Pediatric Anesthesia ISSN 1155-5645
REVIEW ARTICLE
Anesthetic agents in patients with very long-chain acylcoenzyme A dehydrogenase deficiency: a literature review Charlotte Redshaw & Catherine Stewart Department of Anaesthesia, Princess Royal Hospital, Telford, UK
Keywords VLCADD; volatile anesthesia; propofol; rhabdomyolysis; metabolic disease Correspondence Dr Catherine Stewart, Princess Royal Hospital, Apley Castle, Grainger Drive, Telford, Shropshire TF1 6TF, UK Email: [email protected] Section Editor: Barbara Brandom Accepted 2 June 2014 doi:10.1111/pan.12474
Summary Very long-chain acyl-coenzyme A dehydrongenase deficiency (VLCADD) is a rare disorder of fatty acid metabolism that renders sufferers susceptible to hypoglycemia, liver failure, cardiomyopathy, and rhabdomyolysis. The literature about the management of these patients is hugely conflicting, suggesting that both propofol and volatile anesthesia should be avoided. We have reviewed the literature and have concluded that the source papers do not support the statements that volatile anesthetic agents are unsafe. The reports on rhabdomyolysis secondary to anesthesia appear to be due to inadequate supply of carbohydrate not volatile agents. Catabolism must be avoided with minimal fasting, glucose infusions based on age and weight, and attenuation of emotional and physical stress. General anesthesia appears to be protective of stress-induced catabolism and may offer benefits in children and anxious patients over regional anesthesia. Propofol has not been demonstrated to be harmful in VLCADD but is presented in an emulsion containing very long-chain fatty acids which can cause organ lipidosis and itself can inhibit mitochondrial fatty acid metabolism. It is therefore not recommended. Suxamethonium-induced myalgia may mimic symptoms of rhabdomyolysis and cause raised CK therefore should be avoided. Opioids, NSAIDS, regional anesthesia, and local anesthetic techniques have all been used without complication.
Introduction Fatty acids are oxidized in the mitochondria by a complex pathway of enzymes which have chain length specificity. The very long-chain acyl-coenzyme A dehydrogenase (VLCAD) enzyme is one of the first in the fatty acid oxidation spiral and catalyzes a critical point in the supply of electrons to the respiratory chain. It also provides a pathway permissive to the production of ketones. Fatty acids are an essential source of energy for the heart and for slow skeletal muscle fibers during exercise. The brain uses ketones during periods of fasting to reduce the need for glucose as a substrate (1). Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) was first described in 1993 and has autosomal recessive inheritance (2). It is very rare and the incidence is unknown. There are three broad phenotypes that correlate with the degree of enzyme deficiency. The neonatal type is the most severe and © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 1115–1119
occurs during the transition from the continuous glucose supply of the placenta to maternal milk containing 60% fatty acids. It is usually associated with a null mutation resulting in no enzyme activity and presents with hypertrophic cardiomyopathy, metabolic acidosis, myopathy, and high mortality (1). Exclusive glucose metabolism during fetal life means the organs develop normally. Fatty acids in the diet after birth deposit in tissues causing organ lipidosis particularly lipid accumulation in cardiomyocytes with increased degenerative fibers and collogen deposition. This is thought to be a causal factor in cardiomyopathy and sudden death (3). Less severe forms include infantile type presenting later in childhood with hypoketotic hypoglycemia (4) with hepatomegaly (1) and adolescent or adult onset forms with fasting or exercise induced muscle spasms and rhabdomyolysis (5) without hypoglycemia (1). These are associated with some residual enzyme activity, resulting from one or two missense mutations (1). 1115
Anesthesia in VLCADD
C. Redshaw and C. Stewart
This condition is generally managed by preventing catabolism with regular carbohydrate feeds and by the prevention of accumulation of very long-chain fatty acids with a low-fat diet and the substitution of very long-chain fatty acids with medium-chain fatty acids (6). It is recommended to aim for
REVIEW ARTICLE
Anesthetic agents in patients with very long-chain acylcoenzyme A dehydrogenase deficiency: a literature review Charlotte Redshaw & Catherine Stewart Department of Anaesthesia, Princess Royal Hospital, Telford, UK
Keywords VLCADD; volatile anesthesia; propofol; rhabdomyolysis; metabolic disease Correspondence Dr Catherine Stewart, Princess Royal Hospital, Apley Castle, Grainger Drive, Telford, Shropshire TF1 6TF, UK Email: [email protected] Section Editor: Barbara Brandom Accepted 2 June 2014 doi:10.1111/pan.12474
Summary Very long-chain acyl-coenzyme A dehydrongenase deficiency (VLCADD) is a rare disorder of fatty acid metabolism that renders sufferers susceptible to hypoglycemia, liver failure, cardiomyopathy, and rhabdomyolysis. The literature about the management of these patients is hugely conflicting, suggesting that both propofol and volatile anesthesia should be avoided. We have reviewed the literature and have concluded that the source papers do not support the statements that volatile anesthetic agents are unsafe. The reports on rhabdomyolysis secondary to anesthesia appear to be due to inadequate supply of carbohydrate not volatile agents. Catabolism must be avoided with minimal fasting, glucose infusions based on age and weight, and attenuation of emotional and physical stress. General anesthesia appears to be protective of stress-induced catabolism and may offer benefits in children and anxious patients over regional anesthesia. Propofol has not been demonstrated to be harmful in VLCADD but is presented in an emulsion containing very long-chain fatty acids which can cause organ lipidosis and itself can inhibit mitochondrial fatty acid metabolism. It is therefore not recommended. Suxamethonium-induced myalgia may mimic symptoms of rhabdomyolysis and cause raised CK therefore should be avoided. Opioids, NSAIDS, regional anesthesia, and local anesthetic techniques have all been used without complication.
Introduction Fatty acids are oxidized in the mitochondria by a complex pathway of enzymes which have chain length specificity. The very long-chain acyl-coenzyme A dehydrogenase (VLCAD) enzyme is one of the first in the fatty acid oxidation spiral and catalyzes a critical point in the supply of electrons to the respiratory chain. It also provides a pathway permissive to the production of ketones. Fatty acids are an essential source of energy for the heart and for slow skeletal muscle fibers during exercise. The brain uses ketones during periods of fasting to reduce the need for glucose as a substrate (1). Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) was first described in 1993 and has autosomal recessive inheritance (2). It is very rare and the incidence is unknown. There are three broad phenotypes that correlate with the degree of enzyme deficiency. The neonatal type is the most severe and © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 1115–1119
occurs during the transition from the continuous glucose supply of the placenta to maternal milk containing 60% fatty acids. It is usually associated with a null mutation resulting in no enzyme activity and presents with hypertrophic cardiomyopathy, metabolic acidosis, myopathy, and high mortality (1). Exclusive glucose metabolism during fetal life means the organs develop normally. Fatty acids in the diet after birth deposit in tissues causing organ lipidosis particularly lipid accumulation in cardiomyocytes with increased degenerative fibers and collogen deposition. This is thought to be a causal factor in cardiomyopathy and sudden death (3). Less severe forms include infantile type presenting later in childhood with hypoketotic hypoglycemia (4) with hepatomegaly (1) and adolescent or adult onset forms with fasting or exercise induced muscle spasms and rhabdomyolysis (5) without hypoglycemia (1). These are associated with some residual enzyme activity, resulting from one or two missense mutations (1). 1115
Anesthesia in VLCADD
C. Redshaw and C. Stewart
This condition is generally managed by preventing catabolism with regular carbohydrate feeds and by the prevention of accumulation of very long-chain fatty acids with a low-fat diet and the substitution of very long-chain fatty acids with medium-chain fatty acids (6). It is recommended to aim for
