Mechanical Ventilation in Children on Venovenous ECMO
=====================================================

* Matthew L Friedman
* Ryan P Barbaro
* Melania M Bembea
* Brian C Bridges
* Ranjit S Chima
* Todd J Kilbaugh
* Poornima Pandiyan
* Renee M Potera
* Elizabeth A Rosner
* Hitesh S Sandhu
* James E Slaven
* Keiko M Tarquinio
* Ira M Cheifetz

## Abstract

**BACKGROUND:** Venovenous extracorporeal membrane oxygenation (VV-ECMO) is used when mechanical ventilation can no longer support oxygenation or ventilation, or if the risk of ventilator-induced lung injury is considered excessive. The optimum mechanical ventilation strategy once on ECMO is unknown. We sought to describe the practice of mechanical ventilation in children on VV-ECMO and to determine whether mechanical ventilation practices are associated with clinical outcomes.

**METHODS:** We conducted a multicenter retrospective cohort study in 10 pediatric academic centers in the United States. Children age 14 d through 18 y on VV-ECMO from 2011 to 2016 were included. Exclusion criteria were preexisting chronic respiratory failure, primary diagnosis of asthma, cyanotic heart disease, or ECMO as a bridge to lung transplant.

**RESULTS:** Conventional mechanical ventilation was used in about 75% of children on VV-ECMO; the remaining subjects were managed with a variety of approaches. With the exception of PEEP, there was large variation in ventilator settings. Ventilator mode and pressure settings were not associated with survival. Mean ventilator FIO2 on days 1–3 was higher in nonsurvivors than in survivors (0.5 vs 0.4, *P* = .009). In univariate analysis, other risk factors for mortality were female gender, higher Pediatric Risk Estimate Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS), diagnosis of cancer or stem cell transplant, and number of days intubated prior to initiation of ECMO (all *P* < .05). In multivariate analysis, ventilator FIO2 was significantly associated with mortality (odds ratio 1.38 for each 0.1 increase in FIO2, 95% CI 1.09-1.75). Mortality was higher in subjects on high ventilator FIO2 (≥ 0.5) compared to low ventilator FIO2 (> 0.5) (46% vs 22%, *P* = .001).

**CONCLUSIONS:** Ventilator mode and some settings vary in practice. The only ventilator setting associated with mortality was FIO2, even after adjustment for disease severity. Ventilator FIO2 is a modifiable setting that may contribute to mortality in children on VV-ECMO.

*   artificial respiration
*   extracorporeal membrane oxygenation
*   pediatrics
*   acute respiratory distress syndrome
*   ventilator-induced lung injury
*   oxygen

## Introduction

Pediatric ARDS is a common cause of morbidity and mortality in pediatric ICUs.1 Supportive care with mechanical ventilation using a lung-protective strategy is the cornerstone of treatment.2,3 However, there remains a population of patients with severe pediatric ARDS in whom mechanical ventilation cannot provide adequate gas exchange without inducing severe ventilator-induced lung injury. When initiated, venovenous extracorporeal membrane oxygenation (VV-ECMO) relieves the lungs from their usual functions of oxygenation and ventilation, allowing for a reduction of high ventilator settings, which are associated with ventilator-induced lung injury.4,5

Mechanical ventilation strategies in adult and neonatal subjects with acute respiratory failure have been studied.6–14 Conversely, there has been little study of mechanical ventilation in children on ECMO support for respiratory failure, and there are no evidence-based or expert consensus guidelines.15,16 Ventilator management on ECMO has historically focused on a “lung rest” strategy to limit ventilator-induced lung injury.17–20 This approach typically consists of low ventilator rate, moderate PEEP, and low peak inspiratory pressure (PIP). The result is often complete lung collapse and limited native gas exchange. The scope of practice for mechanical ventilation in children on VV-ECMO has not been previously described in the literature, and it is unknown if there are any associations between ventilator practices and outcome.21

The primary aim of this study was to describe mechanical ventilation practice in pediatric subjects on VV-ECMO for acute respiratory failure. The secondary aim was to evaluate whether any mechanical ventilation practices are associated with clinical outcomes.

### QUICK LOOK

#### Current knowledge

Extracorporeal membrane oxygenation allows for a reduction of ventilator settings to reduce the risk of ventilator-induced lung injury. There are no published reports of the management of mechanical ventilation in children on extracorporeal membrane oxygenation across multiple centers.

#### What this paper contributes to our knowledge

There was variability seen in ventilator mode and most settings, such as FIO2 and peak inspiratory pressure, with the exception of PEEP. The only ventilator setting associated with clinical outcomes was ventilator FIO2. After adjusting for severity of illness, every 0.1 increase in ventilator FIO2 was associated with a 38% increase in mortality.

## Methods

A retrospective multi-center cohort study was conducted at 10 quaternary care pediatric academic centers in the United States with established ECMO programs: Riley Hospital for Children, Indianapolis, Indiana; John Hopkins Children's Center, Baltimore, Maryland; Vanderbilt Children's Hospital, Nashville, Tennessee; Cincinnati Children's Hospital, Cincinnati, Ohio; Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Children's Medical Center of Dallas, Dallas, Texas; Helen DeVos Children's Hospital, Grand Rapids, Michigan; Le Bonheur Children's Hospital, Memphis, Tennessee; Children's Hospital of Atlanta, Atlanta, Georgia; and Duke Children's Hospital and Health Center, Durham, North Carolina. Each center is a member of the Pediatric ECMO subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators Network and the Extracorporeal Life Support Organization. Subjects were managed according to local protocols and clinician preferences. Institutional review board authorization was completed for all sites, either centrally at the lead institution (Indiana University) or locally. Need for informed consent was waived.

We reviewed the electronic medical records for children age 14 d through 18 y who were cannulated for VV-ECMO from 2011 to 2016. Exclusion criteria were ECMO as a bridge to lung transplant, asthmas as the primary cause of acute respiratory failure, cyanotic congenital heart disease (ie, unrepaired cyanotic congenital heart disease or single-ventricle physiology), or preexisting chronic respiratory failure (defined as ventilator dependence, positive-pressure ventilation, or home O2 not for obstructive sleep apnea). Data for subjects who were converted to venoarterial ECMO were included in the descriptive analysis, but these subjects were excluded from further analyses of outcome measures.

Data collection was completed via a HIPAA-compliant online data entry web site (REDCap, Vanderbilt University, Nashville, Tennessee). Pre-ECMO data collected included demographics, Pediatric Pulmonary Rescue With Extracorporeal Membrane Oxygenation Prediction variables,22 and Pediatric Risk Estimate Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS) variables.23 Ventilator mode and settings, blood gas values, and ECMO settings were recorded for the first 7 d on ECMO, using values recorded closest to 8 am. The pre-ECMO ventilator settings were the settings documented closest to the 8 am before cannulation. The average for the first 3 d on ECMO were used for analysis based on previous literature.7,9 Subjects were dichotomized based on average oxygen saturation measured via pulse oximetry (SpO2) and average FIO2 over the first 3 d on ECMO, and cutoffs were determined with sensitivity analysis and Youden's J statistic.

## Definitions

Survival was defined as survival to ICU discharge. Cardiac arrest was defined as cessation of a perfusing rhythm requiring cardiopulmonary resuscitation for > 2 min. Driving pressure was estimated as the difference between PEEP and PIP. Plateau pressure was only available for a small number of subjects because most subjects on conventional mechanical ventilation were on a pressure mode of ventilation with variable inspiratory flow. Composite outcomes of ECMO-free days and alive days at 28 d and ventilator-free and alive days at 90 d were determined. ECMO-free days was considered zero for subjects who did not survive ECMO. ECMO-free days for subjects who survived ECMO were calculated by subtracting duration of ECMO from 28 d; if ECMO duration was > 28 d, ECMO-free days was considered zero. Ventilator-free days was considered zero for any subjects who did not survive to extubation or received tracheostomy. Ventilator-free days for other subjects was calculated by subtracting the length of ventilation from 90 d; if subjects were ventilated for > 90 d, ventilator-free days was considered zero. The predominant mode of ventilation was the most frequently used mode within the first 7 d on ECMO. In the case of a tie, the most frequent mode in the first 3 d was used. Acute kidney failure was diagnosed if the subject met criteria based on Kidney Disease Improving Global Outcomes or pediatric risk, injury, failure, loss, and end-stage renal disease criteria.24,25

## Statistical Analysis

Variables of interest were analyzed to compare survivors and nonsurvivors. Distributions of the variables are presented as median (interquartile range). Bivariate associations between survivor groups were assessed with Wilcoxon nonparametric tests. Multivariate logistic regression and Cox proportional hazard models were performed, with survival as the outcome variable and center variability accounted for with a random intercept, also called a mixed-effects logistic regression or hierarchical regression. Variables associated with mortality in bivariate analysis were included in the multivariate analyses, with the exception of variables that were part of the composite mortality risk score (ie, Ped-RESCUERS). Multivariate logistic regression was used for the primary multivariate analysis. The Cox proportional hazard model was used for the analysis with FIO2, SpO2, gender, and Ped-RESCUERS score. Generalized linear models were used to incorporate a random effect for hospital to account for within-hospital correlation. Variables for inclusion in the multivariate model were chosen on the basis of bivariate analyses, where *P* < .05. Days from intubation to ECMO and diagnosis of cancer had *P* < .05 but are included in the Ped-RESCUERS score, a composite mortality risk score for pediatric respiratory ECMO, and were therefore not included.23 Correlation analyses were performed using Spearman nonparametric correlation analyses, both for general analyses and to inform for any collinearity issues with the multivariate models. Chi-square analyses were performed to evaluate for significant heterogeneity between categorical variables. All analyses were performed using SAS 9.4 (SAS Institute, Cary, North Carolina).

## Results

### Cohort Characteristics

After applying exclusion criteria, 204 subjects were included in the cohort, with 6–50 subjects contributed per center. Four higher-volume centers had 28–50 subjects, and the 6 lower-volume centers had 6–14 subjects. The median age was 3.6 y with 53% female subjects. There were 24 patients that were transitioned form V-V ECMO to veno-arterial ECMO, they were included in descriptive analysis but excluded from univariate and multivariate analysis. The etiologies of respiratory failure were viral infection other than respiratory syncytial virus (29%), other causes (28%), respiratory syncytial virus infection (17%), bacterial pneumonia (13%), aspiration (6%), sepsis (4%), fungal pneumonia (2%), and pertussis (1%). The median pre-ECMO oxygenation index was 47 (IQR 35–62). Overall survival was 68%. The most common causes of death were multi-organ failure (30%), bleeding complication (30%), and refractory lung disease (25%). The median duration of ECMO was 190 h (IQR 117–337). Tracheostomy was placed after ECMO in 22 subjects (11%), and 14 subjects (7%) were discharged on home mechanical ventilation.

Select demographic and pre-ECMO variables are presented in Table 1. Female gender (*P* = .03), cancer diagnosis or stem cell transplant (*P* = .002), pre-ECMO duration of ventilation (*P* = .02), and mortality risk score (*P* = .001) differed between survivors and nonsurvivors.

View this table:
[Table 1.](http://rc.rcjournal.com/content/65/3/271/T1)

Table 1. 
Demographics and Pre-ECMO Characteristics

### Description of Mechanical Ventilation and Pulmonary Management on ECMO

Traditional ventilator modes were used on most subject days (73.4%). Among the subjects on conventional modes, pressure-targeted modes were the most common (90.3%), followed by pressure-regulated volume control (8.7%) and volume-targeted modes (1%). A minority of subjects (9%) were ventilated with assist control modes. Nonconventional modes of ventilation were used in about a quarter of subjects on each day of ECMO. Airway pressure release ventilation was the most common nonconventional mode (13.4%). The frequency of ventilator mode and median ventilator settings pre-ECMO and on ECMO days 1, 3, and 5 are presented in Table 2. Prior to ECMO cannulation, FIO2 was ≥ 0.5 in 98% of subjects, and 43% of subjects remained on high FIO2 (defined as FIO2 ≥ 0.5) on day 1 of ECMO, whereas that number decreased to 24% by day 3 of ECMO. Ventilator settings pre-ECMO and on ECMO days 1, 3, and 5 are also displayed in Figure 1. Surfactant was administered to 6 subjects; 3 subjects received a second dose, and one 12-month-old with aspiration received 3 doses. Prone positioning was used for 3 subjects, each for only 1 d.

![Fig. 1.](http://rc.rcjournal.com/https://rc.rcjournal.com/content/respcare/65/3/271/F1.medium.gif)

[Fig. 1.](http://rc.rcjournal.com/content/65/3/271/F1)

Fig. 1. 
Ventilator settings pre-ECMO and on ECMO days 1, 3, and 5. ECMO = extracorporeal membrane oxygenation; PIP = peak inspiratory pressure; P̄aw = mean airway pressure. Boxes represent 25th to 75th percentile values, with median shown as a horizontal line within each box. Whiskers denote 5th to 95th percentiles, and points represent outliers.

View this table:
[Table 2.](http://rc.rcjournal.com/content/65/3/271/T2)

Table 2. 
Mechanical Ventilation Settings Pre-ECMO and on ECMO Days 1, 3, and 5

### Outcomes Analysis

After excluding subjects converted to venoarterial ECMO and the 1 subject transferred on ECMO, 180 subjects were including in the bivariate and multivariate analyses. Ventilator mode, pressure settings, and other ventilator measurements were similar in survivors and nonsurvivors (Table 3). Ventilator FIO2 was higher in nonsurvivors compared to survivors at 0.5 (IQR 25th%–75th%) versus 0.4 (IQR 0.3–0.5) (*P* = .009). ECMO circuit settings did not differ between survivors and nonsurvivors.

View this table:
[Table 3.](http://rc.rcjournal.com/content/65/3/271/T3)

Table 3. 
Ventilator and ECMO Characteristics

Mode of ventilation on ECMO was not associated with ECMO-free days or ventilator-free days. No ventilator pressure setting or measurement was associated with ECMO-free days or ventilator-free days. Ventilator FIO2 was associated with ECMO-free days (Spearman correlation coefficient −0.173, *P* = .02) and ventilator-free days (Spearman correlation coefficient − 0.223, *P* = .003).

Multivariate analysis for mortality included female gender, Ped-RESCUERS score, and mean FIO2 over the first 3 d on ECMO (Table 4). In multivariate analysis, ventilator FIO2 was significantly associated with mortality (odds ratio 1.38 for each 0.1 increase in FIO2, 95% CI 1.09–1.75).

View this table:
[Table 4.](http://rc.rcjournal.com/content/65/3/271/T4)

Table 4. 
Multivariate Model for Mortality

Mortality was higher in subjects on high ventilator FIO2 (≥ 0.50) compared to low FIO2 (46% vs 22%, *P* = .001). Mortality was higher for children with low SpO2 (≤ 85%) compared to high SpO2 (46% vs 30%, *P* = .02). The hazard ratio (HR) for mortality in the high FIO2 group was 2.1 (95% CI 1.05–4.20) with adjustment for high SpO2 (HR 0.9, 95% CI 0.4–1.9), female gender (HR 1.5, 95% CI 0.8–2.9), and Ped-RESCUERS (HR 1.2, 95% CI 0.7–2.1).

A scatter plot of the SpO2 and ventilator FIO2 on ECMO is presented in Figure 2. The points were divided into quadrants based on high or low SpO2 and high or low FIO2. Survival differed significantly based on quadrant (*P* = .002).

![Fig. 2.](http://rc.rcjournal.com/https://rc.rcjournal.com/content/respcare/65/3/271/F2.medium.gif)

[Fig. 2.](http://rc.rcjournal.com/content/65/3/271/F2)

Fig. 2. 
Scatter plot of SpO2 and ventilator FIO2 on extracorporeal membrane oxygenation. Subjects are divided into quadrants based on FIO2 ≥ 0.5 vs < 0.5 and SpO2 and ventilator FIO2 > 85% vs ≤ 85%. ICU survival for subjects in each quadrant is displayed. Survival differed across the four quadrants (*P* = .002).

### Complications

Conversion to venoarterial ECMO was performed in 23 subjects (11%). Subjects converted to venoarterial ECMO had lower survival (44% vs 71%, *P* = .009). Subjects requiring conversion to venoarterial ECMO were older (3.6 vs 1.4 y, *P* = .005), had a higher maximum heart rate (174 vs 159 beats/min, *P* = .009), and were more likely to have an oncological diagnosis or hematopoietic cell transplant (30% vs 13%, *P* = .03). There were 27 pneumothoraces in the first 7 d on ECMO, for an incidence of 2.3% per day. Ventilator settings on the day of or the day before were not associated with pneumothorax. Tracheostomy was performed in 22 subjects, all after ECMO, and 14 subjects were discharged on mechanical ventilation.

## Discussion

There have been many improvements in the care for children on ECMO; however, the contribution of mechanical ventilation management to morbidity and mortality has not been evaluated.26 This study represents the first multi-center study of mechanical ventilation in pediatric subjects on ECMO. We noted variability in ventilator mode and settings for children on VV-ECMO.26 In this study, neither mode of ventilation nor ventilator pressure parameters were associated with survival. Ventilator FIO2, however, was associated with mortality, even after adjustment for severity of illness.

The majority of subjects were ventilated with conventional modes of ventilation; approximately 25% of subjects were on other modes of ventilation each day. We noted higher use of nonconventional modes during ECMO than reported previously, although most adult studies of mechanical ventilation on ECMO have used conventional mechanical ventilation exclusively, with a few recent studies reporting small number of subjects on airway pressure release ventilation.6–11,17,27 Neonates on ECMO predominantly receive conventional mechanical ventilation (88%).11 There was variability in some ventilator settings, including FIO2 and mean airway pressure (P̄aw). The median values of FIO2 and P̄aw in our study were lower than reported in adult studies, but the variability was similar.7–9 Conversely, PEEP and PIP showed very little variability in our cohort. The median and interquartile values for PEEP on ECMO were all 10 cm H2O. Adult and neonatal studies have reported wider variability in PEEP than observed in our study, with adults tending to be supported on higher PEEP and neonates on lower PEEP.6–11 Most subjects in the study had a PIP of 20 cm H2O, which was the median and 25th percentile values on ECMO day 1 and day 3. The PIP used in children in this study is lower than what has been used in most adult studies. 6,8,9

Surveys on the practice of mechanical ventilation on ECMO have reported increasing use of an open-lung ventilation strategy on ECMO.20,28 Open-lung ventilation is accomplished with high PEEP on conventional mechanical ventilation or with high P̄aw-targeted modes of ventilation, such as airway pressure release ventilation or high-frequency oscillatory ventilation. The existing data to support this approach in adults are inconsistent. High-PEEP strategies in adult studies have reported divergent outcomes.6–9,29 Higher PEEP in neonates leads to shorter ECMO duration and fewer complications.11,30 However, low PEEP was defined as 4–6 cm H2O. PEEP this low was rarely seen in our study and is not commonly used in pediatric ECMO. We did not observe any associations between clinical outcomes and PEEP, P̄aw, or high P̄aw-targeted modes; therefore, our data do not support an open-lung strategy on ECMO over traditional rest settings.

Neither estimated driving pressure nor PIP were associated with clinical outcomes in this study, which was a surprising outcome because adult studies have previously reported higher driving pressure to be associated with mortality.6,8,9 The estimated driving pressures observed in our study are lower than those in adult studies, and the detrimental effect of driving pressure is not seen at lower levels, which may explain the difference in results.8,9 Additionally, it is not clear that low tidal-volume ventilation in ARDS is as beneficial in children as it is in adults.31,32

No ventilator pressure settings were associated with the outcomes measured, although most subjects were on settings that would be considered lung-protective. This is consistent with recent reports that markers of biotrauma to the lungs decrease after ECMO initiation and the reduction of ventilator settings, but there were no differences between various ventilator approaches on ECMO.33 Because there is variability between patients regarding lung disease severity and potential for recruitment, an individualized approach to ventilator management while avoiding potentially injurious settings seems reasonable.34

Ventilator FIO2 was also the only ventilator setting that was associated with mortality. In multivariate analysis, with adjustment for severity of illness, for every 0.1 increase in FIO2 there was a 38% increased odds of mortality. Most studies of ventilation on ECMO do not report ventilator FIO2; one study reported that ventilator FIO2 was associated with mortality in univariate analysis but not in multivariate analysis,8 whereas another study noted no relationship.6

Oxygen supplementation is very common in the modern ICU, although it has become increasingly evident that the benefits of oxygen therapy must be weighed against the toxicities.35 High oxygen tension leads to the creation of reactive oxygen species that cause inflammation, edema, damage to cellular components, and cell death.36,37 In air with high FIO2, nitrogen is replaced by oxygen, which washes out nitrogen from alveoli. Oxygen is then readily absorbed into the lung tissues, leading to alveolar collapse, absorptive atelectasis, and increased intrapulmonary shunting.38–40 High FIO2 contributes to ventilator-induced lung injury through the production of reactive oxygen species and atelectrauma.4,5

The association between ventilator FIO2 and mortality observed in our study may be due to the direct toxic effects of FIO2. However, there are potential confounders that could drive this association, such as severity of disease or inadequacy of ECMO support. The multivariate models included adjustment for pre-ECMO severity of disease (Ped-RESCUERS score), and ventilator FIO2 remained associated with mortality. Measures of ECMO support, including circuit flow, circuit sweep, and circuit sweep gas inlet oxygen fraction (FsO2) did not differ between survivors and nonsurvivors, which suggests a similar degree of ECMO support. Children on VV-ECMO with severe lung injury and inadequate ECMO support have lower SpO2 and may be preferentially placed on high ventilator FIO2. The severity of illness and lack of adequate ECMO support could be driving the observed association between mortality and high FIO2. SpO2 was not associated with mortality when analyzed as a continuous variable; in the Cox proportional hazard model that included SpO2 (high vs low), FIO2 (high vs low), and severity of illness, low SpO2 was not associated with mortality. Conversely, high FIO2 predicted a 2.1 times higher risk of death. Therefore, the link between ventilator FIO2 and mortality is not likely due to severe lung injury and inadequate ECMO support.

Ventilator FIO2 is used to increase SpO2 and ultimately to increase systemic oxygen delivery. However, the clinical dilemma is how to weigh the risks of high ventilator FIO2 against the risks of low SpO2. The balance between SpO2 and FIO2 was explored with a scatter plot (Fig. 2). Subjects on high FIO2 with high SpO2 (upper right quadrant), and those on low FIO2 with low SpO2 (lower left quadrant) are most interesting to compare. Hypothetically some patients may be able to move between these 2 quadrants by titrating ventilator FIO2, resulting in a corresponding change in SpO2. Survival in the group with low SpO2 and low FIO2 was slightly better than that in the group with high FIO2 and high SpO2, but the difference was not statistically significant. It is clear, however, that lower SpO2 and lower FIO2 was not worse.

Limiting oxygen therapy with conservative oxygenation goals decreases mortality in critically ill adults.35,40,41 Consensus recommendations for target SpO2 for mechanically ventilated children are graduated, ie, the goal decreases as PEEP increases, with a range of 88–92% for subjects on ≥ 10 cm H2O PEEP.3 There are no consensus guidelines for oxygenation goals in ECMO. We suggest that the oxygen saturation goal should not exceed the 88–92% range suggested for children on mechanical ventilation with high PEEP. Allowing for a lower SpO2 target and limiting ventilator FIO2 may be acceptable, given the results of this study. Prospective investigations of conservative ventilator oxygen management and peripheral oxygen saturation targets in children on VV-ECMO are needed to define optimal SpO2 and FIO2 targets.

This study has several limitations. The retrospective and observational nature of the study does not allow determination of causation. Because we only evaluated mechanical ventilation strategy during the first 7 d on ECMO, the impact of ventilator practice later in the ECMO course could not be determined. Given the lack of a standardized approach to mechanical ventilation, it is possible that differences in ventilator management are a surrogate for other differences in care that are center-specific and potentially have an impact on mortality.

## Conclusions

In this study we found variation in ventilator modes and settings for children on VV-ECMO. No mode or pressure setting was associated with mortality, so this study does not support any specific ventilator strategy for ECMO. Ventilator FIO2 was found to be associated with mortality, even after adjusting for disease severity. A reduction of ventilator FIO2 may help reduce mortality for pediatric patients requiring VV-ECMO. Further prospective study is needed.

## Footnotes

*   Correspondence: Matthew L Friedman MD, Phase 2, Room 4900, 705 Riley Hospital Drive, Indianapolis, IN 46202. E-mail: friedmml{at}iu.edu
*   Dr Friedman presented a version of this paper at the Extracorporeal Life Support Organization Annual Conference, held September 13–16, 2018, in Scottsdale, Arizona.

*   This study was supported financially by grants from the Extracorporeal Life Support Organization and the Pediatrics Department at Indiana University School of Medicine. Dr Barbaro discloses relationships with Extracorporeal Life Support Organization Registry and NHLBI, and the NIH. Dr Bembea discloses relationships with the NIH NICHD and NINDS. Dr Cheifetz discloses relationships with Philips, Up-to-Date, and the NHLBI. The remaining authors have disclosed no conflicts of interest.

*   See the Related Editorial on Page [400](http://rc.rcjournal.com/lookup/doi/10.4187/respcare.07704)

*   Copyright © 2020 by Daedalus Enterprises

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