RHABDOMYOLYSIS is a clinical and biochemical syndrome resulting from skeletal muscle injury with the release of muscle contents into the plasma. It results either from a direct muscle injury or from an altered metabolic relationship between energy production and consumption in muscle. Crush syndrome, extensive burns, electric shock, and prolonged immobilization are the main causes of direct muscle injury. Strenuous physical exercise, malignant hyperthermia, muscle ischemia resulting from compression or vascular injury, infections, myopathies, toxins, and drugs, including alcohol, which accounts for 20% of the cases, can cause nontraumatic rhabdomyolysis. This syndrome has been described with fibrates and statin lipid-lowering drugs, culminating in the recent removal of cerivastatin from the market because of a number of rhabdomyolysis-related deaths. 1Severe cases were reported in elderly patients and in patients taking lipid-lowering drugs. We observed two consecutive cases of severe postoperative rhabdomyolysis in patients who underwent elective laparoscopic surgery for adenocarcinoma of the rectum, and for whom cumulative risk factors were identified in retrospect: long-term treatment with statins and laparoscopic surgery with prolonged immobilization under general anesthesia.
A 52-yr-old male patient (body mass index, 26.6) was scheduled to undergo elective surgery for adenocarcinoma of the rectum. He had a history of myocardial infarction, moderate hypertension, pulmonary embolism, appendectomy, hypercholesterolemia, and diabetes mellitus. His usual medications included aspirin, fosinopril, atenolol, glimepiride, and pravastatin, which were discontinued the day before surgery. Preoperative evaluation of the patient did not show any biologic disturbances, and his chest radiograph was normal. The patient was premedicated with 50 mg hydroxyzine the evening before the surgery and 100 mg hydroxyzine 2 h before his admission to the operating room. Antibiotic prophylaxis (cefoxitin, 2 g) was given intravenously before the induction of anesthesia with propofol (3 mg/kg), sufentanil (0.5 μg/kg), and cisatracurium (0.15 mg/kg) for muscle relaxation. Anesthesia was maintained with isoflurane in an oxygen-air mixture supplemented with sufentanil (1.8 μg · kg−1· h−1) and additional doses of cisatracurium as needed. The support points were protected by gelatin patches and checked at each change of position. The rectotomy lasted 6 h in a lithotomy position. The patient's systolic blood pressure remained above 80 mmHg during the surgery, and his perioperative blood loss was less than 500 ml. Volume replacement was ensured by administering 500 ml of a hydroxylethyl starch solution (200,000/0.5/6%/5) and 4,300 ml of crystalloids. The patient was extubated 1 h after arrival in the intensive care unit. On the first day after the surgery, the patient complained about his calves despite intravenous morphine (patient-controlled analgesia). No compartment syndrome sign was observed, and his abdomen was soft. The serum creatine phosphokinase (CPK) concentration was 7,103 IU/ml (fig. 1). On the second day, the patient's temperature increased (38°C), blood gases showed metabolic acidosis, his serum lactate concentration was 4.75 mm, and a chest radiograph revealed mixed alveolar-interstitial infiltrates. Ventilatory assistance was required as a result of acute respiratory failure. A laparotomy failed to show a surgical complication. On the third day after the surgery, the patient developed oliguric acute renal failure with a serum creatinine concentration of 272 μm and a creatinine clearance of 26 ml/min (fig. 1). Laboratory investigations revealed that his CPK concentration was 2,191 IU/l, his aspartate aminotransferase concentration was 234 IU/l, and his serum myoglobin concentration was 1.98 ng/ml. Continuous venovenous hemofiltration was initiated, and the patient's renal and respiratory function recovered slowly, as did the clinical sign of rhabdomyolysis. Serum CPK reached the maximum concentration 10 days after admission to the intensive care unit and returned to normal values 4 days later. The patient left the intensive care unit 30 days after his admission without apparent sequelae.
A 63-yr-old male patient (body mass index, 32.8) was scheduled for the same surgery. His medical history revealed that he had undergone cardiac surgery (coronary artery bypass grafting) and an appendectomy, and that he had glaucoma and hypercholesterolemia. His usual medications included diltiazem, losartan, a potassium-sparing diuretic (furosemide-amiloride), acenocoumarol (discontinued 5 days before surgery), and fluvastatin (discontinued the day before surgery). Electrocardiogram, chest radiograph, complete blood count, coagulation variables, and serum biochemistry results were normal. Premedication and anesthesia, type of surgery, position during surgery, duration of surgery, blood loss, volume replacement, and time to tracheal extubation were similar to those encountered in the previous case. On the first day after the surgery, the patient felt the same kind of pain he had for the past 2 months, in his left calf and his right arm, without neurologic deficit or sign of ischemia. On the second day, the patient had a raised temperature and a swollen left calf. Doppler ultrasound examination ruled out phlebitis. Nonoliguric acute renal failure was present, with a serum CPK concentration of 17,300 IU/l (fig. 2). The following day, the patient had decreased contraction of the anteroexternal muscles, which led us to perform an aponeurotomy on the left leg. The patient recovered rapidly. His serum CPK concentration decreased steadily, and the renal failure disappeared in 8 days. However, the left common peroneal nerve paralysis persisted at discharge from the intensive care unit.
Statins are a class of drugs (HMG Co-A reductase inhibitors) that lower cholesterol and reduce the risk of coronary heart disease. 2,3Although they have the same mechanism of action, their pharmacokinetics and effect on plasma lipids are different. They are metabolized in the liver via different isoforms of the cytochrome P 450enzyme system. Drugs that are metabolized by the same pathways (especially cytochrome P 4503A4), such as cyclosporin, itraconazole, ketoconazole, and erythromycin, may interact with statins and increase the risk of myopathy. 4All statins have been associated with very rare reports of rhabdomyolysis. 5Fatal cases have been reported more frequently for cerivastatin, especially when it was used at higher doses, in elderly patients, or in combination with gemfibrozil, another lipid lowering drug. 6Pravastatin does not undergo significant hepatic metabolism, and fluvastatin is metabolized by more than one cytochrome P 450isoenzyme. Thus, among the statins, fluvastatin and pravastatin are the least prone to interactions. In this report, however, our patients developed severe postoperative rhabdomyolysis with these drugs. Their usual medications did not include drugs that are likely to interact with these statins. Classic risk factors for rhabdomyolysis, such as myopathy in the family or personal history, endocrine or metabolic disorders, malignant hyperthermia, chronic renal failure, and air embolism, were absent. There was no preoperative or postoperative anemia, perioperative hypotensive episode, or sepsis. Blood volume and urine output were maintained during the surgery. Other risk factors for muscular injuries were identified: a history of atherosclerotic disease, a high body mass index in the second case, and a long duration of surgery in a lithotomy position. 7,8The choice of a laparoscopic approach in the surgical management of colorectal cancer could have contributed to the incidence of muscular injuries in our patients. In a survey of neuromuscular injuries associated with urologic laparoscopic surgery, Wolf et al. 9reported six cases of clinical rhabdomyolysis (0.4%) among a total of 1,651 procedures completed by 18 urologists from 15 institutions in the United States. Patients with rhabdomyolysis were heavier and underwent longer procedures. As in our report, this complication occurred in patients who were not in an extreme lithotomy position. The investigators, however, did not mention their patients’ usual medications. In retrospect, we believe that our patients had an increased risk of muscular injuries as a result of (1) a major surgery with a prolonged immobilization under general anesthesia, (2) a laparoscopic approach with hemodynamic consequences such as decreased regional blood flow and increased systemic vascular resistances 10, and (3) prolonged treatment with a HMG Co-A reductase inhibitor. This risk was probably even higher in the second patient, who had preoperative clinical signs of myopathy.
We retrieved the case notes of 53 other patients who had undergone a similar procedure over the last year in our department. We found three other instances of statin use and no other case of rhabdomyolysis. The association of rhabdomyolysis and statin use was significant (Fisher exact test, P = 0.0067). Eighty percent of the patients, including the two cases of rhabdomyolysis, had received propofol during induction of anesthesia, a drug that could additionally inhibit cytochrome P 4503A4. 11However, this should not have impaired the metabolization of fluvastatin and pravastatin.
In this particular context, and apart from the usual measures to prevent muscular injuries, physicians should systematically look for clinical and biologic signs of rhabdomyolysis in the postoperative period. The question of the preoperative discontinuation of statins should also be raised. In our department, patients usually stopped taking statins the day before surgery. Although the half-life of statins is short (0.5–3 h), and this period seems to be reasonable, the literature on the potential interactions of statin metabolites with drugs administered during or after anesthesia and on possible muscular accumulation of these drugs is sorely lacking. Considering that these drugs are used for long-term prevention, stopping the drug for a few weeks before surgery would not significantly decrease the cardiovascular protection. We suggest much earlier discontinuation of these drugs in the hope of decreasing the risk of rhabdomyolysis.
The authors thank the Department of Pharmacology of the Centre Hospitalier Universitaire de Bordeaux, France, for assistance.