Apnea of Prematurity Pharmacotherapy

Apnea of prematurity (AOP) commonly occurs in infants of less than 37 weeks’ gestation and is characterized by brief episodes of breathing cessation lasting 20 seconds or less with associated bradycardia or cyanosis. It is a diagnosis of exclusion that can only be confirmed once alternate causes of apnea (e.g., sepsis, metabolic disorders, central nervous system [CNS] pathology) have been excluded.¹ The apnea can be classified as being of central origin, obstructive, or mixed type. Periodic breathing represents a normal occurrence of breathing during sleep and is often confused with apnea. (The different types of apnea and periodic breathing are categorized in TABLE 1.) Central apnea refers to the failure of the central CNS to initiate respiratory effort secondary to immaturity of the neurologic pathways. Obstructive apnea, most commonly due to collapse of the pharyngeal airway, results in mechanical interference with respiratory efforts and often leads to bradycardia.² Mixed-type apnea is a combination of both central and obstructive apneas.³ Studies have shown that the majority of apnea events (~50%) in preterm infants are of mixed origin, 40% are of central origin, and 10% are purely obstructive in origin.⁴

Pathophysiology

Several theories exist regarding the pathogenesis of AOP, none of which have been confirmed as being the single cause to date. One theory describes the role of adenosine as a central respiratory inhibitor.^5,6 Adenosine is a nucleoside component of compounds such as adenosine triphosphate (ATP) and cyclic adenosine monophosphate (cAMP), which are crucial to numerous biochemical processes. As a therapeutic agent, adeno-sine is well known for its use and efficacy in the treatment of supraventricular tachycardia.⁷ 

Adenosine also plays a role in cellular signaling via its four main receptor subtypes: A₁, A_2a, A_2b, and A₃. Certain receptor subtypes, specifically A₁ and A_2a, are believed to be directly involved in the control of respiratory drive. One study postulates that activation of pre- and postsynaptic A₁ receptors decreases neuronal activity of the respiratory motor outflow tract, thus impeding respiration itself.⁶ In addition to the role of adenosine, comorbidities like gastroesophageal reflux may further increase the number of apnea episodes in preterm infants.⁸ 

The onset of AOP typically occurs near the end of the first week of life, but may begin as early as the first day of life.⁹ With the occurrence of apnea episodes being inversely related to the gestational age of the infant, a similar association has also been found in its resolution.¹⁰ Resolution of AOP typically occurs by the time “term” gestational age is reached postconception (38-42 weeks’ gestation). Infants having a protracted course of AOP lasting longer than the age of term gestation are often very premature (24-28 weeks’ gestation) and/or have known neurologic dysfunction.^11,12 

Complications

Consequences of untreated or inadequately treated AOP are extensive and include spastic diplegia or quadriplegia, bilateral retrolental fibroplasia resulting in significant visual impairment, sensorineural deafness, varying degrees of mental retardation, and even death.¹³ It is interesting to note, however, that AOP does not seem to be a future determinant of sudden infant death syndrome (SIDS).^9,14 

Goals of Therapy

The clinical management of AOP has not changed in the past three decades and includes both supportive measures and oftentimes pharmacologic therapy. Supportive treatment measures include tactile stimulation, proper positioning to maintain an open airway, and ventilatory support such as supplemental oxygen, continuous positive airway pressure (CPAP), and mechanical ventilatory support. The treatment goals in the management of AOP include preventing apnea episodes, preventing bradycardia and desaturation, improving diaphragmatic activity, and maintaining respiratory ventilation. 

Pharmacologic Management Options

Pharmacologic measures include the use of methylxanthines, particularly theophylline and aminophylline or caffeine citrate, and other respiratory stimulants such as doxapram.¹⁵ The consensus on when to begin pharmacotherapy is not well established. However, if apnea episodes persist despite supportive or nonpharmacologic measures, then drug therapy may be considered. 

Methylxanthines

Since the early 1970s, methylxanthines have been administered as respiratory stimulants in the treatment of AOP and are considered to be the primary treatment option. Chemically, methylxanthines contain a xanthine molecule, which is found in caffeine (1,3,7-trimethylxanthine) and theophylline (1,3-dimethylxanthine) (FIGURE 1). Caffeine is metabolized by the CYP450 isoenzyme 1A2. The chemical structure is demethylated to produce the dimethylxanthines, including theophylline, theobromine, and paraxanthine. Despite their similar chemical structures, these agents possess different kinetic properties.

Although methylxanthines primarily work by stimulating the respiratory drive in the CNS, several other mechanisms have been postulated. Since adenosine is known as a central respiratory depressant, methylxanthines also act by inhibiting phosphodiesterase enzymes. This inhibitory mechanism causes the breakdown of cAMP and cyclic guanosine monophosphate (cGMP), thus increasing its availability in the blood to relax the airway. These agents also work by competitively antagonizing the adenosine receptor or increasing catecholamine release by modulating the flux of calcium.^16,17 Other effects include improving ventilation and neural impulses, reducing rapid eye movement (REM) sleep, improving oxygenation, and improving skeletal muscle contraction to prevent diaphragmatic fatigue.¹⁸ 

Pharmacokinetics: In regard to absorption, aminophylline, the ethylenediamine tetraacetic acid salt, is composed of 80% theophylline. During drug metabolism, theophylline undergoes methylation and may produce caffeine plasma levels of up to 50% of theophylline concentrations in preterm neonates.¹⁹ Linear first-order pharmacokinetics occurs when theophylline is within the normal therapeutic range (6-14 mcg/mL) for the treatment of AOP. Therapeutic levels above normal may produce nonlinear zero-order pharmacokinetics with adverse effects. Clearance is slower in preterm as compared to full-term infants, with half-life approximately 30 hours versus 25 hours.²⁰ On the other hand, caffeine undergoes demethylation to produce theophylline and follows linear first-order pharmacokinetics. Unlike theophylline, caffeine’s half-life is more prolonged (72-96 hours), allowing for once-daily administration.²¹ 

Therapeutic Drug Monitoring: The therapeutic range for the treatment of AOP with theophylline is 6 to 14 mcg/mL, while caffeine has a wider therapeutic range of 8 to 20 mcg/mL. Steady state is achieved much earlier with theophylline compared to caffeine (1-3 days vs. 9-12 days) in full-term infants. Theophylline requires close monitoring and more frequent assessment of drug levels due to its narrow therapeutic window, shorter half-life, and adverse-effect profile. However, caffeine levels are more predictable and require less frequent plasma concentration measurements. Natarajan et al found that approximately 95% of preterm neonates receiving caffeine achieved normal therapeutic levels at standard doses.²² As a result, monitoring caffeine levels is not necessary unless the patient exhibits ongoing apnea episodes or signs of drug toxicity. 

Adverse Effects: Although both agents have similar adverse effects, caffeine exhibits less toxicity than theophylline.²³ Common side effects seen with both agents include diuresis and gastrointestinal (GI) effects including reflux, diarrhea, vomiting, and abdominal pain. Levels above the therapeutic range for theophylline are associated with tachycardia and occasional premature ventricular contractions (PVCs). Theophylline levels >35 mcg/mL may result in ventricular tachycardia and frequent PVCs due to the chronotropic and inotropic effects of theophylline. Seizure activity secondary to increased cerebrovascular resistance has been observed to result in a decrease in cerebral blood flow. Similar adverse effects have been observed with caffeine; however, due to its wider therapeutic window, these toxicities do not occur until levels exceed 50 mcg/mL.²⁴ Since methylxanthines alter cerebral blood flow, long-term sequelae associated with neurodevelopmental function have been studied. A higher incidence of cerebral palsy was found in low-birth-weight infants (<1,501 g) receiving theophylline during follow-up at 14 years of age.²⁵ To date, adverse effects of cognitive delay and cerebral palsy have not been established with caffeine therapy. A recent clinical trial found that low-birth-weight infants (500-1,250 g) receiving caffeine for AOP revealed no neurodevelopmental disability at the 18- to 21-month follow-up visit.²⁶ Further assessment is being conducted to determine the long-term effects of caffeine on cognition and gross and fine motor function at 5 years of age. 

Comparison of Caffeine and Theophylline for the Treatment of AOP: Multiple clinical trials have compared the efficacy and tolerability of theophylline with caffeine.^27-30 The results of these studies suggest that both agents have comparable efficacy in reducing the frequency of apnea episodes. Although caffeine has a higher lipophilicity and can readily cross the blood-brain barrier, both agents induce similar CNS and respiratory stimulation.²⁴ More evidence favors the use of caffeine with fewer drawbacks. Caffeine allows for once-daily administration and infrequent therapeutic drug monitoring; it also has a wider therapeutic margin causing fewer side effects. Adverse effects, primarily tachycardia and GI effects, were significantly greater in infants treated with theophylline than with caffeine. Therefore, caffeine is recommended as the first-line agent to be used in the treatment of AOP. TABLE 2 summarizes the comparison of caffeine and theophylline.

Other Treatment Options

Although other drug therapies are currently in development for the treatment of AOP, caffeine remains the standard of care. Doxapram is indicated for patients unresponsive to methylxanthines and is currently not available in the United States. Doxapram works as a central respiratory stimulant by activating the peripheral carotid chemoreceptors.³² However, severe cardiac adverse effects such as second-degree atrioventricular block, QT interval prolongation, and arrhythmias limit its use. Administration by continuous infusion, the need for therapeutic drug monitoring, and the inclusion of benzyl alcohol in its formulation also restrict the use of doxapram. 

Supplemental agents under investigation for the treatment of AOP include carnitine and creatine. Carnitine facilitates the transfer of fatty acids into the mitochondria for the production of adenosine triphosphate. The lack of energy production from carnitine deficiency in preterm infants may lead to hypotonia. The rationale behind carnitine supplementation is to improve ventilatory weaning and reduce the number of apnea events.³³ Current studies suggest no additional benefits with carnitine supplementation.³⁴ As with carnitine, preterm infants may have a deficiency in creatine.³⁵ Phosphocreatine is essential for ATP synthesis, thus preventing muscle fatigue. However, current evidence does not show symptom improvement of AOP with creatine supplementation. 

Conclusion

In summary, caffeine and theophylline are equally effective in the treatment of AOP. Caffeine is the preferred methylxanthine since it allows for once-daily administration and infrequent monitoring, has a better tolerability profile, and does not significantly cause neurodevelopmental disability in comparison to theophylline. Discontinuation of drug therapy is largely empirical, typically occurring at 40-weeks’ postconceptional age or when AOP ceases. A small percentage of patients may require home monitoring for apnea episodes upon hospital discharge. Although supplemental agents are undergoing investigation, these agents are currently not recommended. 

REFERENCES

1. Taeusch HW, Ballard RA, Gleason CA. Avery’s Diseases of the Newborn. 8th ed. Philadelphia, PA: Elsevier, Inc.; 2005:619-620.
2. Anas NG, Perkin RM. The pathophysiology of apnea of infancy. Perinatal-Neonatal. 1984;8:58-70.
3. Martin RJ, Fanaroff AA, Walsh MC. Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. Philadelphia, PA: Mosby Elsevier; 2006:1135-1141.
4. Martin RJ, Miller MJ, Carlo WA. Pathogenesis of apnea in preterm infants. J Pediatr. 1986;109:733-741.
5. Wilson CG, Martin RJ, Jaber M, et al. Adenosine A2A receptors interact with GABAergic pathways to modulate respiration in neonatal piglets. Respir Physiol  
Neurobiol. 2004;14:201-211.
6. Herlenius E, Lagercrantz H. Adenosinergic modulation of respiratory neurones in the neonatal rat brainstem in vitro. J Physiol. 1999;518:159-172.
7. McIntosh-Yellin NL, Drew BJ, Scheinman MM. Safety and efficacy of central intravenous bolus administration of adenosine for termination of supraventricular tachycardia. J Am Coll Cardiol. 1993;22:741-745.
8. Corvaglia L, Zama D, Gualdi S, et al. Gastro-oesophageal reflux increases the number of apneoas in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94:188-192.
9. Krauss AN. Apnea in infancy: pathophysiology, diagnosis, and treatment. NY State J Med. 1986;86:89-96.
10. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apneoa in newborn babies. Aust Paediatr J. 1981;17:273-276.
11. Eichenwald EC, Aina A, Stark A. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics. 1997;100:354-359.
12. Cheung PY, Barrington KJ, Finer NN, Robertson CM. Early childhood neurodevelopment in very low birth weight infants with pre-discharge apnea. Pediatr Pulmonol. 1999;27:14-20.
13. Jones RA, Lukeman D. Apnoea of immaturity. 2. Mortality and handicap. Arch Dis Child. 1982;57:766-768.
14. Grisemer AN. Apnea of prematurity; current management and nursing implications. Pediatr Nurs. 1990;16:606-611.
15. Bhatia J. Current options in the management of apnea of prematurity. Clin Pediatr (Phila). 2000;39:327-336.
16. Gayan-Ramirez G, Janssens S, Himpens B, Decramer M. Mechanism of theophylline-induced inotropic effects on foreshortened canine diaphragm. Eur Respir J. 1995;8:1915-1921.
17. Polson JB, Krzanowski JJ, Goldman AL, Szentivanyi A. Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharmacol Physiol. 1978;5:535-539.
18. Aubier M, Murciano D, Viires N, et al. Diaphragmatic contractility enhanced by aminophylline: role of extracellular calcium. J Appl Physiol. 1983;54:460-464.
19. Davis JM, Spitzer AR, Stefano JL, et al. Use of caffeine in infants unresponsive to theophylline in apnea of prematurity. Pediatr Pulmonol. 1987;3:90-93.
20. Hendeles L, Jenkins J, Temple R. Revised FDA labeling guideline for theophylline oral dosage forms. Pharmacotherapy. 1995;15:409-427.
21. Erenberg A, Leff RD, Haack DG, et al. Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study. Pharmacotherapy. 2000;20:644-652.
22. Natarajan G, Botica ML, Thomas R, Aranda JV. Therapeutic drug monitoring for caffeine in preterm neonates: an unnecessary exercise? Pediatrics. 2007;119:936-940.
23. Bhatt-Mehta V, Schumacher RE. Treatment of apnea of prematurity. Pediatr Drugs. 2003;5:195-210.
24. Aranda JV, Cook CE, Gorman W, et al. Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. J Pediatr. 1079;94:663-668.
25. Davis PG, Doyle LW, Rickards AL, et al. Methylxanthines and sensorineural outcome at 14 years in children < 1501 g birth weight. J Paediatr Child Health. 2000;36:47-50.
26. Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;257:1893-1902.
27. Brouard C, Moriette D, Murat I, et al. Comparative efficacy of theophylline and caffeine in the treatment of idiopathic apnea of premature infants. Am J Dis Child. 1985;139:698-700.
28. Bairam A, Boutroy MJ, Badonnel Y, et al. Theophylline versus caffeine: comparative effects in the treatment of idiopathic apnea in the preterm infant. J Pediatr. 1987;110:636-638.
29. Scanlon JE, Chin KC, Morgan ME, et al. Caffeine or theophylline for neonatal apnea? Arch J Dis Child. 1992;67:425-428.
30. Larsen PB, Brendstrup, Skov L, Fachs L. Aminophylline versus caffeine citrate for apnea and bradycardia prophylaxis in premature neonates. Acta Paediatr. 1995;84:360-364.
31. Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook. 16th ed. Houston, TX: Lexi-Comp Inc; 2009.
32. Edwards G, Lond MB, Leszczynski SO. A double-blind trial of five respiratory stimulants in patients with acute ventilatory failure. Lancet. 1967;290:226-229.
33. O’Donnell J, Finer NN, Rich W, et al. Role of L-carnitine in apnea of prematurity: a randomized, controlled trial. Pediatrics. 2002;109:622-626.
34. Kumar M, Kabra NS, Paes B. Carnitine supplementation for preterm infants with recurrent apnea. Cochrane Database Syst Rev. 2004;(4):CD004497.
35. Bohnhorst B, Geuting T, Peter CS, et al. Randomized, controlled trial of oral creatine supplementation (not effective) for apnea of prematurity. Pediatrics. 2004;113:e303-e307. 

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