A breath of fresh air: Does spontaneous breathing and early
repair in neonates with very mild congenital diaphragmatic hernia lead
to earlier discharge?
Dear Editor:
We read with great interest the article by Kipfmueller et al. that
investigated the feasibility and outcomes of a spontaneous breathing
approach (SBA) versus immediate intubation in neonates with prenatally
diagnosed very mild CDH and found that it appears to be feasible and
beneficial1. The authors present an approach that is
quite novel - spontaneous breathing and enteral feeding in the
pre-surgical repair phase. We compliment the authors for their attempt
to address an issue very relevant to the acute management of CDH.
Nonetheless, we feel compelled to highlight some aspects that should be
considered for adequate interpretation of their findings.
The study’s sample size is quite small (n=24), but the fact that the
investigators found statistical significance for numerous associations
despite such a small sample size demonstrates the strength of the
relationships. It is a common misconception that statistical
significance due to chance (i.e., Type I error) is more likely when the
sample size is small, although low power due to the small sample size is
actually difficult to overcome2. However, when
evaluating Table 1, after matching on observed-to-expected
lung-to-head-ratio (o/e LHR), liver position, gestational age at
delivery, birth weight, and defect size, we note that prerepair
characteristics such as early feeding, Oxygenation Index (OI) and
FiO2, and Apgar at 10min are still significantly
imbalanced between the SBA and standard treatment groups, which raises
concerns about potential confounding. For this reason, we recommend the
authors complement the unadjusted analyses they report with
multivariable regression analyses that compare SBA versus standard
treatment after controlling for Apgar 10, OI and FiO2,
although the study sample size of n=24 would typically be considered too
small for this kind of multivariable regression analysis. Per the
authors, 39 patients met their prenatal eligibility criteria. A better
and more meaningful comparison of outcomes would be to compare the 8
patients that underwent SBA versus the remaining 31 patient that met
their predetermined ’eligibility criteria’ and did not undergo planed
SBA. Using this approach would diminish the potential differences in
cohort caused by severity of hernia defect, given the fact that some
patients in the standard treatment group required patch repair. In the
study, the authors incorporated the post natally determined CDH defect
size into the matching process; we would advise against using defect
size for matching as it cannot be replicated prospectively.
The authors utilized the Mann-Whitney U test and Fisher’s exact test to
compare the SBA versus standard treatment groups in terms of
quantitative and categorical variables, respectively. These methods
ignore the dependence structure in the data resulting from matching.
Although this type of oversight is common, we would recommend analyzing
the data differently. Utilizing mixed-effects linear models and
generalized estimating equations for quantitative and categorical
outcomes, respectively, would appropriately accommodate the clustering
of study patients due to matching.
We were impressed by the decision to initiate enteral feeding prior to
surgery and wonder if this approach could be a gut priming strategy
favoring outcomes beyond the need for parenteral
nutrition3. However, while novel and potentially
beneficial, this strategy carries with it risks and will need to be
investigated further before others will choose to adopt such a practice.
Overall, the authors tackle an important subject and their findings
raise questions on whether routine intubation is beneficial for infants
with mild CDH. As SBA infants were compared to those with more severe
hernias, the observed differences noted between groups are likely a
reflection of the severity of lung hypoplasia and not a result of the
intervention. We encourage the authors to further explore this strategy
with a larger multicenter study to draw meaningful conclusions from the
study results.
Clinicians should be cautious of implementing guideline changes based on
retrospective studies, as prospective studies do not always validate
inferences derived from retrospectives studies, such as permissive
hypercapnia to prevent bronchopulmonary dysplasia in extremely low birth
weight infants (ELBW)4. Centers that perform early
repair could consider an SBA approach for a well-defined cohort of
infants with mild CDH, as it appears this can decrease the duration of
ventilation and length of hospital stay. However, this precision-based
medicine approach would be best evaluated by a prospective study to
assess the benefits and risks of implementing this strategy.
1. Kipfmueller F, Leyens J, Pugnaloni F, et al. Spontaneous breathing in
selected neonates with very mild congenital diaphragmatic hernia.Pediatr Pulmonol. 2024;59(3):617-624.
2. Jones SR, Carley S, Harrison M. An introduction to power and sample
size estimation. Emerg Med J. 2003;20(5):453-458.
3. Ratsika A, Codagnone MC, O’Mahony S, Stanton C, Cryan JF. Priming for
Life: Early Life Nutrition and the Microbiota-Gut-Brain Axis.Nutrients. 2021;13(2):423.
4. Thome UH, Genzel-Boroviczeny O, Bohnhorst B, et al.
Neurodevelopmental outcomes of extremely low birthweight infants
randomised to different PCO(2) targets: the PHELBI follow-up study.Arch Dis Child Fetal Neonatal Ed. 2017;102(5):F376-F382.
The authors have disclosed no conflicts of interest.