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ABSTRACT

ABSTRACT

BACKGROUND AND OBJECTIVES

The optimum caffeine dose in preterm infants has not been well investigated.
We aimed to compare the efficacy and safety of high versus low-dose caffeine
citrate on apnea of prematurity (AOP) and successful extubation of preterm
infants from mechanical ventilation.

We compared high-dose (loading 40 mg/kg/day and maintenance of 20


mg/kg/day) versus low-dose (loading 20 mg/kg/day and maintenance of 10
mg/kg/day) caffeine citrate in preterm infants <32 weeks gestation, presented
with AOP within the first 10 days of life.
ABSTRACT

METHODS

This was a randomized, pilot, double-blinded, prospective study, comparing two


different dose regimens of caffeine citrate in preterm infants.
We recruited infants with a gestational age <32 weeks, who exhibited apnea of
prematurity within the first 10 days of life. Exclusion criteria were major
congenital malformations and chromosomal anomalies.
ABSTRACT

RESULTS

A total of 120 neonates (60 in each group) were enrolled.


High-dose caffeine was associated with a significant reduction in extubation
failure in mechanically ventilated preterm infants (p<0.05), the frequency of
apnea (p<0.001), and days of documented apnea (p<0.001). High-dose caffeine
was associated with significant increase in episodes of tachycardia (p<0.05)
without a significant impact on physician decision to withhold caffeine.
ABSTRACT

CONCLUSIONS

The use of higher, than current standard, dose of caffeine may decrease the
chance of extubation failure in mechanically ventilated preterm infants and
frequency of AOP without significant side effects.
INTRODUCTION
INTRODUCTION

Apnea of prematurity (AOP) is a developmental disorder that occurs as a result of


immature respiratory control mechanisms and hence exhibited a widely variable
incidence depending on gestational age and birth weight

Apneic pauses might be associated with intermittent hypoxemia, hence


may be related to greater incidence of deleterious neurodevelopmental
outcomes and retinopathy of prematurity (ROP)

AOP and poor respiratory drive may be associated with prolongation of duration
of mechanical ventilation and decrease chances for successful extubation of
preterm infants with respiratory distress

In a Cochrane review of 5 trials that included 108 preterm infants, caffeine was
as effective as theophylline in reducing apnea and extubation failure during the
first week of life with lower adverse effects such as tachycardia and feeding
intolerance
Caffeine is now used as a standard treatment for AOP due to its higher
therapeutic index, better enteral absorption, and longer half-life than other
methylxanthines.

Caffeine has been used as well to shorten the duration of


mechanical ventilation and to facilitate extubation of preterm
infants

Despite the establishment of caffeine therapy in preterm infants, variable


information exist on the optimal loading and maintenance dose in different
neonatal departments aiming to balance benefits and risks.

We hypothesized that a high-dose regimen of caffeine, as an initial therapy for


AOP, might gain more efficacy than the standard-dose regimen in facilitating
successful extubation of preterm infants from mechanical ventilation without
increasing occurrence of adverse effects.
METHODS &
RESULTS
METHODS

METHODS

The study was conducted at the Neonatal Intensive Care


Unit (NICU) of Mansoura University Children’s Hospital,
Mansoura, Egypt between July 2011 and July 2012.
PATIENTS AND STUDY DESIGN

Infants with a gestational age <32 weeks, who exhibited


apnea of prematurity within the first 10 days of life.
Exclusion criteria were major congenital malformations and
chromosomal anomalies.
RANDOMIZATION

Enrolled infants were assigned randomly to treatment


groups using internet-based random table technique with
cards in opaque sealed envelopes.

A designated pharmacist was responsible for the


randomization of selected infants and the preparation of
caffeine dose; the investigators, nursing staff, and family
were blinded to patient’s group.
STUDY PROCEDURES

(A) received a low-dose regimen of intravenous caffeine


citrate (loading dose of 20 mg/kg/day equivalent to 10 mg
/kg/day of caffeine base and maintenance dose of 10
mg/kg/day equivalent to 5 mg /kg/day of caffeine base)

(B) received a high-dose regimen


caffeine (loading dose of 40 mg/kg/day equivalent to 20 mg
/kg/day of caffeine base and maintenance dose of 20
mg/kg/day equivalent to 10 mg /kg/day of caffeine base),
respectively.
STUDY PROCEDURES

Caffeine was administered by intravenous infusion over 30


min combined with equivalent volume of normal saline.
STUDY PROCEDURES

Infant’s oxygen saturation, heart rate, and respiratory rate were


continuously monitored, preductal, using Drager monitors (Infinity®
Delta, Drager, Lübeck, Germany), with the targeted oxygen saturation
maintained between 91 and
95 %.

Blood pressure was checked twice daily, indirectly by oscillometry


(Infinity® Delta, Drager, Lübeck, Germany), and the reading was
considered high if blood pressure was more than 95th percentile.

Apnea was defined as the cessation of breathing for more than 20 s or


cessation of breathing for less than 20 s accompanied by bradycardia
(less than 100 beats perminute) or oxygen desaturation (less than 90
%)
STATISTICAL ANALYSIS

Statistical analysis was performed using SPSS statistical software


(version 16; SPSS, Chicago, Illinois).
Student t test was used to compare continuous parametric variables;
Mann–Whitney U test was used for continuous nonparametric
variables; and Chi-square test or Fisher exact test were used for
categorical variables when appropriate. Kolmogorov–Smirnov test was
done to examine the distribution of data. A p value of <0.05 is
considered to be statistically significant.
Kaplan–Meier was used to study time to event analysis between
studied groups.
RESULTS
RESULTS
RESULTS
ADVERSE EFFECTS

More patients in high-dose caffeine group (23 %) experienced


tachycardia compared to the low-dose group (23 vs
8 %, p<0.05). There was no significant difference in the
incidence of hypertension or time to reach full enteral
feeding. Caffeine therapy was withheld, owing
to a physician concern of a significant side effects, in 6
infants in the high-dose group and 2 infants in the lowdose
group (p=0.27).