Table 1.
Characteristics of included studies
| a) Systematic reviews | ||||
|---|---|---|---|---|
| Citation | Sample Size | Participants | Interventions | Results |
| Steer 2001 | 3 RCTs n = 66 |
Preterm infants (mean gestational age 30 weeks) |
Standard caffeine: loading dose (10–12.5 mg/kg), maintenance dose (1.25–3.0 mg/kg/12 hours) Theophylline: loading dose (5.5–7.5 mg/kg), maintenance dose (2 mg/kg/12 hours, aiming for plasma levels of 5–20 mg/kg) |
No significant difference in failure rates (<50% reduction in apnea/bradycardia) between groups Significantly higher rate of apnea in standard dose of caffeine group at 1–3 days (WMD 0.40, 95% CI 0.33, 0.46/100 minutes) No difference in apnea rate at 5–7 days Significantly lower adverse effects (tachycardia/feed intolerance) in caffeine group (RR 0.17, 95% CI 0.04, 0.72) |
| Henderson 2001 | 2 RCTs n = 100 |
Preterm infants (26–35 weeks gestational age) |
Caffeine citrate: loading dose (10–20 mg/kg base), maintenance dose 2.5–5 mg/kg Placebo: citric acid/sodium citrate |
Caffeine therapy associated with significantly less treatment failure: RR 0.46, 95% CI 0.27, 0.78; RD −0.31, 95% CI −0.49, −0.12; NNT 3, 95% CI 2, 8. No significant difference in the rate of death before discharge, and use of mechanical ventilation. Side effects were not estimable |
| Henderson 2001b | 3 RCTs n = 78 |
Preterm infants (30–32 weeks), term equivalent age (40–44 weeks) |
Caffeine (5–10 mg/kg) vs. placebo |
Few incidences of apnea/bradycardia in infants treated with caffeine compared to placebo: RR 0.09, 95% CI 0.02, 0.34; RD −0.58, 95% CI −0.74, −0.43 Fewer than two infants needed to be treated with caffeine to prevent one from post operative apnea. Hypoxemic episodes detected in fewer treatment (caffeine) than control infants: RR 0.13, 95% CI 0.03, 0.63. No infants required intubation or mechanical ventilation. No side effects were reported. |
| Henderson 1999 | 2 RCTs n = 104 |
Preterm infants less than 34 (31–33) weeks gestation age |
Caffeine citrate: loading dose (10–20 mg/kg), maintenance dose (5 mg/kg) Placebo: saline |
No difference between caffeine and placebo in episodes of apnea, bradycardia, hypoxemic episodes, use of IPPV or side effects. |
| b) Randomised controlled trials | ||||
|---|---|---|---|---|
| Citation / Design | setting | Sample Size / Participants | Interventions | Results |
| Schmidt 2007 Multicentre, randomised, placebo-controlled trial |
United States, Canada, Australia, Europe, Israel |
n = 2006 VLBW infants (500-1250 g) |
Caffeine citrate: 20 mg/kg loading dose given IV followed by 5 mg/kg/day IV or enterally (n = 937) Placebo: equivalent volume of normal saline (n = 932) |
Caffeine improved the rate of survival without neurodevelopmental disability at 18–21 months: OR 0.77, 95% CI 0.64, 0.93, P = 0.008 Caffeine associated with a significant reduction in the incidence of cerebral palsy (adjusted OR 0.58, 95% CI 0.39, 0.87, P = 0.009) and cognitive delay (adjusted OR 0.81, 95% CI 0.66, 0.99, P = 0.04) The number of infants who would need to be treated with caffeine to prevent one adverse outcome was 16 (95% CI 9, 56) No significant difference between groups in rates of death, deafness, blindness, and mean percentiles for height, weight and head circumference |
| Schmidt 2006 Multicentre, randomised, placebo-controlled trial |
United States, Canada, Australia, Europe, Israel |
n = 2006 VLBW infants (500–1250 g) |
Caffeine citrate: 20 mg/kg loading dose given IV followed by 5 mg/kg/day IV or enterally (n = 963) Placebo: equivalent volume of normal saline (n = 954) |
Caffeine significantly reduced rates of bronchopulmonary dysplasia: OR† 0.64, 95% CI 0.52, 0.78 Caffeine therapy was associated with significantly less use of positive airway pressure (P < 0.001) Caffeine reduced weight gain temporarily, with greatest difference occurring at 2 weeks (MD −23g, 95% CI −32, −13, P < 0.001) No significant difference between groups in rates of death, brain injury, ROP and NEC |
WMD – weighted mean difference; RR – relative risk; RD – risk difference; NNT – number needed to treat; IPPV – intermittent positive pressure ventilation.
VLBW – very low birth weight; NEC – necrotizing enterocolitis; ROP – retinopathy of prematurity; MD – mean difference; OR – odds ratio
†
adjusted for center and patient characteristics.