Anesthetic Management for Fracture Head of Radius in a Child with Glutaric Aciduria type-1.

Glutaric aciduria Type 1 (GA-1) is an autosomal recessive metabolic disorder that results from deficiency of enzyme glutaryl-CoA dehydrogenase. This gives rise to elevated neurotoxic glutaric acid and 3-hydroxyglutaric acid as well as nontoxic glutarylcarnitine in body fluids. The enzyme defect leads to secondary damage to central nervous system due to the accumulation of glutaric acid. Approximately 90% people will develop the neurological disease during a finite period of brain development (3-36 months) following an acute encephalopathic crisis often precipitated by gastroenteritis, immunization, surgical intervention, and intercurrent febrile illness. GA-1 can also develop insidiously without clinically apparent crisis in 10%-20% of the patients. We present a 10-year-old male child with GA-1 who required anesthetic care for fracture (left) neck of radius. Strategies for anesthetic management should include prevention of hypoglycemia, dehydration, electrolyte imbalance, and sufficient analgesia to prevent surgical stress.

INTRODUCTION

Glutaric aciduria Type 1 (GA-1) is an uncommon, severe autosomal recessive disorder. It was first described by Goodman et al. in 1975.[1] The estimated overall prevalence is 1 in 100,000 newborns but is considerably higher in some genetic isolates.[2] The disease is more common among the Amish people of the US, the Lake Island Indians in Canada.[34] In developing countries like India, very few cases of this disorder have been reported mainly in the form of isolated case report series without much detail on treatment, prognosis, and outcome. This disorder involves deficiency of mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), which results in an inborn error of metabolism of lysine, hydroxylysine, and tryptophan. Mutations in mitochondrial GCDH gene located on chromosome 19 (19p13.2) lead to deficiency of GCDH, a mitochondrial enzyme involved in the metabolism of lysine, hydroxylysine, and tryptophan.[15] Deficiency of this enzyme leads to elevation of glutaric acid, 3-hydroxyglutaric acid and glutarylcarnitine in urine, plasma, and cerebrospinal fluid (CSF) and lead to neuronal damage. About 90% of the patients, who are not treated, will develop movement disorder with predominant dystonia due to striatal injury. This is precipitated during infectious diseases, surgical interventions, following vaccinations. Irreversible striatal injury can be prevented if the diagnosis in made during the newborn period and treatment with carnitine supplementation, low lysine diet, and intermittent emergency treatment is started immediately during intercurrent illness. We report here a 10-year-old male child who required anesthetic care for closed reduction of fracture neck of radius under sedation. Due to unsuccessful attempts at closed reduction, it was converted to open reduction and internal fixation of fracture head of radius under general anesthesia.

CASE REPORT

The patient a 10-year-old male, weighing 30 kg was scheduled for closed reduction of fracture head of radius under sedation. His history was significant for GA-1 which was diagnosed at 2 months of age. He presented with macrocephaly at the time of birth. 2 weeks after birth, the patient had an episode of febrile illness and was diagnosed to have meningitis with metabolic disorder. He also had an episode of seizure for which no treatment was given. At the age of 1½-year-old patient had a spontaneous subdural hematoma which was diagnosed on magnetic resonance imaging and it resolved on its own. He had delayed developmental milestones. His current home medications include L-carnitine 500 mg (OD), riboflavin 60 mg (OD), and pyridoxine. Preoperative physical examination revealed no acute distress, normal systemic examination. Airway examination revealed a Mallampati Grade I view. Preoperative laboratory evaluations including blood glucose, arterial blood gas (ABG), electrolytes, renal function, hepatic function and coagulation profile were normal. The patient was kept nil per oral 4 h before the procedure when an intravenous infusion of 5% dextrose was started at 70 ml/h. Preoperative blood sugar on the morning of surgery was 88 mg/dl with a room air oxygen saturation of 99%. The patient was premedicated with injection ondansetron 0.1 mg/kg. In the operation theater, intravenous fluid in the form of dextrose normal saline (DNS) was started which continued in the postoperative period as well. After attaching routine monitors such as electrocardiogram, noninvasive blood pressure monitor, pulse oximetry, patient was induced with propofol 120 mg and fentanyl 30 μg, and Proseal laryngeal mask airway (LMA) size 2.5 was placed in the first attempt. Anesthesia was maintained with oxygen, nitrous oxide (33:66) and sevoflurane. Due to unsuccessful closed reduction, procedure was converted to open reduction and internal fixation. Neuromuscular blockade was provided with rocuronium 15 mg loading dose. Injection diclofenac 50 mg was given to provide analgesia. Intraoperative blood sugar 1 h after the surgery was 118 mg/dl and ABG was within the normal limits. The patient remained hemodynamically stable during the surgery and surgery lasted 2 h. Neuromuscular blockade was reversed with injection neostigmine 1.5 mg and glycopyrrolate 0.3 mg and LMA was removed when the patient was fully awake. In the postoperative period, the patient remained hemodynamically stable with a normal blood sugar and ABG and was shifted to the ward 2 h after surgery. The patient had an episode of hypoglycemia with blood sugar of 68 mg% 3 h postoperatively which was accidentally noticed on regular blood sugar monitoring. The patient presented with no clinical manifestations of hypoglycemia during this period. It was managed with 10 ml of dextrose 25%. Oral feeding was resumed 4 h after the surgery, and patient was discharged after 36 h uneventfully with no more episode of hypoglycemia.

DISCUSSION

GA-1 is a rare genetic disorder caused due to deficiency of GCDH. This enzyme is involved in catabolic pathways of amino acids L-lysine, L-hydroxylysine, and L-tryptophan. The metabolic hallmark is combined elevation of glutaric acid, 3-hydoxyglutaric acid and glutarylcarnitine in urine, plasma, and CSF. These organic acids accumulate in the brain and lead to neuronal damage, lymphocyte infiltration, elevated concentrations of inflammatory cytokines and nitric oxide, glial proliferation, atrophy of striatal neurons, and neurological dysfunction.[6] Secondary carnitine deficiency will occur as the accumulated organic acids are detoxified by carnitine. The initial presentation in most of the children is usually nonspecific, and Macrocephaly is frequently found. The prognostically relevant event is the onset of acute encephalopathic crisis which is usually precipitated by episodes that induce catabolic state during a vulnerable period in infancy which leads to irreversible striatal injury and subsequently movement disorders.[7]

Without routine newborn screening, early diagnosis is difficult as there are no pathognomonic signs or symptoms. The key metabolites can be detected by gas chromatography/mass spectrometry of glutaric acid and 3-hydroxyglutaric acid or tandem mass spectrometry(MS/MS) of glutarylcarnitine.[8] Early routine treatment with carnitine supplementation, special restriction diet, and neuroprotective emergency treatment, most patients with GA-1 may have protection against encephalopathic crisis and possibly lead a normal life.[9] Emergency treatment to prevent encephalopathic crisis include prevention of catabolic state by administering high energy intake, reduction of neurotoxic metabolites by transient reduction or omission of natural protein for 24–48 h, prevention of secondary carnitine depletion by carnitine supplementation, maintenance of normal hydration, electrolytes and pH status in enteral/iv fluids.[10]

Brain imaging performed shortly after birth usually shows frontoparietal atrophy with widening of Sylvian fissures and arachnoid cysts, and the brain is vulnerable to head trauma that can lead to acute subdural or retinal hemorrhage. Brain atrophy and neuronal loss following injury to basal ganglia may cause symptoms such as spasticity, rigidity, dystonia, posture impairment, and complications that impair oral feeding and communication.[11]

For patients undergoing surgery with GA-1, in the perioperative period focus should be on prevention of pulmonary aspiration, acute encephalopathic crisis which include prevention of dehydration, hypoglycemia, catabolic state, maintenance of normal hemostasis, adequate analgesia to prevent surgical stress and avoidance of prolonged neuromuscular blockade. In the present case study intravenous fluid supplementation in the form of dextrose 5% was started early, which was followed by DNS intraoperatively and postoperatively to prevent both dehydration and hypoglycemia. Airway was maintained with Proseal LMA size 2.5 as closed reduction of fracture was planned to be done under sedation. Due to unsuccessful attempts at closed reduction, it was converted to open reduction and internal fixation of fracture. As Proseal LMA was already in place, so we decided to continue the procedure with LMA. One of the primary concerns in children with GA-1 or any other chronic debilitating central nervous system (CNS) disorder with loss of function relates to the possibility of pulmonary aspiration of gastric contents during anesthetic induction. Precautions to prevent such problems include preoperative administration of H2-antagonist and the use of modified rapid sequence induction. Medications with extrapyramidal side effects like metoclopramide to facilitate gastric emptying should be avoided in a patient with underlying involvement of the basal ganglia.

Carnitine deficiency is a frequent secondary finding in patients with GA. As carnitine is an essential cofactor in the transport of long-chain fatty acids into the mitochondria and plays a crucial role in fatty acid oxidation, it is suggested that propofol should be avoided in this condition. Propofol can cause lipid overload; it also may impair mitochondrial electron transport with inhibition of oxidative phosphorylation, palmitoyltransferase transport of long-chain fatty acids, and beta-oxidation of fatty acid in mitochondria.[12] This could predispose to propofol infusion syndrome and severe metabolic acidosis in patients with mitochondrial disorders, carnitine deficiency, and inadequate carbohydrate intake. Although its single dose for anesthetic induction has not been questioned, the safety of more prolonged infusions remains questionable. Hence, we preferred single dose use of propofol for induction of anesthesia.

Problems related to poor upper airway control and defective control of ventilation with the associated CNS damage may lead to perioperative respiratory insufficiency. For maintenance of anesthesia, short-acting agents such as sevoflurane and desflurane should be used to preserve postoperative respiratory function. In our patient, we used sevoflurane for maintenance.

Perioperative monitoring of respiratory function is suggested when opioids are required for postoperative analgesia. The use adjunctive agents like acetaminophen is suggested to decrease the need of opioids and their associated side effects.

Due to progressive deterioration of CNS function, seizures can occur in patients with GA-1. To limit perioperative seizures, preoperative management should focus on optimizing and confirming therapeutic anticonvulsant levels before the surgery. Routine anticonvulsant medications should be continued till the morning of surgery. Sodium valproate inhibits mitochondrial beta-oxidation of fatty acids and should be avoided in patients with mitochondrial metabolic disorders.

Another major concern is the increased sensitivity and prolonged response to neuromuscular blocking agents in patients with GA-1. Intermediate-acting neuromuscular blocking agent like rocuronium had been used in patient with GA-1. Due to the presence of CNS involvement, the use of succinylcholine is controversial because of hyperkalemic responses to succinylcholine. To avoid prolonged muscle relaxation, we used rocuronium which was reversed with injection neostigmine and glycopyrrolate at the end of the surgery. To avoid pain and surgical stress fentanyl at the time of induction and diclofenac were used. Removal of LMA was carried out when the patient was awake with the presence of airway protective reflexes, adequate spontaneous respiration.

CONCLUSION

GA-1 is an autosomal recessive mitochondrial disorder due to deficiency of GCDH. Anesthetic management should focus on prevention of encephalopathic crisis, hypoglycemia, dehydration, electrolyte imbalance, and pulmonary aspiration of gastric contents. We administered general anesthesia with propofol, rocuronium, sevoflurane, and appropriate fluid management was done to prevent hypoglycemia. Our patient remained comfortable during surgery and in the postoperative period as well.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.