The advantages of caffeine in the treatment of apnea outweigh the disadvantages in premature infants.

More than 30 years ago, clinicians found that methylxanthine alkaloids (methylxanthines) can reduce the incidence of apnea in premature infants. Since then, methylxanthine alkaloids have become part of the routine clinical treatment of apnea in premature infants, and caffeine is most commonly used in clinical treatment because of its long half-life in infants.

However, caffeine can reduce cerebral blood flow in adults (the dose of caffeine used in adults may be slightly higher than the recommended dose for infant treatment) and inhibit adenosine receptor. This may counteract the protective effect of caffeine on brain cells during hypoxia. These potential adverse reactions may cause damage to the central nervous system and adversely affect long-term neurodevelopment. Caffeine also has a known effect-increasing metabolic rate and oxygen consumption, which may also have an adverse effect on the long-term growth of babies. Although experts have been concerned about the potential long-term risks of caffeine, there is still a lack of research evidence in this area.

Caffeine has obvious therapeutic effect.

Due to the above uncertainties about the benefits and risks of caffeine treatment, the researchers designed a multicenter, randomized, placebo-controlled clinical trial to evaluate the efficacy of caffeine treatment on apnea in premature infants with a birth weight of 500 to 1250g. This follows a study published in the New England Journal of Medicine in which short-term follow-up of premature infants randomly assigned to caffeine showed a significant reduction in the incidence of bronchopulmonary dysplasia (bronchopulmonarydysplasia,BPD). The only adverse outcome observed was that babies in the caffeine group gained less weight than those in the placebo group three weeks before treatment. However, it is not known whether the decrease in the incidence of bronchopulmonary dysplasia translates into an improvement in long-term neurodevelopmental outcomes, or whether weight gain and loss is a harbinger of poor growth in the future.

In the November 8, 2007 issue of the New England Journal of Medicine, Schmidt et al reported long-term follow-up results of this clinical study and found that infants randomly assigned to receive caffeine treatment improved survival without neurological developmental abnormalities at a corrected age of 18 to 21 months, which was the main observation outcome of the study. Moreover, the incidence of cerebral palsy and cognitive lag in infants in the caffeine group was lower than that in the placebo group, and there was no significant difference in the incidence of death, deafness and blindness between the two groups. In addition, caffeine had no effect on the growth of babies (based on height, weight and head circumference) compared with placebo. Factorial analysis (posthocanalysis) of the results showed that although there was no significant difference in the overall incidence of retinopathy of prematurity between the caffeine group and the placebo group, the incidence of severe retinopathy of prematurity decreased. Overall, the researchers estimated that caffeine treatment in 16 infants could prevent one death or one surviving infant from cerebral palsy, cognitive lag, blindness or deafness.

The curative effect still needs long-term follow-up.

Why can methylxanthine alkaloids improve the outcome of apnea in premature infants?

The action mechanism of methylxanthine alkaloids is very complex, mainly by stimulating the respiratory center, blocking adenosine receptors and improving the function of respiratory muscles. Administration of methylxanthine alkaloids (such as caffeine) can increase the sensitivity to carbon dioxide and may also lower the threshold of carbon dioxide, so that respiration can be stimulated when the arterial partial pressure of carbon dioxide (PaCO2) is low, and ventilation can be increased under a certain amount of PaCO2. In addition, caffeine can also increase per minute ventilation (minuteventilation).

As a result, a factorial analysis of previously published results found that caffeine works 55% because it reduces the need for respiratory support, oxygen supplementation, postpartum hormone therapy and patent ductus arteriosus (Patentductusarteriosus,PDA) surgery, as well as because caffeine reduces the incidence of bronchopulmonary dysplasia. All these effects eventually lead to the improvement of respiratory function in children. But half of the role of caffeine is inexplicable. Other effects of caffeine treatment can also be beneficial in the treatment of apnea in premature infants, such as increasing levels of catecholamines, resulting in increased cardiac output and oxygenation capacity. However, there is no data in this study on the effects of caffeine on the incidence and severity of hypopnea and bradycardia associated with apnea. The mechanisms of these two effects may explain why caffeine can improve long-term neurodevelopmental outcomes.

During the growth and development of infants, in addition to the differences between liver function and renal function maturation, there may also be genetic variation in liver enzymes involved in caffeine bioconversion, which may lead to different responses to caffeine therapy among individuals. Some infants will continue to have apnea after caffeine treatment, indicating that there are various causes of apnea in premature infants, and other possible causes of apnea should be considered. for example, lung diseases caused by respiratory obstruction and atelectasis.

Taken together, data from Schmidt and other studies, together with data from a previously published study, suggest that although caffeine treatment of apnea in premature infants leads to weight loss in the first three weeks, caffeine can improve infant survival without neurodevelopmental abnormalities at 18 to 21 months, and the long-term benefits of caffeine outweigh its temporary side effects. Nevertheless, it is important to pay attention to long-term follow-up of infants treated with caffeine, because neurodevelopment at 18 to 21 months does not fully predict future neurodevelopmental outcomes and how these babies will perform in school.

This newly published study provides a support basis for the treatment that has already become a routine treatment in clinic. In this case, the doctor's experience was correct (or lucky) to determine that the benefits of caffeine outweigh the risks before clinical studies prove it. But we will not always be so lucky. For many treatments, they often fail to stand the test of randomized, controlled trials, such as prenatal phenobarbital treatment, which has been shown to fail to prevent intraventricular hemorrhage, and postpartum hormone therapy, which does not prevent bronchopulmonary dysplasia. But for caffeine in the treatment of apnea in premature infants, we can now conclude that the benefits outweigh the possible risks.

(source N Engl J Med,2007, 357 1967-1968)

Long-term effect of caffeine therapy on apnea in premature infants

Background: methylxanthine alkaloids (methylxanthines) are commonly used in the treatment of apnea in premature infants, but there is not enough data to prove its efficacy and safety. It is not clear whether methylxanthine alkaloids have long-term effects on neurological development and the growth of children.

Methods: a total of 2006 premature infants with apnea weighing 500 to 1250g were randomly assigned to receive caffeine or placebo until apnea was no longer needed. The main outcome was death, cerebral palsy and cognitive lag at the corrected age of 18 to 21 months (defined as intellectual development index score with Bayley Infant Development scale).