Discussion
Multi-dose pretreatment regime of systemic steroid starting 12-24 hours
prior to planned extubation reduces PEAO in adult 6-10as well as in pediatric 1,9 patients. Dexamethasone is
preferred over other steroids 1,7,8. Our previous
study (period: 2009-10) demonstrated that 24-hour pretreatment with a
high dose of dexamethasone prevents PEAO and need of reintubation1. Majority of the then patient population in our unit
had multiple risk factors e.g., intubation in uncontrolled situations,
longer duration of intubation and hand ventilation in emergency room,
multiple airway manipulations and hypoalbuminemic edema. Inspired by the
findings of non-superiority of the high dose (versus the low dose) in
the adult patients 8 and lack of similar information
in the pediatric literature, we conducted the present trial (period:
2017-19). It has not only shown the non-inferiority of the low dose
(0.25mg/Kg/dose) pretreatment (versus previously studied high dose,
0.5mg/Kg/dose) in reducing PEAO, but it also demonstrated the changing
clinical scenario in the unit during the last decade.
Comparison of clinical characteristics and potential risk factors for
PEAO during these two study periods is given in the supplemental table
1. While our patients continue to be similarly malnourished, PRISM III
score has increased. Now, we saw more patients with presumptive
diagnosis of CNS infections (e.g., meningitis, meningoencephalitis),
while patients with respiratory infections (e.g., pneumonia, empyema)
has decreased. Frequency of risk factors, as identified in the previous
trial (2009-10), were much lesser during the current study period
(2017-19). Number of patients intubated in uncontrolled situations (89%
vs 76%) got reduced as was duration of intubation and/or
hand-ventilation in pre-PICU areas (PER/wards) (median, 0.9 days vs 12
hours). Number of patients needed to stay in PER/wards for> 24 hours prior to PICU transfer (57% vs 27%) and
undergoing multiple airway manipulations (35% vs 18%) got reduced by
half. Number of patients with >7 days of intubation and/or
ventilation also got reduced by a third (56% vs 38%). Serum albumin
was higher (median, 2.5 gm/dL vs 2.8 gm/dL) at the time of extubation,
while lesser number of patients had hypoalbuminemia (88% vs 75%) and
clinical edema (40% vs 27%). All these led to a notable reduction in
PEAO (73% vs 33%) during the current study period despite using the
same yardstick (i.e., WCS). Reintubation rate remained unchanged over
last 10 years (11% vs 8%). Incidence of PEAO and reintubation in our
unit seems to be approaching towards what is being reported from PICUs
of high-income countries 2,5,14. The two study
cohorts, a decade apart, provide a glimpse of journey of a PICU in a
tertiary care teaching hospital in a lower-middle-income country.
We could not find any new pediatric trial since we published results of
our previous study. Recently, effectiveness of dexamethasone
pretreatment in reducing reintubation due to PEAO was reported in a
retrospective propensity matched study on infants with respiratory
syncytial virus 5. A systematic review and
meta-analysis of 11 adult trials 10 proved efficacy of
steroid pretreatment in prevention of PEAO and reintubation in select
group of at-risk patients. A randomized control trial among at-risk
adult patients (cuff-leak volume <110ml) revealed
effectiveness of dexamethasone pretreatment in reducing PEAO (placebo
group, 30% vs two dexamethasone groups, 9.8% and 7.1% respectively).
However, there was no difference between the low dose (5 mg/dose) and
the high dose (10 mg/dose) regimes 8 similar to the
findings observed in the current study. Low dose dexamethasone reduced
the baseline incidence of PEAO from 30% (in the placebo arm) to 9.8%,
and further reduction could not be achieved with the higher dose.
Similarly, lack of difference in the two dose regimes may be
attributable to the significantly reduced incidence of PEAO itself (73%
vs 33%), with notable weakening of the associated high-risk factors.
However, it is not sure if these findings would be replicable in a
clinical setting similar to what we had a decade ago, i.e., very high
incidence of PEAO with presence of multiple risk factors in the
majority. The study reiterates the situation-specific applicability of
the evidence generated from various clinical settings15.
Dexamethasone pretreatment is found to be effective only among at-risk
adult patients, and not among unselected ones 10. We
also demonstrated a lesser incidence of PEAO with high dose
dexamethasone pretreatment in the subgroup of children intubated for
more than 7 days [RR, 1.52; p-value, 0.07]. Trials to assess
effectiveness of various dexamethasone pretreatment regimes in the
select group of high-risk children are advisable in context of reducing
incidence of PEAO and plateauing of reintubation in the studied clinical
setting. Indices based on pre-extubation airway ultrasound16-19 may help identify high-risk children.
Based on the assumptions used for sample size calculation in ‘Material
& Methods’ section, the power of the study is less than 60%. With
demonstrated PEAO incidence of 32% and 34% in HD and LD arms
respectively in our study, with non-inferiority margin of 12%, one
sided α-error of 0.05 and power of 80%, a sample size of 398 per group
(796 in total) would be required to prove the non-inferiority of LD
compared to HD. With the new assumptions also, the power of study is
less than 60%. The study was a non-funded time-bound dissertation
project. Due to logistics and time-constraints, we could enroll only 238
patients. Two categories of exclusions may raise concerns of bias—
patients with deferred extubation (n=21) and patients who were
reintubated for non-PEAO reasons (n=28). Inclusion of the former would
be unfair as they were not available for assessment of treatment effect.
Results after including those reintubated for non-PEAO reasons (n=28)
was no different. Relying on clinical scores to identify and monitor
PEAO lacks objectivity; respiratory inductance plethysmography and
esophageal manometry (which is not available with us) would have been
better 14. Lack of measurement of observer agreement2 and blinding are other concerns. To limit the
former, minimum of two clinicians assessed the patients for PEAO and/or
need for reintubation. The latter could not have been addressed as
dexamethasone doses were drawn from the same commercially available
preparation, and we do not have in-house pharmacy. A placebo arm in the
trial would have demonstrated the role of dexamethasone pretreatment
better, however it would be unethical when our unit’s standard of care
includes dexamethasone pretreatment for children intubated for> 48 hours. Since it is a single-center study,
external validity may be a concern. Enrolment over a short period of 26
months indicates contemporary nature of the cohort. Stratification of
randomization using intubation duration is a strength. Despite many
limitations, the trial provides clinically relevant data to the
pediatric critical care community working in low- and middle-income
countries (LMICs) and experiencing high incidence of PEAO as ours.