Data was obtained by retrospective chart review that included patients
recruited from the Children’s Hospital of Philadelphia (CHOP) and Johns
Hopkins Children’s Center outpatient BPD clinics, whose initial hospital
discharge was between 2008-2023. All patients were born at or less than
32 weeks-gestation and severity of BPD was based on the 2001 NIH
consensus definition.(16) Participants with cyanotic congenital heart
disease were excluded. Approval was obtained from the Children’s
Hospital of Philadelphia Institutional Review Board (IRB #
20-017614_AM18) and Johns Hopkins IRB (Protocol #NA_00051884). All
caregivers provided informed consent. Birthweight percentile was
corrected by gestational age.(17) Median household income was estimated
through residential zip codes using U.S. Census data.
Chi square tests, t-tests, and ANOVA tests compared clinical
characteristics and demographic data between participants on outpatient
diuretics and those not on outpatient diuretics as well as between
participants on one, two or three diuretic agents and between diuretic
classes. Cox regressions were performed to identify characteristics
associated with slower or faster weaning of diuretic therapy with shared
frailty by study site to account for study site-related differences.
Results with a P value less than or equal to 0.05 were considered
statistically significant. Stata 15.0 was used for data analysis
(StataCorp, College Station TX).
Results
Patient Characteristics: Children with reported use of
diuretics at their first pulmonary outpatient visit (n= 737) were more
likely to have severe BPD (p<0.001), lower birthweight
(p=0.001), and born at an earlier gestational age (p=0.012) compared to
those not prescribed diuretics (n=487) (Table 1).
Subjects on outpatient diuretics were more likely to be older at the
time of initial hospital discharge (p<0.001), however their
first pulmonary appointment occurred at a younger age (p<0.001)
compared to those not prescribed diuretic therapy at discharge. Further,
being on diuretic(s) at the first outpatient pulmonary appointment was
associated with an increased likelihood of home supplemental oxygen
requirement (p<0.001), tracheostomy (p=0.018), ventilator
dependence (p=0.019), gastrostomy tube (p< 0.001), Nissen
fundoplication (p< 0.001), pulmonary hypertension
(p< 0.001) and being prescribed inhaled corticosteroids
(p< 0.001). No association was found between diuretic use at
the first pulmonary outpatient visit and median household income, public
insurance, race, or sex.
Diuretic use: In children prescribed diuretic therapy,
most were either on one (50.1%) or two (47.4%) diuretics
(Table 2). For patients receiving one diuretic, the majority
were prescribed a thiazide diuretic (92.6%), whereas significantly
fewer individuals were prescribed a loop diuretic alone (6.6%). Of
those children with BPD receiving dual diuretic therapy, most were
prescribed a thiazide and potassium sparing agent, (94.5%)). Site
differences were seen in the use of diuretic therapies (data not shown),
however from both sites, thiazides were the predominant diuretic used in
the outpatient setting (96.3% and 96.0% respectively).
We also examined differences in patient characteristics between children
prescribed a potassium sparing diuretic (n=353) versus those not on a
potassium sparing diuretic (n=384). We found that children on a
potassium sparing diuretic were more likely to be seen in pulmonary
clinic at an older age (p=0.010), and more likely to be prescribed an
inhaled corticosteroid (p<0.001) and to have a Nissen
fundoplication (p=0.014) (Supplemental Table 1). Interestingly,
being prescribed a potassium sparing diuretic was not associated with
requiring less electrolyte supplementation compared to those prescribed
another class of diuretic.
In contrast, children in the outpatient setting on loop diuretics (n=62)
were more likely to require electrolyte supplementation
(p<0.001) versus those not on loop diuretics (n=675).
(Supplemental Table 2). Children on a loop diuretic at their
first outpatient pulmonary visit were more likely to have a later age of
initial hospital discharge (p<0.001), to have a tracheostomy
(p<0.001), to be ventilator dependent (p<0.001), to
require home supplemental oxygen (p=0.003), to have a gastrostomy tube
(p<0.001) and Nissen fundoplication (p<0.001), and to
have pulmonary hypertension (p<0.001); characteristics aligning
with more severe respiratory disease.
Only a minority of children were prescribed three diuretics at the time
of their first pulmonary visit (n=19), and when compared to those on one
or two diuretics they were more likely to be older at the time of their
initial hospital discharge (p<0.001), to have a tracheostomy
(p<0.001), to be ventilator dependent (p<0.001), to be
on home supplemental oxygen (p=0.014), to have pulmonary hypertension
(p<0.001), and to have a gastrostomy tube (p<0.001) and
a Nissen fundoplication (p<0.001) (Table 3).
Additionally, almost all subjects prescribed three diuretics received
electrolyte supplementation.
Diuretic weaning: In a multivariate model, the
likelihood of weaning off diuretics in a given month was slower in
patients with a tracheostomy tube, home supplemental oxygen requirement,
pulmonary hypertension, gastrostomy tube, prescribed inhaled
corticosteroids, on public insurance, or born at an earlier gestational
age (Table 4).
Interestingly, BPD severity did not influence the likelihood of weaning
off diuretics in a given month whereas, children who were prescribed
electrolyte supplementation had an increased likelihood of weaning off
diuretics faster in a given month. Weaning of outpatient diuretics was
guided by healthcare providers in over 80% of patients (Table
3). Over 50% of BPD infants prescribed outpatient diuretics were
weaned off by 10 months chronological age with over 75% weaned off
diuretic therapy by 15 months chronologic age (Figure 1).
Diuretics and supplemental oxygen: For children with BPD
on home supplemental oxygen (n=519), the median age of oxygen weaning
was 10.1, 10.2, 14.3 and 33.5 months respectively for children on zero,
one, two and three diuretics. There were no statistical differences in
time to wean off supplemental oxygen between those on one diuretic
compared to those on no diuretics (Figure 2). Children with BPD
on two diuretics and home supplemental oxygen took longer to liberate
from home supplemental oxygen compared to those not prescribed a
diuretic (p < 0.001).