Carnitine supplementation for preterm infants with recurrent
apnea
Kumar M, Kabra NS, Paes B
Dates
Date edited: 21/08/2007
Date of last substantive update: 24/06/2003
Date of last minor update: 11/05/2007
Date next stage expected 24/06/2009
Protocol first published: Issue 4, 2003
Review first published: Issue 4, 2004
Contact reviewer
Dr Manoj Kumar, MBBS, MD
Assistant Clinical Professor, Division of Neonatology
Department of Pediatrics
University of Alberta
Edmonton
Alberta CANADA
T5H 3V9
Telephone 1: 780 735 4670
Telephone 2: 780 445 6240
Facsimile: 780 735 4072
E-mail: manojk2@hotmail.com
Contribution of reviewers
Manoj Kumar conceptualised the paper and was involved in all stages of the review. NS Kabra contributed to the process of literature search, study selection and quality assessment for the review. Bosco Paes contributed to the development of the discussion and conclusions of the review.Internal sources of support
NoneExternal sources of support
NoneWhat's new
This is an update of the previously published version 'Carnitine supplementation for preterm infants with recurrent apnea', published in The Cochrane Library, Issue 4, 2004 (Kumar 2004). No new eligible trials were found. Therefore, there is no change to the conclusion that there are insufficient data to support carnitine supplementation for treatment of apnea of prematurity.
Dates
Date review re-formatted: / /
Date new studies sought but none found: 02/05/2007
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /
Text of review
Synopsis
More research is needed before the use of carnitine for the treatment of apnea of prematurity can be recommended in clinical practice.
Apnea of prematurity is a common problem in preterm infants in the neonatal intensive care setting (NICU). Recurrent apnea episodes are correlated with adverse neurological development in this population. Carnitine deficiency has been shown to be associated with apnea and respiratory failure in infants and in adults. The reviewers investigated whether treatment of premature babies with carnitine will help in the reduction or resolution of apnea episodes, and the need for ventilation. No treatment trials were identified.
Abstract
Background
Apnea of prematurity is a common problem in preterm infants in the neonatal intensive care setting (NICU), often delaying their discharge home or transfer to a step down unit. Premature infants are at increased risk of carnitine deficiency. Carnitine supplementation has been used for both prevention and treatment of apnea.
Objectives
To determine the effect of treatment with carnitine on the frequency of apnea, the duration of ventilation and the duration of hospital stay in preterm infants with recurrent apnea.
Search strategy
Computerised searches were carried out by two reviewers independently. Searches were made of MEDLINE (1966 to May 2007), EMBASE (1988 to May 2007), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), abstracts of annual meetings of the Society for Pediatric Research (1995 - 2007), and contacts were made with the subject experts.
Selection criteria
Only randomized or quasi-randomized treatment trials of preterm infants with a diagnosis of recurrent apnea of prematurity were considered. Trials were included if they involved treatment with carnitine compared to placebo or no treatment, and measured at least one of the following outcomes: failure of resolution of apneas, the duration of ventilation and the duration of hospital stay.
Data collection & analysis
Two reviewers evaluated the papers for inclusion criteria and quality. Corresponding authors were contacted for further information where needed.
Main results
No eligible trials were identified.
Reviewers' conclusions
Despite the plausible rationale for the treatment of apnea of prematurity with carnitine, there are insufficient data to support its use for this indication. Further studies are needed to determine the role of this treatment in clinical practice.
Background
Apnea of prematurity is a common problem in preterm infants in the neonatal intensive care setting, often delaying their discharge home or transfer to a step down unit. Episodes of apnea are generally defined as periods during which there is cessation of neonatal breathing activity for greater than 20 seconds or those of less than 20 seconds with associated bradycardia, pallor and/or cyanosis (NIH 1987). There are reports that suggest that apneic episodes, particularly 20 seconds or more in duration, are correlated with adverse neurological development (Cheung 1999).
At present methylxanthines (aminophylline, theophylline and caffeine) are the mainstay of treatment for this condition, exerting their effect primarily by stimulation of the respiratory centre in the brain. However, there are concerns with the safety of these compounds. Besides the commonly seen side effects of feeding intolerance and tachycardia, these drugs have also been implicated in serious adverse effects such as cardiac arrhythmias and exacerbation of ischemic brain injury (Grosfeld 1983; Schmidt 1999; Thurston 1978). Doxapram is another respiratory stimulant that is sometimes used when methylxanthine treatment has failed. However, this drug is also associated with side effects such as seizures, liver dysfunction and gastrointestinal irritation that have limited its use (Milner 1999).
Carnitine, a quaternary amine synthesized from the amino acid lysine, is essential for the transport of fatty acids across mitochondrial membranes for beta-oxidation metabolism and ketone generation. Deficiency of carnitine leads to a decrease in long chain fatty acids that are available for beta-oxidation, resulting in a decrease in energy production at the muscular level (Borum 1995). Congenital deficiencies of enzymes carnitine palmitoyltransferase or cytochrome-c-oxidase have been noted to result in lower tissue carnitine stores (Bertorini 1980; Sharma 2003; Muller-Hocker 1983). Such cases present with generalized hypotonia, respiratory insufficiency and respiratory failure in neonates (Muller-Hocker 1983; Sharma 2003) and in adults (Bertorini 1980).
In an autopsy series of neonatal deaths occurring within 24 hours of birth, preterm infants were noted to have lower muscle carnitine reserves compared to term infants. Analysis of carnitine levels in these infants demonstrated a strong positive correlation with advancing gestational age (Shenai 1984). This is postulated to be related to poor tissue uptake from the immaturity of the carnitine biosynthetic pathways rather than any congenital enzyme defects. In addition, reduced placental transfer and reduced intakes from breast milk or conventional parenteral nutrition solutions also contribute to low tissue carnitine levels in this population (Shenai 1984; Penn 1985).
Treatment with carnitine has shown benefit in the respiratory status of ventilator dependent adults, as well as stabilization of respiratory parameters and increased physical performance in adult patients with chronic respiratory insufficiency (Prockop 1983; Dal Negro 1986; Dal Negro 1988). In a case series of infants with apnea and periodic breathing, a decrease in such episodes was noted following 48 hours of treatment with oral carnitine (Iafolla 1995a). No unique enzyme deficiency was identified among the cases. Similarly, a study of carnitine supplementation in healthy premature infants of < 34 weeks gestation claimed a significant decrease in the frequency of apnea episodes and early weaning from ventilation (Iafolla 1995b). However, to date there has been no systematic review to evaluate the role of carnitine in the treatment of apnea of prematurity.
Objectives
To determine the effect of carnitine supplementation on the frequency of apnea in preterm infants with recurrent apnea.
The secondary aim is to determine the effect of carnitine supplementation on the duration of ventilation and the duration of hospital stay in preterm infants with recurrent apnea.
Criteria for considering studies for this review
Types of studies
All randomized or quasi-randomized treatment trials
Types of participants
All preterm infants <= 32 weeks or < 1500 grams with a diagnosis of recurrent apnea of prematurity
Types of interventions
Carnitine supplementation (oral or intravenous) in the treatment group versus placebo or no treatment in the control group.
Studies will be eligible whether or not other known treatments for apnea, e.g. methylxanthines, doxapram or positive pressure ventilation (CPAP or low rate IPPV), were provided during the period of carnitine treatment.
Data from studies where carnitine was given for < 24 hours will be excluded.
Types of outcome measures
1. Failure of treatment of apnea, both in terms of frequency of episodes and proportion of infants with continuing apneas
2. Duration of ventilation
3. Duration of hospital stay
Search strategy for identification of studies
Computerised searches were carried out by two reviewers (MK, NS) independently. Searches were made of MEDLINE (1966 to May 2007), EMBASE (1988 to May 2007), and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007). Search terms used were (all headings): (Carnitine OR L-carnitine) AND (respiratory insufficiency OR respiratory failure or ventilation or ventilator OR respirator OR apnea OR apnoea OR "apnea of prematurity" OR "apnoea of prematurity") AND [newborn OR neonate OR infant]. The search was not restricted by language. In addition, abstracts of annual meetings of the Society for Pediatric Research (1995 - 2007), the database of dissertation abstracts and the bibliography of selected articles were reviewed. Contacts were made with manufacturers of carnitine (Sigma-Tau Pharmaceuticals Inc.), authors of previously published works and subject experts for any unpublished material and for ongoing trials.
Methods of the review
Two review authors (MK and NS) separately evaluated studies for eligibility. The results were then compared and any disagreements were resolved by discussion. Decisions to include studies for the review were based on pre-determined criteria. Where data were incomplete, corresponding authors were contacted for further information.
Relative risk (RR) for dichotomous data and weighted mean difference (WMD) for continuous data were selected for estimation of the effect size using a fixed effect model.
Subgroup analysis were planned a priori for separate estimation of effect size including only the trials with blinding of care givers and outcome assessors, and trials where effects of carnitine were studied following the discontinuation of xanthines.
Description of studies
No studies were found which were eligible for inclusion for this review. Specific reasons for exclusion of studies are listed under the characteristics of excluded studies. One treatment trial published as an abstract was identified that met the objectives of this review (Iafolla 1995b).This trial included 24 infants and claimed a significant reduction in frequency of apnea and need for mechanical ventilation. However, the trial was excluded after learning from its authors that the results of the study were found to be incorrect and thus were not submitted for full text publication (CR Roe; email communication March 2003). Two other randomized control trials (O'Donnell 2002; Whitfield 2003) were excluded as carnitine was provided as prophylaxis for apnea of prematurity. The remaining studies (Bonner 1995; Coran 1985; Helms 1990; Larson 1990; Magnusson 1990; Melegh 1986; Rubin 1995; Schmidt-S 1983; Shortland 1998; Sulkers 1990; Pande 2005) were randomized or quasi-randomized trials of carnitine supplementation in preterm infants; however, they were excluded because none required apnea as an entry criterion.
Methodological quality of included studies
No studies were included for this review.
Results
No eligible trials were identified that tested the efficacy of carnitine in the treatment of apnea of prematurity.
Discussion
No trials of carnitine supplementation for treatment of apnea of prematurity were found. The two trials where carnitine was used as prophylaxis for apnea (O'Donnell 2002; Whitfield 2003) did not show a statistically significant difference in the frequency of episodes of apnea or the length of ventilation or the duration of hospital stay. However, these trials enrolled a small number of patients (a total of 105 final study participants), with very few developing recurrent apnea in either of the groups. Thus, the efficacy of carnitine treatment for apnea of prematurity has not been sufficiently evaluated to date.
It is unlikely that an important study that could have been included in the review was missed. The search strategy was broad. Several electronic databases and the abstracts of the last 10 years of scientific meetings of the Society for Pediatric Research were searched, and exhaustive efforts were made to identify unpublished studies. Application of a formal test for publication bias, i.e. a funnel plot, was not possible as there were no eligible studies.
Given the well documented short-term benefits of methylxanthines when used in the primary treatment of apnea of prematurity (Henderson-Smart 2001; Schmidt 2006) their use is standard practice in most neonatal units. Therefore, it will be difficult to conduct a head to head comparative trial between carnitine and methylxanthines, or a placebo control trial with carnitine as primary treatment for recurrent apneas before the institution of methylxanthines. The concerns about the long-term serious adverse effects from the use of methylxanthines (Grosfeld 1983; Schmidt 1999; Thurston 1978) have not been substantiated following the completion of the Caffeine for Apnea of Prematurity trial. Preliminary results of this study presented recently (Pediatric Academic Societies Annual Research Meeting 2007, Abstract# 5130.1) demonstrated that caffeine therapy for apnea of prematurity improves the composite outcome of death or disability in very low birth weight infants at a corrected age of 18 - 21 months.
There are also issues relating to the methods used for ascertainment and reporting of the outcome of apnea in the existing studies. The two prophylaxis trials of carnitine supplementation (O'Donnell 2002; Whitfield 2003) used different methods of continuous objective recording of apnea, such that a recent systematic review of trials of carnitine as prophylaxis in preterm babies at risk of apnea (Kumar 2004) did not consider it appropriate to combine the results for a summary estimate. Whitfield 2003 did not make use of a nasal thermistor probe in their set up and, therefore, likely missed many of the obstructive and mixed apnea episodes. This is evident from reviewing the results of the individual studies; five to ten times higher apnea events were recorded in the O'Donnell 2002 study. In addition, apneas as recorded by the bedside nurse were also reported differently in these trials. Whitfield 2003 calculated nurse recorded apnea frequency as an average of episodes recorded over the entire duration of the NICU stay, whereas O'Donnell 2002 reported the results of this outcome at multiple time points during the period the infants were hospitalized in the NICU. Neither of the studies reported the clinically relevant outcomes of proportion of infants with continuing apneas or the need for ventilation at varying postnatal ages, and neither provided data for significant apnea requiring interventions such as physical stimulation or bag and mask ventilation.
Reviewers' conclusions
Implications for practice
More research is needed before the use of carnitine for the treatment of apnea of prematurity can be recommended in clinical practice. For now the use of carnitine supplementation should be restricted to randomized control trial settings.
Implications for research
The following research questions may be worth exploring in future trials:
1. Carnitine as an add-on therapy, versus placebo, for continuing apneas following the use of methylxanthines in premature infants.
2. Carnitine plus methylxanthine vs methylxanthine alone as primary treatment for recurrent apnea of prematurity.
Researchers undertaking the above trials should ensure the use of a nasal thermistor probe for continuous recording of apnea episodes. In addition, they should include the ascertainment of clinically relevant outcomes: the achievement of an earliest five to seven day apnea free interval, the proportion of patients with continuing apneic episodes or the need for ventilatory support (CPAP or IPPV) at varying postnatal ages, the duration of ventilation, and the frequency of significant apnea episodes requiring interventions. The total duration of ventilation should also be documented with developmental and neurological follow-up forming an essential long-term goal.
Acknowledgements
None
Potential conflict of interest
None
Characteristics of excluded studies
| Study | Reason for exclusion |
| Bonner 1995 | Did not require apnea as an entry criterion. |
| Coran 1985 | Did not require apnea as an entry criterion. |
| Helms 1990 | Did not require apnea as an entry criterion. |
| Iafolla 1995b | Results of the study later found to be incorrect and thus not submitted for a full text publication (CR Roe; email communication, March 2003) |
| Larson 1990 | Did not require apnea as an entry criterion. |
| Magnusson 1990 | Did not require apnea as an entry criterion. |
| Melegh 1986 | Did not require apnea as an entry criterion. |
| O'Donnell 2002 | Carnitine used as prophylaxis for apnea of prematurity. |
| Pande 2005 | Did not require apnea as an entry criterion. |
| Rubin 1995 | Did not require apnea as an entry criterion. |
| Schmidt-S 1983 | Did not require apnea as an entry criterion. |
| Shortland 1998 | Did not require apnea as an entry criterion. |
| Sulkers 1990 | Did not require apnea as an entry criterion. |
| Whitfield 2003 | Carnitine used as prophylaxis for apnea of prematurity. |
References to studies
References to excluded studies
Bonner 1995 {published data only}Bonner CM, DeBrie KL, Hug G, Landrigan E, Taylor BJ. Effects of parenteral L-carnitine supplementation on fat metabolism and nutrition in premature neonates. Journal of Pediatrics 1995;126:287-92.
Coran 1985 {published data only}
Coran AG, Drongowski RA, Baker PJ. The metabolic effects of oral L-carnitine administration in infants receiving total parenteral nutrition with fat. Journal of Pediatric Surgery 1985;20:758-64.
Helms 1990 {published data only}
Helms RA, Mauer EC, Hay WW Jr, Christensen ML, Storm MC. Effect of intravenous L-carnitine on growth parameters and fat metabolism during parenteral nutrition in neonates. JPEN. Journal of Parenteral and Enteral Nutrition 1990;14:448-53.
Iafolla 1995b {published data only}
Iafolla AK, Roe CR. Carnitine deficiency in apnea of prematurity. Pediatric Research 1995;37:309A.
Larson 1990 {published data only}
Larsson LE, Olegard R, Ljung BM, Niklasson A, Rubensson A, Cederblad G. Parenteral nutrition in preterm neonates with and without carnitine supplementation. Acta Anaesthesiology Scandinavica 1990;34:501-5.
Magnusson 1990 {published data only}
Magnusson G, Boberg M, Cederblad G, Meurling S. Plasma and tissue levels of lipids, fatty acids and plasma carnitine in neonates receiving a new fat emulsion. Acta Paediatrica 1990;34:638-44.
Melegh 1986 {published data only}
Melegh B, Kerner J, Sandor A, Vinceller M, Kispal G. Oral L-carnitine supplementation in low-birth-weight newborns: a study on neonates requiring combined parenteral and enteral nutrition. Acta Paediatrica Hungarica 1986;27:253-8.
O'Donnell 2002 {published and unpublished data}
O'Donnell J, Finer NN, Rich W, Barshop BA, Barrington KJ. Role of L-carnitine in apnea of prematurity: a randomized, controlled trial. Pediatrics 2002;109:622-6.
Pande 2005 {published data only}
Pande S, Brion LP, Campbell DE, Gayle Y, Esteban-Cruciani NV. Lack of effect of L-carnitine supplementation on weight gain in very preterm infants. Journal of Perinatology 2005;25:470-7.
Rubin 1995 {published data only}
Rubin M, Naor N, Sirota L, Moser A, Pakula R, Harell D, Sulkes J, Davidson S, Lichtenberg D. Are bilirubin and plasma lipid profiles of premature infants dependent on the lipid emulsion infused? Journal of Pediatric Gastroenterology and Nutrition 1995;21:25-30.
Schmidt-S 1983 {published data only}
Schmidt-Sommerfeld E, Penn D, Wolf H. Carnitine deficiency in premature infants receiving total parenteral nutrition: effect of L-carnitine supplementation. Journal of Pediatrics 1983;102:931-5.
Shortland 1998 {published data only}
Shortland GJ, Walter JH, Stroud C, Fleming PJ, Speidel BD, Marlow N. Randomised controlled trial of L-carnitine as a nutritional supplement in preterm infants. Archives of Disease in Childhood. Fetal Neonatal Edition 1998;78:185-8.
Sulkers 1990 {published data only}
Sulkers EJ, Lafeber HN, Degenhart HJ, Przyrembel H, Schlotzer E, Sauer PJ. Effects of high carnitine supplementation on substrate utilization in low-birth-weight infants receiving total parenteral nutrition. American Journal of Clinical Nutrition 1990;52:889-94.
Whitfield 2003 {published and unpublished data}
Whitfield J, Smith T, Sollohub H, Sweetman L, Roe CR. Clinical effects of L-carnitine supplementation on apnea and growth in very low birth weight infants. Pediatrics 2003;111:477-82.
* indicates the primary reference for the study
Other references
Additional references
Bertorini 1980Bertorini T, Yeh YY, Trevisan C, Stadlan E, Sabesin S, DiMauro S. Carnitine palmityl transferase deficiency: myoglobinuria and respiratory failure. Neurology 1980;30:263-71.
Borum 1995
Borum PR. Carnitine in neonatal nutrition. Journal of Child Neurology 1995;10 Suppl 2:S25-31.
Cairns 2000
Cairns PA, Stalker DJ. Carnitine supplementation of parenterally fed neonates. Cochrane Database of Systematic Reviews 2000, Issue 4.
Cheung 1999
Cheung PY, Barrington KJ, Finer NN, Robertson CM. Early childhood neurodevelopment in very low birth weight infants with predischarge apnea. Pediatric Pulmonology 1999;27:14-20.
Dal Negro 1986
Dal Negro R, Pomari G, Zoccatelli O, Turco P. L-carnitine and rehabilitative respiratory physiokinesitherapy: metabolic and ventilatory response in chronic respiratory insufficiency. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1986;24:453-6.
Dal Negro 1988
Dal Negro R, Turco P, Pomari C, De Conti F. Effects of L-carnitine on physical performance in chronic respiratory insufficiency. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1988;26:269-72.
Grosfeld 1983
Grosfeld JL, Dalsing MC, Hull M, Weber TR. Neonatal apnea, xanthines, and necrotizing enterocolitis. Journal of Pediatric Surgery 1983;18:80-4.
Henderson-Smart 2001
Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 3.
Iafolla 1995a
Iafolla AK, Browning IB 3rd, Roe CR. Familial infantile apnea and immature beta oxidation. Pediatric Pulmonology 1995;20:167-71.
Kumar 2004
Kumar M, Kabra NS, Paes B. Role of carnitine supplementation in apnea of prematurity: a systematic review. Journal of Perinatology 2004;24:158-63.
Milner 1999
AD Milner. Apnoea and bradycardia. In: JM Rennie, NRC Roberton, editor(s). Textbook of Neonatology. 3rd edition. Edinburgh: Churchill Livingstone, 1999:635.
Muller-Hocker 1983
Muller-Hocker J, Pongratz D, Deufel T, Trijbels JM, Endres W, Hubner G. Fatal lipid storage myopathy with deficiency of cytochrome-c-oxidase and carnitine. A contribution to the combined cytochemical-finestructural identification of cytochrome-c-oxidase in longterm frozen muscle. Virchows Archiv. A, Pathological Anatomy and Histopathology 1983;399:11-23.
NIH 1987
National Institutes of Health. Consensus Development Panel on Infantile Apnea and Home Monitoring. Consensus Statement. Pediatrics 1987;79:292-9.
Penn 1985
Penn D, Ludwigs B, Schmidt-Sommerfeld E, Pascu F. Effect of nutrition on tissue carnitine concentrations in infants of different gestational ages. Biology of the Neonate 1985;47:130-5.
Prockop 1983
Prockop LD, Engel WK, Shug AL. Nearly fatal muscle carnitine deficiency with full recovery after replacement therapy. Neurology 1983;33:1629-31.
Schmidt 1999
Schmidt B. Methylxanthine therapy in premature infants: sound practice, disaster, or fruitless byway? Journal of Pediatrics 1999;135:526-8.
Schmidt 2006
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. New England Journal of Medicine 2006;354:2112-21.
Sharma 2003
Sharma R, Perszyk AA, Marangi D, Monteiro C, Raja S. Lethal neonatal carnitine palmitoyltransferase II deficiency: an unusual presentation of a rare disorder. American Journal of Perinatology 2003;20:25-32.
Shenai 1984
Shenai JP, Borum PR. Tissue carnitine reserves of newborn infants. Pediatric Research 1984;18:679-82.
Thurston 1978
Thurston JH, Hauhard RE, Dirgo JA. Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice. Science 1978;201:649-51.
Other published versions of this review
Kumar M
Kumar M, Kabra NS, Paes B. Carnitine supplementation for preterm infants with
recurrent apnea. Cochrane Database of Systematic Reviews 2004, Issue 4.
Contact details for co-reviewers
Dr Nandkishor S Kabra, MBBS, MD, DNB, DM
Neonatologist and Developmental Pediatrician
Neonatal Intensive Care Unit
Surya Children's Hospital
101/102 Mangal Ashirwad
Junction of S V Road and Dattatraya Road
TPS II, Santacruz West
Mumbai, Maharashtra State INDIA
400054
Telephone 1: 91 22 55724276
Facsimile: 91 22 26613598
E-mail: nskabra@hotmail.com
Dr Bosco Paes
Department of Pediatrics
McMaster Children's Hospital
Room 4G40
1200 Main Street West
Hamilton
Ontario CANADA
L8N 3Z5
Telephone 1: 1 905 521 2100 extension: 75607
Facsimile: 1 905 521 5007
E-mail: paes@mcmaster.ca
| This review is published as a Cochrane review in The Cochrane Library,
Issue 4, 2007 (see http://www.thecochranelibrary.com for information).
Cochrane reviews are regularly updated as new evidence emerges and in response
to feedback. The Cochrane Library should be consulted for the most recent
version of the review. |