Introduction
According to the Kangaroo Foundation (KF) database, 11,953
oxygen-dependent (OD) low birth weight infants (LBWI) were followed in
the ambulatory Kangaroo Mother Care Program (KMCP) in Bogotá, Colombia
between 1998 and the first semester of 2021. It was observed that the
frequency of oxygen dependency decreased from 43% between 2003 and 2007
to 7% between 2018 and 2021. Patients <32 weeks gestational
age (GA) were between 41-62%. In addition, hospital stay was variable
according to the severity of perinatal compromise.
For the last 24 years, the KMCP has managed LBWI with ambulatory oxygen.
A first study conducted in 2004 in 12 hospitals of Bogotá, showed that
weight, GA at birth, mechanical ventilation, intrauterine growth
restriction, and type of institution (i.e., low vs. intermediate-high
mortality) were independently associated with bronchopulmonary dysplasia
(BPD) of increasing severity or even death1. Of this
cohort, 194 patients were followed up to 1-year corrected age (CA);
breastfeeding at term was successful in 76%, growth at one year was
appropriate, 74% of the cohort were still receiving home oxygen at 40
weeks and at 3 months 23%. Moreover, around 57 % of the cohort were
readmitted to hospital at least once, 47% of them because of
respiratory conditions2. A latter study was conducted
between 2017 and 2018 with 445 patients ≦33 weeks GA and OD at
admission. It was observed that 56% had a history of sepsis and 49%
had received invasive ventilation. Multivariate analysis also found that
oxygen dependency was associated with low hemoglobin levels at
admission, the number of blood transfusions received, and lower GA. On
the other hand, weight gain and exclusive breastfeeding until oxygen
weaning were identified as protective factors3.
Different therapeutic approaches have been described to prevent and
treat BPD, such as xanthines, diuretics, bronchodilators, vitamin A and
D, corticosteroids, and probiotics, without achieving clear
effectiveness4,5. For more than 40 years, xanthines
have been used to manage premature patients6. Within
this group Caffeine, Aminophylline, Doxapram, and Theophylline stand
out, with the first one being the most well-known. These medications
work by stimulating respiratory centers and promoting diaphragmatic
contractility, improving pulmonary distensibility, and reducing airway
resistance. These effects are of particular importance in apnea of
prematurity and in chronically ventilated newborns who may develop
muscular fatigue with skeletal and diaphragmatic muscular atrophy. By
improving muscle contractility, they contribute to chest wall
stabilization, increasing functional residual capacity and allowing
successful extubation; this last fact has been associated with less days
with oxygen7,8.
Theophylline is an orally administered xanthine used for the treatment
of respiratory diseases such as asthma and chronic obstructive pulmonary
disease9. It is extensively metabolized, and its main
metabolic product is caffeine due to N-methylation. Apnea of prematurity
and BPD treatment has been described as its principal
uses10. Theophylline (1,3-dimethylxanthine) therapy in
newborns has the inconvenience of greater toxicity due to its erratic
absorption and elimination, with a prolonged half-life of approximately
30 hours, nine times longer than in adults, due to the immaturity of the
cytochrome monooxygenase P450 enzymes11. Several
adverse effects associated with Theophylline use have been described,
such as cardiac arrhythmias, nausea, vomiting, headache, diarrhea,
irritability, and insomnia 12,13, without having a
specific antidote.
From 1996 until 2017 oral Theophylline was systematically implemented in
ambulatory KMCPs in Colombia as an adjuvant medication to reduce the
number of days of ambulatory oxygen14. In 2017, in
view of the available evidence of increased risk of toxicity with
Theophylline, routine treatment was discontinued, and recommendations
were modified in the new KMC technical guidelines of the Health
Ministry15.
This study aims to evaluate the effectiveness of oral Theophylline to
reduce the days of oxygen dependency and to assess the frequency of
adverse events related to this drug.
Materials and
Methods
Quasi-experiment before and after withdrawal of systematic Theophylline
given to LBWI with ambulatory oxygen in two KMCPs. We compared two
cohorts of LBWI OD at admission in the outpatient KMCPs of two teaching
hospitals in Bogotá, Colombia (Hospital Universitario San Ignacio and
Hospital Infantil San José).
The first cohort received oral Theophylline up to 40 weeks’ GA between
July 25, 2017 and May 31, 2018. The second cohort included OD LBWI
admitted to the KMCP without Theophylline treatment, between June 01,
2018 and April 20, 2019. Patients with a history of seizures, congenital
heart disease or cardiac arrhythmia were excluded.
We compared days of oxygen requirement, hospital readmissions, number of
KMCP consultations, feeding pattern, anthropometric measures, incidence
of tachycardia, gastroesophageal reflux (GER), colic, seizures and other
side effects that could be attributed to oral Theophylline treatment at
40 weeks GA and at oxygen weaning.
Sample size
It was calculated using the software STATA 14. The main outcome was days
of oxygen dependency during follow-up in the ambulatory KMCPs. According
to the KMCP database, OD patients received on average 70 days of oxygen
(SD 64 days). To obtain a 15 days reduction in oxygen requirement, an
alpha of 0.05 and a power of 80% with two-tailed estimation, and
follow-up losses of 20%, the sample size per group was 344 patients.
Intervention
- In the first cohort, LBWI OD infants at entry received oral
Theophylline (Teolixir®) 4 mg/kg/day dose up to 40 weeks, divided into
three doses and multivitamins. With the new evidence and Kangaroo
Guidelines update published at the end of 2017, Theophylline use was
suspended for the second cohort. There was a progressive transition
over a 4-month period.
- All infants received the same outpatient Kangaroo Protocol
interventions consisting of a close, multidisciplinary follow-up until
oxygen weaning as mentioned below:
- Kangaroo position (KP): newborn in skin-to-skin contact, 24 hours a
day, placed in a firm upright position, between mother’s breasts,
and under mother’s clothes. Mothers not only regulate infants’ body
temperature, but also are the main sources of nourishment and
stimulation. An elastic support is used, allowing the KP provider to
relax and sleep while the infant remains permanently in KP. The
elastic support also helps to prevent the infant’s airway from being
obstructed by position changes, particularly important due to the
hypotonia usually present in premature infants, which can lead to
postural obstructive apneas.
- The baby can be fed at any time, without leaving the KP. Another
person (e.g., the father) can replace KP with the mother. The
caregiver should sleep in a semi-reclined posture to avoid
gastroesophageal reflux.
- The KP is maintained until the infant shows clear signs of
intolerance or discomfort (e.g., sweating, scratching,
screaming)16.
- Exclusive breastfeeding (EBF) is introduced whenever possible and is
initially given on a very strict schedule (i.e., every 2 hours). The
weight gain is aimed to be at least the same as that of intrauterine
development (15-20 g/kg/day). If this goal is not achieved with
exclusive breastfeeding after an intensive intervention called the
ambulatory kangaroo adaptation, and after ruling out other medical
conditions (e.g., anemia, infection, hypothermia, etc.),
supplementation with LBWI formula is administered with a dropper or
spoon to avoid interference with lactation. The supplement is
calculated based on 30% of the recommended daily caloric intake.
After at least one week of adequate growth, a progressive decrease
in supplementation is attempted, to reach 40 weeks GA with exclusive
breastfeeding.
- After discharge, patients were controlled daily, until they reached
daily weight gain of 15-20 g/kg/day. Afterwards, weekly controls were
performed, until term (40 weeks GA). This is an equivalent of minimal
in-hospital care and could be called ”minimal ambulatory neonatal
care”.
- Dynamic oximetry with a pulse oximeter was performed upon patients’
admission. The target was to achieve oxygen saturation between 90-94%
with adequate heart rate frequency while resting, sucking, and
sleeping with adequate growth. Dynamic oximetry was performed weekly
until oxygen weaning according to KMC protocol3.
- At admission, parents were fully educated about oxygen management at
home and provided with an instructional flier.
- Follow-up program includes ophthalmologic screening and early
detection of neurological conditions, with an ultrasound brain
sonography.
- Anthropometric measures were carefully collected and evaluated with
the Fenton-2013 charts17.
Statistical
Analysis
For the analysis Stata 14 was used. Quantitative data was reported as
medians with their interquartile range given their non-normal
distribution. Qualitative data was reported as absolute and relative
frequencies. Bivariate analysis of quantitative data was done with the
Mann Whitney nonparametric test and for qualitative data we used
Chi-square or Fisher’s exact test.
Propensity Score Matching was done for unbalanced baseline variables
between the groups. Then, multivariate analysis was performed with
multiple linear regression having as dependent variable days of oxygen
dependence, and as independent variables those that according to the
evidence, are associated with oxygen dependence.