We know they need caffeine, but how it works on the newborn is the subject of a new study

Jul 21 2004

Every morning, millions of adults consume voluminous cups of coffee, seeking the jolting effect of caffeine. As these adults consume their coffee, they do so unaware that some of the youngest Americans are also getting a treatment of caffeine - not to stay awake, but to assist in treating a major sleep disorder found in some neonates.

Apnea, the absence of breathing, is the most frequently reported disorder of breathing control in premature infants, and neonatal care units habitually use methylxanthine derivatives such as caffeine to treat these patients who are less than a month old. Caffeine treatment for premature infants is supposed to increase breathing frequency, decrease the number of apneic spells, and reduce partial tension of carbon dioxide (PCO2) and the need for (and duration of) mechanical ventilation. Peripheral chemoreceptors, found in the carotid and aortic bodies and stimulated by chemical changes in blood composition, provide feed-forward control of respiration, which can thus terminate apnea and initiate normal breathing. These receptors are believed to be an important target for caffeine action in premature neonates.

Peripheral chemoreceptor activity is typically assessed by monitoring the rapid decline in minute ventilation (in the first minute) after inhalation of pure O2 . This drop in ventilation involves an acute reduction in peripheral chemoreceptor inputs (i.e., physiological chemodenervation) and thus reflects the strength of the peripheral chemoreceptor drive. The decrease is ultimately followed by an increase in ventilation that is centrally mediated.

However, the localization of caffeine’s target site (central nervous system and/or peripheral chemoreceptors) is not well defined, especially for sleeping neonates whose sleep stages interact with respiratory control. The question of an increase in peripheral chemoreceptor responsiveness (associated or not with a direct, central action of caffeine) remains debatable, particularly in human neonates. Past studies were performed in animal models for which chemical loss of nerve supply can alter respiratory behavior and can lead to sudden death.

Only one study has dealt with sleeping neonates: it showed that increased oxygen in the tissues and organs induces a greater decrease in ventilation after ingestion of aminophylline (10 mg/kg). This study was performed in infants who did not suffer from ventilatory problems, and so each infant served as his or her own control, i.e., before and after administration of aminophylline. The apnea frequency and the different sleep stages were not, however, scored.

Now a team of French physiologists has conducted a study to (1) assess whether caffeine treatment in premature neonates stimulates ventilation through peripheral chemoreceptors and (2) determine the potential influence of sleep states. The mechanism of caffeine’s action on the peripheral chemoreflex was assessed by monitoring immediate changes in the respiratory pattern in response to a 30-s hyperoxic test performed during active sleep or quiet sleep.

The authors of the study, entitled “Effect of Caffeine on Peripheral Chemoreceptor Activity in Premature Neonates: Interaction with Sleep Stages,” are Karen Chardon, Ve´ronique Bach, Fre´de´ric Telliez, Virginie Cardot, Jean-Pierre Libert, and Pierre Tourneux, all with the Laboratoire d’Environnement Toxique Pe´rinatal et Adaptations Physiologiques et Comportementales (EA2088), Faculte´ de Me´decine, Universite´ de Picardie Jules Verne, Amiens; and Andre´ Leke, at the Me´decine Ne´onatale et Re´animation Pe´diatrique, University Hospital Center Nord, Amiens, France. Their findings appear in the June 2004 edition of the Journal of Applied Physiology.

Twenty-two premature neonates were included in this study. The caffeine group consisted of 11 neonates receiving an oral caffeine citrate treatment for apnea caused by unknown reasons. The treatment was delivered to neonates who had shown more than one significant apneic episode per hour during the first hours of life. A significant apneic episode was defined as a respiratory arrest of seven seconds or more, associated with either a fall of heart rate below 100 beats/min or a fall in blood oxygen level of at least 10 percent relative to the previous baseline.

After three weeks of treatment, the neonates were compared with a control group (11 neonates not undergoing caffeine therapy) matched for age and body mass. Neonates with neurological or cardiac disorders were excluded from the study.

Two important findings were observed in this study. First, for all neonates, the decrease in minute ventilation observed during increased oxygen was greater during active than during quiet sleep. Neonates receiving caffeine showed a significantly greater decrease in ventilation during hyperoxia in both sleep stages, compared with controls.

Second, the data obtained strongly suggests that the effectiveness of chemoreceptor activity is enhanced during caffeine administration, because the drug amplifies the drop in ventilation compared with controls. The same data clearly indicate that the peripheral chemoreceptors’ contribution is crucial. Unfortunately, the mechanism of action by which caffeine acts on chemoreceptor activity is unknown. However, in the present study the researchers cannot rule out a direct effect of caffeine increasing the responsiveness of the central nervous structures that control ventilation.

This study demonstrates that peripheral chemoreceptor activity is increased by caffeine in premature neonates. However, it is not possible to discard that the increase of effectiveness of chemoreceptor may also reflect a change in the central processes.

Additionally, the findings validate that anti-apneic effect of caffeine is not related to sleep state disturbances but rather to a direct action on processes controlling the infant’s respiration.

Premature neonates are vulnerable to a wide range of disorders. This study provides an important answer as to why a common treatment works in alleviating a problem of “stopped breathing” during the sleep process.