A pilot randomized trial of high-dose caffeine therapy in preterm infants

Abstract

Background Standard-dose caffeine improves white matter microstructural development assessed by diffusion MRI. We hypothesized that early high-dose caffeine would result in further improvement in white matter microstructural development. Methods Seventy-four preterm infants (≤30 weeks gestational age) were randomly assigned to either a high (80 mg/kg IV) or standard (20 mg/kg IV) loading dose of caffeine citrate in the first 24 hours of life. MRI and neurobehavioral testing were undertaken at term equivalent age. Infants returned at 2 years of age for developmental testing. Results Clinical characteristics were similar between groups, with the exception of higher maternal age in the high-dose caffeine group. There was an increased incidence of cerebellar hemorrhage in infants randomized to high-dose caffeine (36% vs. 10%, p=0.03). Infants in the high-dose caffeine group also demonstrated more hypertonicity (p=0.02) and more deviant neurologic signs (p=0.04) at term equivalent age. Diffusion measures at term equivalent age and developmental outcomes at two years of age did not differ between groups. Conclusions Preterm infants randomized to early high-dose caffeine had a higher incidence of cerebellar injury with subsequent alterations in early motor performance. The results of this pilot trial discourage a larger randomized controlled trial.

High versus standard dose caffeine for apnoea: a systematic review

“…They did not find a difference in these outcome measures between the two groups, except for the outcome general quotient only, favouring high-dose caffeine treatment. The only article reporting data using the Bayley Scale Infant Development III29 at 24 months found no difference between the high and standard dose groups 26…”

“…There were no differences in the outcomes NEC, spontaneous intestinal perforation, hyperglycaemia, ROP and IVH between the groups. McPherson  et al 26 reported a higher risk of focal cerebellar haemorrhage diagnosed with MRI in the high-dose group (36%) versus the standard-dose group (10%) (OR 5.0 (95%CI 1.2 to 20.7)). There were no differences in the incidence of extensive cerebellar haemorrhage.…”

Caffeine Prevents Hyperoxia-Induced Functional and Structural Lung Damage in Preterm Rabbits

“…Furthermore, in a recent randomized controlled trial, higher doses of caffeine (40 mg/kg BW followed by 20 mg/kg BW and 10 mg/kg BW always after 24 h) were associated with a higher incidence in neurological impairment (e.g. cerebellar hemorrhaging) and alterations in motor performance [22]. The effects of caffeine can be both anti- and proinflammatory, depending on the serum concentration [18].…”

Response From Committee on Fetus and Newborn

“…2,3 In 1 recent study, infants randomized to high-dose versus standard-dose caffeine had a higher incidence of cerebellar hemorrhage and hypertonicity at term-equivalent age. 4 These results suggest that the possible benefits of caffeine as reported in the Caffeine for Apnea of Prematurity Trial 2,3 may not be extrapolated to higher doses, and as such, until further research is available, higher doses should be used with caution.…”

“…2 There is also evidence correlating caffeine concentration maintenance above 14.5 mcg/mL with reduced chronic lung disease rates in neonates #29 weeks postmenstrual age. 4 We continue to report chronic lung disease rates in the best VON quartile (VON database), which we attribute, in part, to maintenance of caffeine levels in the upper normal therapeutic range.…”