Anaesthetic considerations in a child with methylmalonic acidemia and its literature review

Abstract

Methyl malonyl coenzyme A mutase deficiency is a rare autosomal inherited inborn error in branched-chain amino acid metabolism characterised by the accumulation of methylmalonic acids. There is relative paucity of literature regarding anaesthetic management of these children presenting for incidental major abdominal surgery. Preoperative management includes goal-directed correction of dehydration, metabolic acidosis and hyperammonemia. Anaesthetic goals include avoidance of factors that can trigger metabolic crisis like hypercapnia, hypothermia, hypoxia, surgical stress, hypovolaemia, hypotension and so on. Herein, we are reporting the anaesthetic management of a 17-month-old child with methylmalonic acidemia (MMA) posted for a major upper abdominal surgery for excision of an adrenal mass, which was incidentally diagnosed during admission for an episode of metabolic crisis. We aim to highlight the specific nuances of pathophysiology of the disease, preoperative optimisation, anaesthetic considerations, role of advanced monitoring and regional anaesthesia and current literature on the management of patients with MMA.

Background

Methylmalonic acidemia (MMA) is an autosomal recessive disorder with an estimated incidence of 1:50 000.^{1 2} This disease is characterised by abnormal functioning of methylmalonyl coenzyme A mutase (MCM) leading to accumulation of methyl-malonyl coenzyme A, metabolic acidosis and hyperammonemia. This leads to symptoms of vomiting, dehydration, lethargy and weak muscle tone usually with in the first month of life. Preoperative optimisation keeping in mind the goals of correcting the complex metabolic abnormalities and anaesthetic management tailored explicitly to avoid triggering of metabolic crisis are the cornerstones of management. Multisystem involvement with its widespread pathophysiological effects leads to a multitude of anaesthetic challenges and concerns in a patient with MMA.

Long-term complications associated with the disease include mental retardation, seizures, renal failure, coma and death. The rarity of the disease can lead to delay in diagnosis and poor outcomes.¹

The anaesthetic management of a child with MMA and left suprarenal mass scheduled for left adrenalectomy is reported. An informed consent was taken from the parents of the child.

Case presentation

A 1-year and 5-month-old female child weighing 10 kg, diagnosed as a case of MMA, was found to have a suprarenal mass on abdominal ultrasound during evaluation for severe vomiting and decreased urine output. According to the parents, the child was admitted to neonatal intensive care unit (NICU) at day 4 of life due to lethargy and poor response. Investigations at that time had revealed severe metabolic acidosis with hyperammonemia (299.6 μmol/L), raised urinary ketones, thrombocytopenia (platelet count 32×10⁹/L) and leucopenia (24×10⁹/L). An inborn error of metabolism was suspected, and tandem mass spectrometry/ gas chromatography mass spectrometry showed raised methyl malonic acid. After 2 months of NICU stay, child was discharged on special formula feeds, vitamin B₁₂ injections and oral carnitine. Subsequently the child underwent multiple hospitalisations due to acidosis and hyperammonemia with severe vomiting, dehydration, oliguria.

At the age of 6 months, clinical exome study revealed homozygous mutation in Metabolism Of Cobalamin Associated B (MMAB) (-) gene involving exon-7 and a formal diagnosis of MMA of cbIB complementation type was made.

During her present admission, the child had signs of dehydration, tachycardia, tachypnea and delayed capillary refill time.

Investigations

During present episode, her serum ammonia was raised (138 µmol/L; normal range: 11–32 µmol/L) and arterial blood gases (ABG) revealed severe metabolic acidosis (pH 7.26 and HCO₃ 18 mEq/L, lactate, 2.5 mEq/L), positive urinary ketones and hyponatraemia (Na 122 mEq/L). Serum cortisol, testosterone, dehydroepiandrosterone sulfate (DHEAS), urine 24 hours vanillyl mandelic acid (VMA) and plasma metanephrine levels were normal.

MRI was done in view of tremors, revealed frontotemporoparietal atrophy with normal basal ganglia and brainstem.

Treatment

The surgery was deferred for preoperative optimisation. The child was kept nil per orally and resuscitated with fluid, electrolytes and sodium bicarbonate over next 4 hours, after which dextrose-containing maintenance fluid was started at 1.5 times the maintenance rate. Treatment with sodium benzoate was commenced and optimised to 250 mg/kg/day. The child received antibiotics, oral lactulose syrup, L-carnitine (100 mg/kg/day), hydroxocobalamin 1 mg intramuscularly (IM) on alternate days, oral sodium bicarbonate (1 mEq/kg/day), oral arginine and iron supplements.

Repeated ABG showed improvement (pH 7.38; HCO₃ 19.2 mEq/L), urine ketones became negative and serum ammonia came down to 97 mmol/L. Over next few days, feeds were started using low protein diet. MRI was done in view of tremors, revealed frontotemporoparietal atrophy with normal basal ganglia and brainstem. Serum cortisol, testosterone, DHEAS, urine 24 hours VMA and plasma metanephrine levels were normal.

During preoperative evaluation, the child was active and there were no signs of dehydration. She did not have any dysmorphic facies and airway was normal. Investigations revealed anaemia (haemoglobin 8.3 g/dL), normal electrolytes and venous blood gases. Her coagulation profile, serum ammonia level (32 μmol/L), liver and renal function were within normal limits. ECG and echocardiogram were normal. Intravenous L-carnitine was continued till surgery and infusion were continued intraoperatively. Hydroxocobalamin was given IM night before and on morning of surgery and 10% dextrose (5 ml.kg.h-1) was continued during fasting period and for maintenance intraoperatively.

Standard fasting guidelines were followed. Inside the operating room, five lead electrocardiography, pulse oximetry and non-invasive blood pressure were attached and monitored continually. Heating mattress and intravenous fluid warmer were used intraoperatively. Anaesthesia was induced with propofol 10 mg and fentanyl 20 µg intravenously using existing intravenous line. Atracurium 5 mg intravenous was administered for achieving neuromuscular blockade, and airway was secured using 5 mm internal diameter uncuffed endotracheal tube. Following anaesthesia induction, right internal jugular vein was cannulated with ultrasound guidance using five French central venous catheter. A caudal epidural catheter was inserted. Anaesthesia was maintained with isoflurane (minimum alveolar concentration 0.8%–1.2%), a gas mixture of oxygen and air (FiO₂ 0.4). Analgesia was provided with 1% ropivacaine plus 20 µg/kg morphine through the caudal catheter and paracetamol 150 mg intravenous.

Blood sugar, end-tidal carbon dioxide, ABG, urine output and oropharyngeal temperature were monitored intraoperatively and remained within normal limits. There were no episodes of hypoxia or haemodynamic instability. The surgery lasted for approximately 3 hours with minimal blood loss (25–30 mL). At the end of procedure, ABG showed pH 7.30, pCO₂ 40.6 mm Hg, HCO₃ 19.6 mmol/L and lactate 1.9 mmol/L. Antiemetic prophylaxis was provided with ondansetron 1 mg intravenous. Neuromuscular blockade was reversed using intravenous neostigmine 70 µg/kg and glycopyrrolate 10 µg/kg. Since recovery of respiratory effort was inadequate, the child was mechanically ventilated for 4 hours.

Outcome and follow-up

The trachea could be extubated following return of consciousness and regular breathing pattern.

Postoperatively, treatment for MMA was continued, repeated ABG sampling and serum ammonia level were done and optimised. Analgesia was maintained by epidural morphine 40 µg/kg diluted in 6 mL normal saline administered two times a day and intravenous paracetamol 15 mg/kg four times a day. Epidural catheter was removed on postoperative day 3.

Discussion

MMA is a rare autosomal recessive inborn error of metabolism with variable symptoms and severity depending on mutation.¹ Lack of MCM enzyme, partially active enzyme, or defects in cobalamin metabolism lead to accumulation of methylmalonic acid. Affected children may present with symptoms within first few days or begin to show symptoms later in infancy or childhood depending on genetic inheritance. Usual presentation is poor appetite, frequent vomiting, extreme sleepiness, low muscle tone, lethargy and tremors.

Left untreated, the disease progresses to breathing problems, cardiomyopathy, seizure, stroke, coma and death. Children demonstrate disability, development delay, osteoporosis, hepatomegaly, kidney disorders and vision loss. Management includes low protein diet, L-carnitine, arginine, vitamin B₁₂ (as hydroxocobalamin) and mineral supplementation, antibiotics to reduce intestinal flora, sodium bicarbonate and sodium benzoate.^2–4

Neonates and infants with organic acidurias and severe ketoacidosis present with intracellular dehydration that is often underestimated. Therefore, adequate rehydration is essential. The child in the index report was aggressively resuscitated with fluid, electrolytes and sodium bicarbonate, following which dextrose-containing maintenance fluid was started at 1.5 times the maintenance rate.

However, over aggressive hydration and alkalinisation may cause or exacerbate cerebral oedema. Hence, judicious rehydration and ABG-guided correction of electrolyte and acid–base homeostasis is recommended. In MMA, forced diuresis and alkalinisation of urine with sodium bicarbonate may help to eliminate methylmalonic acid due to its high renal clearance.¹

L-carnitine therapy is mainly given to compensate for secondary carnitine deficiency caused by urinary loss of carnitine-bound to organic acids and is considerably safe.^{1 2} L-carnitine supplementation seems to contribute to the reduction of hyperammonemia and demonstrates antioxidant capacity. Ammonia scavengers are drugs that allow bypassing of the urea cycle, by conjugation of benzoate with glycine to generate hippurate. Sodium benzoate has been reported to be safe and efficacious to treat hyperammonemia.¹ In the present case, sodium bicarbonate, L-carnitine, arginine and sodium benzoate were given to manage acute crisis and continued perioperatively. Hydroxocobalamin was administered on morning of surgery and L-carnitine was continued as infusion throughout the surgery.

Affected children who require surgery need careful preoperative assessment to diagnose and quantify extent of decompensation. Elective surgery should be postponed for optimising metabolic acidosis, dyselectrolytemia or increased blood ammonia levels.⁵ The index case was initially deferred for correction of the metabolic derangements. Hyperkalemia secondary to metabolic acidosis has previously been implicated in cardiac arrest in a child with MMU.⁶ In case of metabolic crisis and emergency surgery, perioperative hemodialysis should be considered.^{5 6}

Though rare, prolonged QTc and cardiomyopathy has been described and should be ruled out by getting a baseline ECG and echocardiography.⁷

Sharar et al⁸ highlighted the importance of minimising preoperative fasting period and starting dextrose-containing fluid during fasting period and continuing it intraoperatively as prolonged fasting can trigger protein catabolism and metabolic crisis. In the present case, fasting period was minimised and dextrose-containing intravenous fluid was continued perioperatively as a metabolic substrate in the dose described by Baba et al.⁵ Previous authors have supplemented dextrose infusion perioperatively in varying doses as dextrose normal saline, 5% or 10% dextrose.^{5 9 10}

Anaesthetic technique needs to be tailored depending on patient status and surgical needs. Intraoperatively factors that can trigger metabolic crisis like hypercapnia, hypothermia, hypoxia, surgical stress, hypotension and so on should be avoided.¹¹ In the index case, diligent care was taken to maintain oxygenation, normothermia, normocapnia, normovolemia and normotension. Avoidance of hypotension and hypovolaemia is of paramount importance.⁵ Hence, invasive monitoring (central venous pressure) was instituted, and central venous pressure, acid–base homeostasis, blood pressure and urine output were maintained in normal range.

Surgical stress was minimised by using ultrasound-guided caudal epidural blockade using ropivacaine with morphine. In addition, paracetamol provided multimodal analgesia. Provision of good postoperative analgesia by continuing the epidural analgesia postoperatively helped to minimise any adverse metabolic consequences of pain. Uemura et al¹⁰ reported anaesthetic management of a case of MMA using a combination of general anaesthesia and rectus sheath block. The patient did not require any rescue analgesics postoperatively and remained metabolically compensated. Our patient also remained pain free and did not develop any metabolic complications postoperatively. Steroids were avoided as a part of multimodal analgesia as their catabolic effects can trigger acute crisis and decompensation.¹ Patients with MMA are at risk for renal insufficiency, so non-steroidal anti-inflammatory drugs (NSAIDs) are avoided as was followed in the present case. Also, NSAIDs such as derivatives of ibuprofen, loxoprofen and flurbiprofen axetil metabolise into methylmalonic acid and should be carefully evaded.¹⁰

Nitrous oxide inhibits adenosylcobalamine and should be avoided, especially in patients responsive to vitamin B₁₂ therapy.⁸ In present case and other previous reports of MMU, combination of air/oxygen was used intraoperatively while vitamin B₁₂ was administered preoperatively.^{9 10}

Safety of propofol in MMA patients has been debated as it was found to be associated with metabolic decompensation in a liver transplant patients.⁵ However, recently propofol has been purported to be safe for short-term use in these patients as its preparation lacks odd chain fatty acids, which were attributed to the associated metabolic decompensation.¹¹ Present case and some recent reports have documented its safe use for anaesthesia induction in such cases.⁹

Anaesthetic management of a case of MMA requires careful preoperative evaluation and maintenance of metabolic and acid–base homeostasis in a tightly regulated way. The anaesthetic management of these children has mainly been reported in relation to the management of liver transplant surgery, which is frequently performed in these cases to reduce the episodes of metabolic crisis. The considerations are totally different than those of our case. We, herein, have reported the successful anaesthetic management of a case of MMA for a major upper abdominal surgery who was deferred for optimisation of the metabolic crisis and operated after metabolic parameters normalised. Continuation of dextrose, methyl cobalamin and carnitine perioperatively, ensuring normovolaemia and normothermia by judicious use of invasive and non-invasive monitoring, multimodal analgesia to minimise perioperative surgical stress were the keys to successful outcome.

Learning points.

• Patients with methylmalonic acidemia need aggressive preoperative interdisciplinary care and vigilant intraoperative management for a successful outcome.

• Preoperative optimisation of acid–base disorder, dyselectrolytemia, ketonemia, hydration status, ammonia levels are mandatory prior to scheduling the patient for an elective surgical procedure.

• Anaesthetic goals are to avoid factors that can trigger metabolic crisis, for example, hypercapnia, hypothermia, hypoxia, surgical stress, hypovolaemia, hypotension and prolonged fasting.

• Judicious use of invasive monitoring and regional anaesthesia (continued postoperatively) can be crucial in improving outcomes and recovery of these patients.

• Infusion of dextrose and carnitine perioperatively, diligent monitoring using invasive and non-invasive modalities, maintaining acid–base homeostasis, providing multimodal perioperative analgesia resulted in favourable results for a major surgery in the index case.