Sevoflurane in anaesthetic management of a patient with methylmalonic acidaemia

Editor, Methylmalonic acidaemia (MMA) is a rare autosomal recessive, inborn error of organic acid metabolism, caused by mutations in the genes playing a role in the conversion of methylmalonyl-CoA into succinyl-CoA. Mutations in the MUT gene, on chromosome 6 encoding the enzyme L-methylmalonyl-CoA mutase, either alter the enzyme's structure (mut0) or reduce the amount of the enzyme (mut-). In another type of MMA there is impaired synthesis of adenosylcobalamin, the cofactor for this enzyme.1 It is always associated with secondary perturbations of propionyl-CoA metabolism, thus producing propionic acadaemia and carnitine deficiency with clinical and metabolic common features. In the most common (mut0) form, deficient activity leads to excessive methylmalonic acid levels in plasma and urine associated with a clinical picture of lethargy, recurrent vomiting, hepatomegaly, metabolic acidosis, encephalopathy and even multiorgan failure in the first few months of life. Most affected infants show subsequent developmental delay. The survival rate is poorest in the early onset forms and is often complicated with acute episodes of metabolic decompensation. Nevertheless, the outcome of either early or late onset forms of MMA is exacerbated by intercurrent infections, immunisations, trauma, fasting, dehydration and stress during surgery and anaesthesia.2 In this report, we present the anaesthetic management of a patient with MMA, scheduled to have achilloplasty for bilateral pes equinovarus deformity. Case report Our 5.5-year-old female patient with a history of MMA was followed from the age of 18 months. The diagnosis was made after urine organic acid analysis. She was the third child of unrelated parents with no history of other affected members. Pre-operatively, her weight and height were 16.5 kg and 107 cm. In the clinical examination, in addition to having failure to thrive, she was observed to have difficulty in walking and sitting with deformities in the foot. Haemoglobin, serum electrolytes, fasting blood sugar, mental status and social development were all normal. She had been on a low-protein, high calorie diet with maltodextrin formula and carnitine supplementation. During the fasting period, intravenous vascular access was obtained with Emla cream and D10 1/4 saline-dextrose solution was started. On arrival in the operating room, non-invasive blood pressure, ECG, pulse oximetry and end-tidal CO2 were used for monitoring. After preoxygenation with 5 l min−1 oxygen, induction was via inhalation of sevoflurane (8%) in O2 – air through a facemask. A caudal block was then performed by 1 ml kg−1 of 0.25% bupivacaine for intra-operative and post-operative analgesia. Afterwards, anaesthesia was maintained with 50% air in oxygen and 1.5–2.0% sevoflurane. Manual ventilation was provided in the spontaneously breathing child to maintain oxygen saturation at or above 95%. We did not take any arterial blood gas samples; however, blood glucose was controlled twice, corresponding to the beginning and the end of surgery and the child was found to be mildly hyperglycaemic (165 and 155 mg dl−1, respectively). Sevoflurane was continued until after the last suture was inserted. When spontaneous ventilation was judged to be satisfactory, the child was transferred initially to the recovery room, breathing air supplemented by oxygen 4 l min−1 and then to the ward with an uneventful recovery. During the post-operative follow-up, frequent monitoring of clinical and metabolic status was done; and enough water and metronidazole were administered for short-term treatment. Besides, classic analgesics producing propionates were avoided in this patient. Discussion This study not only reports the importance of avoidance of fasting and the choice of suitable anaesthetic agents for anaesthesiologists, but also serves as a reminder for close follow up of metabolic status to physicians caring for these patients in the surgical ward post-operatively. The phenotypic variants of MMA are associated with times of relative health and intermittent metabolic decompensations. A common form of isolated MMA presents during the first months or years of life. The affected infants, who are normal at birth, exhibit feeding problems, failure to thrive, hypotonia with a risk for episodic decompensation associated with intercurrent infections and stress. Also, a further metabolic complication ensues from the role of reduced hydroxy-B12, involved in remethylation of homocysteine to methionine. Therefore, vitamin B12 therapy is involved in the management of the disease.2 In the current report, our patient's clinical picture typically beginning at age of 1.5 years with almost normal follow-up strongly suggested the diagnosis of this intermediate form. However, Matsui et al.3 described a more common, but catastrophic neonatal presentation of isolated MMA in 1983. The metabolic changes leading even to death are severe metabolic acidosis, ketosis and ketonuria, hyperammonaemia, and hyperglycinaemia. The accumulating methylmalonic acid suppresses bone marrow as well as affects target organ systems. Thus, white matter spongiosis or grey matter vacuolisation and progressive renal insufficiency resulting in end-stage renal disease have been reported.4 A primary anaesthesia concern with these patients is fasting, because during this period, the patients require intravenous fluids containing dextrose and sodium bicarbonate to reduce utilisation of fats and protein, in order to minimise methylmalonic acid production and subsequent acidosis intra-operatively.4 Our patient's pre-operative acid–base status was good and she was well regulated by diet. In this patient, by sevoflurane we managed both deep anaesthesia to reduce stress response, which may contribute to catabolism, and also haemodynamic stability to provide adequate organ perfusion for the prevention of anaerobic metabolism. We did not use narcotic analgesics and nitrous oxide. It was reported that a child who had 80 min of anaesthesia with nitrous oxide developed neurologic deterioration and pancytopenia probably as a result of inhibition of vitamin B12.5 Moreover, it has been recommended to avoid the use of muscle relaxants metabolised by ester hydrolysis and having odd chain organic molecule metabolites. In our patient, sevoflurane anaesthesia was used safely without using neuromuscular blockers. It provided not only smooth, fast and pleasant induction, but also suitable loss of muscle tone with no emergence excitement. We did not make any arterial blood gas analysis, as the procedure lasted 40 min. However, increasing fluids and glucose as well as reducing protein intake is important to deliver adequate calories and to prevent lipolysis, so we aimed to prevent hypoglycaemia by D10 1/4 saline-dextrose solution. This case report described successful anaesthetic management of a patient with MMA under sevoflurane anaesthesia. There is some anaesthetic experience with these patients in long procedures, but in short procedures, experience is limited.6 We propose that sevoflurane appears to be a useful and well tolerated agent for these patients. Additionally, our management strategy aimed to maintain acid–base status at near normal ranges in the post-operative period, including frequent monitoring of clinical and metabolic status with blood glucose, ammonium and lactate levels, as a metabolic decompensation can indeed occur even after short surgery with very low stress reactions, including fever and vomiting. Enough water for the prevention of dehydration and metronidazole to reduce propionate production in the gut were given. We preferred a caudal block for intra-operative and post-operative analgesia instead of administering classic analgesics post-operatively to prevent secondary propionic acidaemia, as agents such as ibuprofen and ketoprofen are also converted to propionates during metabolism. As a conclusion, we want to emphasise not only the importance of careful pre-operative evaluation, peri-operative monitoring and suitable choice of anaesthetic agents which is of anaesthesiologic relevance, but also a careful post-operative care in terms of intermittent decompensation, and late organ system failure for both surgeons and clinicians.