Apnea of Prematurity Medication

Updated: Nov 06, 2016
  • Author: Dharmendra J Nimavat, MD, FAAP; Chief Editor: Ted Rosenkrantz, MD  more...
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Medication Summary


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. [119] 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. [120]

For the purpose of this review, pharmacotherapy is based on the 2006 NeoFax. [110] This is the source for information regarding the administration, adverse effects, and interactions of methylxanthines (eg, drug and solution compatibility).


Caffeine is the preferred drug for treating apnea of prematurity. [85] Caffeine is also the most acceptable prophylactic agent to facilitate successful extubation in preterm infants. [121] Caffeine therapy may reduce the rate of bronchopulmonary dysplasia in very low-birth-weight infants. [122]

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. [123] They also suggest starting caffeine early in the high-risk premature neonate, since caffeine has been associated with better long-term outcome. [124] 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. [125]

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. [126]

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. [127]


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. [128, 129] This latter effect may be desired in infants with bronchopulmonary dysplasia.

One concern is that aminophylline may decrease cerebral blood flow. [130, 131, 132, 133, 134]

Early reports in the literature also indicate a concern about the role that aminophylline may play in the occurrence or severity of necrotizing enterocolitis. [135, 136, 137]


Doxapram is excluded as a therapy for apnea of prematurity because it is associated with reduced cerebral blood flow. [138, 139] Use of doxapram was not strongly recommended in a Cochrane Review. [140] 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.



Class Summary

Aminophylline appears to stimulate skeletal and diaphragmatic muscle contraction, increase the sensitivity of the ventilatory center to CO2, and stimulate the central respiratory drive.

Aminophylline, theophylline, and caffeine act as nonspecific inhibitors of adenosine A1 and adenosine A2a receptors. [119] It is this last effect that raises concerns about the safety of methylxanthine therapy in preterm infants.

Aminophylline (Aminophyllin)

Indications include AOP (eg, apnea after extubation from assisted ventilation, apnea after general anesthesia, apnea during use of prostaglandin E1 to treat ductal-dependent heart defects).

Stimulates central respiratory drive and peripheral chemoreceptor activity; may increase diaphragmatic contractility.

Aminophylline salt is 78.9% theophylline; theophylline PO is 80% bioavailable. May need to adjust dose when changing from IV aminophylline to PO theophylline. In neonates, aminophylline significantly (30-80%) interconverted to caffeine.

IV and PO forms effective in about 80-85% of infants with central apnea.

Caffeine citrate (Cafcit)

Indications include AOP (eg, apnea after extubation from assisted ventilation, apnea after general anesthesia). Therapeutic index more favorable than that of aminophylline.

Increases output of respiratory center, sensitivity of chemoreceptor to CO2, smooth muscle relaxation, and cardiac output.

Serum half-life 40-230 h, which declines until 60-wk postmenstrual age.