Caffeine Citrate for the Treatment of Apnea of Prematurity
Caffeine Citrate for the Treatment of Apnea of Prematurity
Study Objective. To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity.
Design. Multicenter, parallel, randomized, double-blind, placebo-controlled trial with open-label rescue.
Setting. Nine neonatal intensive care units.
Patients. Eighty-five infants, 28-32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours.
Intervention. Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double-blind therapy could receive open-label rescue.
Measurements and Main Results. Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7-10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight-adjusted dosing of caffeine citrate.
Conclusion. Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28-32 weeks postconception.
Apnea in preterm infants, defined as cessation of breathing for 20 seconds or longer, is one of the most common respiratory disorders in the neonatal intensive care unit. Its etiology is unknown; if no problem associated with apnea, such as anemia, hypoxemia, or infection, is identified, the infant is considered to have apnea of prematurity. The pathogenesis of the disorder is thought to be related to an immature central nervous system, decreased ventilatory response to carbon dioxide, and diaphragmatic fatigue caused by the amount of work necessary to generate an adequate tidal volume. The incidence of apnea of prematurity is inversely related to gestational age, with apnea occurring in approximately 80% of newborns weighing less than 1000 g at birth, but only 25% of infants weighing less than 2500 g or 34 weeks' gestation at birth. As the survival rate of preterm infants with low birthweight increases and advances in techniques of care decreases the time the infant is on mechanical ventilation, the absolute number of infants with this condition increases.
Apnea of prematurity is treated initially with tactile stimulation. Supplemental oxygen is provided for infants with documented hypoxemia. Since the 1970s, methylxanthines, caffeine citrate and theophylline, have been administered both parenterally and orally to decrease the frequency of apnea and prevent the need for assisted ventilation. Caffeine citrate is similar in efficacy to theophylline but has advantages of a larger therapeutic index, once-daily administration, smaller fluctuations in plasma concentrations due to a longer half-life, fewer peripheral adverse events, and greater penetration into cerebrospinal fluid. The agent's major disadvantage is its limited availability; since it is not commercially available, formulations must be prepared in the hospital pharmacy. Most reported adverse events associated with caffeine citrate, such as irritability, tachycardia, tachypnea, compromised circulation, vomiting, and convulsions, were reported in infants receiving overdoses due to incorrectly prepared formulations.
Although methylxanthines have been administered for over 2 decades and are advocated as treatment for apnea of prematurity in textbooks on neonatology, no placebo-controlled trials have been performed to confirm their efficacy and to describe the natural history of the disorder in infants not receiving intervention. The efficacy of caffeine citrate was compared with that of theophylline in several studies, but it was assumed that nontreated infants continued to have apnea spells. Since caffeine citrate potentially has a positive effect, double-blind, placebo-controlled trials must have a safety net to ensure that placebo groups receive treatment if clinically indicated.
Study Objective. To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity.
Design. Multicenter, parallel, randomized, double-blind, placebo-controlled trial with open-label rescue.
Setting. Nine neonatal intensive care units.
Patients. Eighty-five infants, 28-32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours.
Intervention. Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double-blind therapy could receive open-label rescue.
Measurements and Main Results. Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7-10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight-adjusted dosing of caffeine citrate.
Conclusion. Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28-32 weeks postconception.
Apnea in preterm infants, defined as cessation of breathing for 20 seconds or longer, is one of the most common respiratory disorders in the neonatal intensive care unit. Its etiology is unknown; if no problem associated with apnea, such as anemia, hypoxemia, or infection, is identified, the infant is considered to have apnea of prematurity. The pathogenesis of the disorder is thought to be related to an immature central nervous system, decreased ventilatory response to carbon dioxide, and diaphragmatic fatigue caused by the amount of work necessary to generate an adequate tidal volume. The incidence of apnea of prematurity is inversely related to gestational age, with apnea occurring in approximately 80% of newborns weighing less than 1000 g at birth, but only 25% of infants weighing less than 2500 g or 34 weeks' gestation at birth. As the survival rate of preterm infants with low birthweight increases and advances in techniques of care decreases the time the infant is on mechanical ventilation, the absolute number of infants with this condition increases.
Apnea of prematurity is treated initially with tactile stimulation. Supplemental oxygen is provided for infants with documented hypoxemia. Since the 1970s, methylxanthines, caffeine citrate and theophylline, have been administered both parenterally and orally to decrease the frequency of apnea and prevent the need for assisted ventilation. Caffeine citrate is similar in efficacy to theophylline but has advantages of a larger therapeutic index, once-daily administration, smaller fluctuations in plasma concentrations due to a longer half-life, fewer peripheral adverse events, and greater penetration into cerebrospinal fluid. The agent's major disadvantage is its limited availability; since it is not commercially available, formulations must be prepared in the hospital pharmacy. Most reported adverse events associated with caffeine citrate, such as irritability, tachycardia, tachypnea, compromised circulation, vomiting, and convulsions, were reported in infants receiving overdoses due to incorrectly prepared formulations.
Although methylxanthines have been administered for over 2 decades and are advocated as treatment for apnea of prematurity in textbooks on neonatology, no placebo-controlled trials have been performed to confirm their efficacy and to describe the natural history of the disorder in infants not receiving intervention. The efficacy of caffeine citrate was compared with that of theophylline in several studies, but it was assumed that nontreated infants continued to have apnea spells. Since caffeine citrate potentially has a positive effect, double-blind, placebo-controlled trials must have a safety net to ensure that placebo groups receive treatment if clinically indicated.
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