NEODOSE

INDICATIONS

• Apnea: Pharmacological treatment with caffeine is the standard of care for apnea of prematurity. The rate of bronchopulmonary dysplasia in neonates with apnea of prematurity was reduced with caffeine, started within the first 10 days of life, in a randomized, placebo-controlled trial (n=1917). Caffeine was started to prevent apnea, treat apnea, or to facilitate the removal of an endotracheal tube . A follow-up of the study at 18 months corrected age demonstrated that the risk of death or disability (cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness) was reduced with caffeine . At a 5-year follow-up, there was no difference in disability or death between the caffeine and placebo group . At an 11-year follow-up, the combined rate of academic, motor, and behavioral impairment did not differ between the caffeine and placebo group. There was a reduced risk of motor impairment with caffeine compared with placebo (adjusted OR 0.66 (95% CI, 0.48 to 0.9)) . A secondary analysis (n=675) of a retrospective, multicenter cohort study demonstrated an association of less frequent early acute kidney injury in preterm neonates with caffeine administered by 7 ays of life; 11.2% vs 31.6% with and without caffeine, respectively (adjusted odds ratio 0.2 (95% CI, 0.11 to 0.34)).
  • High-dose (caffeine citrate 40 mg/kg/day loading dose, 20 mg/kg/day maintenance): A significant reduction in extubation failure (22% vs 47%), the frequency of apnea (9 vs 16), and days of documented apnea (2.5 days vs 5 days) were observed with high-dose oral caffeine citrate compared with standard dose (20 mg/kg/day loading dose, 10 mg/kg/day maintenance) in a randomized, double-blind study in 120 preterm (less than 32 weeks gestation; 10 days or younger) with apnea of prematurity. Tachycardia was significantly more frequent (23% vs 8%) in the high-dose vs low-dose group
  • Initiation: The optimal time to start treatment with caffeine is unknown. A reasonable approach is to start caffeine when apnea develops in infants greater than 28 weeks’ gestation who do not require positive pressure support. Earlier (younger than 3 days) prophylactic caffeine in infants who require mechanical ventilation compared with later (3 days or older) has been studied but the safety and efficacy need further study. Caffeine administered within the first 24 hours of life was associated with less mechanical ventilation (71.3% vs 83.2%) and a shorter duration of mechanical ventilation (mean 5 vs 10.8 days) than later caffeine initiation (median of 4 days) in an analysis of an observational study (n=286). Lower rates of patent ductus arteriosus and intraventricular hemorrhage (IVH) were associated with early versus late initiation; however, higher grades of IVH were not reduced. Premature infants (32 weeks’ gestational age or less) with respiratory distress syndrome and treated with surfactant were included.
  • Duration: The optimal duration of treatment with caffeine is unknown. Consider a trial off of caffeine in infants who have been free of clinically significant apnea/bradycardia events after 5 to 7 days off positive pressure or at 33 to 34 weeks postmenstrual age, which ever comes first. Extending caffeine treatment beyond when it is normally discontinued (apnea resolution) reduced the number and severity of intermittent hypoxia episodes in infants; however, the long-term benefits and risks to extended treatment are unknown. The postmenstrual age (PMA) at randomization to caffeine or placebo was 34 to 37 weeks (n=95) and continuous pulse oximeter data were collected up until 39 weeks PMA. More studies are needed before implementing extended caffeine treatment beyond apnea resolution.
• Mechanical Ventilation Weaning: The age at first successful extubation did not differ between early caffeine use (median 24 days of age; interquartile range (IQR), 10 to 41 days) and placebo group (median 20 days of age; IQR, 9 to 43 days; p=0.703) in preterm infants born at 23 to 30 weeks of gestation requiring mechanical ventilation in the first 5 postnatal days in a randomized, double-blind, placebo-controlled trial (n=83). Additionally, no differences were detected in secondary outcomes (duration of mechanical ventilation and oxygen supplementation, bronchopulmonary dysplasia, or death). The trial was terminated early due to a trend of higher mortality; 22% for caffeine and 12% (p=0.22) for placebo. The mean ages were approximately 3 hours at intubation and 2 days at randomization. The dosage for caffeine citrate was 20 mg/kg followed by 5 mg/kg/day.

FDA APPROVED INDICATION

Indicated for the short-term treatment of apnea of prematurity in infants between 28 to younger than 33 weeks of gestational age. The use of caffeine for sudden infant death syndrome prophylaxis or prior to extubation in mechanically-ventilated infants has not been established.

PRECAUTIONS

• Cardiovasculer:
  • Use with caution in infants with cardiovascular disease; caffeine may increase heart rate, left ventricular output, and stroke volume.
• oncomitant Use:
  • With theophylline is not recommended.
• Endocrine & metabolic:
  • Hypoglycemia and hyperglycemia has been reported; monitoring recommended.
• Hepatic:
  • Use with caution in infants with hepatic impairment; monitoring and dose adjustment recommended.
• Neurologic:
  • Seizures have been reported; use with caution in infants with seizure disorders.
• Renal:
  • Use with caution in infants with renal impairment; monitoring and dose adjustment recommended

ADVERSE EFFECTS

Adverse effects are usually mild, and include restlessness, vomiting, and functional cardiac symptoms. There has been a suggested association with NEC, but causality has never been proven. Loading doses of 25 mg/kg caffeine (50 mg/kg caffeine citrate) have been reported to decrease cerebral and intestinal blood flow velocity.

ADMINISTRATION

Administer the IV loading dose over 30 minutes and the maintenance dose over 10 minutes.

MONITORING

• Laboratory Monitoring / Concentration
  • Measuring serum concentrations is probably not necessary.
  • Baseline caffeine levels are recommended in neonates previously treated with theophylline and neonates born to mothers who consumed caffeine prior to delivery. Monitor serum concentrations in the presence of renal or hepatic impairment.
  • If monitoring of serum drug concentration is performed, measure the trough level on approximately day 5 of therapy. Therapeutic trough serum concentration is 5 to 25 mcg/mL. Concentrations greater than 40 to 50 mcg/mL are toxic. Assess for agitation. Monitor heart rate; consider withholding dose if greater than 180 beats per minute.
• Other Laboratory Values: Periodically monitor serum glucose.
• Physical Findings: Watch for signs and symptoms of necrotizing enterocolitis