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High-flow nasal cannula (HFNC) is a safe, well-tolerated, and noninvasive method of respiratory support that has seen increasing use in the care of children with respiratory distress. High-flow nasal cannula may be able to prevent intubations in infants and children with respiratory distress.The objective of this study was to determine the clinical and patient characteristics that predict success or failure of HFNC therapy in children presenting to the pediatric emergency department (PED) with respiratory distress.A retrospective cohort review was conducted of all children younger than 2 years evaluated in 2 PEDs between June 2011 and September 2012 who received HFNC therapy within 24 hours of initial triage. Data extraction included clinical variables, demographic variables, and patient outcomes. Therapy failure was defined as the clinical decision to intubate a patient after an antecedent trial of HFNC. Multivariable logistic regression was performed to identify factors associated with intubation following HFNC.Four hundred ninety-eight cases meeting criteria for inclusion were identified. The most common final diagnosis was acute bronchiolitis (n = 231, 46%), followed by pneumonia (n = 138, 28%) and asthma (n = 38, 8%). Of the 498 patients, 42 (8%) of patients failed therapy and required intubation following HFNC trial. Risk factors associated with HFNC failure were triage respiratory rate greater than 90th percentile for age (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.01–4.43), initial venous PCO2 greater than 50 mm Hg (OR, 2.51; 95% CI, 1.06–5.98), and initial venous pH less than 7.30 (OR, 2.53; 95% CI, 1.12–5.74). A final diagnosis of bronchiolitis was observed to be protective with respect to intubation (OR, 0.40; 95% CI, 0.17–0.96).In infants with all-cause respiratory distress presenting in the PED, triage respiratory rate greater than 90th percentile for age, initial venous PCO2 greater than 50 mm Hg, and initial venous pH less than 7.30 were associated with failure of HFNC therapy. A diagnosis of acute bronchiolitis was protective with respect to intubation following HFNC. This finding may help guide clinicians who use HFNC by identifying a patient population at higher risk of failing therapy.