Caffeine therapy in preterm infants

Table 1 Pharmacokinetics of caffeine compared to theophylline

	Caffeine	Theophylline
Mechanism of action:
CNS stimulation	More active	Less active
Cardiac stimulation	Less active	More active
Diuresis	Less active	More active
Loading dose	20 to 40 mg/kg per dose IV/PO	4 to 8 mg/kg per dose IV
Maintenance dose	5 to 8 mg/kg per dose once daily IV/PO	1.5 to 3 mg/kg per dose every 8 to 12 h IV
Plasma half-life (h)	40 to 230 (mean, 103)	12 to 64 (mean, 30)
Therapeutic level (mg/L)	5 to 25	7 to 12
Toxic level (mg/L)	> 40 to 50	> 20
Adverse effects:
Cardiovascular	Tachycardia, dysrhythmia	Tachycardia, dysrhythmia
Gastrointestinal	Feeding intolerance, GER	Feeding intolerance, GER
CNS	Jitteriness, irritability, seizures	Jitteriness, irritability, seizures, decreased CBF
Signs of toxicity	Tachycardia, cardiac failure, pulmonary edema, hypertonia, sweating, metabolic disturbances	Tachycardia, agitation, hypokalemia, diuresis, gastric bleeding, seizure
Metabolism	Excreted unchanged or N-demethylation via CYP P450 (CYP1A2) liver-methyltransferase pathway	Excreted unchanged or undergoes 8-hydroxylation via CYP1A2 and CYP2E1
Inter-conversion	3% to 8% converted to theophylline via CYP1A2	25% converted to caffeine via methylation
Routine blood level	Not required	Required
Elimination	86% unchanged in urine	50% unchanged in urine
CSF level	Similar to plasma concentrations	Crosses into the CSF
Clearance (L/kg per hour)[9,43]	0.002 to 0.017	0.02 to 0.05

CNS: Central nervous system; CBF: Cerebral blood flow; CSF: Cerebrospinal fluid; GER: Gastroesophageal reflux; GIT: Gastrointestinal tract.

Table 2 Recommended caffeine doses

Trial	Design	Population	Intervention	Outcomes	Main results
Scanlon et al[48] United Kingdom	Prospective, randomized, controlled trial	44 preterm infants less than 31 wk gestation	High (loading 25 mg/kg and maintenance 6 mg/kg per day) vs low (loading 12.5 mg/kg and maintenance 3 mg/kg per day) caffeine citrate given 24 h prior to extubation	Frequency of apnea	High dose caffeine significantly decreased the frequency of apnea
Steer et al[52] Australia	Prospective, randomized, blinded, controlled trial	127 preterm infants less than 32 wk gestation	Three dosing regimens of caffeine citrate (3, 15 and 30 mg/kg) for peri-extubation management of ventilated preterm infants	Successful extubation defined as staying off ventilation for 7 d post-extubation	No statistically significant difference in the incidence of successful extubation however, infants in the two higher dose groups had statistically significantly less documented apnea
Steer et al[53] Australia	Prospective, randomized, blinded, controlled trial	234 preterm infants less than 30 wk gestation on mechanical ventilation	High (loading 80 mg/kg and maintenance 20 mg/kg per day) vs low (loading 20 mg/kg and maintenance 5 mg/kg per day) caffeine citrate given 24 h prior to extubation	Primary: Successful extubation of mechanically ventilated infants Secondary: Frequency of apnea	High dose caffeine significantly increased the chance for successful extubation, decreased the frequency of apnea and shortened the duration of respiratory support
Shah et al[54] Singapore	Prospective, case control trial	Preterm infants less than 34 wk gestation	High (loading 20 mg/kg and maintenance 5 mg/kg per day) vs low (loading 10 mg/kg and maintenance 2.5 mg/kg per day) caffeine citrate	Primary: Frequency of apnea, desaturation, and shallow breathing Secondary: Side effect of caffeine, BPD, and ROP	High-dose caffeine significantly reduced episodes of apnea and shallow breathing without side effects
Gray et al[125] Australia	Prospective, randomized, blinded, controlled trial	287 preterm infants less than 30 wk gestation exhibit AOP or require mechanical ventilation	Loading dose of 40 mg/kg followed by two maintenance doses of either 20 or 5 mg/kg per day	Primary: Cognitive development at 1 yr of age on the Griffiths Mental Development Scales Secondary: Neonatal morbidity, death and disability, temperament at 1 yr and behavior at 2 yr of age	High maintenance dose was associated with borderline benefit in cognitive outcome without increasing morbidity, temperament or behavior disorders
Mohammed et al[55] Egypt	Prospective, randomized, blinded, controlled trial	120 preterm infants less than 32 wk gestation exhibit AOP or require mechanical ventilation	High (loading 40 mg/kg and maintenance 20 mg/kg per day) vs low (loading 20 mg/kg and maintenance 10 mg/kg per day) caffeine citrate	Primary: Successful extubation of mechanically ventilated infants Secondary: Frequency and documented days of apnea	High dose caffeine significantly increased the chance for successful extubation, decreased frequency of apnea

BPD: Bronchopulmonary; ROP: Retinopathy of prematurity; AOP: Apnea of prematurity.