Predicting Mortality in Children With Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome. DESIGN: Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children's Hospital of Philadelphia. SETTING: The derivation cohort represented 100 centers worldwide; the validation cohort was from Children's Hospital of Philadelphia. PATIENTS: There were 624 and 640 subjects in the derivation and validation cohorts, respectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and PaO2/FIO2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts. CONCLUSIONS: We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

Age-Stratified Risk of Critical Illness in Young Children Presenting to the Emergency Department with Suspected Influenza.

OBJECTIVE: To investigate the risk of critical illness by age group among young children without a chronic condition presenting to the emergency department (ED) with suspected influenza. STUDY DESIGN: Retrospective study of patients aged <2 years presenting to the ED with suspected influenza (defined by diagnostic codes for influenza or influenza-like illness) from 2009 to 2017 in 49 hospitals in the Pediatric Health Information System. Patients with chronic conditions were excluded. The main clinical outcomes were intensive care unit (ICU) admission, ventilatory support, vasopressor administration, and mortality, which were compared independently by age group (<3 months, 3 to <6 months, 6 to <12 months, and 12 to <24 months). To compare outcomes by age, we estimated the prevalence of each outcome by age group after fitting logistic regression models to control for demographic differences between groups. RESULTS: A total of 55 986 children were studied. Overall admission and ICU admission rates were 20% and 2%, respectively. After adjustment for demographic variables, infants aged <3 months had higher rates of ICU admission (2.7%; 95% CI, 2.0%-3.3%; P < .001 compared with other age groups) and ventilatory support (2.5%; 95% CI, 1.9%-3.2%; P < .001 compared with other age groups); however, there were no differences in vasopressor administration. The overall case fatality rate was low (0.007%) and thus could not be compared across age groups. CONCLUSIONS: Infants aged <3 months with suspected influenza are at greatest risk for critical illness. Although critical illness is uncommon, these findings should be incorporated into acute management decisions, including the need for specified outpatient follow-up or hospitalization, and public health efforts should focus on prevention and disease-modifying interventions in this high-risk population.

Body Habitus and Risk of Mortality in Pediatric Sepsis and Septic Shock: A Retrospective Cohort Study.

OBJECTIVE: To investigate the association between body habitus and mortality in critically ill children with sepsis or septic shock. STUDY DESIGN: This was a retrospective cohort study of prospectively collected data of children admitted to US pediatric intensive care units (PICUs) with a primary or secondary diagnosis of sepsis or septic shock. We separated body habitus into underweight, normal weight, overweight, and obese. Outcomes were mortality (primary), treatment with invasive mechanical ventilation (secondary), and time to PICU discharge for survivors (secondary). Multivariable analyses using mixed-effects logistic regression and shared frailty models clustered by unit and adjusted for confounding variables were used to assess the association between body habitus and outcomes. RESULTS: There were 7038 children with sepsis or septic shock. Mortality was 10.1% (n = 714) and 52.9% (n = 3720) required invasive mechanical ventilation. Body habitus was not associated with mortality after controlling for hospital level effects and confounding variables. Children who were overweight and obese had greater odds of invasive mechanical ventilation (overweight OR 1.23 [95% CI 1.05-1.45], P = .011 and obese OR 1.57 [95% CI 1.37-1.80], P < .001) compared with children of normal weight. In survivors treated with invasive mechanical ventilation, children who were obese had a longer time to PICU discharge than children of normal weight (obese hazard ratio for discharge 0.84 [95% CI, 0.77-0.92], P < .0001). CONCLUSIONS: There was no association between body habitus and mortality in critically ill children with sepsis. Children who were overweight and obese were more likely to receive invasive mechanical ventilation and mechanically ventilated survivors who were obsese had a longer time to PICU discharge.

Risk Stratification Using Oxygenation in the First 24 Hours of Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVE: Oxygenation measured 24 hours after acute respiratory distress syndrome onset more accurately stratifies risk, relative to oxygenation at onset, in both children and adults. However, waiting 24 hours is problematic, especially for interventions that are more efficacious early in the disease course. We aimed to delineate whether oxygenation measured at timepoints earlier than 24 hours would retain predictive validity in pediatric acute respiratory distress syndrome. DESIGN: Observational cohort study. SETTING: Two large, academic PICUs. PATIENTS: Invasively ventilated children with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PaO2/FIO2 and oxygenation index (mean airway pressure × FIO2 × 100)/PaO2) were measured at acute respiratory distress syndrome onset, at 6, 12, 18, and 24 hours after in 459 children at the Children's Hospital of Philadelphia. Neither PaO2/FIO2 nor oxygenation index at acute respiratory distress syndrome onset discriminated outcome. Between 6 and 24 hours, both PaO2/FIO2 (area under receiver operating curve for mortality between 0.57 and 0.62; p = 0.049-0.002) and oxygenation index (area under receiver operating curve, 0.60-0.62; p = 0.006-0.001) showed good discrimination and calibration across multiple outcomes, including mortality, ventilator-free days at 28 days, ventilator days in survivors, and probability of extubation, given competing risk of death. The utility of oxygenation at 12 hours was confirmed in an independent cohort from the Children's Hospital of Los Angeles. CONCLUSION: Oxygenation measured between 6 and 12 hours of acute respiratory distress syndrome onset accurately stratified outcomes in children. Our results have critical implications for the design of trials, especially for interventions with greater impact in early acute respiratory distress syndrome.

The Relationship between High Flow Nasal Cannula Flow Rate and Effort of Breathing in Children.

OBJECTIVE: To use an objective metric of effort of breathing to determine optimal high flow nasal cannula (HFNC) flow rates in children <3 years of age. STUDY DESIGN: Single-center prospective trial in a 24-bed pediatric intensive care unit of children <3 years of age on HFNC. We measured the percent change in pressure∙rate product (PRP) (an objective measure of effort of breathing) as a function of weight-indexed flow rates of 0.5, 1.0, 1.5, and 2.0 L/kg/minute. For a subgroup of patients, 2 different HFNC delivery systems (Fisher & Paykel [Auckland, New Zealand] and Vapotherm [Exeter, New Hampshire]) were compared. RESULTS: Twenty-one patients (49 titration episodes) were studied. The most common diagnoses were bronchiolitis and pneumonia. Overall, there was a significant difference in the percent change in PRP from baseline (of 0.5 L/kg/minute) with increasing flow rates for the entire cohort (P < .001) with largest change at 2.0 L/kg/min (-21%). Subgroup analyses showed no significant difference in percent change in PRP from baseline when comparing the 2 different HFNC delivery systems (P = .12). Patients ≤8 kg experienced a larger percent change in PRP as HFNC flow rates were increased (P = .001) than patients >8 kg. CONCLUSIONS: The optimal HFNC flow rate to reduce effort of breathing in infants and young children is approximately 1.5-2.0 L/kg/minute with more benefit seen in children ≤8 kg.

Comparison of Effort of Breathing for Infants on Nasal Modes of Respiratory Support.

OBJECTIVE: To directly compare effort of breathing between high flow nasal cannula (HFNC), nasal intermittent mechanical ventilation (NIMV), and nasal continuous positive airway pressure (NCPAP). STUDY DESIGN: This was a single center prospective cross-over study for patients <6 months in the cardiothoracic or pediatric intensive care unit receiving nasal noninvasive respiratory support after extubation. We measured effort of breathing using esophageal manometry with pressure-rate product (PRP) on all 3 modes. NIMV synchrony was determined by comparing patient efforts (esophageal manometry) with mechanically delivered breaths (spirometry in ventilator circuit). On NIMV, PRP and synchrony was also measured after adding a nasal clip on 26 patients. RESULTS: Forty-two children were included. Median (IQR) age was 2 (0.5, 4) months. There was no difference in median PRP between HFNC 6 liters per minute, 355 (270,550), NIMV 12/5 cm H2O, 341 (235, 472), and NCPAP 5 cm H2O, 340 (245,506) (P?=?.33). Results were similar regardless of HFNC flow rate or NIMV inspiratory pressure. Median PRP on CPAP of 5 cm H2O prior to extubation 255 (176, 375) was significantly lower than all postextubation values (P??.07)). However, as NIMV synchrony improved (>60%), PRP on NIMV was lower than on HFNC. CONCLUSIONS: For infants, effort of breathing is similar on HFNC, NIMV, and NCPAP after extubation, regardless of flow rate or inspiratory pressure. We speculate that bi-level NIMV may be superior if high levels of synchrony can be achieved.

Volume and Pressure Delivery During Pediatric High-Frequency Oscillatory Ventilation.

OBJECTIVE: Identify variables independently associated with delivered tidal volume (VT) and measured mean airway pressure during high-frequency oscillatory ventilation across the range of pediatric endotracheal tube sizes. DESIGN: In vitro study. SETTING: Research laboratory. INTERVENTIONS: An in vitro bench model of the intubated pediatric respiratory system during high-frequency oscillatory ventilation was used to obtain delivered VT and mean airway pressure (in the distal lung) for various endotracheal tube sizes. Measurements were taken at different combinations of ventilator set mean airway pressure (Paw), amplitude (ΔP), frequency, and test lung compliance. Multiple regression analysis was used to construct multivariable models predicting delivered VT and mean airway pressure. MEASUREMENTS AND MAIN RESULTS: Variables independently associated with higher delivered VT for all endotracheal tube sizes include higher ΔP (p < 0.001), lower frequency (p < 0.001), and higher test lung compliance (p < 0.001). A multiplicative interaction between frequency and ΔP magnifies the delivered VT when ΔP is high and frequency is low (p < 0.001). Delivered mean airway pressure becomes lower than set Paw as ΔP increases (p < 0.001) and frequency increases (p < 0.05). Ventilator set Paw is the largest determinant of delivered mean airway pressure; however, increasing ΔP resulted in a lower delivered mean airway pressure. For example, in a 4.0 mm ID endotracheal tube, increasing ΔP by 10 cm H2O resulted in an average decrease of delivered mean airway pressure by 4.5%. CONCLUSIONS: This is the first study to quantify the interaction between ΔP and frequency in delivered VT and the effect of ΔP and frequency on delivered mean airway pressure. These results demonstrate the need to measure or estimate VT and delivered pressures during high-frequency oscillatory ventilation and may be useful in determining optimal strategies for lung protective ventilation during high-frequency oscillatory ventilation.

Impact of gender on sepsis mortality and severity of illness for prepubertal and postpubertal children.

OBJECTIVE: To investigate differences in sepsis mortality between prepubertal and postpubertal males and females. STUDY DESIGN: This was a retrospective review of the Virtual PICU Systems (VPS) database (including 74 pediatric intensive care units [PICUs]) for 2006-2008. We included prepubertal (aged 2-7 years) and postpubertal (aged 16-21 years) children with a primary diagnosis of sepsis admitted to a participating PICU. RESULTS: Prepubertal females (n = 272; 9.9% mortality) and prepubertal males (n = 303; 10.9% mortality) had similar mortality and severity of illness (Pediatric Index of Mortality 2 risk of mortality [PIM 2 ROM]). Postpubertal females (n = 233; mortality, 5.6%) had lower mortality than postpubertal males (n = 212; mortality, 11.8%; P = .03). PIM 2 ROM was higher for postpubertal males than postpubertal females (P = .02). After controlling for hospital specific effects with multivariate modeling, in postpubertal children, female gender was independently associated with a lower initial severity of illness (PIM 2 ROM: OR, 0.77; 95% CI, 0.62-0.96; P = .02). CONCLUSION: Sepsis mortality is similar in prepubertal males and females. However, postpubertal males have a higher sepsis mortality than postpubertal females, likely related to their greater severity of illness on PICU admission. These outcome differences in postpubertal children may reflect a hormonal influence on the response to infection or differences in underlying comorbidities, source of infection, or behavior.