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From Sections of Pediatrics and Congenital Heart Disease Anesthesia, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Address correspondence to: Dr. Julie Tome, Staff Anesthesiologist, The Cleveland Clinic Foundation, Division of Anesthesia and Critical Care Medicine, 9500 Euclid Ave., Cleveland, OH 44195, USA. Phone: 216-444-8389; Fax: 216-445-2536; E-mail: TOMEJ{at}CCF.ORG
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Clinical features: An 11-yr-old girl with GAII manifested as severe hypoglycemia since she was a newborn and generalized muscle weakness. She underwent open-heart surgery for VSD correction with CPB. The anesthetic management avoided inhalational anesthetics, maintained the blood sugar within normal limits and continued normothermia during CPB in order to avoid the stress of hypothermia for her abnormal mitochondria. The patient tolerated the procedure well and experienced a good recovery.
Conclusion: The anesthetic management of patients with any mitochondrial disease requires normoglycemia, normothermia and the avoidance of metabolic stress in order to preserve energy production by the diseased mitochondria.
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Case report |
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Patient’s past medical history
She was born at 33 weeks gestation with a VSD and atrial septal defect (ASD). At seven days of age, she had a cardiac arrest at home and was diagnosed with severe apnea and a seizure disorder. A failure to thrive investigation at seven months included a skin biopsy and fibroblast culture, which were consistent with GAII. She remained on an apnea monitor until 18 months, at which time her ASD had closed spontaneously. The patient became progressively more symptomatic with gastric dysmotility, asthma and proximal muscle weakness often requiring wheelchair use by the age of nine years. Mental status and intelligence were normal for age. The family history was significant in that her mother, brother, and maternal aunts were all diagnosed with mitochondrial disorders. Echocardiography showed normal left ventricle function and size and a small perimembranous VSD with left to right flow maximum velocity of 4.7 m•sec–1. No other abnormalities were detected. Her intolerance to lorazepam resulted in severe agitation.
Anesthetic management
During preoperative fast, the patient received 10% dextrose in 0.25% normal saline infusions at 90 mL•hr–1. After routine monitors were applied, induction of anesthesia was managed with ketamine 50 mg (1 mg•kg–1) and fentanyl 100 µg (2 µg•kg–1); intubation was facilitated with rocuronium 25 mg (0.5 mg•kg–1). A 20 gauge arterial catheter was inserted into the left radial artery and a central venous pressure line (CVP) into the right internal jugular vein. Anesthesia was maintained with N2O in O2 in pre-CPB period then with 100% O2 after bypass period with intermittent doses of ketamine (total 150 mg) to prevent awareness and rocuronium was titrated to train-of-four (TOF) response. Analgesia was provided by a remifentanyl infusion at the dose of 0.2 µg•kg–1•min–1 and a morphine infusion at 40 µg•kg–1•hr–1. Body core temperature was maintained between 35.9°C and 36.4°C throughout the procedure and during CPB. Serum blood glucose was 5 mmol•L–1 after anesthetic induction with a lactate level of 1.3 mmol•L–1. During CPB serum blood sugar was in the 10–12.9 mmol•L–1 range and serum lactate level peaked at 2.6 mmol•L–1 (normal up to 2.0 mmol•L–1) measured immediately post-CPB. Total bypass time was 33 min and aortic cross-clamp time was 11 min. The CPB pump was primed with a solution containing dexamethasone in the dose of 0.25 mg•kg–1, plasmalyte, 25% albumin, NaHCO3 and calcium chloride. The pump flow was kept at 100–128 mL•kg–1•min–1 to maintain a cardiac index of 2.4 L•m2•min–1 and venous oxyhemoglobin saturation was between 75–80%. Closure of the VSD was confirmed by a transesophageal echocardiography contrast study. Central venous pressure was maintained post-bypass at 6 mmHg with boluses of 0.9% normal saline as needed. During recovery, insulin was administered to keep blood glucose at 10–12 mmol•L–1. Sodium nitroprusside 1.5 µg•kg–1•min–1 was administered for two hours postoperatively to control blood pressure. She was transfused to a hematocrit of 30% after CPB with pump blood. The postoperative course was uneventful and the patient was discharged from the hospital on the third day.
The child denied awareness and discomfort during the procedure, and family or caretakers have denied any increase in muscle weakness or other neurologic disturbances. Her medications on discharge were the same as preoperatively: Coenzyme Q10, Vitamin B, carnitine, amitriptyline, and paroxetine.
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GAII was first described by Przyrembel in 1976 as a deficiency in the electron transfer flavoprotein (ETF) that moves electrons from flavine-adenine dineclotide (FAD) of acyl CoA dehydrogenases to coenzyme Q in the respiratory chain. This leads to the accumulation of free fatty acids in the plasma and the urinary excretion of large amounts of organic acids. This condition differs from glutaric aciduria type 1, characterized by the accumulation of glutaric acid, which is due to a recessively inherited deficiency of glutaryl CoA dehydrogenase.5–8 GAII has been categorized into three subgroups. The first group is the neonatal onset GAII that includes congenital anomalies such as dysmorphic facies (potter type), polycystic kidneys and other general abnormalities. The second group is the neonatal onset GAII without congenital abnormalities, which presents immediately after birth or in the first days of neonatal life. The patients usually have symptoms of respiratory distress, hypoglycemia and metabolic acidosis without ketosis. The third group is the late onset GAII which is characterized by repeated episodes of hypoglycemia accompanied by elevated serum concentrations of free fatty acids without ketosis, fatty infiltration of the liver, hepatic dysfunction and proximal myopathy. This disease is usually characterized by a "generalized sweaty foot odour." The urine of these patients contains increased amounts of organic acids such as glutaric acid, ethylmalonic acid and dicarboxylic acids with six to ten carbons. The hypoglycemia is due to impaired oxidation of fatty acids resulting in decreased hepatic gluconeogenesis. The increased amounts of glutaryl CoA and ethylmalonic acid lead to the inhibition of mitochondrial uptake of malate, which is a rate-limiting step in gluconeogenesis.9 GAII is usually accompanied by lactic acidosis, which arises from a severe energy deficiency in the muscle and from an impaired recycling of lactate to glucose via the Cori cycle.9 The acidosis leads to impaired renal excretion of uric acid resulting in hyperuricemia.9 Riboflavin which acts as the precursor of FAD which is the common coenzyme of acyl CoA dehydrogenase, can be used as a treatment for GAII exacerbations.10
There is no single scheme or method to follow for the anesthetic management of patients with mitochondrial cytopathies. By reviewing the literature, every agent and technique have been used successfully, however, there are certain controversial issues that should be considered.4,11 Volatile anesthetics have been used uneventfully in several case reports.12,13 However, in one case report a malignant hyperthermia type episode occurred when inhalation anesthetics and succinylcholine were used.14 In our case, potent inhalational anesthetics were avoided due to the fear of lactic acidosis and the inability to distinguish post-bypass hyper metabolic states from anesthesia-induced malignant hyperpyrexia. Additionally, myocardial depressant effects can be caused by volatile anesthetics due to reductions in intracellular calcium concentration, and inhibition of the sodium-calcium exchange mechanism. Recently it has been shown that halothane and sevoflurane have inhibitory effects upon norepinephrine-induced glucose uptake in neonatal cardiomyocytes. This decrease in glucose uptake is associated with lowered intracellular calcium and diminished myocardial contractility. Glucose represents the sole energy supply to the newborn heart in contrast to the adult heart, which depends mainly upon fatty acids as a source of energy.15 This finding emphasizes the importance of avoiding hypoglycemia in pediatric patients in order to avoid myocardial depression. This is especially important when dealing with children who have impaired glucose homeostasis and are unable to utilize fatty acids as in the child presented in this report. In spite of the age of the patient, the myocardial cells can still be immature due to mitochondrial disease. It has been documented that the mitochondrial cytopathies in general can be accompanied by cardiomyopathy,16,17 however, fortunately, our patient has normal cardiac function. One of the sites of action of inhalation anesthetics is the gas-1 (general anesthetic sensitive) gene, which encodes 49-KDa (IP) subunit of complex 1 of the respiratory chain. The proteins 49-KDa (IP) are essential for the proper function of complex 1 of the respiratory chain. The volatile anesthetics inhibit gas-1 gene and decrease the function of complex 118 thus enhancing the inhibitory effects of volatile anesthetics in the patients with mitochondrial diseases. N2O in vitro increases NO and is known to inhibit cis-acotinase and iron containing electron transport enzymes and may also affect energy production.4 However, we chose to use N2O to reduce the risk of awareness, in lieu of benzodiazepines. In order to maintain metabolic homeostasis in our patient, Ringer’s lactate was avoided to prevent an exacerbation of lactic acidosis. Instead, dextrose 10% in 0.25% normal saline was titrated to serum glucose levels of 10–12 mmol•L–1. Third space losses were replaced with a normal saline infusion.
The use of hypothermic CPB (to 28°C) has been reported in a patient with mitochondrial disease.19 The 41-yr-old patient with Kearns-Sayre syndrome underwent hypothermic CPB for aortic coarctation repair, aortic valve repair and patent ductus arteriosus ligation. However, a normothermic CPB technique was used in our patient to achieve many goals. Liver function and hepatic mitochondrial redox potentials are measured by arterial ketone body ratio (AKBR) and hepatic venous ketone body ratio, which is usually calculated by the ratio of acetoacetate to 3-hydroxybutarate. This potential is better maintained with normothermic CPB than with hypothermic CPB. The complement system activity and the immune system are better maintained with normothermic CPB due to a better AKBR thus decreasing the production of immune mediators during CPB and inflammatory processes as well. Also with low hepatic mitochondrial activity, phagocytosis by Kupffer cells and the reticuloendothelial system activity decline which increases in the incidence of postoperative infections.20,21 In this case, AKBR was not measured, however, lactic acid level was measured as a global index of anaerobic metabolism. Also, during hypothermic CPB the increase of free radical potential is high due to increased tissue PaO2 levels, which can have a deleterious effect upon cellular functions especially in patients with mitochondrial disease.22 Because mitochondria uses oxidative metabolism to produce energy to achieve and maintain normothermia in the early postoperative period, we felt that compulsive maintenance of core and surface body temperatures during CPB and the post-CPB periods were essential to avoid further metabolic stress in this patient.
Although it has been reported that patients with mitochondrial cytopathies may have decreased ventilatory response to hypoxia and hypercarbia,23,24 this did not occur in the present case. Vigilant monitoring of respiratory function should be maintained post major surgery in an intensive care unit. Muscle relaxants are often avoided in mitochondrial cytopathy patients due to reports of prolonged recovery times.25,26 We chose intermittent doses of rocuronium for lack of its cardiovascular effects and intermediate duration. The relaxation was adequate and the patient did not show impaired neuromuscular function, with a complete recovery time of less than one hour after the last dose.
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Revision received July 22, 2002. Accepted for publication March 22, 2002.
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