Intraoperative rhabdomyolysis in a patient receiving pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor.

Abstract

Lovastatin (Mevacor Registered Trademark; Merck & Co., West Point, PA), simvastatin (Zocor Registered Trademark; Merck & Co.), and pravastatin (Pravachol Registered Trademark; Squibb, New Brunswick, NJ) are 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors prescribed for hypercholesterolemia [1,2]. We report a case of intraoperative myoglobinuria, rhabdomyolysis, and renal failure during spinal instrumentation and fusion in a patient receiving pravastatin. The effect of HMG CoA reductase inhibitors on muscle mitochondria and adenosine triphosphate (ATP) production is presented [3-6]. Anesthesiologists should be aware of the side effects and current recommendations concerning use of these drugs [2,3,7-9]. Case Report A 56-yr-old, 183-cm, 107-kg male with a long history of progressive low back pain, occasional paresthesias to the midcalf, and radiographic studies demonstrating multiple level spinal stenosis and instability was scheduled for L2-L5 decompressive lumbar laminectomy with posterior spine fusion, instrumentation, and iliac bone graft. Preoperative electromyography and nerve conduction studies demonstrated no evidence of a myopathy. His history was significant for hypertension, hypercholesterolemia, and palpitations. Medications included sustained-release verapamil 240 mg, pravastatin 20 mg, digoxin 0.25 mg, enalapril maleate 5 mg, terazosin hydrochloride 2 mg b.i.d., and terfenadine. Serum electrolytes were normal. The blood urea nitrogen (BUN) was 13 mg/dL and creatinine 1.1 mg/dL. One preoperative urinalysis was normal while another revealed 3+ glucose, 3+ blood, 2+ ketones, and 1+ protein with many red blood cells. Premedication included cimetidine 400 mg per os metoclopromide 10 mg per os, cefazolin 1 g intravenously (IV), and intramuscular morphine 10 mg, benadryl 50 mg, and glycopyrrolate 0.2 mg. Anesthesia was induced with d-tubocurarine 3 mg, fentanyl 250 micro gram, thiamylal 400 mg, and succinylcholine 120 mg IV; anesthesia was maintained with N (2) O/O2, fentanyl, and vecuronium. Body temperature was maintained with the aid of a forced warm air blanket. The intraoperative course remained stable without any episodes of hypotension, hypertension, hypocarbia, or hypercarbia. Five hours after incision the urine became dark reddish brown. The patient had received cell salvaged blood (500 mL) and one unit of autologous blood. A transfusion reaction was suspected. IV fluids were changed to normal saline, infusion rates were increased, and furosemide 20 mg, mannitol 12.5 g, and sodium bicarbonate were administered. A low-dose dopamine infusion (1.5 micro gram centered dot kg-1 centered dot min-1) was started. Urine color improved and output increased. Postoperatively, the patient developed nonoliguric renal failure with peak BUN of 82 mg/dL and creatinine 8.8 mg/dL. Although the initial urinalysis indicated hemoglobinuria, the official urinalysis identified myoglobinuria. Laboratory results demonstrated urine myoglobin 1430 ng/mL (normal <15), serum creatine kinase 3090 IU/L (normal 26-74), serum lactate dehydrogenase 624 IU/L (normal 109-193), and serum haptoglobin 15 mg/nL (normal 13-163). Postoperatively, renal function improved and at discharge the BUN was 10 mg/dL and the creatinine 1.0 mg/dL. Discussion HMG CoA reductase inhibitors block conversion of HMG CoA to mevalonate, an early step in cholesterol synthesis [10]Figure 1. Occasional side effects of these drugs include increased creatine kinase levels and myalgias worsened by exertion [4,9]. Rarely, a severe myopathy and rhabdomyolysis leading to myoglobinuria and renal failure have been reported to occur [1,2]. Concomitant medications, such as gemfibrozil (Lopid Registered Trademark; Parke-Davis, Morris Plains, NJ), cyclosporin, niacin, or erythromycin, increase the incidence of rhabdomyolysis [2,11-14]. Drug manufacturers recommend that HMG CoA reductase inhibitors be avoided in physiologic situations that increase the risk for rhabdomyolysis, such as severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled seizures [9]. The concern is that there is an increased chance for muscle damage and rhabdomyolysis under these conditions, and concomitant administration of HMG CoA reductase inhibitors may increase the likelihood of rhabdomyolysis.Figure 1: Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, blocks conversion of HMG CoA to mevalonate, an early step in cholesterol synthesis.Although rhabdomyolysis is associated with HMG CoA reductase inhibitors administered to reduce cholesterol, the drug probably causes rhabdomyolysis through inhibition of another pathway [5]. These medications block production of mevalonate, an intermediate in both cholesterol and coenzyme Q 10 (CoQ10) production [6,15]Figure 2. CoQ10 plays a major role in the electron transport chain of oxidative phosphorylation. This process takes place inside mitochondria and is responsible for ATP production [5,16,17].Figure 2: The conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonic acid is important for production of cholesterol and coenzyme Q 10 [6,15].CoQ10 deficiency can result in a mitochondrial myopathy with reduced mitochondrial ATP production, mitochondrial dysfunction, and in severe cases cell death resulting from malfunction of sodium-calcium exchange, elevation of intracellular calcium levels, and cell destruction [16,17]. Simvastatin has induced rhabdomyolysis and a mitochondrial myopathy in a 63-yr-old female in whom muscle CoQ10 levels were below normal and symptoms improved with CoQ10 replacement [5]. CoQ10 is important for skeletal and cardiac muscle function [6,10]. Folkers et al. [6] demonstrated improvement in patients with cardiomyopathy treated with CoQ10 and subsequent deterioration when lovastatin was administered. Removal of lovastatin improved cardiac function. What predisposed our patient to mitochondrial dysfunction, rhabdomyolysis, and myoglobinuria? While rhabdomyolysis can occur de novo in patients on statin medications, drug manufacturers do warn to discontinue these medications before major surgery. In this patient, the use of the drug in combination with the extensive muscle stripping and muscle trauma associated with the spinal surgery may have resulted in rhabdomyolysis. Many major surgical procedures have been performed in patients receiving HMG CoA reductase inhibitors without problems. However, the degree of direct muscle trauma involved in our patient's spinal fusion, instrumentation, and iliac bone graft is significantly greater than most general surgical or cardiac procedures. What other possible mechanisms can explain the myoglobinuria in our patient? Succinylcholine can produce myoglobinuria; however, the problem did not occur until 5 h after its administration. Since a urinary catheter was present, myoglobinuria would have been detected soon after the succinylcholine administration [18,19]. If succinylcholine plays a role in producing rhabdomyolysis, it may be secondary to succinylcholine-induced fasciculations in a patient predisposed to muscle damage because of receiving HMG CoA reductase inhibitors [18,19]. Myoglobinuria can also be seen in malignant hyperthermia. Since the urine contained myoglobin, and not hemoglobin, a blood transfusion reaction was ruled out. The urine blood test is based on hemoglobin's peroxidase-like activity and is sensitive for both myoglobin and hemoglobin. Blood collected in cell salvage machines can contain myoglobin, but since it is washed more rigorously during orthopedic procedures this remains an unlikely source of myoglobin. Anesthesiologists should be aware of potential complications associated with HMG CoA reductase inhibitors and be prepared to treat them. When possible, HMG CoA reductase inhibitors should be discontinued preoperatively in the patient undergoing major surgery, especially surgery that may result in significant skeletal muscle damage. Based on a half-life of 77 h for pravastatin's active metabolites, it is suggested that the medication be discontinued 4-7 days preoperatively. There is no known concern about any short-term rebound effect or side effects from stopping the medication. In patients undergoing major surgery, we also suggest avoiding succinylcholine, placing a urinary catheter for early diagnosis, instituting rapid treatment to prevent renal failure should rhabdomyolysis occur, and avoiding conditions, such as shivering, that may cause increased metabolic demands on muscle.