Benjamin E. Orwoll

Biomarkers in Pediatric ARDS: Future Directions

Acute respiratory distress syndrome (ARDS) is common among mechanically ventilated children and accompanies up to 30% of all pediatric intensive care unit deaths. Though ARDS diagnosis is based on clinical criteria, biological markers of acute lung damage have been extensively studied in adults and children. Biomarkers of inflammation, alveolar epithelial and capillary endothelial disruption, disordered coagulation, and associated derangements measured in the circulation and other body fluids, such as bronchoalveolar lavage, have improved our understanding of pathobiology of ARDS. The biochemical signature of ARDS has been increasingly well described in adult populations, and this has led to the identification of molecular phenotypes to augment clinical classifications. However, there is a paucity of data from pediatric ARDS (pARDS) patients. Biomarkers and molecular phenotypes have the potential to identify patients at high risk of poor outcomes, and perhaps inform the development of targeted therapies for specific groups of patients. Additionally, because of the lower incidence of and mortality from ARDS in pediatric patients relative to adults and lack of robust clinical predictors of outcome, there is an ongoing interest in biological markers as surrogate outcome measures. The recent definition of pARDS provides additional impetus for the measurement of established and novel biomarkers in future pediatric studies in order to further characterize this disease process. This chapter will review the currently available literature and discuss potential future directions for investigation into biomarkers in ARDS among children.

A Simple and Robust Bedside Model for Mortality Risk in Pediatric Patients With Acute Respiratory Distress Syndrome

Objectives: Despite declining mortality, acute respiratory distress syndrome is still involved in up to one third of pediatric intensive care deaths. The recently convened Pediatric Acute Lung Injury Consensus Conference has outlined research priorities for the field, which include the need for accurate bedside risk stratification of patients. We aimed to develop a simple yet robust model of mortality risk among pediatric patients with acute respiratory distress syndrome to facilitate the targeted application of high-risk investigational therapies and stratification for enrollment in clinical trials. Design: Prospective, multicenter cohort. Setting: Five academic PICUs. Patients: Three hundred eight children greater than 1 month and less than or equal to 18 years old, admitted to the ICU, with bilateral infiltrates on chest radiograph and PaO2/FIO2 ratio less than 300 in the clinical absence of left atrial hypertension. Interventions: None. Measurements and Main Results: Twenty clinical variables were recorded in the following six categories: demographics, medical history, oxygenation, ventilation, radiographic imaging, and multiple organ dysfunction. Data were measured 0–24 and 48–72 hours after acute respiratory distress syndrome onset (day 1 and 3) and examined for associations with hospital mortality. Among 308 enrolled patients, mortality was 17%. Children with a history of cancer and/or hematopoietic stem cell transplant had higher mortality (47% vs 11%; p < 0.001). Oxygenation index, the PaO2/FIO2 ratio, extrapulmonary organ dysfunction, Pediatric Risk of Mortality-3, and positive cumulative fluid balance were each associated with mortality. Using two statistical approaches, we found that a parsimonious model of mortality risk using only oxygenation index and cancer/hematopoietic stem cell transplant history performed as well as other more complex models that required additional variables. Conclusions: In the PICU, oxygenation index and cancer/hematopoietic stem cell transplant history can be used on acute respiratory distress syndrome day 1 or day 3 to predict hospital mortality without the need for more complex models. These findings may simplify risk assessment for clinical trials, counseling families, and high-risk interventions such as extracorporeal life support.

Simulated spaceflight produces a rapid and sustained loss of osteoprogenitors and an acute but transitory rise of osteoclast precursors in two genetic strains of mice

Loss of skeletal weight bearing or skeletal unloading as occurs during spaceflight inhibits bone formation and stimulates bone resorption. These are associated with a decline in the osteoblast (Ob.S/BS) and an increase in the osteoclast (Oc.S/BS) bone surfaces. To determine the temporal relationship between changes in the bone cells and their marrow precursor pools during sustained unloading, and whether genetic background influences these relationships, we used the hindlimb unloading model to induce bone loss in two strains of mice known to respond to load and having significantly different cancellous bone volumes (C57BL/6 and DBA/2 male mice). Skeletal unloading caused a progressive decline in bone volume that was accompanied by strain-specific changes in Ob.S/BS and Oc.S/BS. These were associated with a sustained reduction in the osteoprogenitor population and a dramatic but transient increase in the osteoclast precursor pool size in both strains. The results reveal that bone adaptation to skeletal unloading involves similar rapid changes in the osteoblast and osteoclast progenitor populations in both strains of mice but striking differences in Oc.S/BS dynamics, BFR, and cancellous bone structure. These strain-specific differences suggest that genetics plays an important role in determining the osteoblast and osteoclast populations on the bone surface and the dynamics of bone loss in response to skeletal unloading.

Incorporating Inflammation into Mortality Risk in Pediatric Acute Respiratory Distress Syndrome.

Objectives: In pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes. Design: Multicenter prospective observational study. Setting: We enrolled patients from five academic PICUs between 2008 and 2015. Patients: Patients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of acute respiratory distress syndrome. Interventions: Eight proinflammatory and anti-inflammatory cytokines were measured on acute respiratory distress syndrome day 1 and correlated with mortality, ICU morbidity as measured by survivor Pediatric Logistic Organ Dysfunction score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin. Measurements and Main Results: We measured biomarker levels in 194 patients, including 38 acute respiratory distress syndrome nonsurvivors. Interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating oxygenation index, interleukin-8, and tumor necrosis factor-R2 was superior to a model of oxygenation index alone in predicting the composite outcome of mortality or severe morbidity (area under the receiver operating characteristic, 0.77 [0.70–0.83] vs 0.70 [0.62–0.77]; p = 0.042). Conclusions: In pediatric acute respiratory distress syndrome, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the oxygenation index to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies.

Gamification and Microlearning for Engagement With Quality Improvement (GAMEQI): A Bundled Digital Intervention for the Prevention of Central Line–Associated Bloodstream Infection

Central line–associated bloodstream infections (CLABSIs) cause major patient harm, preventable through attention to line care best practice standards. The objective was to determine if a digital self-assessment application (CLABSI App), bundling line care best practices with social gamification and in-context microlearning, could engage nurses in CLABSI prevention. Nurses caring for children with indwelling central venous catheters in 3 high-risk units were eligible to participate. All other units served as controls. The intervention was a 12-month nonrandomized quality improvement study of CLABSI App implementation with interunit competitions. Compared to the preceding year, the intervention group (9886 line days) CLABSI rate decreased by 48% (P = .03). Controls (7879 line days) did not change significantly. In all, 105 unique intervention group nurses completed 673 self-assessments. Competitions were associated with increased engagement as measured by self-assessments and unique participants. This model could be extended to other health care–associated infections, and more broadly to process improvement within and across health care systems.

PS-138 Fluid Overload Is Associated With Mortality In Paediatric Acute Respiratory Distress Syndrome (ards) Only In The Setting Of Acute Kidney Injury (aki)

Background Cumulative fluid balance on day 3 is associated with mortality in paediatric ARDS (Valentine 2012, Willson 2013). Whether this association is modified by AKI is unknown. Aim To test the effect of AKI on the association between fluid and mortality in ARDS. Methods We calculated cumulative fluid balance 3 days after ARDS onset in a multi-centre cohort. AKI was defined as ‘Injury’ or ‘Failure’ by pRIFLE criteria (Akcan-Arikan 2007). Results Patient characteristics are shown in Table 1. Mortality was higher in patients with AKI. Fluid balance was associated with mortality independent of sex, age, race, PRISM 3 and vasopressor use; upon stratification, this association was to limited patients with AKI (Table 2 and Figure). Abstract PS-138 Table 1 Patient characteristics Characteristic (Mean ± SD) No AKI (n = 153) AKI (n = 56) Age, Months 86 ± 73 86 ± 74 Male (%) 86(56) 31(55) P/F Ratio 174 ± 106 156 ± 103 PRISM 3* 13 ± 8 21 ± 11 Day 3 Fluid Balance (100 mL/kg)* 0.61 ± 0.97 1.1 ± 1.59 Mortality (%)* 12(7.8) 14(25) **p < 0.01; all other p-values >0.05. Abstract PS-138 Table 2 Logistic regression model adjusted for age, sex, race, PRISM 3 and inotrope useoutcome: mortality predictor: day 3 fluid balance (100 mL/kg) n OR 95% CI p All Patients 209 1.64 1.14–2.37 0.008 Patients Without AKI 153 1.35 0.68–2.7 0.394 Patients With AKI 56 1.89 1.08–3.31 0.027 Abstract PS-138 Figure Conclusions Day 3 cumulative fluid balance and AKI are associated with mortality. The association with fluid balance is limited to patients with AKI. This has important implications for fluid management in ARDS patients.

Challenging the One-Dose-Fits-All Model for Insulin in the Acute Treatment of Pediatric Diabetic Ketoacidosis. A Critical Appraisal of "Low-Dose Versus Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial" by Nallasamy et al (JAMA Pediatrics 2014; 168:999-1005).

Objective: To review the findings and discuss the implications of the use of low-dose insulin infusions in pediatric diabetic ketoacidosis compared with standard-dose insulin. Data Sources: A search of the electronic PubMed database was used to perform the clinical query as well as to search for additional relevant literature. Study Selection and Data Extraction: The article by Nallasamy K et al “Low-Dose vs Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial. JAMA Pediatrics 2014; 17:e477–e480” was selected for critical appraisal and literature review. Data Synthesis: The authors performed a randomized controlled trial among 50 consecutive patients of 0–12 years old presenting to the emergency department in diabetic ketoacidosis. They found that low-dose (0.05 U/kg/hr) insulin infusion was noninferior to standard-dose (0.1 U/kg/hr) insulin in terms of resolution of hyperglycemia and acidosis with a trend toward lower rates of therapy-related complications in the low-dose group. Conclusions: Low-dose insulin infusion is noninferior to standard-dose insulin in the treatment of younger pediatric patients with diabetic ketoacidosis and may lead to fewer therapy-related complications.