Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity

Abstract

Background. Hypoxic ventilatory depression in mice and muscle fatigue in adult humans are improved by creatine supplementation (CS). Because these issues may be operative in apnea of prematurity (AOP), we hypothesized that CS reduces episodes of hypoxemia and bradycardia in infants with AOP. Methods. Infants were eligible for this double-blind, controlled trial if gestational age was <32 weeks and AOP was severe enough to require treatment with caffeine. If they had ≥1 desaturation (pulse oximeter saturation [SpO2] ≤ 80%) or bradycardia (heart rate ≤ two thirds of baseline) per hour in an initial 6-hour recording, they were randomized to a 2-week course of oral CS (200 mg/kg per day) or placebo (P). Infants then underwent 2 additional 6-hour recordings of breathing movements, nasal airflow, heart rate, pulse oximeter saturation (SpO2) and pulse waveforms after 7 and 14 days of treatment. Urinary creatine excretion was measured also. Recordings were analyzed for the frequency of bradycardia and desaturation, the primary outcome parameter, as well as for apnea (≥10 seconds), baseline heart and respiratory rate, and SpO2. Results. Of 38 infants enrolled, 34 completed the study (17 in each group). Median (range) gestational age at birth was 27 (25–30) vs 27 (25–30) weeks, and at study 29 (26–36) vs 29 (27–33) weeks. Oral CS was well tolerated; no side effects were noted. Urinary creatine excretion was low in the P group (median: 27 mmol/mol of creatinine; range: 18–102) and increased in the CS group (6949 mmol/mol of creatinine; range: 1427–11807). CS, however, had no effect on the combined rate of bradycardia and desaturation (P: 2.7 per hour [range: 0.2–10.3]; CS: 4.1 per hour [range: 0.6–12.1]), nor was there any decrease in apnea rate (P: 1.7 per hour [range: 0–4.5]; CS: 2.2 per hour [range: 0.2–5.1]). Conclusion. Despite a significant increase in creatine excretion, suggesting good enteral absorption, CS did not, in the dose and for the duration given in this study, improve symptoms of AOP in these infants.