Role of L-Carnitine in Apnea of Prematurity: A Randomized, Controlled Trial Jane O’Donnell, MD*; Neil N. Finer, MD*; Wade Rich, RCP*; Bruce A. Barshop, MD, PhD‡; and Keith J. Barrington, MD* ABSTRACT. Objective. Carnitine is thought to be a conditionally essential biological cofactor for premature infants. A preliminary study suggested that carnitine could significantly reduce apnea of prematurity. The ob- jective of this study was to evaluate critically the role of carnitine in idiopathic apnea of prematurity and to de- termine whether the use of carnitine would facilitate discontinuation of mechanical ventilatory support, shorten the duration of ventilatory support, and reduce the amount of time that such infants are exposed to both mechanical ventilation and oxygen. We also wanted to determine the effects of supplemental carnitine on weight gain, time to regain birth weight, time to achieve full enteral feedings, and length of hospital stay. Methods. A prospective, randomized, blinded trial was conducted on 44 preterm infants who were from the same neonatal intensive care unit and who were <32 weeks’ gestational age with a postnatal age <48 hours and a birth weight <1500 g and required total parenteral nutrition (TPN). Infants were randomized to receive car- nitine supplementation or placebo without crossover. Carnitine-supplemented infants received 30 mg/kg/d car- nitine in their TPN until the they were tolerating 120 mL/kg/d enteral feedings, and then they received 30 mg/ kg/d oral carnitine. The placebo group received TPN without supplemental carnitine; when they tolerated 120 mL/kg/d enteral feedings, they received an oral placebo. The 2 groups continued on their respective supplemental carnitine or placebo until 34 weeks’ adjusted age, at which time the study period was completed. Twelve- hour cardiorespiratorygrams to record heart rate, respira- tory impedance, and oxygen saturation, and a nasal ther- mistor to detect expiratory airflow were performed every 4 days on 3 occasions and at 30 and 34 weeks’ adjusted age. Plasma carnitine levels were measured at day 14. Results. There were no significant differences be- tween the 2 groups in the occurrence of apnea as detected by cardiorespiratorygram or nursing observation. There were no significant differences between the groups in regard to total days on ventilator, days of nasal continu- ous positive airway pressure, time to regain birth weight, time to reach enteral feedings of 120 mL/kg/d, discharge weight, adjusted age at discharge, need for oxygen at 28 days’ and 36 weeks’ adjusted age, or length of stay. The plasma carnitine level was a median of 15.5 mol/L (range: 7.6 –30.5) for the placebo infants compared with a median of 195.3 mol/L (range: 71.7–343.6) for the carni- tine infants. Conclusions. In this blinded, randomized, placebo- controlled study, we found that infants who received supplemental carnitine did not demonstrate any reduc- tion in apnea of prematurity, ventilator or nasal contin- uous positive airway pressure days, or the need for sup- plemental oxygen therapy. Although carnitine may be of significant nutritional benefit for very low birth weight infants, our study does not support its use to reduce apnea of prematurity or decrease dependence on me- chanical ventilation. Pediatrics 2002;109:622– 626; prema- turity, apnea, carnitine. ABBREVIATIONS. TPN, total parenteral nutrition; CPAP, contin- uous positive airway pressure; CRG, cardiorespirogram. W ith increasing survival of extremely low birth weight infants, apnea of prematurity has become the most common recurring problem within the neonatal intensive care unit. l-Carnitine is synthesized from the amino acid l- lysine and is necessary for the transfer of fatty acids across the inner mitochondrial membrane for -oxi- dation metabolism and the subsequent production of adenosine triphosphate. Premature infants are par- ticularly prone to carnitine deficiency because the fetus receives carnitine by placental transport, the majority of which occurs during the third trimester. 1 Deficiency of carnitine leads to a decrease in long- chain fatty acids that are available for -oxidation, resulting in an accumulation of long-chain fatty acids in the cytosol, a decrease in ketone production, and a decrease in energy production. Carnitine deficiency is associated with hypotonia, which may be second- ary to the inability of skeletal muscle to metabolize the fatty acids through -oxidation. The premature infant is at risk of developing l-carnitine deficiency because of the immaturity of the l-carnitine biosyn- thetic pathways, lack of sufficient placental trans- port, and lack of exogenous carnitine supplementa- tion. Carnitine supplementation of preterm infants who receive total parenteral nutrition has been reported to improve carnitine concentrations and nitrogen balance 2 and to improve triglyceride tolerance and overall growth. 3,4 Idiopathic apnea of prematurity is universal in infants of 34 weeks’ gestation. 5 Cur- rent therapy used to treat apnea of prematurity, pri- marily using methylxanthines, does not completely eradicate such apnea. 6 A preliminary study has pur- From the Department of Pediatrics, Divisions of *Neonatology and ‡Bio- chemical Genetics, University of California, San Diego, San Diego, Califor- nia. Received for publication May 7, 2001; accepted Sep 11, 2001. Reprint requests to (J.O.) Children’s Hospital and Health Center, 3020 Children’s Way, MC 5008, San Diego, CA 92123. E-mail: mjo7@hotmail.com PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- emy of Pediatrics. 622 PEDIATRICS Vol. 109 No. 4 April 2002