Research ArticleOriginal Research

Clinical Outcomes of Acute Respiratory Failure Associated With Noninvasive and Invasive Ventilation in a Pediatric ICU

James M Kyle, Julie M Sturza, Ronald E Dechert, Joseph R Custer, Mary K Dahmer, Thomas G Saba and Heidi R Flori
Respiratory Care August 2022, 67 (8) 956-966; DOI: https://doi.org/10.4187/respcare.09348

Abstract

BACKGROUND: It remains unknown if pediatric patients failing initial noninvasive ventilation (NIV) experience worse clinical outcomes than those successfully treated with NIV or those primarily intubated.

METHODS: This was a single-center, retrospective review of patients admitted with acute respiratory failure to the University of Michigan pediatric intensive care or cardiothoracic ICUs and receiving NIV or invasive mechanical ventilation as first-line therapy.

RESULTS: One hundred seventy subjects met inclusion criteria and were enrolled: 65 NIV success, 55 NIV failure, and 50 invasive mechanical ventilation alone. Of those failing NIV, median time to intubation was 1.8 (interquartile range [IQR] < 1–7) h. On multivariable regression, ICU-free days were significantly different between groups (NIV success: 22.9 ± 6.9 d; NIV failure: 13.0 ± 6.6 d; invasive ventilation: 12.5 ± 6.9 d; P < .001 across all groups). Multivariable regression revealed no difference in ventilator-free days between NIV failure and invasive ventilation groups (15.4 ± 10.1 d vs 15.9 ± 9.7 d, P = .71). Of 64 subjects (37.6%) meeting Pediatric Acute Lung Injury Consensus Conference pediatric ARDS criteria, only 14% were successfully treated with NIV. Ventilator-free days were similar between the NIV failure and invasive ventilation groups (11.6 vs 13.2 d, P = .47). On multivariable analysis, ICU-free days were significantly different across pediatric ARDS groups (P < .001): NIV success: 20.8 + 31.7 d; NIV failure: 8.3 + 23.8 d; invasive alone: 8.9 + 23.9 d, yet no significant difference in ventilator-free days between those with NIV failure versus invasive alone (11.6 vs 13.2 d, P = .47).

CONCLUSIONS: We demonstrated that critically ill pediatric subjects unsuccessfully trialed on NIV did not experience increased ICU length of stay or fewer ventilator-free days when compared to those on invasive mechanical ventilation alone, including in the pediatric ARDS subgroup. Our findings are predicated on a median time to intubation of < 2 h in the NIV failure group and the provision of adequate monitoring while on NIV.

Introduction

Acute respiratory failure is the most common indication for admission to pediatric ICUs (PICUs) worldwide and is responsible for up to 30–40% of all PICU deaths.1-3 Endotracheal intubation and mechanical ventilation can confer significant risk including injury to the lung parenchyma (known as ventilator-induced lung injury), nosocomial infections, neuromuscular weakness, and complications related to the use of sedative medications.4,5 Over the past 3 decades, noninvasive ventilation (NIV) has been increasingly employed as an alternative form of ventilation in an attempt to alleviate complications associated with endotracheal intubation and mechanical ventilation in both adult and pediatric populations.6-11 However, some patients will fail NIV and require endotracheal intubation. In adults, delay in transition to invasive mechanical ventilation initiation may result in short-term complications including, but not limited to, hypotension, desaturation, and aspiration12 and worse clinical outcomes, including ICU length of stay and mortality.13,14 In pediatrics, although many have examined potential risk factors for NIV failure,11,15-17 few pediatric studies robustly compare the clinical outcomes of those patients primarily managed with NIV who transition to intubation versus those managed with immediate invasive ventilation.

Recently, a large secondary analysis of the RESTORE trial of sedation practices in pediatric patients with acute respiratory failure secondary to airways or pulmonary disease demonstrated worse outcomes including duration of mechanical ventilation and PICU length of stay in subjects treated with NIV prior to intubation compared with no pre-intubation NIV.18 As this was a subanalysis of subjects ultimately intubated, the cohort of patients successfully treated with NIV could not be evaluated. With limited endogenous respiratory reserve, and increased risk for hemodynamic instability, pediatric patients may be at an even greater risk than adults for more harmful complications experienced when intubation is delayed.2 The pediatric mechanical ventilation consensus conference (PEMVECC) recommendations include research to determine the optimal method and timing of NIV.19

The objectives of this study were to compare relevant PICU clinical outcomes of children with acute respiratory failure who were successfully treated with NIV, those who failed NIV and required intubation, and those who were intubated as a first-line intervention without receiving a trial of NIV (invasive mechanical ventilation alone group), with a planned subanalysis of those patients also meeting pediatric ARDS criteria. Specifically, we hypothesized that patients failing NIV have potentially worse clinical outcomes, such as PICU stay and duration ventilation, than those successfully treated with NIV, or those on invasive ventilation alone, independent of presenting severity of illness.

QUICK LOOK

Current Knowledge

Noninvasive ventilation (NIV) has been increasingly employed to alleviate complications associated with endotracheal intubation and invasive ventilation in both adult and pediatric populations. However, some patients fail NIV and require endotracheal intubation. In adults, delay in transition to invasive ventilation may result in short-term complications and worse long-term clinical outcomes, including ICU length of stay and mortality.

What This Paper Contributes to Our Knowledge

Pediatric subjects with acute respiratory failure that were successfully treated with NIV alone exhibited the shortest ICU length of stay and lowest risk of mortality compared to those initially or secondarily invasively ventilated. Interestingly, NIV was not associated with longer ICU length of stay, increased duration of mechanical ventilation, or increased risk of mortality when compared to children primarily intubated at the onset of critical illness. This held true on subanalysis of subjects with pediatric ARDS.

Methods

This study was a single-center, retrospective analysis of pediatric patients admitted to the University of Michigan C.S. Mott Children’s Hospital PICU and/or pediatric cardiothoracic unit with acute respiratory failure. The study was approved with a waiver of consent by the University of Michigan Institutional Review Board (IRBMED HUM00124616). The PICU and pediatric cardiothoracic unit are separate units, each with 30 beds. All patients with acute respiratory failure admitted from January 1, 2015–December 31, 2016, and > 1 month < 18 y old treated with NIV or invasive mechanical ventilation were evaluated. For patients with multiple admissions for acute respiratory failure, each separate episode of acute respiratory failure was evaluated independently.

We determined, a priori, to evaluate all acute respiratory failure types whether primarily related to hypoxia, hypercarbia (ventilatory failure), or both. Consistent with American Association for Respiratory Care and American Thoracic Society standards, we defined acute respiratory failure as hypoxemia (PaO2 < 60 mm Hg, SpO2 < 90% on room air, PaO2/FIO2 < 300, or SpO2/FIO2 < 264) and/or hypercarbia (pH < 7.35 and/or PCO2 > 45 mm Hg).20 Patients treated with NIV or invasive ventilation for reasons other than acute respiratory failure, such as post-surgical recovery, and patients with chronic respiratory failure requiring any form of home invasive or NIV were excluded from the study. Patients receiving heated, high-flow nasal cannula (HFNC) were not included as HFNC has not been demonstrated to be equivalent to NIV and Pediatric Acute Lung Injury Consensus Conference (PALICC) guidelines21 do not recommend HFNC use for severe disease. Noninvasive respiratory support modes used at our institution included variations of CPAP, bi-level positive airway pressure, or average volume-assured pressure support. Interfaces included nasal masks, RAM cannula (Neotech, Valencia, California), and full face masks. The modes of ventilation and interfaces used were adjusted throughout the admission for each subject in order to improve gas exchange and accommodate to each subject’s facial anatomy, pathophysiology, and comfort.

Data Collection

Variables collected from the electronic medical record included age, sex, weight, height, ethnicity, race, comorbidities, type of acute respiratory failure (hypoxemic, hypercarbic, or both), etiology of acute respiratory failure, and pediatric ARDS diagnosis as defined by PALICC.21 Pediatric Risk of Mortality IV (PRISM IV) scores,20 defined between 2 h prior to 4 h after admission, were collected.

Outcome Measures

The primary aim of the study was to compare the PICU stay defined by ICU-free days over a 28-d cycle21-23 between 3 subgroups of subjects: subjects diagnosed with acute respiratory failure who were successfully treated with NIV, subjects who failed a trial of NIV, and subjects who were primarily intubated without a trial of NIV (invasive mechanical ventilation alone). NIV was delivered as either CPAP, bi-level positive airway pressure, or average volume-assured pressure support according to the needs of the subject and clinician preference. NIV failure was defined as any need for tracheal intubation and mechanical ventilation occurring immediately after a trial of NIV. The need for tracheal intubation and mechanical ventilation was at the discretion of individual clinician judgment to assure patient safety. The indication for NIV or invasive mechanical ventilation support, the date and time of onset of acute respiratory failure, and all other data collection were independently reviewed by the primary author (JK) via manual chart review with over 20% of those charts randomly and independently double-checked by the coauthor (HF). Secondary outcomes included duration of mechanical ventilation defined by ventilator-free days over a 28-d cycle,23-25 PICU mortality, ventilator-associated pneumonia,26 and central venous catheter line days.

Statistical Consideration

Data were compared using parametric and nonparametric methods based on sample size and data skewness. As this was a retrospective review with a fixed subject subset, a power calculation was estimated, powered by PICU length of stay. Given an alpha error of 0.05, power of 80%, effect size of 2 d, and SD of 2.7 d, it was estimated that we would need 50 subjects in each of the 3 groups studied.

The demographic and clinical features were tabulated using descriptive statistics (Pearson correlation, analysis of variance, chi-square, and Fisher exact tests). Multivariable analysis applied linear (ICU-free days, ventilator-free days) and logistic (mortality) regression techniques. The NIV success group was excluded from analyses when the research hypothesis was focused solely on the differences between the NIV failure and invasive mechanical ventilation alone groups. A significance level of 0.05 was used for all statistical tests. Cohen’s d was utilized for calculating effect size for the comparison between 2 means, with a difference of 0.2 indicating a small effect size, 0.5 representing a medium effect size, and ≥ 0.8 indicating a large effect size.27

Due to the observational nature of this study, and to reduce potential bias due to confounding variables that may have led to clinician choice of NIV versus invasive mechanical ventilation, we completed a propensity score analysis, specifically stratification and propensity score matching. The following set of confounding variables that might be related to both the treatment with NIV and the primary and secondary outcomes was selected: diagnosis of asthma, PRISM IV score, age, ARDS, chronic lung disease as comorbidity, diagnosis of bronchiolitis, and diagnosis of sepsis. Using these variables, we fitted a logistic regression model, with initial intubation as the outcome, and computed propensity scores (probability of primary intubation). We assessed the balance of confounding variables by comparing the distribution between the treated and control groups (NIV success + NIV failure vs invasive mechanical ventilation alone). Propensity score stratification was ultimately not a good fit for our analyses because we were unable to achieve an acceptable variable balance within the strata, despite changes to the set of included variables, changes of the specification of the propensity score model, or an increase in the number of strata. Thus, we used propensity score matching instead. For propensity score matching, we used the optimal variable ratio-matching method, with 1-to-1 matching; n = 50 primarily intubated, n = 50 trialed on NIV (n = 33 NIV failure; n = 17 NIV success). Standardized mean differences (NIV group vs invasive mechanical ventilation alone group) of potential confounders were significantly reduced in the matched observations; standardized differences were less than the recommended upper limit of 0.25 (0.04–0.25), and variance ratios between the 2 groups were within the recommended range of 0.5–2.0 (0.51–1.77).

Statistical analysis was performed using SAS version 9.4 (SAS Institute, Cary, North Carolina). For the purpose of creating Kaplan-Meier curves, subjects who died were considered censored.

Results

During the study time frame, 401 patients were admitted to the PICU or pediatric cardiothoracic unit and initiated on NIV or invasive mechanical ventilation. Of these, 170 subjects met inclusion criteria and were analyzed (Fig. 1). The 3 groups compared were reasonably well divided: 65 with NIV success, 55 with NIV failure, and 50 with invasive mechanical ventilation alone.

Fig. 1.
Fig. 1.

Flow chart. Patients were excluded if they were treated with noninvasive ventilation (NIV) or invasive mechanical ventilation for reasons other than acute respiratory failure and/or if they had chronic respiratory failure requiring any form of home invasive ventilation or NIV.

Baseline Data Comparisons

The subject baseline characteristic comparisons can be found in Table 1. There was no significant difference in age, gender, race, ethnicity, or type of respiratory failure (hypercapnic, hypoxemic, or mixed) when comparing the 3 groups. Severity of illness scores, as measured by PRISM IV, were significantly different across the 3 groups (P < .001). For those failing NIV, the median time to intubation from NIV onset was 1.8 (IQR <1.0–7.0) h.

View this table:
Table 1.

Baseline Clinical Data

Table 1 includes the primary diagnoses associated with acute respiratory failure. The frequency of the diagnosis did not vary between groups except for the asthma diagnosis (P < .001), with 23.1% of subjects diagnosed with asthma and successfully treated with NIV, 3.6% in those who failed NIV and 2% in those requiring invasive mechanical ventilation alone.

Evaluation of relevant comorbidities revealed that the proportion of subjects with a history of asthma differed significantly between the 3 groups (P = .02 across all 3 groups), with 55% of those with a history of asthma successfully treated with NIV, 23% failing NIV, and 21% requiring invasive mechanical ventilation alone (Table 1). The proportion of subjects with chronic lung disease was also significantly different between the 3 groups (P = .02 across all 3 groups).

Primary Outcome

The primary outcome measure was ICU length of stay as measured by ICU-free days. After controlling for severity of illness (PRISM IV score),20 our results indicated a statistically significant difference in ICU-free days across the 3 groups analyzed (Table 2, Fig. 2). Cohen’s d analysis comparing NIV success versus failure and NIV success versus invasive mechanical ventilation alone revealed large effect sizes of 1.47 and 1.51, respectively. There was no significant difference in ICU-free days between the NIV failure and invasive mechanical ventilation alone groups (P = .75; Cohen’s d effect size = 0.07).

Fig. 2.
Fig. 2.

Kaplan-Meier curve indicating length of pediatric ICU (PICU) stay for all 3 groups examined: noninvasive ventilation (NIV) success, NIV failure, primarily intubated. Numbers under the curve indicate the number of subjects in each group at each time point.

View this table:
Table 2.

ICU-Free Days Across All 3 Groups Tested

On bivariate analysis, several covariates were statistically significantly associated with differences in ICU-free days (history of asthma, history of repaired congenital heart disease, primary diagnosis of status asthmaticus on presentation, type of respiratory failure, and presence of pediatric ARDS at start of therapy). In multivariable models that included these covariates, ICU-free days remained significantly different between those treated with NIV successfully (20.7 d), those who had NIV failure (12.4 d), and those with invasive mechanical ventilation alone (12.2 d, P < .001) (Table 2). Cohen’s d effect size calculations when comparing NIV success vs failure and NIV success vs invasive mechanical ventilation alone indicated effect sizes of 0.71 and 0.73, respectively, (Table 2). When comparing NIV failure directly to subjects with invasive mechanical ventilation alone, there was no significant difference in ICU-free days (P = .95; Cohen’s d effect size = 0.02) (Table 2). When we replicated the analysis using propensity score matching, the results were similar (Table 3).

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Table 3.

Replication of Primary and Secondary Analyses With Propensity Score Matching Data Set

Secondary Outcomes

Duration of mechanical ventilation (as measured by ventilator-free days) was compared between the NIV failure and invasive mechanical ventilation alone groups. Bivariate analysis indicated that history of repaired congenital heart disease and presence of pediatric ARDS were associated with significant differences in ventilator-free days. Multivariable analysis adjusting for severity of illness, history of repaired congenital heart disease, and pediatric ARDS indicated that there was no significant difference in ventilator-free days between the NIV failure group (15.4 d) and the invasive mechanical ventilation alone group (15.9 d, P = .71). Corresponding Kaplan-Meier curves describing duration of invasive mechanical ventilation over a 28-d period are shown in Figure 3. When we replicated the analysis using propensity score matching, the results were similar (Table 3).

Fig. 3.
Fig. 3.

Kaplan-Meier curve indicating duration of invasive mechanical ventilation for those primarily intubated versus those intubated after noninvasive ventilation (NIV) failure. Numbers under the curve indicate the number of subjects in each group at each time point.

Very few subjects in this cohort died (7/170, 4.1%), thus limiting extensive statistical analyses related to mortality. There was a significant difference in mortality between those successfully treated with NIV (0%), those who failed NIV (9%, n = 5), and those with invasive mechanical ventilation alone (4%, n = 2; P = .044 across all 3 groups). When comparing failure to the invasive mechanical ventilation alone group directly, there was no significant difference (P = .44). When we replicated the analysis using propensity score matching (Table 3) with 2 NIV cases for every one primarily intubated case, there was no difference in mortality (P = .32 across the 3 groups; P = .68 comparing NIV failure vs invasive mechanical ventilation alone groups).

Outcomes for the subgroup of subjects diagnosed with pediatric ARDS.

The baseline characteristic comparisons for those subjects diagnosed with pediatric ARDS are described in Table 4. Sixty-four subjects (37.6%) met the PALICC pediatric ARDS criteria21 at the start of therapy. As expected, pediatric ARDS distribution was significantly different across the 3 groups, with a minority being successfully treated with NIV alone. Age also differed significantly across the 3 groups (P = .009), with subjects successfully treated with NIV being older when compared to subjects with NIV failure and those with invasive mechanical ventilation alone (Table 4). There was no significant difference in gender, race, ethnicity, severity of illness, or type of respiratory failure (primary hypercapnia, primary hypoxemia, or hypoxia/hypercarbia combined) when comparing the 3 groups. For subjects with pediatric ARDS failing NIV, the median time to intubation was 2.95 (IQR 1.20–8.50) h. As expected, the distribution of primary diagnoses associated with pediatric ARDS across all 3 groups differed significantly (P = .007 across all 3 groups). Most notable differences occurred in those with pediatric ARDS associated with bronchiolitis, in which no subjects were successfully treated with NIV compared to those with pediatric ARDS associated with pneumonia wherein almost one third of subjects was successfully treated with NIV alone. Evaluation of relevant comorbidities in the pediatric ARDS subgroup indicated that the proportion of subjects with a history of prematurity was significantly different between the 3 groups (P = .054 across all 3 groups), with none treated successfully with NIV. There were no other significant differences between the groups for the other comorbidities examined (Table 4).

View this table:
Table 4.

Baseline Clinical Data for Subjects Diagnosed With Pediatric ARDS

On multivariable analysis of the subgroup of subjects with pediatric ARDS and controlling for severity of illness (PRISM-IV), ICU-free days were significantly different (P < .001) between the 3 groups, with greater ICU-free days in the cohort successfully treated with NIV alone (Table 5). There was no difference in ICU days between subjects with pediatric ARDS with NIV failure compared to those with pediatric ARDS with invasive mechanical ventilation alone. Similarly, when examining ventilator-free days, there was no significant difference between the NIV failure group and those with invasive mechanical ventilation alone. Given the smaller number of subjects with pediatric ARDS as well as the severity of illness of the subjects, propensity score analysis was not feasible.

View this table:
Table 5.

Clinical Outcome Measures in the Pediatric ARDS Subgroup Alone

Discussion

We demonstrated here that certain pediatric subjects diagnosed with acute respiratory failure could successfully be treated with NIV and experience a shorter PICU length of stay compared to subjects who either failed NIV therapy or those requiring invasive mechanical ventilation alone without a trial of NIV. Perhaps most importantly, we demonstrated that subjects who failed NIV did not sustain an increased risk of mortality, a more prolonged course of mechanical ventilation, or an increased PICU length of stay compared to those primarily intubated, even after controlling for severity of illness and after propensity score analysis. Also interesting in our study, those with a primary diagnosis of asthma, a group that historically was rarely considered for NIV, were very often successfully treated with NIV alone.

Our results are similar to those reported in a study of 173 adult subjects diagnosed with acute respiratory failure, which also did not identify differences in patient outcomes when comparing adults who failed NIV with those treated with invasive mechanical ventilation as first-line therapy.14 Median duration of NIV treatment prior to failing and being intubated was 7.0 h in the adult study and 1.8 h in our study. A post hoc analysis of our dataset of the 55 subjects failing NIV also revealed no statistical difference in ventilator-free days (P = .78), ICU-free days (P = .30), or mortality (P = .11) between the 40 subjects trialed on NIV for < 6 h vs the 15 subjects failing NIV trial after 6 h (data not shown).

Our research also analyzed NIV use, success, and failure in the subgroup with pediatric ARDS. Use of NIV in patients with pediatric ARDS remains controversial. The multi-center PARDIE study included 160 subjects treated with NIV,28 of which 50% required intubation. PICU mortality in the PARDIE NIV group requiring subsequent intubation was 25% as compared to 5% in the group with NIV success. The recently published large secondary analysis of the RESTORE trial showed longer PICU length of stay, longer duration of mechanical ventilation, and increased mortality in subjects with pediatric ARDS who failed a trial of NIV compared to those primarily intubated.18 Unfortunately, that study could not include an NIV success cohort in comparison. In the RESTORE subanalysis of subjects with pediatric ARDS, the median duration of NIV treatment prior to failing and being intubated was 6.50 h compared to 2.95 h in our study. Also, in the RESTORE analysis, 24% of the subjects were on NIV for > 24 h prior to intubation, many more than in our cohort (7%). Finally, even though only 24% of subjects with pediatric ARDS initially treated with NIV alone were treated successfully, those subjects experienced shorter PICU length of stay, even when adjusted for severity of illness.

Taken together, we suggest that NIV may be carefully trialed in many pediatric patients with acute respiratory failure, particularly those with a primary diagnosis of asthma, provided very close, time-sensitive monitoring in a PICU environment is also instituted so that a decision of whether to intubate can be made within a few hours of the start of the NIV trial. Future prospective investigations should plan to further examine (1) indications for intubation versus NIV trial by bedside clinicians; (2) the appropriate length of time to trial NIV; (3) an expanded cohort of subjects with pediatric ARDS, sepsis, and immunocompromised patients; (4) cohorts including patients trialed on HFNC; and (5) cohorts large enough to more fully evaluate other relevant clinical outcome measures, such as health care acquired conditions and new and progressive organ system failures. Ideally, a prospective, multi-center trial is warranted to confirm our results. In the interim, these results should be interpreted with caution and should not replace clinical judgment regarding the appropriateness, timing, and monitoring of children on noninvasive support.

This study has several limitations. First, this is a retrospective study from a single-center and may be biased by clinician preferences in managing children on NIV therapy in the PICU. As this is a retrospective review, we do not have granular data on the exact clinical determinants of the decision to intubate versus trial NIV. As severity of presenting illness remains a key determinant of need for intubation, we adjusted all multivariable models with PRISM IV. To further assess for clinician preference, propensity scores were calculated, with our primary findings remaining unchanged. Ultimately, no degree of propensity scoring can account for all potential confounders in a retrospective cohort, hence our recommendation for prospective validation, if not formal randomized controlled trials in the future. Finally, whereas some adult and pediatric studies of subjects with immunosuppression and/or cancer suggest increased risk of mortality in those subjects trialed on NIV prior to intubation,14,29 our cohort included only 9 children with oncologic diagnoses. Consequently, it is difficult to make any meaningful observations in this subgroup.

Our study has several strengths. Key investigations in pediatric NIV studies have lacked inclusion of the cohort of subjects successfully managed on NIV.18 Identifying the cohort of subjects successfully treated with NIV is relevant to determining which disease processes and what time course of acute respiratory failure offer optimal chances of successful management using NIV.19,21 Also, with a sample size of 170 subjects, this study is one of the larger pediatric studies evaluating NIV effectiveness for acute respiratory failure.30,31

Conclusions

Pediatric subjects with acute respiratory failure that were successfully treated with NIV alone exhibited the shortest ICU length of stay compared to those initially or secondarily invasively ventilated. Importantly, failure of NIV was not associated with increased ICU length of stay, duration of mechanical ventilation, or risk of mortality when compared to those children primarily intubated at the onset of critical illness on both multivariate and propensity score analyses. A brief, initial trial of NIV therapy, with careful monitoring in a critical care setting, may be justified in pediatric patients who present in acute respiratory failure.

Acknowledgments

We would like to thank Ms Caroline Dugan for her outstanding work with our database entry for this research project.

Footnotes

  • Correspondence: Heidi R Flori MD, University of Michigan C.S. Mott Children’s Hospital, Department of Pediatrics, Division of Critical Care, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109. E-mail: heidiflo{at}med.umich.edu

  • The authors have disclosed no conflicts of interest.

  • Funding for statistical support was provided in kind by Department of Pediatrics Research Program, University of Michigan.

  • The study was performed at the University of Michigan.

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