Medication Summary

Methylxanthines
Methylxanthines may help reduce the incidence of events in a neonate with central apnea, though
apnea in 15-20% of infants does not respond to methylxanthines.
Questions have been raised regarding short- and long-term adverse effects in preterm infants.
[108]
The relationship of methylxanthine therapy to neurodevelopmental outcomes over time is
especially of concern. For this reason, a clinical trial related to the safety of caffeine in preterm
infants with apnea of prematurity (AOP) is in progress. [109]
For the purpose of this review, pharmacotherapy is based on the 2006 NeoFax.[105]This is the
source for information regarding the administration, adverse effects, and interactions of
methylxanthines (eg, drug and solution compatibility).

Caffeine
Caffeine is the preferred drug for treating apnea of prematurity.[81] Caffeine is also the most
acceptable prophylactic agent to facilitate successful extubation in preterm infants. [110] Caffeine
therapy may reduce the rate of bronchopulmonary dysplasia in very low-birth-weight infants. [111]
In addition, caffeine has a therapeutic margin wider than that of other methylxanthines, such as
theophylline. Therefore, an overdose is less likely to occur with caffeine than with other drugs in its
class.
Caffeine has been proposed as an adjunct treatment for successful extubation from the ventilator
during first week of life of a very low birth weight premature neonate and the authors support this
practice based on their own experience and evidence from the current literature. [112] They also
suggest starting caffeine early in the high-risk premature neonate, since caffeine has been
associated with better long-term outcome.[113] At this time they do not suggest starting caffeine
prophylaxis in a preterm neonate only based on prematurity, and current literature review also
supports this.[114]
The results from one study suggest that while neonatal caffeine therapy for apnea of prematurity
reduces the rates of cerebral palsy and cognitive delay at age 18 months, the improvement was no
longer realized at age 5 years.[115]
The benefits of caffeine therapy during the NICU stay are not controversial for many reasons,
although long-term benefits of caffeine have been questioned. Caffeine has been linked with
improved rates of survival without neurodevelopmental disability on 18- to 21-month follow-up.
However, recently published data suggest that this benefit is no longer associated with a
significantly improved rate of survival without disability in children who were of very low birth
weight and assessed at age 5 years. That being said, caffeine remains the preferred drug of
choice to treat the apnea of prematurity.[116]

Aminophylline
Aminophylline is the alternative methylxanthine. Aminophylline may be preferred when the
physician wants to enhance contractility in the thoracic musculature or if the infant might benefit
from the bronchodilator properties of aminophylline. [117, 118] This latter effect may be desired in infants
with bronchopulmonary dysplasia.
One concern is that aminophylline may decrease cerebral blood flow.[119, 120, 121, 122, 123]
Early reports in the literature also indicate a concern about the role that aminophylline may play in
the occurrence or severity of necrotizing enterocolitis. [124, 125, 126]

Doxapram
Doxapram is excluded as a therapy for apnea of prematurity because it is associated with reduced
cerebral blood flow.[127, 128] Use of doxapram was not strongly recommended in a Cochrane Review.
[129]
Doxapram should be reserved for infants in whom appropriate methylxanthine therapy and
continuous positive airway pressure (CPAP) fail to control severe apneic events. If the caregiver
wishes to use this agent, they should consult other resources regarding its administration.

Home Monitoring

Home monitoring after discharge is always necessary for infants whose apneic episodes continue
despite the administration of methylxanthine. Infants undergoing methylxanthine therapy should
rarely be sent home without a monitor because apnea may recur when they outgrow their
therapeutic level.
Some families cannot manage monitoring in the home. In these cases, caffeine may be the only
possible therapy.
For more information about follow-up care, see Follow-up.

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