Discussion
As the leading cause of oxygen dependency, BPD, has presented important
changes in its clinical presentation and definition compared to the
first study performed in 1967 by Northway19 or with
the study conducted by Kangaroo Foundation in 2004 in
Bogotá1. With neonatal care advances, patients
nowadays are more immature but with less lung injury, and oxygen
dependency is associated with restriction of alveolar septation due to
antenatal infections among other causes 20. Currently,
most units define BPD as OD >28 days and/or ≧ 36 weeks GA
or even OD/ respiratory support ≧40 weeks, according to GA at
birth21–24.
Since 1937 Theophylline therapy has been employed in patients with
different respiratory diseases, mainly inflammatory processes such as
bronchial asthma or chronic obstructive pulmonary
disease9. In newborns, especially premature infants,
it has been used to manage apnea of prematurity and prevent BPD, given
its diuretic and anti-inflammatory properties and its effect on
diaphragmatic contractility. Because of N-methylation, Theophylline is
metabolized to caffeine10, and can be available in
oral presentation for outpatient treatment. It became a good alternative
for KMCPs managing LBWI with ambulatory oxygen, therefore its use became
part of the routine management for this population14.
Over the years, toxicity concerns were found with Theophylline
administration in animal models and some human case reports. Research in
mice revealed that Theophylline-exposed groups presented a higher risk
of involuntary movements, tachyarrhythmias, ischemic changes with
ST-segment depression and increased risk of gastric ulcers25. In humans, Theophylline overdose has been
associated with probable status epilepticus induction and a potential
mortality of 10%11.
On the other hand, treatment with caffeine has shown short- and
long-term effectiveness, with a lower risk of toxicity than
Theophylline. Although its primary objective has been the management of
apnea of prematurity, since 2006, a possible association with a decrease
in BPD was described, as well as a decrease in death or disability at 18
to 21 months. These findings are probably associated with a decrease in
days of mechanical invasive ventilation and by the anti-inflammatory
and/or diuretic effects of xanthines 5. Early
initiation of caffeine (<2 days of life) showed a reduction in
mortality and BPD incidence26. A 2020 systematic
review, including studies with a total of 63,315 newborns, found
evidence of non-inferiority in the effectiveness of caffeine compared to
the other methylxanthines for treating apneas with lower tachycardia
range and complications, especially when administered early and at low
doses 27. Other caffeine benefits are the once-daily
administration and wide therapeutic range with reduced need for serum
level monitoring28. Given these advantages, caffeine
is the xanthine of choice in newborns.
The increasing evidence of safer management with caffeine makes
Theophylline a secondary option. However, in ambulatory KMCPs in low or
middle-income countries it remained in use, due to the lack of
ambulatory oral caffeine. Evidence from recent years has indicated that
the use of xanthines in premature infants is limited to treatment of
apnea of prematurity, without finding a clear benefit in the reduction
of days of oxygen dependency or long-term effects6. We
performed this study to obtain more evidence on this statement, given
the controversy of the benefit of xanthines in reducing oxygen
dependency. When adjusting for aspects related to better care over time,
such as ventilatory support practices and nutrition variables, we did
not find any effect of Theophylline in reducing days of OD; on the other
hand, EBF and weight gain were significative.
These results support the decision to discontinue the systematic use of
this medication in our ambulatory program and the importance of
nutrition based on EBF and monitored with weight gain. For several
years, emphasis has been placed on nutrition as a crucial factor for
lung growth and repair 29. Researchers suggest that
these patients should receive a total daily intake between 135 to 150
cc/kg/day with a caloric supply between 120 to 150 kcal/kg/day, meaning
high energy intake and small volumes30. Other studies
have also found that patients who were breastfed (with or without
fortification) had a reduction in the frequency of BPD. In a systematic
review by Villamor et al. with a total of 15 studies (4984 patients and
1416 cases of BPD), it was found that EBF was associated with a
significant reduction in the risk of BPD adjusting for gestational age
in the meta-regression (RR 0.74, 95%CI 0.57-0.96, 5 studies). The
authors argue that this is related to the known presence of bioactive
nutritional components in breast milk that counteract factors such as
oxidative stress, inflammation and nutritional deficiencies involved in
the pathogenesis of BPD. Additionally, indirectly, the effect of
breastfeeding on reducing the incidence of necrotizing enterocolitis and
late sepsis may contribute to a lower frequency of this
entity31. In our study, a high percentage of patients
in both cohorts received EBF or formula+ breastfeeding at weaning
(89%), probably because of the KMC benefits on
breastfeeding32,33, but only those with EBF had the
advantage of less days with oxygen as in Villamor’s study.
We found no significant differences between groups in the frequency of
BPD at 40 weeks, ROP, IVH, neurological abnormalities and
re-hospitalizations up to 40 weeks.
Regarding side effects, there were no differences in gastrointestinal or
neurological problems associated with Theophylline. However, as reported
in the literature, there was a greater number of tachycardia
episodes12,34.
In the multivariate analysis, it seems that weight at ambulatory KMCPs
admission, weight gain during ambulatory follow-up and EBF have a
greater factor effect on days of oxygen dependency than the fact of
receiving or not Theophylline. This results could be related to the
already known nutritional impact on BPD31,35,36. In
fact, we found a similar association between weight at weaning and days
of oxygen dependence in another recent analysis published in
20213. This multivariate analysis explained 63% of
the variance of days of oxygen dependency for our population.
Given these results we hypothesize that EBF enhanced with KMC, increases
pulmonary tissue repair, nutritional recovery and growth, with the
consequent effect on the reduction of days with oxygen.
Numerous newborn units are now being opened in low- and middle-income
countries, increasing the survival of the most immature LBW infants but
with very aggressive management. Goals of non-aggressive ventilation,
nutrition with breast milk as early as possible, humanization and early
discharge to ambulatory KMCPs should be part of the management of these
units to allow survival with quality and reduced morbidity such as that
caused by oxygen dependency. Current evidence shows that pharmacological
therapies have no significant effect in oxygen dependence
treatment37.
The main limitation of this study was the effect of improvement in
perinatal care during the two periods of assessment, which generated the
baseline difference between the two groups. We controlled for this
effect of time by applying propensity score matching and multivariate
analysis, which allowed us to hypothesize possible associations on days
of supplementary oxygen.
In conclusion, we did not find evidence of an effect of oral
Theophylline on the reduction of days of oxygen dependency for LBWI
managed with ambulatory oxygen. On the contrary, there was a higher
frequency of tachycardia. For the current management of oxygen
dependency in the newborn, the importance of optimal nutrition,
including EBF that allows adequate weight gain with pulmonary tissue
repair, is a challenge.