Propionic acidemia (PA) is a rare autosomal recessive inborn error of metabolism resulting from a lack of propionyl-CoA carboxylase (PCC), a mitochondrial enzyme essential for converting propionyl-CoA to methylmalonyl-CoA.1–3 Without the enzyme, propionyl-CoA is converted to propionic acid. PCC is also necessary for the catabolism of fatty acids, proteins, and amino acids. It is also necessary for metabolizing certain medications including some IV anesthetics and analgesic drugs.
The patient gave permission for the authors to publish this report.
A 26-year-old, gravida 3 para 0, presented at 39 weeks and 2 days gestational age after sustaining abdominal trauma from a fall. Her medical history was significant for PA with mild developmental delay. The patient was admitted for fetal monitoring to observe for possible abruption or the onset of labor. She was offered an elective induction of labor with the goal of preventing a catabolic state. Earlier in her pregnancy, as a part of her prenatal care, a cardiologist was consulted and a transesophageal echocardiogram and an electrocardiogram were performed; both of which were normal. Based on recommendations from the metabolic team, she was kept nil per os (NPO) and received D10 0.45% NaCl at 1.5 times maintenance fluid replacement (144 mL/h) and an infusion of intralipid 20% at 2 g/kg/d, with a plan to administer these fluids continuously throughout labor, delivery, and after delivery. Carnitine IV, which enhances excretion of propionyl-CoA as propionylcarnitine, was given throughout the hospitalization. Before induction of labor, an epidural catheter was placed at the L3-L4 interspace and after a test dose of 3 mL of 2% lidocaine without epinephrine, and an infusion of bupivacaine 0.0625 mg/mL and fentanyl 2 mcg/mL was started at 10 mL/h.
After 28 hours of labor, a cesarean delivery was performed for arrest of descent, which she tolerated well. A healthy baby girl was delivered with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. Postoperatively, serial blood gases and a complete metabolic panel were obtained to assess pH, lactate, electrolytes, and ammonia level. A urine sample was also obtained to check for urine organic acids. The laboratory variables remained normal throughout her stay. Her pain was controlled with ketorolac 30 mg IV every 6 hours, acetaminophen 1000 mg IV every 6 hours, and an epidural infusion of bupivacaine 0.1% at 6mL/h. She was also given ondansetron 4 mg every 8 hours to prevent nausea. Intravenous fluids and dietary supplements were maintained as described above until her diet was advanced to a low-protein diet. She had an uncomplicated postoperative course and was discharged to home on postoperative day 3.
PA was first described in 1961 and found to occur in approximately 1 in 350,000 individuals, most commonly in those of Amish, Saudi Arabian, or Greenland Inuit descent. PA is an autosomal recessive inborn error of metabolism, caused by a mutation in the genes encoding the mitochondrial enzyme PCC located on chromosome 13 and the long arm of chromosome 3. PCC is essential for catalyzing the conversion of propionyl-CoA to methylmalonyl-CoA, a step in the normal process of converting threonine, isoleucine, valine, methionine, cholesterol, and odd chain fatty acids into carbohydrates for energy. Anaerobic fermentation in the gastrointestinal tract also produces propionic acid. Without the enzyme, there is a buildup of PA, which then inhibits the citric acid cycle enzymes, thereby causing ketoacidosis. This is generally precipitated by protein intake, constipation, infection, or an otherwise catabolic state. PA accumulation also inhibits acetyl glutamate synthetase, thereby leading to hyperammonemia. Acute metabolic decompensation and death can occur quickly after the onset of acidemia.1–3
The initial presentation of PA typically occurs in the neonatal period, or during infancy particularly when the infants’ diets are changed from breast milk to a higher protein formula. Uncommonly, PA can also present in adulthood. The disease course is characterized by relapsing and remitting episodes of severe ketoacidosis. Patients in the early stages of metabolic decompensation typically present with symptoms of poor feeding, lethargy, hypotonia, vomiting, dehydration, neutropenia, thrombocytopenia, and seizures. Signs of late decompensation include lactic acidosis, ketoacidosis, hyperammonemia, hypoglycemia, progressive encephalopathy, and eventual death if left untreated. Acute decompensation often necessitates hospitalization and active management to prevent or treat catabolism and acidosis. Chronic management is focused on protein restriction and nutritional supplementation. Long-term sequelae include cardiomyopathy, arrhythmias, gastroesophageal reflux, seizures, hypotonia, and developmental delay. Diagnosis is made with a genetic analysis after eliminating other common causes of acidosis.1–3
An interdisciplinary team approach may be considered in the pregnant woman with PA. Before any procedure, blood glucose, ammonia, and pH levels are obtained for baseline measurement, as well as to assess for any underlying metabolic abnormalities. Because of the association between PA and structural heart disease, a cardiology consult can be considered to exclude cardiomyopathy, QT prolongation, or arrhythmias. In addition, as a part of the patient’s prenatal care, dietary management is generally directed by a metabolic team composed of a geneticist and a dietician. Patients are generally maintained on a protein-restricted diet and dietary supplements. Upon admission to the hospital, an IV infusion with dextrose may be considered in addition to an intralipid infusion to provide glucose as a primary energy source because laboring patients are made NPO and perioperative fasting can induce catabolism.4 We suggest avoiding lactated Ringer’s solution because the lactate can contribute to acidosis.4 We suggest that a scheduled delivery is desirable because the peripartum period places significant stress on the patient, which necessitates close monitoring and prevention of acute decompensation.
The anesthesiologist should become familiar with the pathophysiology of the disease and how to avoid acute exacerbations and end-organ complications, as well as knowing what medications can be safely administered. For example, it may be best to avoid medications that are either derived from PA, for example, etomidate and nonsteroidal anti-inflammatory drugs, with the exception of ketorolac, or those that are metabolized by ester hydrolysis, for example, succinylcholine, atracurium, cisatracurium, mivacurium, and ester local anesthetics, because their metabolites contain odd chain organic molecules that may precipitate acidosis.4–6 Propofol is best avoided because the emulsion contains soybean oil, which is high in polyunsaturated fats.5,6 In addition, medications decreasing gastric motility are best avoided since nausea/vomiting can lead to dehydration and subsequent acidemia.6,7 Patients with PA may have central nervous system (CNS) involvement, which can include lethargy, hypotonia, depressed airway reflexes, seizures, developmental delay, etc. If present, these patients may be more sensitive to the CNS-depressant effects of opioids, and theoretically also be at an increased risk for pulmonary aspiration.5,6,8
We were prepared to induce anesthesia via rapid sequence with ketamine and rocuronium in the event that an emergent cesarean delivery became indicated. Initially, we also had concerns about our labor epidural because the infusion medication we use contains fentanyl. However, because our patient did not exhibit abnormal or unusual CNS symptoms, other than developmental delay, and because the amount of opioid per milliliter is so small (fentanyl 2 mg/mL), we used our standard medication and dose as described above. Our patient received 1:1 nursing supervision, and was monitored using continuous pulse oximetry during labor. We did not believe it was necessary to repeat laboratory data during labor because we were readily able to monitor her mental status for signs of decompensation.
Postoperative pain control was multimodal with minimal opioid use. Postoperatively, the dextrose infusion was continued until the patient could tolerate oral intake adequately because discontinuing the infusion could have precipitated hypoglycemia and catabolism.6
In summary, the pathophysiologic implications for the patient with PA undergoing anesthesia are significant. Management of the patient with an interdisciplinary team is helpful to a successful outcome. We recommend administering a neuraxial anesthetic, if possible, which has the advantage of maintaining airway reflexes while avoiding medications that may precipitate an exacerbation of acidemia, and also allows for postoperative pain relief without requiring systemic opioids.
1. Pena L, Franks J, Chapman KA, Gropman A, Ah Mew N, Chakrapani A, Island E, MacLeod E, Matern D, Smith B, Stagni K, Sutton VR, Ueda K, Urv T, Venditti C, Enns GM, Summar ML. Natural history of propionic acidemia. Mol Genet Metab. 2012;105:5–9
2. Sutton VR, Chapman KA, Gropman AL, MacLeod E, Stagni K, Summar ML, Ueda K, Ah Mew N, Franks J, Island E, Matern D, Peña L, Smith B, Urv T, Venditti C, Chakarapani A. Chronic management and health supervision of individuals with propionic acidemia. Mol Genet Metab. 2012;105:26–33
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