Harker, H. Eugene MD, PhD*; Emhardt, John D. MD*; Hainline, Bryan E. MD, PhD†
With significant improvements in the methodology to detect and treat patients with metabolic defects, the need for specific plans for anesthetic management has increased. The authors report one approach to the management of a rare autosomal recessive inborn error of organic acid metabolism.
A four-month old male with propionic acidemia was scheduled for urgent placement of a Tenckhoff catheter required for peritoneal dialysis. He was a term infant born to a family with no history of genetic diseases. Initial diagnosis was made at 3 days of age when he presented with lethargy and hyperammonemia. A urine organic acid profile was positive for 3-hydroxypropionate and 3-hydroxyisovalerate, and acylcarnitine blood spot analysis (Duke University) demonstrated elevated propionyl-carnitine. Propionyl-CoA carboxylase deficiency was confirmed by enzyme assay obtained using cultured fibroblasts (OR Health Sciences University, Portland, OR). Specific mutations were identified in the long arm of chromosome 3 [PCCB] locus as G112D and 1204delG (Prof. Magdalena Ugarte, Madrid, Spain).
One day before surgery, the patient was admitted for severe ketoacidosis, hyperammonemia, lethargy, and feeding intolerance. Initially, his hyperammonemia and acidosis were managed medically with oral Pedialyte®, IV fluids consisting of D5 1/2NS with potassium and sodium bicarbonate (4–8 meq/day), and l-carnitine. As soon as enteral feeding was possible, a special protein free formula (ProPhree–20 kcal/oz, Ross Products) was started. Because of persistent hyperammonemia, he was brought to the operating room for placement of the catheter. Because he could receive nothing by mouth for the surgery, his IV fluids consisted of D5 1/2NS with 20 meq KCl/L and 27 meq NaHCO3/L at 45 mL/h.
Physical examination revealed a 7.79-kg male with a blood pressure of 110/60 mm Hg, a heart rate of 125 bpm, and a respiratory rate of 34 breaths/min. He was fussy but consolable, and hypotonic. Auscultation of the heart revealed a regular rate and rhythm with no murmur. The lung examination was significant for bilateral course breath sounds with fine expiratory wheezes. A chest radiograph demonstrated clear lung fields, and no cardiomegaly. There was no sign of heart failure, such as peripheral edema, or jugular venous distention. Laboratory results were as follows: ammonia 337 micromol/L, albumin 3.1 gm/dL, serum glutamic oxalocetic transaminase 81 IU/L, alkaline phosphatase 171 IU/L, creatine kinase 227 IU/L, glucose 156 mg/dL, and a platelet count of 270,000.
In the operating room, routine monitors were used, including noninvasive blood pressure, electrocardiography, pulse-oximetry, end-tidal CO2, and esophageal temperature. IV induction was initiated with atropine 100 μg, thiopental 37.5 mg, and mivacurium 3 mg. Cricoid pressure was applied, and the patient was tracheally intubated without trauma on the first attempt with a 3.5 cuffed endotracheal tube. There was a leak at <40 cm H2O, and the tube was taped at 12 cm at the gum. N2O, O2, and isoflurane were used for anesthetic maintenance with all gases humidified throughout the case. The maintenance fluid was D5 1/2NS with 20 meq KCl/L and 27 meq NaHCO3/L at 45 mL/h with NS available if a bolus was needed. The case was uneventful and lasted 2 h.
During emergence, the patient exhibited spontaneous respirations with minimal gag in response to suction and was transported intubated to recovery. After discharge from recovery, he was transferred to the intensive care unit where his lungs remained mechanically ventilated for 2 days because of lethargy and weak respiratory effort. A chest radiograph taken in the intensive care unit demonstrated small bilateral pleural effusions and right upper lobe atelectasis. On tracheal extubation, he immediately developed respiratory distress secondary to decreased clearance of secretions and was tracheally reintubated. It was believed that his difficulty clearing secretions was associated with his baseline hypotonia and weakness. Extubation 3 days later was complicated by stridor that responded to racemic epinephrine, heliox, and dexamethasone. This stridor was likely caused by the prolonged presence of an endotracheal tube despite frequent checks for a leak.
When his hyperammonemia did not respond promptly to peritoneal dialysis, a dialysis catheter was placed at the bedside and hemodialysis was instituted. Hemodialysis removes ammonia more efficiently than peritoneal dialysis because the dialysis membrane offers more surface area for diffusion than the peritoneal cavity. With hemodialysis, the ammonia level rapidly normalized. The remainder of his hospital stay was uneventful. He tolerated a progressive increase of protein in his medical diet, his Tenckhoff catheter was removed, and he was discharged.
Propionic acidemia is a rare autosomal recessive inborn error of metabolism with an estimated incidence of 1 in 350,000 (1). This disorder of organic acid metabolism is a clinically and genetically heterogeneous disease and results from deficient activity of the mitochondrial enzyme propionyl-CoA carboxylase. The enzyme occurs as a tetrameric protein whose two protein subunits are encoded by genes located on chromosome 13 and the long arm of chromosome 3 (2). Propionyl-CoA carboxylase functions as part of the catabolic pathways for odd chain fatty acids, cholesterol, and the amino acids threonine, methionine, isoleucine, and valine. Propionic acid is also produced by anaerobic fermentation of odd-chain fatty acids in the gastrointestinal tract. The disorder is characterized by a relapsing course of severe metabolic ketoacidosis, usually precipitated by excessive protein intake, constipation, or intercurrent infection (3). Ketoacidosis develops because propionic acid inhibits citric acid cycle enzymes. Along with the acidosis, manifestations of the disease may include seizures, developmen-tal retardation, hypotonia, coma, episodic vomiting/gastroesophageal reflux, protein intolerance, hyperammonemia (caused by inhibition of acetylglutamate synthetase by propionic acid), hypogammaglobulinemia, bone marrow dysfunction, osteopenia, pancreatitis, and cardiomyopathy.
The acute management of acidosis and hyperammonemia focuses on hydration with fluids containing dextrose and bicarbonate and the treatment of precipitating events (e.g., infection). Enteral feeding with low-protein formula and special medical food is started as soon as possible to promote anabolic processes. To limit potential brain damage and encephalopathy, severe hyperammonemia that is unresponsive to medical management is treated with dialysis. Chronic management focuses on nutritional support that consists of a restriction in natural proteins and supplementation with special medical foods tailored for propionic acidemia (e.g., Propimex, Ross Products). The medical foods supply the remaining amino acids and trace nutrients. Patients are also given supplemental l-carnitine, and biotin. Fasting, which initiates catabolism of protein and subsequent acidosis, must be avoided. Appropriate nutritional management has dramatically reduced the severity and frequency of acute and chronic manifestations (1–6).
Preoperative evaluation of the patient with propionic acidemia should focus on acid-base balance, nutritional state, muscle tone, mental status, and gastrointestinal function. These factors have the greatest impact on anesthetic management. The primary concern for the anesthesiologist is to avoid events that precipitate metabolic acidosis. An acidotic crisis can be initiated by inadequate caloric intake, hypoxia, dehydration, hypotension, or the use of an inappropriate anesthetic.
When patients with propionic acidemia are fasting, they require glucose in their IV fluids to suppress protein catabolism and subsequent acidosis. Dextrose contents of 10% or 12.5% may be needed. Also, bicarbonate, at the patient’s usual daily dose, is used to limit the effects of any propionic acid produced by protein breakdown initiated by fasting or surgical stress. IV l-carnitine is given to enhance renal excretion of abnormal organic acids. In addition, it is prudent to avoid lactic acid-containing fluids (e.g., lactated Ringer’s) that not only contribute to the patient’s acid load, but also may be poorly metabolized by dysfunctional mitochondria. Ammonia level, pH, and glucose should be included in the preoperative laboratory tests. These specialized preoperative needs may require the patient to be admitted the day before surgery.
Intraoperatively, a rapid sequence induction should be considered in patients experiencing reflux or vomiting. Drugs that are metabolized to propionic acid, odd-chain organic acids, odd-chain alcohols, acrylic acid, or odd-chain fatty acids are likely to initiate problems in patients with propionic acidemia. These drug metabolites cause problems because they are further metabolized to propionic acid, which can inhibit the urea and citric acid cycles. Muscle relaxants metabolized by ester hydrolysis [succinylcholine (7), cisatracurium (8), atracurium (9)], including mivacurium (10), which was used during the anesthetic described in this case report, should be avoided because their metabolites include odd-chain organic molecules. Propofol should be avoided because it is administered as an aqueous solution containing soybean oil, which is high in polyunsaturated fats (11). A small portion of polyunsaturated fats may be metabolized to propionic acid (12). Ibuprofen and other drugs derived from propionic acid [naproxen, naproxen sodium fenoprofen, ketoprofen, flurbiprofen, and oxaprozin (13)] should be avoided in the preoperative and postoperative periods.
If prolonged anesthesia is contemplated, arterial pH should be monitored. Hypoglycemia should be avoided by intermittent measurement of blood glucose levels and the use of dextrose in IV fluids. Lactic acidosis can be prevented by maintaining adequate tissue perfusion. Because lethargy and hypotonia are common clinical findings, these patients may be particularly sensitive to the central nervous system depressant effects of volatile anesthetics and narcotic analgesics. For patients with immune suppression, sterile technique should be carefully maintained.
Patients with known or suspected osteoporosis require special attention to positioning and transfers to prevent bone fractures. Fortunately, recent improvements in the dietary management of these patients has made osteoporosis less likely to occur, and fractures are a rare problem. Similarly, the cardiomyopathy previously associated with propionic acidemia is rarely seen because of the use of l-carnitine, which functions as a scavenger of propionic acid and promotes its excretion from the body. During the postoperative period, these patients may be prone to develop respiratory distress secondary to fatigue or upper airway obstruction. The use of humidified supplemental oxygen may be of help in the postanesthesia care unit.
In summary, propionic acidemia has profound systemic effects that influence anesthetic management. Anesthetic strategies should be designed to avoid metabolic acidosis and prevent airway complications. The key to limiting the severity of acidosis during a surgical procedure is to maintain adequate tissue perfusion, and to limit protein catabolism by providing dextrose in IV fluids. Bicarbonate and IV l-carnitine are also necessary to compensate for the acid produced by the catabolic state associated with surgical stress. Airway complications can be minimized if tracheal extubation is delayed until the patient has regained baseline muscle strength and vigor. Even if extubation is delayed, postoperative vigilance is essential because respiratory fatigue and upper airway obstruction are ever-present dangers.
The authors would like to thank Rebecca S. Wappner, MD, for her review of this case report. Her comments made a valuable contribution to this project.
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