Limitations
This study has some limitations to acknowledge. The lower sample size
than initially planned may have caused a beta error (absence of
significance in the intubation rate due to a low number of patients).
Failure of therapy with a PEEP of 5 was extremely high (78%) and it is
possible that further
continuation of the study might have required an interim analysis to
discuss eventual amendments. Furthermore, even if not pre-designed by
our protocol, we were not able to identify any specific subgroup of
patients who might have benefit by different PEEP regimes. However, it
must be remarked that patients with respiratory insufficiency due to
bronchiolitis have frequently very similar clinical characteristics and
those with bacterial coinfection be well represent a subgroup of more
severe patients, refractory to CPAP approach. This study is also lacking
a third “NIV arm” (applying a different interface, i.e., face mask)
that may be a potentially interesting comparator, especially in most
severe cases. However, the initial intention of this study was to apply
helmet in all bronchiolitis. HCPAP support requires a learning curve for
optimization of the effectiveness. In this study, we recruited centers
with proven and skilled experience in HCPAP treatment for bronchiolitis,
thus limiting the external validity of the study. It is also likely that
this contributed to the early interruption of the trial, given the
unexpectedly low enrollment rate with respect to the planned schedule.
Furthermore, the intubation rate was heterogeneous across study sites,
likely representing the challenge of the non-invasive respiratory
management of these patients and the potential differences in HCPAP
setup. However, in all centers, the primary outcome was not associated
with initial PEEP level. Another potential weakness of the study was the
absence of control regarding the timing of admission to PICU for
bronchiolitis; this may vary significantly among different centers due
to organizational aspects and availability of PICU beds. However, the
ideal timing for PICU transfer is currently unknown, this did not appear
to be different in the two groups and even if proactive admission to a
PICU may affect the outcomes, this has not yet been proven. Furthermore,
among the inclusion criteria, the maximum duration of 72 hours of HFNC
therapy partially limited this weakness. Finally, bacterial coinfection
was diagnosed through a nasal swab, which do not allow a definitive
diagnosis of actual lung infection.