What is the mechanism of caffeine in newborns?

From the Guidelines

Caffeine works differently in newborns compared to adults due to their immature metabolism and developing nervous system, and its mechanism in newborns is primarily as an adenosine receptor antagonist, blocking adenosine's inhibitory effects on respiratory drive. In newborns, particularly premature infants, caffeine citrate is commonly used to treat apnea of prematurity at a loading dose of 20 mg/kg followed by maintenance doses of 5-10 mg/kg daily 1. This stimulates the respiratory center in the brain, increases sensitivity to carbon dioxide, strengthens diaphragmatic contractions, and reduces periodic breathing episodes. Newborns metabolize caffeine much more slowly than adults, with a half-life of 60-140 hours compared to 5-6 hours in adults, due to their immature liver enzyme systems 1. This extended half-life means caffeine remains active in newborns' systems much longer, requiring less frequent dosing but also necessitating careful monitoring for side effects such as tachycardia, feeding intolerance, or irritability.

Some key points to consider when using caffeine in newborns include:

• The therapeutic benefits typically outweigh these potential side effects when caffeine is used appropriately under medical supervision 1
• Caffeine has been shown to improve pulmonary function in infants with chronic lung disease of infancy and childhood, and is commonly used in the NICU for the treatment of apnea of prematurity 1
• The use of inhaled bronchodilators is preferred, especially after NICU discharge, once the risk of apnea of prematurity is past, due to the significant side effects of orally administered theophylline and caffeine 1
• Strict attention should be paid to dose, and serum levels should be monitored (5–15 mg/L for theophylline, 5–20 mg/L for caffeine), as the therapeutic window can be quite narrow for these agents 1

The most recent and highest quality study, from 2018, supports the early use of caffeine in preterm infants, and discusses the benefits of delayed cord clamping and, if required, cord milking for cesarean delivery 1. However, larger prospective trials are required to fully understand the effects of caffeine on intubation, intraventricular hemorrhage, and long-term outcome (chronic lung disease/neurodevelopmental outcomes) 1.

From the FDA Drug Label

Although the mechanism of action of caffeine in apnea of prematurity is not known, several mechanisms have been hypothesized These include: (1) stimu­lation of the respiratory center, (2) increased minute ventilation, (3) decreased threshold to hypercapnia, (4) increased response to hypercapnia, (5) increased skeletal muscle tone, (6) decreased diaphragmatic fatigue, (7) increased meta­bolic rate, and (8) increased oxygen consumption Most of these effects have been attributed to antagonism of adenosine recep­tors, both A1 and A2 subtypes, by caffeine, which has been demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically The mechanism of action of caffeine in newborns is not fully understood, but several mechanisms have been hypothesized, including:

• Stimulation of the respiratory center
• Increased minute ventilation
• Decreased threshold to hypercapnia
• Increased response to hypercapnia
• Increased skeletal muscle tone
• Decreased diaphragmatic fatigue
• Increased metabolic rate
• Increased oxygen consumption These effects are thought to be due to antagonism of adenosine receptors by caffeine 2.

From the Research

Caffeine Mechanism in Newborns

• Caffeine is widely used to prevent and treat apnea associated with prematurity and facilitate extubation in preterm infants 3.
• The standard dosing regimen for caffeine in preterm infants has been widely recognized, but higher doses have been suggested to further improve neonatal outcomes 3, 4.
• High-dose caffeine strategies may have little or no effect on mortality prior to hospital discharge, but may reduce the rate of bronchopulmonary dysplasia 3.
• The evidence is very uncertain for the effect of high-dose caffeine on major neurodevelopmental disability, duration of hospital stay, or seizures 3.
• Caffeine has been shown to be effective in reducing the rate of apnea in preterm infants, with some studies suggesting that early or high doses may be more effective 5.
• However, the optimal dosing regimen for caffeine in preterm infants is still unclear, and further studies are needed to determine the best approach 6.

Dosing Regimens

• Standard dosing regimens for caffeine in preterm infants typically involve a loading dose of 20 mg/kg or less, followed by a maintenance dose of 10 mg/kg/day or less 3.
• High-dose regimens may involve a loading dose of more than 20 mg/kg, followed by a maintenance dose of more than 10 mg/kg/day 3.
• Some studies have suggested that increasing the standard caffeine citrate dose every 1-2 weeks to a goal dose of 8 mg per kilogram every 24 hours may help maintain therapeutic effect 6.

Safety and Efficacy

• Caffeine has been shown to be safe and effective in reducing the rate of apnea in preterm infants, but high-dose regimens may increase the risk of cerebellar hemorrhage and seizures 3, 6.
• The evidence for the safety and efficacy of caffeine in preterm infants is generally of moderate to low certainty, and further studies are needed to fully understand its effects 3, 5.