Abstract:High Flow Nasal Cannula (HFNC) provides non-invasive respiratory support for critically ill children who may tolerate it more readily than other Non-Invasive (NIV) techniques. Timely prediction of HFNC failure can provide an indication for increasing respiratory support. This work developed and compared machine learning models to predict HFNC failure. A retrospective study was conducted using EMR of patients admitted to a tertiary pediatric ICU from January 2010 to February 2020. A Long Short-Term Memory (LSTM) model was trained to generate a continuous prediction of HFNC failure. Performance was assessed using the area under the receiver operating curve (AUROC) at various times following HFNC initiation. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) of predictions at two hours after HFNC initiation were also evaluated. These metrics were also computed in a cohort with primarily respiratory diagnoses. 834 HFNC trials [455 training, 173 validation, 206 test] met the inclusion criteria, of which 175 [103, 30, 42] (21.0%) escalated to NIV or intubation. The LSTM models trained with transfer learning generally performed better than the LR models, with the best LSTM model achieving an AUROC of 0.78, vs 0.66 for the LR, two hours after initiation. Machine learning models trained using EMR data were able to identify children at risk for failing HFNC within 24 hours of initiation. LSTM models that incorporated transfer learning, input data perseveration and ensembling showed improved performance than the LR and standard LSTM models.