Complication of Prematurity Clinical Trial
Official title:
Effects of Parenteral L-carnitine Supplementation in Premature Neonates
Background: Carnitine is the essential cofactor for various enzyme activities of human
metabolism, especially for the mitochondrial carnitine shuttle that transfers long-chain
fatty acids as acylcarnitine esters across the inner mitochondrial membrane for
Beta-oxidation and energy production. Intracellular carnitine deficiency induces an
impairment of long-chain fatty acid oxidation. In human, approximately 75% of carnitine comes
from the diet and 25% from endogenous liver synthesis. In the neonatal period, more
specifically in the premature, liver synthesis capacity is reduced because of immaturity of
the biosynthetic pathway, and carnitine levels are related to exogenous sources.
Traditionally, carnitine is not added to parenteral nutrition. Indeed, without enteral feeds
and carnitine supplementation of parenteral nutrition, preterm infants' plasma carnitine
levels fall during the first weeks of life, particularly in subjects requiring a prolonged
exclusive parenteral nutrition. The potential deleterious role of carnitine deficiency has
not been clearly demonstrated in these infants. However, most patients with primary carnitine
deficiency, a genetic defect of carnitine transport inducing a severe carnitine deficiency,
commonly develop liver symptoms (encompassing visceral steatosis, hyperammonemia and
recurrent hypoketotic hypoglycemias) and/or cardiomyopathy and myopathy. In these latter
patients, carnitine supplementation improves all the symptoms.
Hypothesis: Carnitine deficiency of the premature and very low birth weight infants may be
one of the factors involved in the liver disease frequently associated with prolonged
parenteral nutrition, and may have deleterious effects on cardiac and muscle metabolism and
functions.
Aims: To demonstrate beneficial effects of parenteral carnitine supplementation in premature
neonates for liver, heart and muscle metabolism and functions.
Study Type: Multicentric prospective and randomised study
Subjects: Premature and very low birth weight neonates, defined by gestational age minor or
equal to 28 weeks and/or birth weight minor or equal to 1000 grams, 80 subjects will be
enrolled during 2.5 years
Interventions: Arm 1 (experimental): parenteral carnitine supplementation (9 ± 1 mg/kg/d),
from day 4, until than enteral nutrition provides sufficient carnitine source; Arm 2 (Placebo
comparator): parenteral supplementation with an equivalent volume of sterile water.
Background: Carnitine is the essential cofactor for various enzyme activities of human
metabolism, especially for the mitochondrial carnitine shuttle that transfers long-chain
fatty acids as acylcarnitine esters across the inner mitochondrial membrane for
Beta-oxidation and energy production. Intracellular carnitine deficiency induces an
impairment of long-chain fatty acid oxidation. In human, approximately 75% of carnitine comes
from the diet and 25% from endogenous liver synthesis. In the neonatal period, more
specifically in the premature, liver synthesis capacity is reduced because of immaturity of
the biosynthetic pathway, and carnitine levels are related to exogenous sources.
Traditionally, carnitine is not added to parenteral nutrition. Indeed, without enteral feeds
and carnitine supplementation of parenteral nutrition, preterm infants' plasma carnitine
levels fall during the first weeks of life, particularly in subjects requiring a prolonged
exclusive parenteral nutrition. The potential deleterious role of carnitine deficiency has
not been clearly demonstrated in these infants. However, most patients with primary carnitine
deficiency, a genetic defect of carnitine transport inducing a severe carnitine deficiency,
commonly develop liver symptoms (encompassing visceral steatosis, hyperammonemia and
recurrent hypoketotic hypoglycemias) and/or cardiomyopathy and myopathy. In these latter
patients, carnitine supplementation improves all the symptoms.
Hypothesis: Carnitine deficiency of the premature and very low birth weight infants may be
one of the factors involved in the liver disease frequently associated with prolonged
parenteral nutrition, and may have deleterious effects on cardiac and muscle metabolism and
functions.
Aims: To demonstrate beneficial effects of parenteral carnitine supplementation in premature
neonates for liver, heart and muscle metabolism and functions.
Study Type: Multicentric prospective and randomised study
Subjects: Premature and very low birth weight neonates, defined by gestational age minor or
equal to 28 weeks and/or birth weight minor or equal to 1000 grams, 80 subjects will be
enrolled during 2.5 years
Interventions: Arm 1 (experimental): parenteral carnitine supplementation (9 ± 1 mg/kg/d),
from day 4, until than enteral nutrition provides sufficient carnitine source; Arm 2 (Placebo
comparator): parenteral supplementation with an equivalent volume of sterile water.
Primary Outcome: Plasma Gamma Glutamyl Transferase level after 21 days of parenteral
supplementation.
Secondary Outcomes: Short- (during parenteral supplementation) and long- (3 to 5 months of
age) term outcomes: 1) Liver function (levels of ammonemia, hyaluronic acid, bilirubin,
prothrombin time test, ursodeoxycholic acid therapy), 2) cardiac function (echocardiography,
EKG), 3) muscle integrity (CK levels), 4) neurological injuries (brain ultrasound and MRI),
5) respiratory immaturity, 6) acylcarnitine profile and other fatty acid derivatives.
Expected Findings: Systematic parenteral carnitine supplementation will prevent systemic
carnitine deficiency, and will improve liver dysfunction (decreased duration and severity of
liver disease) associated with prolonged parenteral nutrition, will improve cardiac and
muscle functions, and will prevent cerebral injury in premature infants with very low birth
weight.
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