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Carnitine supplementation for preterm infants with recurrent apnoea

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Authors

Manoj Kumar1, Nandkishor S Kabra2, Bosco Paes3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Pediatrics, University of Alberta, Edmonton, Canada [top]
2Neonatal Intensive Care Unit, Surya Children's Hospital, TPS II, Santacruz West, India [top]
3Department of Pediatrics, McMaster Children's Hospital, Hamilton, Canada [top]

Citation example: Kumar M, Kabra NS, Paes B. Carnitine supplementation for preterm infants with recurrent apnoea. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004497. DOI: 10.1002/14651858.CD004497.pub2.

Contact person

Manoj Kumar

Department of Pediatrics
University of Alberta
Edmonton Alberta T5H 3V9
Canada

E-mail: manojk2@hotmail.com

Dates

Assessed as Up-to-date: 28 December 2010
Date of Search: 28 December 2010
Next Stage Expected: 01 May 2012
Protocol First Published: Issue 4, 2003
Review First Published: Issue 4, 2004
Last Citation Issue: Issue 4, 2004

What's new

Date / Event Description
03 January 2011
Updated

This review updates the review "Carnitine supplementation for preterm infants with recurrent apnoea", published in the Cochrane Database of Systematic Reviews , Issue 4, 2003.

Updated search found no new treatment trials for inclusion.

Changes incorporated in 'discussion' and in the 'implications to research' sections in view of new evidence available about the long-term effects of caffeine from a large randomised controlled trial of caffeine for apnoea of prematurity (CAP trial).

History

Date / Event Description

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 apnoea.

Objectives

To determine whether treatment with carnitine will reduce the frequency of apnoea, the duration of ventilation and the duration of hospital stay in preterm infants with recurrent apnoea.

Search methods

Computerised searches were carried out independently by two reviewer authors. We searched MEDLINE (1966 to December 2010), EMBASE (1988 to December 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010), abstracts of annual meetings of the Society for Pediatric Research (1995 to 2010), and contacts were made with the subject experts.

Selection criteria

Only randomised or quasi-randomised treatment trials of preterm infants with a diagnosis of recurrent apnoea 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 and analysis

Two reviewer authors evaluated the papers for inclusion criteria and quality. Corresponding authors were contacted for further information where needed.

Results

No eligible trials were identified.

Authors' conclusions

Despite the plausible rationale for the treatment of apnoea 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.

Plain language summary

Carnitine supplementation for preterm infants with recurrent apnoea

More research is needed before the use of carnitine for the treatment of apnoea 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 apnoea episodes are correlated with adverse neurological development in this population. Carnitine deficiency has been shown to be associated with apnoea and respiratory failure in infants and in adults. The review authors investigated whether treatment of premature babies with carnitine will help in the reduction or resolution of apnoea episodes, and the need for ventilation. No treatment trials were identified.

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Background

Description of the condition

Apnea of prematurity is a common problem in preterm infants in the neonatal intensive care setting, often delaying their discharge home or transfers to a step down unit. Episodes of apnoea 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.

Description of the intervention

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 adults (Bertorini 1980) and in neonates (Muller-Hocker 1983; Sharma 2003).

How the intervention might work

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 apnoea 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 apnoea episodes and early weaning from ventilation (Iafolla 1995b). 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; these levels showing 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).

Why it is important to do this review

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 some concerns with the safety of these compounds. The commonly seen side effects are feeding intolerance and tachycardia, however, these drugs have also been implicated in serious adverse effects such as cardiac arrhythmias and exacerbation of is chemic brain injury (Grosfeld 1983; Thurston 1978; Schmidt 1999 ). Doxapram is another respiratory stimulant that was historically used when methylxanthine treatment was not sufficient but wider awareness about its side effects such as seizures, liver dysfunction and gastrointestinal irritation (Milner 1999) has practically eliminated its use from neonatology. Given the relative carnitine deficiency state in preterm infants and the biological rationale for its supplementation, it would be worthwhile to investigate systematically the benefits of carnitine. To date, there has been no systematic review to evaluate the role of carnitine in the treatment of apnoea of prematurity.

Objectives

The primary aim of this review is to determine whether carnitine will reduce the frequency of apnoea in preterm infants with recurrent apnoea.
The secondary aim is to determine whether carnitine will reduce the duration of ventilation and the duration of hospital stay in preterm infants with recurrent apnoea.

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Methods

Criteria for considering studies for this review

Types of studies

All randomised or quasi-randomised treatment trials.

Types of participants

All preterm infants less than/or equal to 32 weeks or < 1500 grams with a diagnosis of recurrent apnoea 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 apnoea, 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

Primary outcomes

Failure of treatment of apnoea, both in terms of frequency of episodes and proportion of infants with continuing apneas.

Secondary outcomes

Duration of ventilation (days).
Duration of hospital stay (days).

Search methods for identification of studies

Electronic searches

Computerised searches were carried out by two review authors (MK, NS) independently. Searches were made of MEDLINE (1966 to December 2010), EMBASE (1988 to December 2010), and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010). 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]. Our search was not be restricted by language.

Searching other resources

In addition, we reviewed abstracts of annual meetings of the Society for Pediatric Research (1995 to 2010), the database of dissertation abstracts and the bibliography of selected articles. 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.

Clinical trials registries were also searched for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

The standard methods of the Cochrane Neonatal Review Group Guidelines were employed in creating this update.

Selection of studies

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 predetermined criteria. Where data were incomplete, corresponding authors were contacted for further information.

Data extraction and management

If eligible studies were identified, we planned on having the review authors separately extract, assess and code all data for each study using a form that was designed specifically for this review.

Assessment of risk of bias in included studies

If eligible studies were identified, we planned on assessing the methodological quality of the studies using the following key criteria: allocation concealment (blinding of randomisation), blinding of intervention, completeness of follow-up, and blinding of outcome measurement/assessment. For each criterion, assessment would be yes, no, can't tell. We planned to have two review authors separately assess each study.

For the Risk of Bias Table, we planned on evaluating the following issues:

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?
    For each included study, we planned to categorize the method used to generate the allocation sequence as:
    • adequate (any truly random process e.g. random number table; computer random number generator);
    • inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number);
    • unclear.
  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
    For each included study, we planned to categorize the method used to conceal the allocation sequence as:
    • adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    • unclear.
  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
    For each included study, we planned to categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We planned to categorize the methods as:
    • adequate, inadequate or unclear for participants;
    • adequate, inadequate or unclear for personnel;
    • adequate, inadequate or unclear for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?
    For each included study and for each outcome, we planned to describe the completeness of data including attrition and exclusions from the analysis. We planned to note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.If sufficient information was reported or supplied by the trial authors, we planned to re-include missing data in the analyses. We planned to categorize the methods as:- adequate (< 20% missing data);
    • inadequate (greater than/or equal to 20% missing data):
    • unclear.
  5. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
    For each included study, we planned to describe how we investigated the possibility of selective outcome reporting bias and what we found. We planned to assess the methods as:
    • adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    • unclear.
  6. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
    For each included study, we planned to describe any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We planned to assess whether each study was free of other problems that could put it at risk of bias as:
    • yes;no;or unclear.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

Statistical analyses were planned using Review Manager software. We planned to analyse categorical data using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). Continuous data were to be analysed using weighted mean difference (WMD). We planned to report the 95% Confidence interval (CI) on all estimates.

Assessment of heterogeneity

We planned to estimate the treatment effects of individual trials and examine heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I-squared statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses. We planned to use a fixed effects model for meta-analysis.

Data synthesis

If appropriate, we planned on performing meta-analysis using Review Manager software (RevMan 5), supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. We planned on using the fixed effect model for all meta-analyses.

Subgroup analysis and investigation of heterogeneity

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.

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Results

Description of studies

No eligible trials were identified that tested the efficacy of carnitine in the treatment of apnoea of prematurity.

Excluded studies

Specific reasons for exclusion of studies are listed in the table 'Characteristics of excluded studies'. One treatment trial published as an abstract was identified which met the objectives of this review (Iafolla 1995b).This trial included 24 infants and claimed a significant reduction in frequency of apnoea 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). Three other randomised control trials (O'Donnell 2002; Whitfield 2003; Crill 2006) were excluded as carnitine was provided as prophylaxis for apnoea of prematurity. The remaining studies were randomised or quasi-randomised trials of carnitine supplementation in preterm infants (Bonner 1995; Coran 1985; Helms 1990; Larson 1990; Magnusson 1990; Melegh 1986; Pande 2005; Rubin 1995; Schmidt-S 1983; Shortland 1998; Sulkers 1990; Seong 2010); however, were excluded as none reported on the outcome of apnoea (published data only) .

Risk of bias in included studies

No studies were included for this review.

Effects of interventions

No studies were included for this review.

Discussion

Summary of main results

We found no trials of carnitine for treatment of apnoea of prematurity. The three trials where the carnitine was initiated as prophylaxis for apnoea (O'Donnell 2002; Whitfield 2003; Crill 2006) did not show a statistically significant difference in the frequency of episodes of apnoea, the duration of ventilation or the duration of hospital stay. However, the power of these trials was limited as a small number of patients were enrolled, with very few subjects developing recurrent apnoeas. One of these trials reported decrease in time spent as periodic breathing (Crill 2006) but no such trend noted in the other two trials. Thus the efficacy of carnitine as prophylaxis or treatment for apnoea of prematurity has not been sufficiently evaluated to date.

Overall completeness and applicability of evidence

It is unlikely that we would have missed an important study that could have been included in the review. Our 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 apnoea of prematurity and better risk-benefit profile of caffeine as compared to the other agents in this class (Henderson-Smart 2001; Schmidt 2006), the use of methylxanthines has become the 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 have not been substantiated following the publication of long-term neurodevelopmental outcomes of the Caffeine for Apnea of Prematurity trial (Schmidt 2007).

There are also issues relating to the methods used for ascertainment and reporting of the outcome of apnoea in the existing studies. The above quoted trials of carnitine supplementation which reported on the outcome of apnoea, used different methods of continuous objective recording of apnoea, such that a previous systematic review of trials of carnitine as prophylaxis in preterm babies at risk of apnoea (Kumar 2004) did not consider it appropriate to combine the results for a summary estimate. Whitfield 2003 and Crill 2006 did not make use of a nasal thermistor probe in their set up and, therefore, likely missed many of the obstructive and mixed apnoea episodes. This is evident from reviewing the results of the individual studies; five to ten times higher apnoea events were recorded in the O'Donnell 2002 study as compared to the study by Whitfield 2003. In addition, apneas as recorded by the bedside nurse were also reported differently across these trials. None of the studies reported the clinically relevant outcomes of proportion of infants with continuing apneas or the need for ventilation at varying postnatal ages.

Authors' conclusions

Implications for practice

More research is needed before the use of carnitine for the treatment of apnoea of prematurity can be recommended in clinical practice. For now its use should be restricted to randomised control trial settings.

Implications for research

We think 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 versus methylxanthine alone as primary treatment for recurrent apnoea of prematurity.

Researchers undertaking the above trials should ensure the use of a nasal thermistor probe for continuous recording of apnoea episodes. In addition, they should include the ascertainment of clinically relevant outcomes: the achievement of an earliest five to seven day apnoea 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 apnoea 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

Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

All review authors contributed to the review.

Declarations of interest

No conflict of interest.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Characteristics of excluded studies

Bonner 1995

Reason for exclusion

Did not require apnoea as an entry criterion.

Coran 1985

Reason for exclusion

Did not require apnoea as an entry criterion.

Crill 2006

Reason for exclusion

Carnitine used as prophylaxis for apnoea of prematurity.

Helms 1990

Reason for exclusion

Did not require apnoea as an entry criterion.

Iafolla 1995b

Reason for exclusion

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

Reason for exclusion

Did not require apnoea as an entry criterion.

Magnusson 1990

Reason for exclusion

Did not require apnoea as an entry criterion.

Melegh 1986

Reason for exclusion

Did not require apnoea as an entry criterion.

O'Donnell 2002

Reason for exclusion

Carnitine used as prophylaxis for apnoea of prematurity.

Pande 2005

Reason for exclusion

Did not require apnoea as an entry criterion.

Rubin 1995

Reason for exclusion

Did not require apnoea as an entry criterion.

Schmidt-S 1983

Reason for exclusion

Did not require apnoea as an entry criterion.

Seong 2010

Reason for exclusion

Did not require apnoea as an entry criterion.

Shortland 1998

Reason for exclusion

Did not require apnoea as an entry criterion.

Sulkers 1990

Reason for exclusion

Did not require apnoea as an entry criterion.

Whitfield 2003

Reason for exclusion

Carnitine used as prophylaxis for apnoea of prematurity.

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References to studies

Included studies

  • None noted.

Excluded studies

Bonner 1995

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(2):287-92.

Coran 1985

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(20):758-64.

Crill 2006

Crill CM, Storm MC, Christensen ML, Hankins CT, Bruce Jenkins M, Helms RA. Carnitine supplementation in premature neonates: effect on plasma and red blood cell total carnitine concentrations, nutrition parameters and morbidity. Clin Nutr 2006;25(6):886-96. Epub 2006 Jun 30.

Helms 1990

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(5):448-53.

Iafolla 1995b

Iafolla AK, Roe CR. Carnitine deficiency in apnea of prematurity. Pediatric Research 1995;37:309A.

Larson 1990

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(6):501-5.

Magnusson 1990

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 1997;86(6):638-44.

Melegh 1986

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(3):253-8.

O'Donnell 2002

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(4):622-6.

Pande 2005

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(7):470-7.

Rubin 1995

Rubin M, Naor N, Sirota L, Moser A, Pakula R, Harell D, et al. Are bilirubin and plasma lipid profiles of premature infants dependent on the lipid emulsion infused? Journal of Pediatric Gastroenterology and Nutrition 1995;21(1):25-30.

Schmidt-S 1983

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(6):931-5.

Seong 2010

Seong SH, Cho SC, Park Y, Cha YS. L-carnitine-supplemented parenteral nutrition improves fat metabolism but fails to support compensatory growth in premature Korean infants. Nutr Res 2010;30(4):233-9..

Shortland 1998

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(3):185-8.

Sulkers 1990

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(5):889-94.

Whitfield 2003

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(3):477-82.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Bertorini 1980

Bertorini T, Yeh YY, Trevisan C, Stadlan E, Sabesin S, DiMauro S. Carnitine palmityl transferase deficiency: myoglobinuria and respiratory failure. Neurology 1980;30(3):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. Art. No.: CD000950. DOI: 10.1002/14651858.CD000950 .

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(1):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(8):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(5):269-72.

Grosfeld 1983

Grosfeld JL, Dalsing MC, Hull M, Weber TR. Neonatal apnea, xanthines, and necrotizing enterocolitis. Journal of Pediatric Surgery 1983;18(1):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. Art. No.: CD000140. DOI: 10.1002/14651858.CD000140 .

Iafolla 1995a

Iafolla AK, Browning IB 3rd, Roe CR. Familial infantile apnea and immature beta oxidation. Pediatric Pulmonology 1995;20(3):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(3):158-63.

Milner 1999

Milner AD. 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(1):11-23.

NIH 1987

National Institutes of Health. Consensus Statement National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, Sept 29 to Oct 1, 1986. Pediatrics 1987;79(2):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(3):130-5.

Prockop 1983

Prockop LD, Engel WK, Shug AL. Nearly fatal muscle carnitine deficiency with full recovery after replacement therapy. Neurology 1983;33(12):1629-31.

Schmidt 1999

Schmidt B. Methylxanthine therapy in premature infants: sound practice, disaster, or fruitless byway? Journal of Pediatrics 1999;135(4):526-8.

Schmidt 2006

Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. New England Journal of Medicine 2006;354(20):2112-21.

Schmidt 2007

Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long-term effects of caffeine therapy for apnea of prematurity. The New England Journal of Medicine 2007;357(19):1893-902.

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(1):25-32.

Shenai 1984

Shenai JP, Borum PR. Tissue carnitine reserves of newborn infants. Pediatric Research 1984;18(7):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(4356):649-51.

Other published versions of this review

Kumar 2003

Kumar M, Kabra NS, Paes B. Carnitine supplementation for preterm infants with recurrent apnea. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004497. DOI: 10.1002/14651858.CD004497.pub2.

Classification pending references

  • None noted.

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Data and analyses

  • None noted.

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Figures

  • None noted.

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Sources of support

Internal sources

  • No sources of support provided.

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2011 (see http://www.thecochranelibrary.com External Web Site Policy 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.