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Background Continuous beta-agonist therapy, typically in the form of inhaled albuterol, is the first line therapy for the treatment of acute and severe bronchospasm in children. Although this treatment is commonly used, concerns about cardiotoxicity have been raised. We aimed to investigate the cardiotoxic effects of continuous beta-agonist therapy in children. Methods We conducted a retrospective review of children admitted to the intensive care unit (ICU) between May 2008 and April 2009, who were treated with continuous beta-agonist therapy (intravenous and nebulized). Results Twenty of the 36 children treated with continuous albuterol had repeated serum troponin-T and lactate levels measured. Eleven patients (55%) were also treated with continuous intravenous terbutaline. Elevated levels of troponin-T levels were found in 25% of children, and elevated lactate levels were found in 60%. However, all returned to normal levels within 48 hours of ICU admission, despite continued beta-agonist therapy. No children experienced arrhythmias during therapy. There was no association between intravenous terbutaline use and elevated troponin-T [odds ratio (OR), 1.3; 95% CI, 0.2–10.3] or with elevated serum lactate (OR, 0.6; 95% CI, 0.1–3.7). There was also no association between elevated troponin-T or lactate and ICU or hospital length of stay. Conclusions In this small study, a significant proportion of children had elevated serum troponin-T and lactate levels while receiving inhaled continuous beta-agonist therapy, irrespective of intravenous therapy. However, these abnormal values all returned to normal within 48 hours of ICU admission and were not associated with increased duration of hospitalization.

Background Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction. Methods This was a prospective observational study of 432 patients aged 2 weeks—17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses. Results sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality ( n  = 432, adjusted HR = 1.003, p  = 0.02) and worse OI in the first 5 days after intubation ( n  = 252, Estimate = 0.02, p  < 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003, p  < 0.0001; and slope, Estimate = 0.01, p  = 0.0009, n  = 386). Conclusions Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies. Trial registration : https://clinicaltrials.gov/ct2/show/NCT00814099 . In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.

Background The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure. Methods This was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure ( RESTORE ). Plasma IL-8 levels were measured within 24 h of consent and 24 and 48 h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped. Results Five hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373 pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4–12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level. Conclusions When measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted.

Patients who survive pediatric critical illness and their caregivers commonly experience physical, emotional, and cognitive sequelae. However, the rate and duration of school absence among patients and work absence among their caregivers are unknown. To determine the rates and duration of school absence among children who survived hospitalization with acute respiratory failure and work absence among their caregivers. The Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) cluster randomized trial included 2449 children from 31 sites to protocolized sedation (intervention) vs usual care (control) from June 6, 2009, to December 2, 2013. In total, 1360 children survived hospitalization and were selected for follow-up at 6 months after pediatric intensive care unit (PICU) discharge, which was completed from January 12, 2010, to April 13, 2015. This secondary analysis was conducted from July 1, 2020, to September 30, 2021. PICU hospitalization for acute respiratory failure, including invasive mechanical ventilation. Postdischarge assessments with caregivers of eligible participants at 6 months after PICU discharge, including questions about school and work absence. Risk factors associated with longer absence from school and work were identified. Postdischarge assessments were completed for 960 children who survived treatment for acute respiratory failure, of whom 443 (46.1%) were girls and 517 (53.9%) were boys; 509 of 957 (53.2%) were non-Hispanic White. Median age was 1.8 years (IQR, 0.4-7.9 years). In total, 399 children (41.6%) were enrolled in school, of whom 279 (69.9%) missed school after discharge. Median duration of postdischarge absence was 9.1 days (IQR, 0-27.9 days) among all children enrolled in school and 16.9 days (IQR, 7.9-43.9 days) among the 279 children with postdischarge absence. Among 960 primary caregivers, 506 (52.7%) were employed outside the home, of whom 277 (54.7%) missed work. Median duration of postdischarge work absence was 2 days (IQR, 0-10 days) among all employed primary caregivers, and 8 days (IQR, 4-20 days) among the 277 caregivers who missed work after discharge. The odds of postdischarge school absence and greater duration of absence increased for children 5 years or older (compared with 0-4 years, odds ratios [ORs] for 5-8 years, 3.20 [95% CI, 1.69-6.05] and 2.09 [95% CI, 1.30-3.37], respectively; ORs for 9-12 years, 2.49 [95% CI, 1.17-5.27] and 2.32 [95% CI, 1.30-4.14], respectively; and ORs for 13-18 years, 2.37 [95% CI, 1.20-4.66] and 1.89 [95% CI, 1.11-3.24], respectively) and those with a preexisting comorbidity (ORs, 1.90 [95% CI, 1.10-3.29] and 1.76 [95% CI, 1.14-2.69], respectively). In this secondary analysis of a cluster randomized trial, 2 in 3 children hospitalized for acute respiratory failure missed school after discharge, for a median duration of nearly 2 weeks. In addition, more than half of primary caregivers missed work after discharge. The magnitude of school absenteeism suggests that children may be at increased risk for lower educational achievement, economic hardship, and poor health outcomes in adulthood.