SEVERE hypercapnia, muscle rigidity, hyperthermia, and rhabdomyolysis characterize malignant hyperthermia (MH) in fulminant form. 1However, during cardiac operations using cardiopulmonary bypass (CPB), typical symptoms of MH may not be present. We observed a patient undergoing aortic valve replacement, in whom severe postoperative rhabdomyolysis and arrhythmias developed after treatment with enoximone during CPB and cardioplegic arrest. Subsequently, in vitro contracture testing showed that the patient was susceptible to MH.
A 48-yr-old man (weight, 92 kg; height, 169 cm) was scheduled to undergo aortic valve replacement. Family history was unremarkable. No allergies to medications were known. There was no history of surgery or anesthesia. Enalapril (Pres; Boehringer, Ingelheim, Germany) 10 mg/day was the only preoperative medication. Laboratory data were normal except for a γ glutamate transferase of 41 U/l (normal, < 28). Creatine kinase (CK) concentration was 53 U/l.
The patient received 2 mg flunitrazepam (Rohypnol; Hoffmann LaRoche, Basel, Switzerland) orally the evening before surgery and another 2 mg flunitrazepam and 0.3 mg clonidine (Catapresan; Boehringer) orally on the morning of surgery. Anesthesia was induced using 1 mg/kg intravenous propofol (Disoprivan; Zeneca, Plankstadt, Germany) and 25 μg intravenous sufentanil (Sufenta; Janssen, Neuss, Germany), muscle relaxation was achieved using 0.2 mg/kg intravenous pancuronium bromide (Pancuronium; Curamed Schwabe, Karlsruhe, Germany).
Anesthesia was maintained using propofol (4 mg · kg−1· h−1) and sufentanil (0.5 μg · kg−1· h−1). The patient received 2 g cephazolin sodium (Gramaxin; Boehringer, Mannheim, Germany) intravenously. A membrane oxygenator (Quadrox; Jostra, Hirrlingen, Germany) was used together with a roller pump. The priming solution of CPB (1,600 ml) contained lactated Ringer’s solution, mannitol (15%), and sodium bicarbonate, and 5,000 IU unfractionated heparin (Heparin Braun; Braun Melsungen, Melsungen, Germany) and aprotinin (Antagosan; Behringwerke AG, Marburg, Germany). Standard CPB was established with a flow rate of 2.5 l · min−1· m−2, which was reduced during hypothermia to 2.0 1 · min−1· m−2at 34.2°C (rectal temperature). After implantation of a mechanical valve (Medtronic Hall; Medtronic, Minneapolis, MN), the ascending aorta was closed and the aortic cross-clamp removed. During reperfusion, the patient exhibited ST elevations, with maximal values of 12 mV in all leads. The left ventricle appeared to be ischemic and hypokinetic. A triple bypass was performed using saphenous grafts to the left anterior descending, first diagonal branch and the circumflex artery. The patient was then successfully weaned from CPB using a moderate dose of adrenalin (4 μg/min) and 50 mg enoximone (Perfan; Hoechst, Bad Soden am Ts., Germany). However, toward the completion of the operation, the urine became dark and the minute ventilation necessary to maintain normocapnia were increased from 8 to 14.2 l/min, whereas pH decreased to 7.19.
On the first postoperative day, a potassium concentration of 6 mm, a CK concentration of 9,348 U/l, and an increase of creatinine concentration to 2.5 mg/dl were noted. Rectal temperatures remained normal. Ventricular arrhythmias and atrial fibrillation occurred on the second postoperative day, and administration of increasing amounts of intravenous adrenalin was necessary to achieve hemodynamic stability. A serum myoglobin concentration of 8,887 μg/l was noted. There were no signs of compartment syndrome in any extremity. Because malignant hyperthermia was suspected, the patient was treated with 220 mg dantrolene (Dantrolen; Procter & Gamble Pharmaceuticals, Weiterstadt, Germany) intravenously. The hemodynamic profile of the patient improved, and catecholamine therapy could be discontinued. Because of renal impairment, hemofiltration was started and was continued for 19 days. On the third postoperative day, a second dose of 25 mg enoximone was administered. Shortly thereafter, partial pressure of carbon dioxide (Pco2) increased to 48.3 mmHg during mechanical ventilation, and CK concentration increased to 9,348 U/l. This response was treated again with 220 mg dantrolene intravenously. Patient serum muscle enzyme concentrations gradually returned to normal, and he was discharged in good condition on the thirty-third postoperative day.
Five months postoperatively, the patient was examined for malignant hyperthermia susceptibility and other muscular diseases. After the patient had given informed consent, muscle biopsy was performed using regional anesthesia. The muscle bundle was excised carefully from the vastus lateralis muscle, and an additional small muscle sample was obtained for evaluation of histomorphologic changes.
The in vitro contracture tests (IVCTs) with halothane and caffeine were performed according to the protocol of the European Malignant Hyperthermia Group (EMHG). 2The muscle bundle was dissected into eight strips. Only viable muscle samples (twitch response to supramaximal electrical stimulation > 10 mN) were used. Two samples were tested with each drug. The muscle specimens of this patient developed abnormal contracture responses to 0.44 mm halothane and 2.0 mm caffeine, indicating susceptibility to MH. After administration of 1 μm ryanodine, an accelerated and increased contracture development was observed. 3The contracture test results are presented in table 1.
Two additional muscle samples were tested using enoximone. The IVCTs were performed with cumulative administration of enoximone in concentrations of 0.2, 0.4, 0.6, 0.8, 1.2, and 1.6 mm, and as a bolus administration of 0.6 mm enoximone, as described previously. 4The original tracings of the enoximone–IVCTs are shown in figure 1. In the IVCTs with cumulative enoximone administration, the muscle sample showed contracture development at a concentration of 0.6 mm enoximone. Moreover, a single bolus administration of 0.6 mm enoximone induced a contracture maximum of 23.4 mN. Both results are comparable with findings from MH-susceptible muscle fascicles in the different IVCTs with enoximone. 5Histomorphologic evaluation was performed for the additional muscle sample; all investigations of this muscle specimen (e.g. , morphometry, immunohistochemistry, fiber size, and ratio analysis) showed normal findings.
Preparation of DNA and oligonucleotides, genotyping, and detection of mutations in the ryanodine receptor gene were performed as described previously. 6Mutation screening led to the discovery of a substitution of A for G7297. The patient was heterozygous for this mutation. This mutation results in the substitution of arginine for glycine in position 2433, which was shown to be associated with malignant hyperthermia. 6
In this unusual case, two MH-like episodes developed in a patient after cardiac operation with CPB and concomitantly after the administration of the phosphodiesterase-III (PDE-III) inhibitor enoximone. The patient was not administered any of the known trigger substances of MH, 1such as volatile anesthetics or succinylcholine. None of the substances administered to the patient contained 4-chloro-m-cresol, a preservative with MH-trigger potency. 7Both treatments with dantrolene were successful and the patient recovered completely. Five months later, susceptibility to MH was diagnosed by use of IVCTs with halothane and caffeine. The diagnosis was supported by the detection of the G7297A mutation, which is known to be associated with MH susceptibility. Furthermore, skeletal muscle specimens showed altered contracture responses in IVCTs with enoximone. Although the trigger mechanisms of the MH-like episodes in this patient remain unclear, it could be suggested that enoximone potentiated a current myotoxic reaction or maybe was the MH-triggering agent alone.
The PDE-III inhibitors are substances with receptor-independent, positive inotropic effects on cardiac muscle. PDE-III inhibitors act by decreasing the rate of cyclic adenosine monophosphate (cAMP) degradation. The cAMP activates protein kinase A, which results in altered transport rates of different intracellular calcium channels. In cardiac muscle cells, the main effect of PDE-III inhibition is an increased sarcoplasmic calcium release via the ryanodine receptor. 8,9Additionally, PDE-III–inhibiting compounds can sensitize the myofibrils to calcium and enhance the cardiac calcium release channel.
Phosphorylation of the skeletal muscle ryanodine receptor by intracellular PDE-III inhibition modulates the calcium release only slightly. 9However, previous studies have shown enoximone-induced contracture development in human skeletal muscles in vitro . 4,5These muscle contractures started at lower enoximone concentrations and were greater in preparations from MH-susceptible patients than from MH-normal patients. The authors suggested from their investigations that enoximone might be a trigger substance of MH. We performed IVCTs with enoximone in muscle preparations from our patient. In the two tests, the muscle specimens developed marked contractures at a concentration of 0.6 mm enoximone, which was comparable with the results from MH-susceptible patients in previous studies. 4,5
The cAMP system seems to play a role in pathogenesis of MH. In skeletal muscle cells from MH-susceptible patients, higher cAMP concentrations could be measured and compared with concentrations from MH-normal patients. 10Furthermore, during and after physical exercise, the cAMP concentrations in blood serum increased to a higher extent and were more prolonged in MH-susceptible than in MH-normal patients. 11However, the triggering mechanism of MH, the defect in all human MH cases, and the variability of clinical presentation is not clear. Administration of PDE-III inhibitors to MH-susceptible patients might enhance intracellular release of Ca2+and potentiate an MH crisis. However, MH is a heterogenous disorder, and possibly PDE-III inhibitors have an MH-trigger potency in some MH patients.
Rhabdomyolysis during or after CPB is not uncommon. 12,13Preoperative medication seems to be causative with certain preparations. Hydroxymethylglutaryl– coenzyme A reductase inhibitors are substances with known myotoxic side effects, and several cases of rhabdomyolysis after CPB have been reported as a result of administration of hydroxymethylglutaryl–coenzyme A. 12A retrospective analysis of 931 patients undergoing major cardiac surgery identified risk factors for rhabdomyolytic acute renal failure associated with surgical procedure. 13A correlation of rhabdomyolysis and direct femoral artery cannulation, arteriopathy, prolonged extracorporal circulation, low cardiac output syndrome, and continuous intravenous infusion of epinephrine could be shown. A range of relevant causes of rhabdomyolysis during surgery has been identified. 14
Although rhabdomyolysis can occur from various sources during CPB, the direct effect of enoximone in inducing contracture behavior in isolated skeletal muscle suggests that activation of an MH episode probably is a cause in this case. Further in vivo investigations should determine the MH trigger potency of enoximone. Administration of enoximone to MH-susceptible patients might be dangerous and should be performed with care.