Caffeine—respiratory stimulant or magic bullet?

Key points

Caffeine is the respiratory stimulant of choice to prevent or treat apnea of prematurity.
The standard loading is 20 mg/kg of caffeine citrate, and the daily maintenance dose is 5 to 10 mg/kg.
Beneficial effects of this caffeine regimen include reduced risks of motor impairment, bronchopulmonary dysplasia, and severe retinopathy of prematurity.
Lasting harmful effects have not been detected with standard doses of caffeine up to 11 years after preterm birth.
The safety of higher doses of caffeine remains uncertain.
Initiation of caffeine therapy may be considered in all extremely preterm infants soon after birth unless they are fully ventilated and there are no immediate plans for a trial of extubation. Moderately and late preterm infants should not receive caffeine therapy unless they manifest apnea of prematurity.
Termination of caffeine therapy should be individualized and guided by the infants’ gestational age and their need for respiratory support.

Introduction

Apnea of prematurity is a common developmental disorder of respiratory control characterized by periodic breathing with pathological apnea. An apneic spell is defined as the cessation of respiratory air flow for at least 20 seconds, or any respiratory pause of shorter duration that is associated with cyanosis (desaturation), marked pallor, hypotonia, or bradycardia (<100 beats per minute). Apnea can be central (no respiratory effort), obstructive (mostly due to upper airway obstruction), or mixed. Most apneic events are either mixed or obstructive. The frequency, severity, and time to resolution of apnea are usually correlated inversely with gestational age at birth. ^, Apnea of prematurity resolves spontaneously by 44 weeks’ postmenstrual age. The two main treatment options are drug therapy with a respiratory stimulant, most commonly a methylxanthine, and the application of positive airway pressure.

Caffeine is the respiratory stimulant of choice for preterm infants

The methylxanthines theophylline, aminophylline, and caffeine appear to have similar beneficial effects on neonatal apnea. Caffeine is the methylxanthine of choice because of its pharmacokinetic advantages over theophylline and aminophylline. These advantages include the following:

Longer plasma elimination half-life enabling once-per-day administration
Wider therapeutic margin and lower risk of toxicity
No need for routine therapeutic drug monitoring with standard doses
Reliable enteral absorption that is unaffected by feedings

How big is the immediate caffeine treatment effect on apnea of prematurity? The largest and most recent placebo-controlled trial to address this question included 82 infants with gestational ages of 28 to 32 weeks who had experienced at least 6 apneas in a 24-hour period. An intravenous loading dose of 20 mg/kg bodyweight caffeine citrate was followed by a daily maintenance dose of 5 mg/kg for a planned treatment period of 10 days. However, only 47% of infants in the caffeine group and 32% of infants in the placebo group completed 10 days of double-blind therapy. The remaining infants received open-label caffeine or were withdrawn from the study altogether.

The US Food and Drug Administration (FDA) used these trial results in 1999 to approve caffeine for the treatment of apnea of prematurity. Table 17.1 summarizes the relevant endpoints in this study as tabulated in the FDA label. At the doses used in this trial, caffeine reduced the frequency of apnea, but did not entirely eliminate apneic events in most patients.

TABLE 17.1

Effect of Caffeine on Apnea of Prematurity

Outcome	Caffeine N = 45	Placebo N = 37	P Value
Apnea rate on day 2 (mean per 24 h)	4.9	7.2	0.13
Patients with no apneas on day 2	27%	8%	0.03
Patients with 50% reduction of apneas from baseline on day 2	76%	57%	0.07

Caffeine for apnea of prematurity trial

Over the past 15 years, caffeine has been transformed from a regularly used but insufficiently tested drug into one of the most evidence-based and commonly prescribed medications in neonatal medicine. The Caffeine for Apnea of Prematurity (CAP) trial played a prominent role in this shift. ^,

Rationale for the caffeine for apnea of prematurity trial

By the late 1990s, more than a dozen randomized trials had been published in which a methylxanthine—caffeine, aminophylline, or theophylline—was tested against a comparator such as placebo or continuous positive airway pressure. Methylxanthines had been shown to reduce the frequency of apnea in preterm infants and their need for mechanical ventilation during the first 7 days of therapy. In addition, methylxanthines were known to facilitate the removal of an endotracheal tube and to reduce the risk of postoperative apnea, bradycardia, and desaturation in infants born preterm. However, beyond these short-term benefits, little was known about the clinical effects of methylxanthine therapy because of small sample sizes and a short median duration of follow-up of only 7 days. The effects of methylxanthines on clinically important outcomes such as mortality, common neonatal morbidities, growth, and child development remained unknown.

The lack of rigorous evaluation of neonatal caffeine therapy in randomized clinical trials (RCTs) was especially worrying because experimental evidence had accumulated suggesting that acute administration of methylxanthines may exacerbate hypoxemic and ischemic brain injury. ^, At standard treatment doses, caffeine and other methylxanthines are competitive inhibitors of A1 and A2 _A adenosine receptors. By reducing the risk of energy failure and cell death, adenosine is neuroprotective during hypoxemia and ischemia in various animal models. Extensive investigations of the adenosine receptor system and its inhibition in several species of laboratory animals had produced concerning but also conflicting results:

The physiological and pathophysiological roles of the adenosine receptor system in the immature brain are complex and, as yet, incompletely understood. Therefore, one cannot, at present, predict the in vivo effects of non-specific adenosine receptor blockade with methylxanthine therapy, either during times of oxygen sufficiency or during the brief hypoxic-ischaemic episodes that are so common in very preterm infants.

This uncertainty about the safety of the routine use of methylxanthines in preterm infants became the rationale for the international CAP trial.

Conduct of the caffeine for apnea of prematurity trial

Concern about the safety of methylxanthine therapy at the time of the CAP trial design was reflected in the wording of the original study question:

Among infants with birth weights of 500 to 1250 g who are at risk of apnea of prematurity during the first 10 days of life, does the use of caffeine compared with placebo increase the risk of death or disability at a corrected age of 18 months?

Caffeine was chosen over aminophylline and theophylline because of its wider therapeutic margin. The intravenous loading dose of 20 mg/kg of caffeine citrate was followed by a daily maintenance dose of 5 mg/kg. If apneas persisted, the daily maintenance dose could be increased to a maximum of 10 mg/kg of caffeine citrate. The maintenance doses were adjusted weekly for changes in body weight and could be given orally once an infant tolerated full enteral feedings. Excerpts from the instructions in the CAP trial study aid are reproduced in Box 17.1 .

BOX 17.1

EXCERPTS FROM THE CAFFEINE FOR APNEA OF PREMATURITY (CAP) STUDY AID

How to give cap study drug?

CAP Study Drug should be used in lieu of methylxanthines during the entire stay in the neonatal nursery.
The loading dose of CAP Study Drug is 20 mg/kg caffeine citrate (equivalent to 10 mg/kg caffeine base) or normal saline placebo.
The maintenance dose of CAP Study Drug is 5 mg/kg/day caffeine citrate (equivalent to 2.5 mg/kg/day caffeine base) or normal saline placebo. Doses should be adjusted once a week for changes in body weight.
You can increase the maintenance dose to a maximum of 10 mg/kg/day caffeine citrate (equivalent to 5 mg/kg/day caffeine base) or normal saline placebo.
You can give the Study Drug orally once the infant tolerates full enteral feeds.

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