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Prevention of metabolic decompensation in an infant with mutase deficient methylmalonic aciduria undergoing cardiopulmonary bypass
Raymond Y Wang, Richard C Chang, Mary E Sowa, Anthony C Chang, Jose E Abdenur
Orange, CA, USA
Author Affiliations: Division of Metabolic Disorders, CHOC Children's Foundation, Department of Pediatrics, University of California Irvine School of Medicine, Orange, CA, USA (Wang RY, Chang RC, Abdenur JE); Department of Clinical Nutrition and Lactation, CHOC Children's, Orange, CA, USA (Sowa ME); Division of Cardiology, Pediatric Subspecialty Faculty, Heart Institute, CHOC Children's, Orange, CA, USA (Chang AC)
Corresponding Author: Raymond Y Wang, MD, Division of Metabolic Disorders, CHOC Children's, 1201 W. La Veta Ave, Orange 92868, CA, USA (Tel: 714-509-8852; Fax: 714-509-3921; Email: rawang@choc.org)
doi: 10.1007/s12519-014-0458-0
Background: Effects of circulatory arrest upon an inborn error of metabolism patient are unknown.
Methods: A retrospective chart review was performed of outcome and biochemical parameters obtained during palliative cardiac surgery for a mutase-deficient methylmalonic aciduria patient with Ebstein's cardiac anomaly was performed.
Results: The levels of ammonia, methylmalonic acid, free carnitine, and propionylcarnitine of the patient were improved. The patient survived surgery following institution of four metabolic treatment principles: 1) restriction of toxic substrate; 2) promotion of anabolism via administration of carbohydrate and lipid calories; 3) administration of detoxifying levocarnitine and sodium benzoate; and 4) cobalamin enzymatic co-factor administration. The patient died from post-operative dysrhythmia and was posthumously determined to have compound heterozygosity for mutations predicting severe, cobalamin non-responsive disease: c.322C>T/c.1233del3 (p.R108C/p.¦¤I412).
Conclusion: Metabolic decompensation is preventable during cardiopulmonary bypass and cardioplegia using four principles of metabolic treatment.
Key words: bypass; management; methylmalonic aciduria
World J Pediatr 2014;10(1):83-85
Introduction
ethylmalonic aciduria due to methylmalonyl-coenzyme-A (CoA) mutase deficiency (mut-MMA, OMIM#251000) results in deficient breakdown of methylmalonyl-CoA from valine, methionine, isoleucine, threonine, and odd-chain fatty acyl-CoAs, to succinyl-CoA. Catabolic patients develop metabolic decompensation with lethargy, anorexia, vomiting, and potentially death. Biochemically, elevated methylmalonic acid (MMA) body fluid levels and secondary hyperammonemia, carnitine depletion, hypoglycemia, and metabolic acidosis are observed.[1]
Attention must be paid to prevent metabolic decompensation during catabolic circumstances, such as surgery. Patients with metabolic disorders can decompensate from fasting required for anesthesia and stresses induced by surgery.[2] However, effects of cardioplegia, hypothermia, and cardiopulmonary bypass in mut-MMA patients are unknown. While hypothermia reduces cellular metabolism, cardiac arrest creates energy-deficient conditions from reduced tissue perfusion.
A neonate referred to our institution with cyanotic congenital heart disease from Ebstein's anomly with pulmonary atresia was found to have mut0-MMA via newborn screening and underwent cardiopulmonary bypass for a Starnes palliative procedure.[3] The clinical outcome and results of pre- and intra-operative metabolic monitoring were reported herein.
Case report
This study was approved by the CHOC Children's Institutional Review Board.
The neonate was the third child of nonconsangui-neous hispanic parents without a family history of congenital heart disease or recurrent miscarriages. He demonstrated cyanosis refractory to supplemental oxygen and was evaluated for congenital heart disease. Physical examination noted a reactive newborn with a harsh holosystolic murmur, palpable precordial thrill, acrocyanosis, and palpable liver 2 centimeters below the right costal margin. Echocardiogram demonstrated Ebstein's anomaly with thickened, inferiorly displaced and regurgitant tricuspid valve, severely dilated right atrium, pulmonary atresia, and secundum atrial septal defect. Surgical palliation with the Starnes procedure was elected.
The patient received 3.5 g/kg parenteral protein per day until newborn screening demonstrated an elevated propionylcarnitine level of 19.3 micromolar (normal <6.5 ¦Ìmol/L) and a propionylcarnitine:acetylcarnitine ratio of 0.74 (normal <0.25). Confirmatory testing showed high levels of urine MMA, with normal plasma homocysteine. Other biochemical results are summarized in Table 1. Genetic sequencing of the MUT gene demonstrated compound heterozygous mutations predicting severe, cobalamin-nonresponsive (mut0) disease: c.322C>T and c.1233del3 (p.R108C/p.¦¤I412).[4]
Following treatment, secondary carnitine deficiency corrected; blood levels of MMA, propionylcarnitine, and ammonia improved (Table 1). Specific management principles included the following: 1) protein intake to 1 g/kg per day was given to reduce toxic substrate (60 mg/kg per day each of isoleucine and valine). The infant's unstable clinical status precluded enteral feeding and necessitated parenteral nutrition. Plasma amino acid measurements were performed to ensure target amino acid levels at a lower limit of reference ranges; 2) promotion of anabolism was effected by administration of dextrose, 13 mg/kg per minute (18.72 g dextrose/day) and fat emulsion, 3 g/kg per day, while adhering to fluid restrictions imposed by the cardiac defects. Total caloric intake was 72 kcal/kg per day; 65% from carbohydrate and 31% from fat; 3) detoxification agents were given in the form of intravenous levocarnitine, 200 mg/kg per day, and enteral sodium benzoate 250 mg/kg per day to treat hyperammonemia (initial 111 ¦Ìmol/L, increasing to 160 µmol/L in twelve hours; normal <80 ¦Ìmol/L); 4) prior to knowledge of the cobalamin non-responsive phenotype, intramuscular hydroxocobalamin injections, 1000 ¦Ìg daily, were administered to attempt enhancing enzymatic activity of mutase.
Similar management was employed throughout surgery. Core temperature was lowered to 35 ºC to reduce metabolic rate. Protein-free intravenous dextrose was provided at 13 mg/kg per minute, lipid infusion discontinued; levocarnitine and hydroxocobalamin were given prior to surgery. Arterial blood gas, blood glucose, ammonia, lactic acid, and acylcarnitines were measured regularly throughout the perioperative period.
Cardiopulmonary bypass time was 94 minutes; arrest time was 28 minutes. Table 2 demonstrates the results of intraoperative biochemical monitoring; hypoglycemia and hyperammonemia never developed during surgery. A dextrose bolus was given in the first hour, when glucose dropped from 161 mg/dL to 103 mg/dL. Post-bolus hyperglycemia (Table 2) was treated with insulin 0.45 units/kg per hour. The Starnes procedure was successful, but junctional tachyarrhythmia developed during cardiac re-animation requiring multiple attempts to cardiovert to sinus rhythm.
Six hours afterwards, the infant displayed poor peripheral perfusion secondary to ventricular tachycardia, degenerating to ventricular fibrillation and sinus bradycardia resistant to anti-arrhythmics and cardioversion. The etiology was a right intra-ventricular thrombus impairing cardiac output. Twelve hours later, the patient died from refractory hypoxemia after the thrombus extended into the Blalock-Taussig shunt.
Discussion
Successful intra-cardiac surgery has been reported, without detailing intra-operative biochemical markers, in two patients with cobalamin C/D-deficient methylmalonic aciduria who successfully underwent passive hypothermia and cardiopulmonary bypass for ventricular septal defect repair.[5,6] To our knowledge, our case represents the first report of cyanotic congenital heart disease or Ebstein's anomaly in mut0-MMA.
Biochemical data sampled throughout the patient's surgical cardiac palliation indicate pre-operative optimization of metabolic control, and peri-operative prevention of decompensation. This was enabled by restricting methylmalonic acid precursors via reduction of parenteral amino acid intake. Provision of dextrose stimulated insulin production, preventing catabolism and allowing safe tolerance of 1 g/kg of protein per day. Detoxification agents were administered to reduce deleterious ammonia, methylmalonic and propionic acid levels. Finally, because the patient was critically ill and cobalamin-responsiveness was unknown, mut enzyme enhancement was attempted via hydroxocobalamin. Since mutations were posthumously identified as cobalamin-nonresponsive, most likely the first three principles accounted for the metabolic control.
Transient metabolic acidosis following discontinua-tion of bypass (Table 2, +131 minutes) may have reflected reperfusion and release of ischemic metabolites into the circulation, or resulted from intra-operative hyperglycemia. However, the pro-anabolic effects of insulin should have mitigated any lactic acidosis arising from hyperglycemia. Significant metabolic acidosis and hyperammonemia (Table 2, +6.3 hours) developed only after prolonged, hemodynamically significant ventricular tachycardia and poor systemic perfusion. At death, the patient had intact metabolic control, with bicarbonate and lactic acid at pre-operative levels.
Patients with Ebstein's anomaly are at high risk of developing tachyarrhythmias, a common cause of their mortality.[7] The infant had intra-operative difficulty maintaining sinus rhythm because of the arrhythmogenic, severely dilated right atrium, so death occurred likely from complications associated with Ebstein's anomaly. However, ventricular tachycardias have been reported in mut-MMA patients. One experienced the dysrhythmia in the context of peri-anesthetic hyperkalemia (serum potassium: 5.8-7.4 mmol/L, normal: less than 5.5 mmol/L) and the other following worsening cardiomyopathy with ejection fraction of 18%.[8,9]
With adherence to basic principles of metabolic management, metabolic control can be successfully maintained even for a patient with a severe metabolic disorder and cyanotic congenital heart defects experiencing profound catabolic stress induced by cardiopulmonary bypass and cardioplegia.
Funding: Commission for Families and Children of Orange County.
Ethical approval: This study was approved by the CHOC Children's Institutional Review Board.
Competing interest: No competing interests or financial relationships to disclose.
Contributors: Wang RY contributed to concept and design, data acquisition, interpretation, article drafting and critical revision, final approval; Chang RC and Sowa ME performed data acquisition, analysis, interpretation, article critical revision, final approval; Chang AC and Abdenur JE contributed to concept and design, data acquisition, analysis, interpretation, article critical revision, final approval.
References
1 Ogier de Baulny H, Dionisi-Vici C, Wendel U. Branched chain organic acidurias/acidaemias. In: Saudubray JM, Van Den Berghe G, Walter JH, eds. Inborn metabolic diseases: diagnosis and treatment. Berlin: Springer-Verlag, 2012: 277-298.
2 Roe CR, Wiltse HE, Sweetman L, Alvarado LL. Death caused by perioperative fasting and sedation in a child with unrecognized very long chain acyl-coenzyme-A dehydrogenase deficiency. J Pediatr 2000;136:397-399.
3 Reemtsen BL, Fagan BT, Wells WJ, Starnes VA. Current surgical therapy for Ebstein anomaly in neonates. J Thorac Cardiovasc Surg 2006;132:1285-1290.
4 Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, et al. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat 2006;27:31-43.
5 Tomaske M, Bosk A, Heinemann MK, Sieverding L, Baumgartner ER, Fowler B, et al. CblC/D defect combined with haemodynamically highly relevant VSD. J Inherit Metab Dis 2001;24:511-512.
6 Heinemann MK, Tomaske M, Trefz FK, Bosk A, Baden W, Ziemer G. Ventricular septal defect in a neonate with combined methylmalonic aciduria/homocysteinuria. Ann Thorac Surg 2001;72:1391-1392.
7 Attenhofer Jost CH, Connolly HM, Edwards WD, Hayes D, Warnes CA, Danielson GK. Ebstein's anomaly-review of a multifaceted congenital cardiac condition. Swiss Med Wkly 2005;135:269-281.
8 Chao PW, Chang WK, Lai IW, Liu C, Chan KH, Tsao CM. Acute life-threatening arrhythmias caused by severe hyperkalemia after induction of anesthesia in an infant with methylmalonic acidemia. J Chin Med Assoc 2012;75:243-245.
9 Prada CE, Al Jasmi F, Kirk EP, Hopp M, Jones O, Leslie ND, et al. Cardiac disease in methylmalonic acidemia. J Pediatr 2011;159:862-864.
Received February 21, 2012Accepted after revision July 18, 2013
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