Glutaric aciduria type I (GA-I) is a rare neurometabolic disorder caused by an autosomal recessive inherited deficiency of glutaryl-coenzyme A (CoA) dehydrogenase.1 This enzyme catalyzes oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the degradative pathways of lysine, hydroxylysine, and tryptophan resulting in increased formation of putatively neurotoxic dicarboxylic acids, glutaric (GA) and 3-hydroxyglutaric acid (3-OH-GA), and nontoxic glutarylcarnitine.2 The majority of untreated patients develop acute basal ganglia injury, particularly affecting the striatum (putamen and caudate) and, subsequently, a complex movement disorder with predominant dystonia during infancy or early childhood. Striatal injury occurs acutely during encephalopathic crises precipitated by catabolic stress or insidiously without preceding crises.3 Infectious diseases, vaccinations, and surgery have been associated with striatal injury in these patients.4 Recommended metabolic treatment consists of low lysine diet and carnitine supplementation and emergency treatment during potentially threatening episodes such as infectious diseases.5 The major biochemical effect of metabolic treatment is reduction of cerebral GA and 3-OH-GA.6,7 Although early diagnosis and start of metabolic treatment prevents irreversible striatal injury in the majority of patients,8 there are only a few reports on the neuroprotective effect of metabolic treatment during and after surgery.9–11 To the best of our knowledge, this is the first report of the anesthetic and perioperative management of a child with GA-I undergoing cardiac surgery with extracorporeal circulation (ECC). The parents of this child gave written consent to publish this exceptional case report.
In this child, GA-I was suspected by the national newborn screening program and confirmed by identification of 2 known disease-causing mutations, p.Arg88Cys and p.Arg227Pro, in the GCDH gene (gene map locus 19p13.2). Family history did not reveal any evidence for another family member being affected by GA-I. Low lysine diet and carnitine supplementation were started after confirmation of the diagnosis. During the following 3 years, the girl was admitted to hospital 19 times for IV metabolic emergency treatment preventing the secondary dystonia (Barry-Albright dystonia rating scale: 0 point). Neuropsychological testing showed normal results. Cranial magnetic resonance imaging studies at ages 12, 25, and 38 months demonstrated unaffected basal ganglia and normal brain maturation. At age 3.5 years, the girl was admitted to our hospital for surgical correction of a secundum atrial septal defect (ASD). Cardiomegaly had been detected during an episode of pneumonia at age 19 months. Subsequently, echocardiography showed a large ASD resulting in volume overload of the right ventricle. Since regular follow-up monitoring demonstrated hemodynamically relevant progression, the indication for percutaneous device closure of the ASD was present. This intervention failed due to an adverse position and size of the defect and, therefore, cardiac surgery was required. To minimize the risk of developing acute striatal injury during or after cardiac surgery, a detailed strategy was discussed in advance.
To minimize the risk of catabolism due to 6 hours of preoperative fasting before elective surgery,12 we simultaneously started an infusion of glucose in saline (8 g glucose/kg body weight [BW] per day IV) and L-carnitine (100 mg/kg BW per day IV).5 Low-dose insulin infusion was used to maintain normal serum glucose. Electrocardiogram showed sinus rhythm with incomplete right bundle block, and the transthoracic electrocardiogram demonstrated good biventricular heart function. Routine laboratory investigation, specifically coagulation, was normal. Oral premedication consisted of 0.5 mg/kg BW midazolam.
After placing standard noninvasive monitors, general anesthesia was induced by midazolam, thiopental, fentanyl, and rocuronium and maintained with sevoflurane, fentanyl, and remifentanil. Ventilation was set to avoid hyperventilation and maintain normal cerebral circulation. Initially, paracetamol suppository (30 mg/kg BW) was given to prevent pyrexia. Routinely, cefuroxime (40 mg/kg BW) as antibiotic therapy and furosemide (0.2 mg/kg BW) were given. Central venous and arterial catheters were inserted, and additional monitoring included a urethral catheter, noninvasive cerebral monitoring (near infrared spectroscopy), and rectal and nasopharyngeal temperature measurement. Anticoagulation using heparin maintained the activated coagulation time at >400 seconds. ECC was established under pH-STAT conditions to avoid hypocarbia. Anesthesia during cardiopulmonary bypass (CPB) was maintained with midazolam and remifentanil.
Surgical Intervention and Perfusion Procedure
After median sternotomy, ECC was established by cannulating the distal ascending aorta and both venae cavae. Antegradely administered cardioplegia was entirely aspirated close to the orifice of the coronary sinus to avoid any efflux into the ECC circuit. We used Custodiol™ which contains L-tryptophan (408.5 mg/L) as cardioplegic solution. However, because L-tryptophan can be metabolized to neurotoxic GA and 3-OH-GA, we reduced the tryptophan load by almost complete aspiration of the cardioplegic solution. The residual solution (approximately 8 mL) contained 3 mg L-tryptophan (i.e., 1% of her daily tryptophan intake). To minimize the protein load of and inflammatory response to ECC, we reduced the total volume of the ECC system, used red cell concentrates, and omitted fresh frozen plasma and, subsequently, used effective hemofiltration. Separation from ECC after 51 minutes of CPB (4000 IU protamine sulfate) was uneventful without any vasopressors or inotropic drugs. In addition to 150 mL of red cells for ECC priming and 100 mL during CPB, 3 mL/kg BW of red cells were given to achieve stable hemodynamics after which the patient was transferred to the pediatric cardiac intensive care unit under stable hemodynamic conditions.
Postoperative Management and Follow-Up
Postoperative metabolic management was continued with glucose saline (8 g glucose/kg per day IV) and L-carnitine (100 mg/kg per day IV) for 24 hours. Since stepwise introduction of oral dietary treatment was delayed, transient total parenteral nutrition was introduced after 24 hours to achieve the daily demand of lysine (60 mg/kg per day), other essential amino acids, energy supply (90 kcal/kg per day), minerals, and micronutrients. Total parenteral nutrition was adapted to the dietary protocol of this girl. Subsequently, oral dietary treatment was reintroduced over 7 days, and parenteral nutrition was concomitantly reduced and finally discontinued. Low lysine diet (60 mg lysine/kg per day) was based on natural food with a low lysine content and was supplemented with a lysine-free amino acid mixture. This diet provides adequate supply of protein (2.6 g/kg per day), energy (90 kcal/kg per day), minerals and micronutrients, and agrees with recent guideline recommendations.5 Intense metabolic monitoring from 1 day before to 10 days after cardiac surgery revealed normal results for serum glucose, blood gases, and plasma amino acids. Free carnitine levels in plasma were in the upper normal range or above. Urinary ketones were negative. Urinary GA (1–4 mmol/mol creatinine; normal <8) and 3-OH-GA (16–32 mmol/mol creatinine; normal <10) concentrations remained in the same range as before.
Follow-up monitoring until 5 years of age revealed no evidence for acute striatal injury and dystonia. Her electroencephalogram was normal, and psychological testing showed a normal IQ at 50 months of age.
The metabolic and anesthetic management in children with GA-I may be challenging because there are limited data regarding the perioperative strategy. Given the central focus on prevention of acute striatal injury, our anesthetic strategy was to avoid a high protein load by substitution with fresh frozen plasma, high-dose inotropics, especially epinephrine associated with impaired glucose utilization, forced hyperventilation with reduced cerebral circulation, and prevention of systemic inflammatory response syndrome.
High protein and concomitantly high lysine intake and release of lysine from body protein during catabolism increases the cerebral lysine influx and, secondarily, stimulates cerebral lysine oxidation and the accumulation of neurotoxic dicarboxylic metabolites (GA, 3-OH-GA, glutaryl-CoA) in the brain compartment. These metabolites are thought to be trapped in the brain due to the blood–brain barrier which provides only weak transport capacity for dicarboxylic acids.13–15 Accumulation of these metabolites has negative consequences on brain energy metabolism, because tricarboxylic acid flux is impaired (by glutaryl-CoA) and the astrocyte-to-neuron dicarboxylate shuttle is blocked (by GA and 3-OH-GA).16,17 In addition, weak excitotoxic cell damage is induced (by 3-OH-GA).18 Therefore, keeping cerebral concentrations of these dicarboxylic metabolites in a low range is a major biochemical goal of all metabolic treatment strategies for GA-I. A biochemical proof of principle, i.e., oral lysine intake influencing cerebral concentrations of these metabolites and the neurological outcome, has been demonstrated in Gcdh-deficient mice.6,7 Furthermore, recommended therapeutic strategies that aim to reduce cerebral lysine influx and oxidation, such as low lysine diet, carnitine supplementation, and emergency treatment (to prevent catabolism), have been associated with the best outcome in neonatally diagnosed GA-I patients.3,8
This case report highlighting treatment designed to prevent basal ganglia injury in patients undergoing cardiac surgery with ECC5 can only be achieved, however, after appropriate interdisciplinary perioperative strategy has been implemented. E
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