The use of high flow nasal cannula (HFNC) respiratory support in children in critical care, emergency departments, and general wards has increased in recent years [1-8]. HFNC provides an alternative to other noninvasive ventilation (NIV) techniques and endotracheal intubation, has fewer associated risks and complications, and is well-tolerated by children [3,5,6,8]. Nevertheless, many patients require escalation to a higher level of respiratory support [3,8]. Importantly, for those who require escalation, recent research indicates better clinical outcomes for patients who were escalated to higher levels of respiratory support earlier: lower hospital and intensive care unit (ICU) mortality rates, higher extubation success rate, higher ventilator-free days, and lower hospital and ICU lengths of stay [9,10]. These findings suggest that early identification of children in whom HFNC will not be successful could allow more timely institutions of advanced respiratory support and decrease morbidity and mortality.

This study aims to develop a model to make reliable, real-time predictions of a child’s response to HFNC. Such a model could help clinicians differentiate three groups: (1) children likely to do well on HFNC alone, (2) children likely to need a higher level of support, and (3) children whose HFNC response is unclear. Differentiating these 3 groups would help clinicians resolve the dilemma of appropriate NIV while not unduly and potentially harmfully prolonging it. The last group may benefit from the closest and most frequent monitoring. The second group, although still monitored frequently, could be escalated by clinicians to a higher level of support earlier. A further goal is to compare different algorithms, from logistic regressions (LRs) to long short-term memory (LSTM)-based recurrent neural networks, for predicting HFNC response. Other techniques, such as transfer learning (TL), input data perseveration, and ensembling, are also explored and evaluated for their impact on performance when used with LSTMs.

The authors are unaware of any studies developing a predictive model of HFNC failure, although a few studies have investigated risk factors for escalation from HFNC to a higher level of respiratory support. Guillot et al [11] found that high pCO₂ (partial pressure of carbon dioxide) was a risk factor for HFNC failure in children with bronchiolitis. Er et al [12] reported that respiratory acidosis, low initial oxygen saturation and SF (oxygen saturation [SpO₂] divided by the fraction of inspired oxygen [FiO2]) ratio, and SF ratio <195 during the first few hours were associated with unresponsiveness to HFNC in children with severe bacterial pneumonia in a pediatric emergency department. In a small study of children with bacterial pneumonia, Yurtseven and Saz [13] saw higher failure rates in those with higher respiratory rates. Kelley et al [8] found that a high respiratory rate, high initial venous pCO₂, and a pH <7.3 were associated with failure of HFNC.

Data for this study came from deidentified clinical observations collected in electronic medical records (EMRs; Cerner) of children admitted to the pediatric intensive care unit (PICU) of Children’s Hospital Los Angeles (CHLA) between January 2010 and February 2020. An episode represents a single admission and a contiguous stay in the PICU. Patients may have >1 episode. EMR data for an episode included irregularly, sparsely, and asynchronously charted physiological measurements (eg, heart rate and blood pressure), laboratory results (eg, creatinine and glucose level), drugs (eg, epinephrine and furosemide), and interventions (eg, intubation, bilevel positive airway pressure [BiPAP], or HFNC). Data previously collected for Virtual Pediatric Services, LLC participation [14], including diagnoses, gender, race, and disposition at discharge, were linked with the EMR data before deidentification.

The CHLA institutional review board reviewed the study protocol and waived the requirement for consent and institutional review board approval.

For ease of reference, Textbox 1 lists the terminologies and definitions used throughout the sections which follow.

In an episode where HFNC is initiated only once, there is exactly 1 HFNC period and 1 HFNC trial. Episodes can have multiple HFNC initiations. In such cases, a single episode may have multiple HFNC periods, and each has an associated HFNC trial. Note that not all HFNC initiations have a corresponding HFNC period. For instance, if a child started on HFNC for the first time during an episode, then this marked the start of the HFNC period. If HFNC was withdrawn 2 hours later, and the child again received HFNC an hour after that, then this new HFNC initiation did not mark the start of a new HFNC period as the original HFNC period had not yet ended. In contrast, if this second HFNC initiation took place >24 hours after the first HFNC was stopped, then this second initiation marked the start of a new HFNC period as it was initiated after the first HFNC period had already ended. Finally, at least 30 minutes was required between any de-escalation (step-down) from NIV or intubation before the start of the HFNC period. This rule was necessary as patients on a higher level of support may be stepped down to HFNC to assess their ability to breathe on their own. If such breathing trials fail, which is not an uncommon occurrence, these patients immediately escalate back to mechanical ventilation or NIV, technically becoming HFNC failures but were, in fact, extubation failures and are not representative of the escalation scenarios of interest in this study. Figure 1 illustrates these terminologies.

Only episodes in which HFNC was used were included. Episodes of patients aged ≥19 years at admission were excluded, as were episodes associated with sleep apnea. Any episode that ended <24 hours into an HFNC period where the patient next went to the operating room was also excluded. Episodes with a do not intubate or do not resuscitate order were also excluded.

For each HFNC trial, the target of interest was escalation to a higher level of support (BiPAP, noninvasive mechanical ventilation, and intubation) within the 24-hour window (HFNC period) after HFNC initiation. Each HFNC trial was labeled either a failure (if there was an escalation within the associated HFNC period) or a success (if there was no such escalation within the associated HFNC period).

When a patient was discharged from the PICU within 24 hours of HFNC initiation, the target label was determined by the patient’s disposition at discharge (Textbox 2). Episodes with the dispositions operating room, another hospital’s ICU, or another ICU in current hospital were excluded as the outcome was ambiguous. HFNC trials associated with a favorable disposition (general care floor, home, or step-down unit) during the HFNC period were labeled as success.

The HFNC definitions and outcomes, combined with the exclusion criteria, resulted in 834 HFNC trials that were randomly divided into training, validation, and hold-out test sets. All HFNC trials of an individual patient were assigned in only one of these 3 sets to prevent leakage and bias during model evaluations. No additional stratifications were applied.

Recall that the task is to predict HFNC failure (escalation of care) for each HFNC trial. Data processing starts at the beginning of the HFNC trial, with a model trained to output a prediction each time a new measurement becomes available. Figure 2 illustrates how the time series data of each HFNC trial were labeled for this process. All prediction times during the HFNC period were labeled as either 1 (failure) or 0 (success). Predictions at times before the HFNC period were labeled NaN (Not a Number) to exclude the predictions from error metrics during model training and performance evaluations.

As described in the study by Ledbetter et al [18], LSTMs exhibit predictive lag, wherein the model fails to react quickly to new clinical information. A previous study [18] demonstrated that an LSTM trained with input data perseveration (ie, the input is replicated k times) responds with more pronounced changes in predictions when new measurements become available while maintaining overall performance relative to a standard LSTM. As timely model responsiveness to acute clinical events is critical in determining the necessity of escalating support, input data perseveration was assessed as a training augmentation technique.

TL is a technique of applying insights (eg, data representations) that were previously learned from one problem to a new, related task [19-22]. It can be particularly beneficial when one task has significantly more training data than the other. As the number of children on HFNC is significantly smaller than the number of ICU episodes in the CHLA PICU data set, TL techniques were considered to generate initial data representations and facilitate training of the HFNC prediction models. LSTM-based recurrent neural networks using the same input variables as those for the HFNC task were trained on >9000 CHLA PICU episodes to predict ICU mortality [23]. The first layer of one of these mortality models was then used as the first layer of some of the LSTM-based HFNC prediction models in Textbox 3.

Ensemble methods combine multiple algorithms to achieve a higher predictive performance than each component could obtain [24]. The predictions from each component are averaged to yield a single final prediction. Here, different seed values were used to generate multiple LSTM-based models, with each seed value initializing a different set of pseudorandom starting weights for a particular model. Different seed values led to slightly different models. Different seeds were used to train the mortality models used for TL and train the final LSTM models on HFNC-specific data. Owing to the relatively small size of the cohort available to develop the HFNC prediction model, it was hypothesized that training models with different seeds would result in high variance and low bias models that may be decorrelated. Ensembling provides a method to average the results across decorrelated models to reduce variance but maintain a low bias.

A total of 8 models were developed: a 14-variable LR (LR-14) using variables previously identified as risk factors for HFNC failure [8,11-13], a 517-variable LR (LR-517), a standard LSTM, an LSTM with input perseveration (LSTM+3xPers, where 3 indicates the number of replications described in the study by Ledbetter et al [18]), an LSTM with TL (LSTM+TL), an LSTM with both input perseveration and TL (LSTM+3xPers+TL), a simple ensemble of LSTMs with input perseveration and TL (Simple-EN-LSTM+3xPers+TL), and an ensemble of ensembles of LSTMs with input perseveration and TL (Multi-EN-LSTM+3xPers+TL). All models were trained to generate a prediction every time new measurements became available within the HFNC period.

Textbox 3 describes the parameters of all the models. Each model was developed on the training set to maximize the average of the validation set area under the receiver operating characteristic (AUROC) curves measured hourly from 0 to 14 hours into the HFNC period. This window was selected to prioritize the most clinically impactful period.

Figure 3 illustrates how the ensemble models were formed. An LSTM mortality model was trained (seed A), and its first layer was used as the first layer (TL weights) of a 3-layer LSTM with input perseveration. Layers 2 and 3 of this model were trained on the HFNC data 5 times (seeds 1-5), resulting in 5 slightly different HFNC models whose predictions were averaged to generate the Simple-EN-LSTM+3xPers+TL model predictions. This process was repeated 4 times to generate an ensemble of ensembles model: 4 LSTM mortality models were trained (seeds A-D), each providing a different set of TL weights. For each of these 4 sets of TL weights, 5 different seeds were used to train with the HFNC data, resulting in 20 models whose predictions were averaged together to generate the Multi-EN-LSTM+3xPers+TL model predictions.

Model performance was assessed on the test set by evaluating the AUROC of predictions every 30 minutes within the 24-hour HFNC period. AUROC performance for the subset of patients with respiratory diagnoses was also compared every 30 minutes within the 24-hour HFNC period. In the rolling cohort AUROC computations, failures or successes that had already occurred before the time of evaluation were excluded. For example, any HFNC failures or successes that took place ≤4.5 hours into the HFNC period were not considered in computing the 5-hour AUROC. Including these in the 5-hour AUROC calculation would artificially boost the result. This was followed for all time points of interest. Therefore, the number of HFNC failures and successes in the test set steadily decreased from 0 to 24 hours in the HFNC period. The fixed cohort AUROC and area under the precision–recall curve in the first 15 hours were also computed, wherein only those who were on HFNC for at least 15 hours were included to ensure a constant cohort (and, consequently, a constant incidence rate of HFNC failures) at each evaluation point.

In addition, receiver operating characteristic (ROC) curves, sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) of predictions 2 hours after HFNC initiation were generated to evaluate model performance early in the HFNC period, on both the entire test set cohort and the respiratory subcohort.

Table 1 describes the demographics and characteristics of the data, whereas Figure 4 shows the histogram (in cyan) and cumulative density (orange) for the time to HFNC failure for the entire data set. Approximately 50% (87/175) of failures occurred within 7.6 hours, and 80% (140/175) occurred within 14.1 hours.

Figure 5 shows the 8 models’ rolling cohort AUROCs in 30-minute increments within the 24-hour HFNC period of all HFNC trials in the test set. Table S7 in Multimedia Appendix 7 shows the number of remaining HFNC trials in the test cohort at various evaluation times. Table S8 in Multimedia Appendix 8 presents the test set AUROC values associated with Figure 5 at several times of interest in the first 12 hours of the HFNC period. Table S9 in Multimedia Appendix 9 presents the corresponding AUROCs in the respiratory cohort. The fixed cohort AUROCs and areas under the precision–recall curve are shown in Figures S10 and S11 in Multimedia Appendices 10 and 11. Both the rolling and fixed cohort AUROCs generally increased over time.

Figure 6 presents the test set 2-hour ROC curves and AUROC for the 8 models, showing predictive performance just 2 hours into the HFNC period, whereas Figure 7 presents the same metrics corresponding to the respiratory cohort.

Table 2 shows the specificity, PPV, and NPV for the 2-hour predictions of the Multi-EN-LSTM+3xPers+TL model that correspond to different values of sensitivity. These metrics provide a more intuitive understanding of performance in a deployment scenario. At the 2-hour mark, 204 HFNC periods remained (40 [19.6%] failures and 164 [80.4%] successes); setting the operating point at 25% sensitivity correctly identified 10 of the HFNC failures (PPV=67%) and 159 of the nonfailures (NPV=84%). Among the correctly identified HFNC failures, the time to failure (at the 2-hour mark) ranged from a few minutes to 19 hours (median=2.6 hours). Tables S12 to S14 in Multimedia Appendices 12-14 show a comparison of these metrics across all models.

The ability to predict a child’s response to HFNC reliably and in real time could help guide clinical differentiation among three groups: (1) children most likely to do well on HFNC alone, (2) children most likely to need a higher level of support, and (3) children whose likely HFNC outcome is unclear and who may require additional observation. Patients identified from the first group may require less clinical intervention and free up scarce ICU resources. Identifying children in the second group may enable clinicians to intervene more rapidly and provide adequate support to prevent decompensation. Owing to clinical uncertainty, children in the third group may benefit from more careful and frequent observation with the continuous prediction of the likelihood of failure.

The granular longitudinal data captured from children in the ICU presents a tremendous amount of information available for learning and developing tools to help differentiate children’s responses to numerous ICU interventions such as HFNC, including ventilation, extracorporeal membrane oxygenation, and dialysis. Deep learning models, especially those with sequential processing capabilities such as LSTMs, have the potential to use rich time-dependent data in ways that more traditional machine learning models (eg, LR) cannot; however, LSTMs may require sizable training data to construct generalizable models. The results from this study showed this to be the case: a standard, 3-layer LSTM was generally the worst performing model on the hold-out test set.

TL was incorporated to address the issue of training LSTMs with insufficient data. The models with TL had the advantage of learning representations from >9000 PICU episodes, whereas the models without TL learned from >600 HFNC trials (approximately 500 episodes). The results demonstrate considerable gains from using TL and are consistent with the theory [14]. Figure 5, Figure S10, and Table S8, in particular, highlight the significant and time-independent performance increase delivered by TL in the LSTM models.

Input perseveration by itself (LSTM+3xPers) provided a performance boost relative to the standard LSTM, especially in the first 12 hours of the HFNC period in respiratory patients (Table S9, Multimedia Appendix 9). When combined with TL (LSTM+3xPers+TL), it continued to provide additional, although slight, gains. As demonstrated in the study by Ledbetter et al [18], LSTMs can exhibit a predictive lag phenomenon, wherein they fail to react rapidly to new data reflecting sudden clinical events and changes in patient status. In the context of HFNC use and decisions about whether to escalate a child to higher levels of support, this predictive lag may be deleterious in a time-constrained environment such as the PICU.

Finally, the ensemble models (Simple-EN-LSTM+3xPers+TL and Multi-EN-LSTM+3xPers+TL) were built to address another consequence of limited training data: the relatively high variability of any one particular realization of the model. This is a byproduct of randomly chosen initialization seeds used to initialize LSTM weights and biases and for random dropout techniques used for regularization purposes. The ensemble methods provided a consistently higher performance on the hold-out test set than the nonensemble models. The ensemble models provided a slight performance boost over just a single LSTM+3xPers+TL model. Not surprisingly, the multiensembling of multiple models (both of those used to generate TL weights and those used to generate HFNC predictions) provided the best overall model (Multi-EN-LSTM+3xPers+TL).

Regardless of the model, the performance generally increased over time (Figure 5 and Figure S10). This is not surprising as the lead time (the interval between the times of prediction and outcome) decreases [25].

Model performance in patients with respiratory diagnoses is of interest as the pathophysiology of respiratory illness is particularly amenable to HFNC therapy [1-4]. Approximately 70% of HFNC initiation in this cohort were in patients with respiratory illnesses. Table S8 shows that all models except LR-14 generally performed better in the respiratory group over time. Figure 7 shows that the best performing models in the overall cohort—those that incorporated TL—performed even better in the respiratory group after 2 hours of observation, demonstrating the TL models’ potential clinical impact.

The 2-hour mark after HFNC initiation is an important clinical decision point as a child has had adequate time to adapt to HFNC, and the effects of treatment can be assessed. This motivated the additional analyses of 2-hour predictions shown in Figure 6 and Figure 7 (ROC curves) and Table 2 (sensitivity, specificity, PPV, and NPV at various decision thresholds). The Multi-EN-LSTM+3xPers+TL model had the highest AUROC. In this model’s ROC curve for the entire cohort, 2 operating points are of particular interest: the first corresponds to 95% sensitivity (20% specificity), and the second corresponds to 25% sensitivity (97% specificity, 67% PPV, and 84% NPV). The first point can be used to identify children most likely to do well in HFNC (group 1), whereas the second can identify those most likely to fail HFNC (group 2). Successfully identifying 20% of group 1 can reduce the observational burden, whereas identifying 25% of group 2 could lead clinicians to intervene earlier with an escalation to a higher level of O₂ support, potentially improving outcomes for these children [9,10]. This system could potentially enable intervention 2 to 3 hours earlier in those most likely to fail HFNC. Children for whom the model predictions fall between the 2 thresholds are in the third group: those whose HFNC outcome is unclear and who may benefit from more frequent observations.

This study had several limitations. First, it was based on a single-center retrospective cohort. Second, the target definition considered only the first 24 hours following HFNC initiation. Further work can refine the target to consider the subsequent 24 hours, regardless of how long the patient has already been on HFNC.

Finally, this study is limited by the exclusion of children experiencing apnea, making the predictive model’s applicability to such children unclear. Although less than ideal, this exclusion was deemed necessary as it is difficult to determine whether escalation to BiPAP in these children is because of clinical necessity (ie, true escalation) or prophylactic caution (to guard against sleep apnea).

This study demonstrated the feasibility of applying advanced machine learning methodology to a complex and challenging clinical situation. This work demonstrated that clinically relevant models can be trained to predict the risk of escalation from HFNC within 24 hours of initiation of therapy and could be obtained by using an LSTM with the application of TL and input perseveration to boost AUROC performance.