Wongsiridej et al.
Serum Theophylline Concentrations in very Preterm
Neonates Receiving Intravenous Aminophylline for
Apnea
Pimol Wongsiridej, M.D.*, Sopapan Ngerncham, M.D.*, Siripa Usaha, M.D.*, Weerawadee Chandranipapongse,
M.D.**, Tim R. Cressey, M.D.***, ****, *****, Walaiporn Bowornkitiwong, M.D.*
*Department of Pediatrics, **Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Tailand,
***PHPT, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Tailand, ****Department of Molecular & Clinical
Pharmacology, University of Liverpool, UK, *****MIVEGEC, University. Montpellier, CNRS, IRD, Montpellier, France.
ABSTRACT
Objective: To determine the percentage of neonates who achieved therapeutic theophylline level (TTL) afer receiving
standard IV loading/maintenance aminophylline doses. To assess factors associated with achieving therapeutic
theophylline concentrations and to describe adverse effects of aminophylline.
Materials and Methods: Tis was a pilot, cross-sectional study. Preterm neonates ≤34 weeks’ gestation for which
aminophylline was indicated for treatment of apnea were enrolled. Standard IV aminophylline dosage is 8 mg/
kg loading dose, followed by 1.5 mg/kg maintenance dose every 8 hours. Serum theophylline concentrations were
measured prior to the 8th maintenance dose. Descriptive statistics, univariate and multivariate analyses were
performed.
Results: Twenty-five neonates (52% female) were enrolled: mean (standard deviation) gestational age and birth
weight were 30.4 (2) weeks and 1,277 (415) grams, respectively. Aminophylline was initiated at a median (25%tile,
75%tile) postnatal age of 4 (1, 8) days. Baseline heart rate prior to the loading dose was 153 (13) beats-per-minute.
Sixty percent of neonates achieved a therapeutic theophylline level. In the univariate analysis, being male and
postnatal age ≤5 days were associated with successfully achieving a TTL. Afer adjusting for gender, postnatal age
≤5 days was the only factor associated with achieving a TTL (adjusted odds ratio 17.7, 95% confidence interval: 1.9,
164.4). Tachycardia and feeding intolerance were observed in 44% and 24% of neonates, respectively.
Conclusion: Current IV aminophylline dosing conditions in Tailand achieved TTL in approximately two-thirds
of neonates, suggesting therapeutic drug monitoring is beneficial for guiding dosing. A higher maintenance dose
could be considered for neonates older than 5 days.
Keywords: Aminophylline; apnea of prematurity; therapeutic drug monitoring; serum theophylline concentration;
therapeutic drug level (Siriraj Med J 2021; 73: 526-531)
INTRODUCTION
Intermittent hypoxia secondary to AOP may activate
Apnea of prematurity (AOP) is one of the most
pro-inflammatory cytokines and cascades, disturb bone
common problems in very preterm neonates. Te incidence
metabolism, retinal development and cause cardiovascular
of AOP is inversely correlated with gestational age.1
instability.2 Prolonged apnea and delayed resolution
Corresponding author: Walaiporn Bowornkitiwong
E-mail: valaiporn.bow@mahidol.ac.th, walbj@hotmail.com
Received 7 May 2021 Revised 29 June 2021 Accepted 9 July 2021
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beyond 36 weeks of postmenstrual age is associated with
such as phenobarbital, phenytoin, erythromycin and
an increased risk of neurodevelopmental disturbances.3
propranolol; had received aminophylline within 7 days prior
Treatment for AOP, including respiratory support and
to enrollment; had acute renal insufficiency or abnormal
medications, should be considered when apneic episodes
liver function test result; had congenital anomalies with
become frequent and/or prolonged.4 Methylxanthine
CNS involvement; were referred back to local hospital;
therapy is considered the first-line treatment for AOP
were dead; had no inform consent obtained from their
while doxapram is the second-line treatment used for
parents.
refractory cases.4 Caffeine citrate is the preferred choice for
Aminophylline dosing used to treat AOP at Siriraj
methylxanthine due to its once-a-day dose, broad therapeutic
Hospital was an 8 mg/kg loading dose, followed by an
index and good safety profile.1 Unfortunately, widespread
initial maintenance dose of 1.5 mg/kg every 8 hours.
access to Caffeine citrate is not yet available in Tailand
Te aminophylline dose was prescribed by the attending
and aminophylline remains the main methylxanthine
physician as per standard of care. Prior to the 8th maintenance
available for treatment of AOP. Aminophylline is made
dose, one milliliter of blood was drawn for quantification
up of theophylline and ethylenediamine (approximately
of STC. Drug concentrations were determined using
80% theophylline).
the ARCHITECT ci4100 Integrated Immunoassay and
Theophylline-induced seizures have also been
Clinical Chemistry System (Abbott 2009 USA).
reported in neonates.5 Due to its narrow therapeutic index,
serum theophylline concentration (STC) measurement
Outcome measurement
is commonly performed to ensure that a therapeutic
Te primary outcome was the percentage of neonates
drug level (TDL) between 7-12 mcg/mL is administered
who achieved TDL. Meanwhile, secondary outcomes were
and to avoid any toxic reaction.6,7 As routine STC is
factors associated with success in achieving TDL and the
not available in many local hospitals in Tailand, we
adverse effects of aminophylline, including tachycardia,
performed this pilot study to evaluate the necessity of
feeding intolerance and abnormal neurological symptoms.
measuring STC when following standard aminophylline
Demographic data and clinical characteristics
IV dosing recommendations of 8 mg/kg per loading
of neonates were collected from medical records. All
dose, then 1.5-3 mg/kg/dose every 8-12 hours.8
neonates were monitored for adverse effects and toxicity
Te objectives of this study were as follows: (1)
of aminophylline by bedside nurses at NICU.
determine STC in neonates receiving standard aminophylline
IV dosing in Tailand; (2) assess factors associated with
Operational definitions
achieving TDL of theophylline; and (3) to describe adverse
Acute renal insufficiency was defined as oliguria
effects of aminophylline in neonates.
<1 ml/kg/h within 12 hours before enrollment or serum
creatinine ≥1.6 mg/dL, 1.1 mg/dL and 1 mg/dL in preterm
MATERIALS AND METHODS
neonates ≤27 weeks, 28-29 weeks and 30-32 weeks gestation,
Design
respectively.9 An abnormal liver function test was defined
A single center, observational, cross-sectional study.
as total bilirubin >2 mg/dL, Aspartate aminotransferase
(AST) >140 IU/L, or Alanine transaminase (ALT) >50
Setting
IU/L.10
Te study was conducted at the Division of Neonatology,
Adverse effects of aminophylline recorded were
Department of Pediatrics, Faculty of Medicine Siriraj
tachycardia, which is defined as a heart rate of >180
Hospital, Mahidol University between August 2015 and
beats-per-minute within 24 hours afer loading dose;
July 2016. Siriraj Hospital is a tertiary referral center with
feeding intolerance, defined as residual gastric content
approximately 8,000 deliveries per year. Neonates were
>50% of feeding volume at least once within 24 hours
recruited for the study while in the neonatal intensive
afer loading dose, and abnormal neurological symptoms,
care unit (NICU) or the intermediate care unit.
i.e., seizure and lethargy.
Participants and intervention
Statistical analysis
We enrolled preterm neonates less than or equal
Tis was a pilot study of 25 neonates. Te data was
to a 34 week gestation period who were prescribed IV
analyzed using PASW Statistics 18.0 (SPSS Inc., Chicago,
aminophylline for treatment of AOP. Neonates were
IL, USA). Descriptive statistics, including frequency and
excluded if they were receiving concomitant medications
percentage, mean and standard deviation (SD), or median
that could affect the pharmacokinetics of aminophylline
and 25%tile and 75%tile were used as appropriate for type
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Wongsiridej et al.
and distribution of data. A comparison of continuous data
who achieved TDL, there was a higher percentage of
was carried out using unpaired t-test or Mann-Whitney
males and had a lower postnatal age compared to those
U test depending on data distribution. Chi-square test or
neonates who did not achieve therapeutic STC (Table 2).
Fisher’s exact test was used for categorical variables and
Afer adjusting for gender, a postnatal age of ≤5 days was
those with a p-value <0.2 from univariate analysis were
significantly associated with achieving TDL (adjusted
chosen for multivariate analysis using binary logistic
odds ratio 17.7; 95% confidence interval 1.9, 164.4).
regression analysis. A p-value of <0.05 was accepted as
Tachycardia was reported in 11 (44%) neonates and
statistically significant.
spontaneously resolved over time without any treatment.
Feeding intolerance occurred in 6 (24%) neonates: and
Ethics
4 neonates were placed on NPO until the results of
Te study protocol was approved by the Siriraj
work up for cause of apnea came back normal, afer
Institutional Review Board of the Faculty of Medicine
which feeding was resumed; one neonate was treated
Siriraj Hospital, Mahidol University, Bangkok, Tailand
for suspected sepsis, and the remaining neonate had
(Si 317/2015). A written informed consent was obtained
continuation of feeding but with less milk. None of
from all parents.
the enrolled neonates had any abnormal neurological
symptoms.
RESULTS
Between August 2015 and July 2016, 99 neonates
DISCUSSION
born at less than or equal to 34 weeks’ gestation were
Following the current standard IV aminophylline
assessed for eligibility. A total of 25 neonates were enrolled
dosing conditions for AOP in Tailand, 60% of neonates
(Fig 1) and the baseline characteristics of neonates are
achieved TDL of theophylline. Factors associated with
summarized in Table 1.
achieving TDL were being male and a postnatal age of
Median (25%tile, 75%tile) loading dose of aminophylline
≤5 days. Afer adjusting for gender, postnatal age was
was 8 (8, 8.5) mg/kg and median (25%tile, 75%tile)
the only factor associated with achieving TDL. Adverse
maintenance dose was 1.5 (1.5, 1.5) mg/kg/dose every 8
effects associated with intravenous aminophylline were
hours. Mean STC was 6.9 ± 1.6 mcg/mL and the percentage
tachycardia and feeding intolerance in 44% and 24% of
of neonates who achieved TDL was 60%. None of the
neonates, respectively.
neonates had a STC >12 mcg/mL. Among the neonates
Fig 1. Diagram demonstrating the flow of participants.
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TABLE 1. Demographic and clinical characteristics of infants (N=25).
Characteristics
N = 25
Female, n (%)
13 (52)
Gestational age, week*
30.4 ± 2
Birth weight, gram*
1278 ± 415
Weight for gestational age, n (%)
Small for gestational age
6 (24)
Appropriate for gestational age
18 (72)
Large for gestational age
1 (4)
Apgar score†
1 minute
8 (4.25, 8.75)
5 minute
9 (7.25, 9)
Postnatal age, day†
4 (1, 8)
Heart rate before aminophylline loading, bpm*
152.8 ± 13.1
†median (25%tile, 75%tile)
*mean ± standard deviation
Abbreviation: bpm, beat-per-minute
TABLE 2. Factors associated with achieving therapeutic drug level of theophylline and adverse effects of aminophylline.
Achieving therapeutic drug level
p-value
Yes
No
(n=15)
(n=10)
Gestational age, week
30.8 ± 1.9
29.9 ± 2.2
0.30
Birth weight, gram
1354 ± 371.9
1161 ± 468.8
0.26
Gender, n (%)
0.04*
Female
5 (33.3)
8 (80)
Male
10 (66.7)
2 (20)
Small for gestational age, n (%)
0.65
Yes
3 (20)
3 (30)
No
12 (80)
7 (70)
Postnatal age, day†
2 (1, 4)
7.5 (5.5, 15)
0.005*
Postnatal age ≤ 5 days, n (%)
13 (86.7)
2 (20)
0.002*
Serum theophylline concentration†
7.5 (7.4, 8.1)
5.5 (5.0, 6.3)
<0.001*
Adverse effects
Tachycardia, n (%)
7 (46.7)
4 (40)
1.0
Feeding intolerance, n (%)
6 (40)
0
0.05
† median (25%tile, 75%tile)
*p-value <0.05 indicates statistical significance
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Wongsiridej et al.
Due to the narrow therapeutic range of theophylline,
of postnatal age had a wide confidence interval, likely
it is common practice to measure STC. Adjustments of
due to the relatively small sample size.
aminophylline dosage and repeated blood draws for STC
Pharmacodynamics in preterm neonates is also affected
is ofen necessary to obtain drug levels in the therapeutic
by developmental changes of the organs, resulting in
range. Tis iatrogenic blood loss can lead to excessive
differences in the expected efficacy or toxicity of theophylline.
blood transfusion in some cases. Several studies have
We observed tachycardia in 44% of participants, however,
assessed different aminophylline dosing regimens to
there was no association between TDL of theophylline
ensure TDL of theophylline and to reduce the need for
and the occurrence of tachycardia. Feeding intolerance
dosage adjustments and repeating STC. A study of infants
may be associated with STC since we observed this
with birth weight ≤1,500 g with postnatal age range of
adverse event only in neonates who achieved TDL of
1-52 days comparing the loading dose of 8 mg/kg versus
theophylline. However, feeding intolerance is common in
6 mg/kg of aminophylline, followed by the maintenance
premature infants, especially during the first week of age.
dose of 2 mg/kg every 8 hours, had a 79% and 74% success
None of the participants had any abnormal neurological
rate in achieving TDL respectively.6 Tese success rates
symptoms. Tough these adverse effects were not severe
were higher than the success rate observed in our study,
and resolved spontaneously, we recommended that adverse
possibly due to a higher maintenance dose. Another
effects should always be monitored and therapeutic drug
study, performed in infants with gestational age less than
monitoring is necessary to avoid aminophylline toxicity.
35 weeks, birth weight less than 2,000 g with postnatal
age range of 0.4-81.2 hours, compared low loading dose
Limitation of this study
(5 mg/kg) and high maintenance dose (6 mg/kg/day,
Due to concerns of excessive blood loss in these
divided into 3 times) vs high loading dose (8 mg/kg) and
preterm neonates, we only collected one time-point
low maintenance dose (4 mg/kg/day, divided twice) and
for the measurement of STC. Also, as this was a pilot
noted a TDL success rates of 86% and 68% respectively.11
study with a small sample size, the ability to make firm
Tis indicates that our starting maintenance dose of 1.5
conclusions is limited.
mg/kg every 8 hours may be suboptimal. None of the
participants in our study had a STC higher than 12 mcg/
CONCLUSION
mL, so we still have room within the therapeutic window
Te current standard intravenous aminophylline
to increase the maintenance dose of aminophylline.
dosing achieved TDL in 60% of neonates. A maintenance
Interestingly, this previous study limited the postnatal
dose higher than 1.5 mg/kg every 8 hours could be
age of participants to less than 7 days11 which related
considered, especially for neonates older than 5 days’
to our finding that a lower postnatal age (≤5 days) was
postnatal age. Terapeutic drug monitoring should be
associated with achieving TDL. Developmental changes
performed where possible to ensure therapeutic levels
in organs of premature neonates can have a major impact
and reduce the risk of theophylline toxicity.
on drug distribution, metabolism and elimination.
Tese developmental changes in pharmacokinetics have
ACKNOWLEDGEMENTS
been shown to be highly dependent on postnatal age,
Te authors gratefully acknowledge Professor Kulkanya
gestational age and postmenstrual age of the neonate.7
Chokephaibulkit, Director of the Siriraj Institute of Clinical
Te relationship between postnatal age and achieving
Research (SICRES), Faculty of Medicine Siriraj Hospital,
TDL in our study supports postnatal age as a major
Mahidol University for her invaluable comments. Te
factor. However, we did not find any association between
authors would like to acknowledge the Siriraj Poison
gestational age and achieving TDL. Bhatt, et al12 used
Control Center, Faculty of Medicine Siriraj Hospital,
different equations to predict maintenance theophylline
Mahidol University for performing serum theophylline
dosages for neonates younger than and older than 30
concentration. Te authors would like to thank Kanokwan
weeks’ gestation and the overall success rate of achieving
Sommai, Department of Pediatrics, Faculty of Medicine
TDL was 74% with requirements for dosage adjustments
Siriraj Hospital, Mahidol University for assistance with
reduced by 50%.12 We found that males had a higher
statistical analysis.
chance of achieving TDL of theophylline than females.
However, after adjusting for postnatal age ≤5 days,
Conflict of interest statement: All authors declare no
gender was not significantly associated with achieving
personal or professional conflicts of interest relating to
TDL. Te only factor associated with achieving TDL was
any aspect of this study.
a postnatal age ≤5 days. However, the adjusted odds ratio
Funding: Tis study was supported by a grant from Siriraj
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Original Article SMJ
Research Fund, Faculty of Medicine Siriraj Hospital, Mahidol
of aminophylline. J Perinatol 2002;22:275-8.
7.
Bhatt-Mehta V, Schumacher RE. Treatment of apnea of
University, Bangkok, Tailand (grant no. R015831071).
prematurity. Pediatr Drugs 2003;5:195-210.
8.
McClary JD. Terapeutic agents. In: Martin RJ, Fanaroff AA,
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