Background: The risk factors for peri-intubation cardiac arrest in critically ill children are incompletely understood. The study objective was to derive physiologic risk factors for deterioration during tracheal intubation in a pediatric emergency department (PED). Methods: This was a retrospective cohort study of patients undergoing emergency tracheal intubation in a PED. Using the published literature and expert opinion, a multidisciplinary team developed high-risk criteria for periintubation arrest: 1) hypotension, 2) concern for cardiac dysfunction, 3) persistent hypoxemia, 4) severe metabolic acidosis (pH < 7.1), 5) post-return of spontaneous circulation (ROSC), and 6) status asthmaticus. We completed a structured review of the electronic health record for a historical cohort of patients intubated in the PED. The primary outcome was peri-intubation arrest. Secondary outcomes included tracheal intubation success rate, extracorporeal membrane oxygenation (ECMO) activation, and in-hospital mortality. We compared outcomes between patients meeting one or more versus no high-risk criteria. Results: Peri-intubation cardiac arrest occurred in 5.6% of patients who met at least one high-risk criterion compared to 0% in patients meeting none (5.6% difference, 95% confidence interval [CI] = 1.0 to 18.1, p = 0.028). Patients meeting at least one criterion had higher rates of any postintubation cardiac arrest in the PED (11.1% vs. 0%, 11.1% difference, 95% CI = 4.1 to 25.3, p = 0.0007), in-hospital mortality (25% vs. 2.3%, 22.7% difference, 95% CI = 11.0 to 38.9, p < 0.0001), ECMO activation (8.3% vs. 0%, 8.3% difference, 95% CI = 2.5 to 21.8, p = 0.004), and lower likelihood of first-pass intubation success (47.2% vs. 66.1%, À18.9% difference, 95% CI = À35.5 to À1.5, p = 0.038), respectively. Conclusions: We have developed criteria that successfully identify physiologically difficult airways in the PED. Children with hypotension, persistent hypoxemia, concern for cardiac dysfunction, severe metabolic acidosis, status asthmaticus or who are post-ROSC are at higher risk for peri-intubation cardiac arrest and in-hospital mortality. Further multicenter investigation is needed to validate our findings.