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\begin{document}

\title{Theophylline impact on weaning in oxygen-dependent infant followed in an
outpatient Kangaroo Program}



\author[1]{Adriana Montealegre}%
\author[2]{Nathalie Charpak}%
\author[3]{Catalina Lince}%
\affil[1]{Pontificia Universidad Javeriana}%
\affil[2]{Fundacion Canguro}%
\affil[3]{Hospital Universitario San Ignacio}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
\emph{Background:} Theophylline was an orally administered xanthine used
for the treatment of apnea of prematurity and Bronchopulmonary Dysplasia
in the ambulatory follow-up of Low-Birth-Weight infants (LBWI) with
oxygen-dependency in the Kangaroo Mother Care Program (KMCP).
Theophylline's main metabolic product is caffeine; therefore, it was an
alternative due to the frequent lack of ambulatory oral caffeine in low
and middle-income countries. \emph{Purpose:} to assess the effectiveness
of oral Theophylline in decreasing days with oxygen and to describe
frequency of adverse related events. \emph{Method:} quasi-experiment
before and after withdrawal of Theophylline given systematically to LBWI
with ambulatory oxygen in two KMCPs. \emph{Results:} 729 patients were
recruited; 319 with Theophylline and 410 after Theophylline withdrawn.
The Theophylline cohort had less gestational age, less weight at birth,
more days in Neonatal Intensive Care Unit, more days of
oxygen-dependency at KMCP admission, and more frequencies of
Intrauterine Growth Restriction and apneas. After adjusting with
propensity score matching, multiple linear regression was done, and
analysis showed that nutrition had a greater effect on days of
oxygen-dependency than the fact of receiving Theophylline. No
differences were found in readmissions up to 40 weeks, nor in the
frequency of intraventricular hemorrhage or neurodevelopmental problems.
The Theophylline group had more tachycardia episodes.
\emph{Conclusions:} we did not find evidence of oral Theophylline effect
on the reduction of days of oxygen-dependency. For the current
management of oxygen- dependency in newborns, the importance of KMCPs
nutritional protocols based on exclusive breast feeding whenever
possible, is the challenge for these fragile infants.%
\end{abstract}%



\sloppy


\textbf{Theophylline impact on weaning in oxygen-dependent infant
followed in an outpatient Kangaroo Program}

\textbf{Short title:} Theophylline impact in oxygen-dependent infant

Adriana Montealegre-Pomar, MD, MSc PhD(c)\textsuperscript{a, b, c},
Nathalie Charpak, MD*\textsuperscript{a}, Catalina Lince,
MD\textsuperscript{a,c}

\textbf{Institutional Affiliations:} \textsuperscript{a}Kangaroo
Foundation, \textsuperscript{b}Pontificia Universidad
Javeriana,\textsuperscript{c}Hospital Universitario San Ignacio.

Bogot\selectlanguage{ngerman}á, Colombia

*Contributed equally as co-first author.

ORCID Dr. Montealegre: 0000-0001-5464-2701.

ORCID Dr. Charpak: 0000-0001-6697-5837.

ORCID Dr. Lince: 0000-0002-4293-6822.

\textbf{Address correspondence to:} Adriana Montealegre-Pomar, Hospital
Universitario San Ignacio, Carrera 7 No 40-62, Bogota, Colombia. Tel:
+57 1 594-6161 Ext 2491. Cell Phone: +57 315-670-1641

e-mail: montealegre.a@javeriana.edu.co

\textbf{Word count of the manuscript body:} 3023 words.

\textbf{Acknowledgments}

\selectlanguage{english}The authors thank Drs Andrea Conde, Johana Forero, and Claudia Giraldo,
Pediatric residents at the Javeriana University, for their collaboration
in data collection and Dr. Mar\selectlanguage{ngerman}ía Calume, who collaborated in
coordinating the study, and to the nurses from the KMCP who helped in
the study development.

\textbf{Declarations}

\textbf{Funding Statement:} This project was supported by the Kangaroo
Foundation and the Integral Kangaroo Mother Care Program in Bogotá,
Colombia.

\textbf{Financial Disclosure} : The authors have no financial
relationships relevant to this article to disclose.

\textbf{Conflict of Interest:} The authors have no conflicts of interest
relevant to this article to disclose.

\textbf{Availability of data and material:} on request from the authors.

\textbf{Code availability:} Not applicable.

\textbf{Authors' Contributions:}

\begin{itemize}
\tightlist
\item
  Dr. Montealegre was responsible for generating research protocol,
  processing of the database, overseeing all data collection, analysis,
  writing and revising the manuscript.
\item
  Dr Charpak was responsible for processing of the database, analysis,
  writing and revising the manuscript.
\item
  Dr Lince was responsible for writing and revising the manuscript.
\end{itemize}

The three authors approved the final manuscript as submitted and agree
to be accountable for all aspects of the work.

\textbf{Ethics approval:} this study was conducted in agreement with the
principles established in the Declaration of Helsinki and with the
standards of Good Clinical Practice of the country. The ethics and
research committee of the Kangaroo Foundation approved the protocol.

\textbf{Consent for publication:} The authors certify the accuracy of
content given to the journal, in particular, the names of coauthors
present and correctly spelt, and that addresses, and affiliations are up
to date. The corresponding author ensures that the co-author have agreed
to all of the contents and will notify to the co-author when the
manuscript is accepted. The corresponding author is answerable to all
the inquiries on behalf of the co-author. The corresponding author
ensures that both authors have seen and approved the final version of
the paper and are aware of the submission of the paper. The
corresponding author is solely responsible for maintaining a proper
communication with the journal and with co-author, before and after
publication.

\section*{Abstract (249/250)}

{\label{abstract-249250}}

\emph{Background:} Theophylline was an orally administered xanthine used
for the treatment of apnea of prematurity and Bronchopulmonary Dysplasia
in the ambulatory follow-up of Low-Birth-Weight infants (LBWI) with
oxygen-dependency in the Kangaroo Mother Care Program (KMCP).
Theophylline's main metabolic product is caffeine; therefore, it was an
alternative due to the frequent lack of ambulatory oral caffeine in low
and middle-income countries. \emph{Purpose:} to assess the effectiveness
of oral Theophylline in decreasing days with oxygen and to describe
frequency of adverse related events. \emph{Method:} quasi-experiment
before and after withdrawal of Theophylline given systematically to LBWI
with ambulatory oxygen in two KMCPs. \emph{Results:} 729 patients were
recruited; 319 with Theophylline and 410 after Theophylline withdrawn.
The Theophylline cohort had less gestational age, less weight at birth,
more days in Neonatal Intensive Care Unit, more days of
oxygen-dependency at KMCP admission, and more frequencies of
Intrauterine Growth Restriction and apneas. After adjusting with
propensity score matching, multiple linear regression was done, and
analysis showed that nutrition had a greater effect on days of
oxygen-dependency than the fact of receiving Theophylline. No
differences were found in readmissions up to 40 weeks, nor in the
frequency of intraventricular hemorrhage or neurodevelopmental problems.
The Theophylline group had more tachycardia episodes.\emph{Conclusions:}
we did not find evidence of oral Theophylline effect on the reduction of
days of oxygen-dependency. For the current management of oxygen-
dependency in newborns, the importance of KMCPs nutritional protocols
based on exclusive breast feeding whenever possible, is the challenge
for these fragile infants.

\emph{Keywords:} Theophylline; Infant, Low Birth Weight; Kangaroo-Mother
Care Method; Therapy, Oxygen Inhalation.

\emph{What is known:}

Theophylline was an alternative for the ambulatory management of oxygen
dependent preterm infants in face of the lack of availability of oral
caffeine.

\emph{What is new:}

\begin{itemize}
\tightlist
\item
  In this quasi-experiment before and after withdrawal of Theophylline
  given systematically to all LBW infants with ambulatory oxygen, there
  was no evidence of Theophylline effect on decreasing days of oxygen
  dependence.
\item
  Infants in Theophylline group had more tachycardia episodes.
\item
  In the multivariate analysis, daily weight gain and exclusive breast
  feeding had important effect on reducing days of oxygen dependency.
\end{itemize}

\textbf{List of abbreviations in alphabetical order}

\textbf{BPD:} Bronchopulmonary Dysplasia

\textbf{CA:} Corrected Age

\textbf{EBF:} Exclusive Breast Feeding

\textbf{GA:} Gestational Age

\textbf{IQR:} Interquartile range

\textbf{IUGR:} Intrauterine Growth Restriction

\textbf{IVH:} Intraventricular Hemorrhage

\textbf{KF:} Kangaroo Foundation

\textbf{KMCP:} Kangaroo Mother Care Program

\textbf{LBWI:} Low Birth Weight Infants

\textbf{OD:} Oxygen-Dependent

\textbf{ROP:} Retinopathy of Prematurity

\textbf{SD:} Standard Deviation



\textbf{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 \textless{}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
\selectlanguage{english}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 death\textsuperscript{1}. Of this
cohort, 194 patients were followed up to 1-year corrected age (CA);
\selectlanguage{english}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 conditions\textsuperscript{2}. 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 factors\textsuperscript{3}.

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
effectiveness\textsuperscript{4,5}. For more than 40 years, xanthines
have been used to manage premature patients\textsuperscript{6}. 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 oxygen\textsuperscript{7,8}.

Theophylline is an orally administered xanthine used for the treatment
of respiratory diseases such as asthma and chronic obstructive pulmonary
disease\textsuperscript{9}. 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
uses\textsuperscript{10}. 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 enzymes\textsuperscript{11}. Several
adverse effects associated with Theophylline use have been described,
such as cardiac arrhythmias, nausea, vomiting, headache, diarrhea,
irritability, and insomnia \textsuperscript{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 oxygen\textsuperscript{14}. 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
Ministry\textsuperscript{15}.

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.

\textbf{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 Bogot\selectlanguage{ngerman}á, 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.

\subsection*{\texorpdfstring{\emph{Sample
size}}{Sample size}}

{\label{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.

\subsection*{\texorpdfstring{\emph{Intervention}}{Intervention}}

{\label{intervention}}

\begin{itemize}
\tightlist
\item
  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.
\item
  All infants received the same outpatient Kangaroo Protocol
  interventions consisting of a close, multidisciplinary follow-up until
  oxygen weaning as mentioned below:
\item
  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.
\item
  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.
\item
  The KP is maintained until the infant shows clear signs of intolerance
  or discomfort (e.g., sweating, scratching,
  screaming)\textsuperscript{16}.
\item
  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.
\end{itemize}

\begin{itemize}
\tightlist
\item
  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''.
\item
  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 protocol\textsuperscript{3}.
\item
  At admission, parents were fully educated about oxygen management at
  home and provided with an instructional flier.
\item
  Follow-up program includes ophthalmologic screening and early
  detection of neurological conditions, with an ultrasound brain
  sonography.
\item
  Anthropometric measures were carefully collected and evaluated with
  the Fenton-2013 charts\textsuperscript{17}.
\end{itemize}

\subsection*{\texorpdfstring{\emph{Statistical
Analysis}}{Statistical Analysis}}

{\label{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.

\section*{Results}

{\label{results}}

A total of 729 patients were recruited: 319 in the Theophylline group
and 410 in the non-Theophylline group.

Tables 1 and 2 summarize the two groups' baseline characteristics. No
differences were found in sociodemographic variables, but significant
clinical differences were identified, being infants in Theophylline
group more fragile (less GA at birth and at KMCP entry, less weight at
birth and at entry, more hospital stay, and less non-invasive
ventilation).

Table 3 describes the follow-up results. The Theophylline group had more
BPD defined as OD \textgreater{}28 days and GA \selectlanguage{english}[?] 36 weeks, but when BPD
was defined as OD \textgreater{}28 days and GA \selectlanguage{english}[?]40 weeks, there was no
difference between groups\textsuperscript{18}. Infants who received
Theophylline had a higher frequency of apneas during the hospital stay
and ambulatory follow-up. Additionally, chronological age at oxygen
weaning and weight at 40 weeks were higher than in the non-Theophylline
group. Although the feeding pattern at oxygen weaning was similar
between the two groups, the non-Theophylline group had a higher
proportion of exclusive breast milk (EBM) at 40 weeks (46 vs 36\%).

No differences were found in the number of readmissions up to 40 weeks.
Neither in the frequency of intraventricular hemorrhage (IVH),
retinopathy of prematurity (ROP) or neurodevelopmental problems.

Regarding the possible side effects associated with Theophylline
treatment, we found no differences in GER or gastrointestinal disorders.
However, more tachycardia episodes were recorded in the Theophylline
group (1.3\% vs 0).

Finally, patients in the Theophylline group had a higher percentage of
losses (3.5\% vs 1\%), although in general, these were minor for the two
cohorts.

In order to adjust for baseline differences between groups (GA, birth
weight, GA at study recruitment, frequencies of IUGR and apnea, days in
NICU and days with oxygen at study recruitment), we performed propensity
score matching. Then, multiple linear regression with total days of
oxygen dependency as the outcome variable and having received
Theophylline as the exposure variable. The control variables were
frequency of EBF at O2 weaning, days of mechanical ventilation, weight
at study recruitment, weight gain between study recruitment and oxygen
weaning and weight reached at oxygen weaning. Probable interactions were
entered, and model diagnostics were performed (after individual
evaluation, 6 outliers were excluded).

Tables 4 and 5 show the propensity score matching and multiple linear
regression analysis. After adjusting for baseline differences between
groups with propensity score matching, it was found that controlling for
days of mechanical ventilation, weight at study recruitment and weight
gain to reach the oxygen weaning weight (Figure 1), EBF could reduce
oxygen dependency in 9 days; on the other hand, for each day with
mechanical ventilation, oxygen dependency increases in 2 days. No effect
of Theophylline administration was found between the two groups (682
observations, R2 0.63, 95\% CI (-1.01, 4.66) p=0.21).

\section*{Discussion}

{\label{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 Northway\textsuperscript{19} or with
the study conducted by Kangaroo Foundation in 2004 in
Bogota\textsuperscript{1}. 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 \textsuperscript{20}. Currently,
most units define BPD as OD \textgreater{}28 days and/or \selectlanguage{english}[?] 36 weeks GA
or even OD/ respiratory support \selectlanguage{english}[?]40 weeks, according to GA at
birth\textsuperscript{21--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
disease\textsuperscript{9}. 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 caffeine\textsuperscript{10}, 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 population\textsuperscript{14}.

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
ulcers\textsuperscript{25}. In humans, Theophylline overdose has been
associated with probable status epilepticus induction and a potential
mortality of 10\%\textsuperscript{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 \textsuperscript{5}. Early
initiation of caffeine (\textless{}2 days of life) showed a reduction in
mortality and BPD incidence\textsuperscript{26}. 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 \textsuperscript{27}. Other caffeine benefits are the once-daily
administration and wide therapeutic range with reduced need for serum
level monitoring\textsuperscript{28}. 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 effects\textsuperscript{6}. 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 \textsuperscript{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 volumes\textsuperscript{30}. 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
entity\textsuperscript{31}. 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
breastfeeding\textsuperscript{32,33}, 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
episodes\textsuperscript{12,34}.

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 BPD\textsuperscript{31,35,36}. In
fact, we found a similar association between weight at weaning and days
of oxygen dependence in another recent analysis published in
2021\textsuperscript{3}. 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
treatment\textsuperscript{37}.

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.

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\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Graph-1-Theophylline/Graph-1-Theophylline}

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\verb`Table 1.  Theophylline.docx`  available at \url{https://authorea.com/users/376937/articles/641485-theophylline-impact-on-weaning-in-oxygen-dependent-infant-followed-in-an-outpatient-kangaroo-program}

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\verb`Table 2. Theophylline.docx`  available at \url{https://authorea.com/users/376937/articles/641485-theophylline-impact-on-weaning-in-oxygen-dependent-infant-followed-in-an-outpatient-kangaroo-program}

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\verb`Table 3. Theophylline.docx`  available at \url{https://authorea.com/users/376937/articles/641485-theophylline-impact-on-weaning-in-oxygen-dependent-infant-followed-in-an-outpatient-kangaroo-program}

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\verb`Table 4. Theophylline.docx`  available at \url{https://authorea.com/users/376937/articles/641485-theophylline-impact-on-weaning-in-oxygen-dependent-infant-followed-in-an-outpatient-kangaroo-program}

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\verb`Table 5. Theophylline.docx`  available at \url{https://authorea.com/users/376937/articles/641485-theophylline-impact-on-weaning-in-oxygen-dependent-infant-followed-in-an-outpatient-kangaroo-program}

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