acute respiratory distress syndrome diagnosis and used multivariable logistic regression to identify factors associated with subsequent pediatric acute respiratory distress syndrome. Frequency of at risk for pediatric acute respiratory distress syndrome was 3.8% (95% CI, 3.4-5.2%) among the 8,122 critically ill children who were screened and 5.8% (95% CI, 5.2-6.4%) among the 5,334 screened children on positive pressure ventilation or high-flow oxygen. Among the 310 at-risk children, median age was 2.1 years (interquartile range, 0.5-7.3 yr). Sixty-six children (21.3%) were subsequently diagnosed with pediatric acute respiratory distress syndrome, a median of 22.6 hours (interquartile range, 9.8-41.0 hr) later. Subsequent pediatric acute respiratory distress syndrome was associated with increased mortality (21.2% vs 3.3%; p < 0.001) and longer durations of invasive ventilation and PICU care. Subsequent pediatric acute respiratory distress syndrome rate did not differ by respiratory support modality at the time of meeting at risk criteria but was independently associated with lower initial saturation:Fio2 ratio, progressive tachycardia, and early diuretic administration. CONCLUSIONS: The Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria identify critically ill children at high risk of pediatric acute respiratory distress syndrome and poor outcomes. Interventional trials aimed at pediatric acute respiratory distress syndrome prevention should target patients early in their illness course and include patients on high-flow oxygen and positive pressure ventilation.

Genetic cause of epilepsy in a Greek cohort of children and young adults with heterogeneous epilepsy syndromes.

We describe a cohort of 10 unrelated Greek patients (4 females, 6 males; median age 6.5 years, range 2-18 years) with heterogeneous epilepsy syndromes with a genetic basis. In these patients, causative genetic variants, including two novel ones, were identified in 9 known epilepsy-related genes through whole exome sequencing. A patient with glycine encephalopathy was a compound heterozygote for the p.Arg222Cys and the p.Ser77Leu AMT variant. A patient affected with Lafora disease carried the homozygous p.Arg171His EPM2A variant. A de novo heterozygous variant in the GABRG2 gene (p.Pro282Thr) was found in one patient and a pathogenic variant in the GRIN2B gene (p.Gly820Val) in another patient. Infantile-onset lactic acidosis with seizures was associated with the p.Arg446Ter PDHX gene variant in one patient. In two additional epilepsy patients, the p.Ala1662Val and the novel non-sense p.Phe1330Ter SCN1A gene variants were found. Finally, in 3 patients we observed a novel heterozygous missense variant in SCN2A (p.Ala1874Thr), a heterozygous splice site variant in SLC2A1 (c.517-2A>G), as a cause of Glut1 deficiency syndrome, and a pathogenic variant in STXBP1 (p.Arg292Leu), respectively. In half of our cases (patients with variants in the GRIN2B, SCN1A, SCN2A and SLC2A1 genes), a genetic cause with potential management implications was identified.

Introducing a Radiography-based Score in Children With Acute Respiratory Failure: A Cross-sectional Study.

PURPOSE: Respiratory failure (RF) is one of the most common reasons for hospitalization in pediatric intensive care units (PICU). We propose a radiography-based severity score for the assessment of children with RF and investigate the possible associations with severity indices and outcome. MATERIALS AND METHODS: Children with acute RF admitted in PICU were enrolled. Disease severity scores [Pediatric Risk of Mortality (PRISM) and Pediatric Logistic Organ Dysfunction (PELOD)], the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FiO2) ratios, duration of ventilator support (DVS), length of PICU and hospital stay (LOS), and outcome were recorded. A 5-point radiography score that considered potential radiographic findings was derived through stepwise multivariable logistic regression analysis, and validated. Radiographs upon PICU admission and on the worst RF day (maximum respiratory support and worst oxygenation/ventilation parameters) were blindly reviewed and independently scored by 2 radiologists and 2 clinicians, following training. RESULTS: We enrolled 104 children [median age 2.7 (interquartile range, 0.5 to 9.6) y, 65.4% boys]. Overall, 163 radiographs (PICU admission: 86, worst RF day: 77) were assessed. Radiography scores correlated positively with predicted mortality (PELOD, PRISM), DVS, LOS (all P<0.001) and inversely with PaO2/FiO2 (P<0.001). Scores differed among diagnostic categories (P<0.05); patients with acute respiratory distress syndrome, air-leaks, drowning, and pneumonia scored the highest (P<0.005). Radiography scoring trends indicating deterioration were associated with prolonged DVS, PICU, and hospital LOS (P<0.001). Agreement between all raters was good (κ=0.7, P<0.001). CONCLUSIONS: This novel radiography score for children with RF, associated with clinical severity scores, mortality risk, duration of ventilatory support, and hospitalization, follows a simple structured approach and can be readily utilized by radiologists and pediatricians as a bedside tool for stratification of disease severity and prognosis.

Adherence to Lung-Protective Ventilation Principles in Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: To describe mechanical ventilation management and factors associated with nonadherence to lung-protective ventilation principles in pediatric acute respiratory distress syndrome. DESIGN: A planned ancillary study to a prospective international observational study. Mechanical ventilation management (every 6 hr measurements) during pediatric acute respiratory distress syndrome days 0-3 was described and compared with Pediatric Acute Lung Injury Consensus Conference tidal volume recommendations (< 7 mL/kg in children with impaired respiratory system compliance, < 9 mL/kg in all other children) and the Acute Respiratory Distress Syndrome Network lower positive end-expiratory pressure/higher Fio2 grid recommendations. SETTING: Seventy-one international PICUs. PATIENTS: Children with pediatric acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analyses included 422 children. On pediatric acute respiratory distress syndrome day 0, median tidal volume was 7.6 mL/kg (interquartile range, 6.3-8.9 mL/kg) and did not differ by pediatric acute respiratory distress syndrome severity. Plateau pressure was not recorded in 97% of measurements. Using delta pressure (peak inspiratory pressure - positive end-expiratory pressure), median tidal volume increased over quartiles of median delta pressure (p = 0.007). Median delta pressure was greater than or equal to 18 cm H2O for all pediatric acute respiratory distress syndrome severity levels. In severe pediatric acute respiratory distress syndrome, tidal volume was greater than or equal to 7 mL/kg 62% of the time, and positive end-expiratory pressure was lower than recommended by the positive end-expiratory pressure/Fio2 grid 70% of the time. In multivariable analysis, tidal volume nonadherence was more common with severe pediatric acute respiratory distress syndrome, fewer PICU admissions/yr, non-European PICUs, higher delta pressure, corticosteroid use, and pressure control mode. Adherence was associated with underweight stature and cuffed endotracheal tubes. In multivariable analysis, positive end-expiratory pressure/Fio2 grid nonadherence was more common with higher pediatric acute respiratory distress syndrome severity, ventilator decisions made primarily by the attending physician, pre-ICU cardiopulmonary resuscitation, underweight stature, and age less than 2 years. Adherence was associated with respiratory therapist involvement in ventilator management and longer time from pediatric acute respiratory distress syndrome diagnosis. Higher nonadherence to tidal volume and positive end-expiratory pressure recommendations were independently associated with higher mortality and longer duration of ventilation after adjustment for confounding variables. In stratified analyses, these associations were primarily influenced by children with severe pediatric acute respiratory distress syndrome. CONCLUSIONS: Nonadherence to lung-protective ventilation principles is common in pediatric acute respiratory distress syndrome and may impact outcome. Modifiable factors exist that may improve adherence.