Ⅵ CASE REPORTS Anesthesiology 2001; 94:355–7 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Rhabdomyolysis following Cardiopulmonary Bypass and Treatment with Enoximone in a Patient Susceptible to Malignant Hyperthermia Friedrich-Christian Riess, M.D.,* Marko Fiege, M.D.,† Sina Moshar, M.D.,‡ Heinz Bergmann, M.D.,§ Niels Bleese, M.D.,ʈ Joachim Kormann, M.D.,# Ralf Weißhorn, M.D.,† Frank Wappler, M.D.†† SEVERE hypercapnia, muscle rigidity, hyperthermia, and After implantation of a mechanical valve (Medtronic Hall; Medtronic, rhabdomyolysis characterize malignant hyperthermia Minneapolis, MN), the ascending aorta was closed and the aortic 1 cross-clamp removed. During reperfusion, the patient exhibited ST (MH) in fulminant form. However, during cardiac opera- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 elevations, with maximal values of 12 mV in all leads. The left ventricle tions using cardiopulmonary bypass (CPB), typical symp- appeared to be ischemic and hypokinetic. A triple bypass was per- toms of MH may not be present. We observed a patient formed using saphenous grafts to the left anterior descending, first undergoing aortic valve replacement, in whom severe post- diagonal branch and the circumflex artery. The patient was then operative rhabdomyolysis and arrhythmias developed after successfully weaned from CPB using a moderate dose of adrenalin (4 ␮ treatment with enoximone during CPB and cardioplegic g/min) and 50 mg enoximone (Perfan; Hoechst, Bad Soden am Ts., Germany). However, toward the completion of the operation, the arrest. Subsequently, in vitro contracture testing showed urine became dark and the minute ventilation necessary to maintain that the patient was susceptible to MH. normocapnia were increased from 8 to 14.2 l/min, whereas pH de- creased to 7.19. On the first postoperative day, a potassium concentration of 6 mM, Case Report a CK concentration of 9,348 U/l, and an increase of creatinine concen- tration to 2.5 mg/dl were noted. Rectal temperatures remained normal. A 48-yr-old man (weight, 92 kg; height, 169 cm) was scheduled to Ventricular arrhythmias and atrial fibrillation occurred on the second undergo aortic valve replacement. Family history was unremarkable. postoperative day, and administration of increasing amounts of intra- No allergies to medications were known. There was no history of venous adrenalin was necessary to achieve hemodynamic stability. A surgery or anesthesia. Enalapril (Pres; Boehringer, Ingelheim, Ger- serum myoglobin concentration of 8,887 ␮g/l was noted. There were many) 10 mg/day was the only preoperative medication. Laboratory no signs of compartment syndrome in any extremity. Because malig- data were normal except for a ␥ glutamate transferase of 41 U/l nant hyperthermia was suspected, the patient was treated with 220 mg (normal, Ͻ 28). Creatine kinase (CK) concentration was 53 U/l. dantrolene (Dantrolen; Procter & Gamble Pharmaceuticals, Weiters- The patient received 2 mg flunitrazepam (Rohypnol; Hoffmann La- tadt, Germany) intravenously. The hemodynamic profile of the patient Roche, Basel, Switzerland) orally the evening before surgery and an- improved, and catecholamine therapy could be discontinued. Because other 2 mg flunitrazepam and 0.3 mg clonidine (Catapresan; Boehr- of renal impairment, hemofiltration was started and was continued for inger) orally on the morning of surgery. Anesthesia was induced using 19 days. On the third postoperative day, a second dose of 25 mg 1 mg/kg intravenous propofol (Disoprivan; Zeneca, Plankstadt, Ger- enoximone was administered. Shortly thereafter, partial pressure of many) and 25 ␮g intravenous sufentanil (Sufenta; Janssen, Neuss, Germa- carbon dioxide (PCO2) increased to 48.3 mmHg during mechanical ny), muscle relaxation was achieved using 0.2 mg/kg intravenous pancu- ventilation, and CK concentration increased to 9,348 U/l. This re- ronium bromide (Pancuronium; Curamed Schwabe, Karlsruhe, Germany). sponse was treated again with 220 mg dantrolene intravenously. Pa- Ϫ1 Ϫ1 Anesthesia was maintained using propofol (4 mg ⅐ kg ⅐ h ) and tient serum muscle enzyme concentrations gradually returned to nor- Ϫ1 Ϫ1 sufentanil (0.5 ␮g ⅐ kg ⅐ h ). The patient received 2 g cephazolin mal, and he was discharged in good condition on the thirty-third sodium (Gramaxin; Boehringer, Mannheim, Germany) intravenously. A postoperative day. membrane oxygenator (Quadrox; Jostra, Hirrlingen, Germany) was Five months postoperatively, the patient was examined for malig- used together with a roller pump. The priming solution of CPB (1,600 nant hyperthermia susceptibility and other muscular diseases. After the ml) contained lactated Ringer’s solution, mannitol (15%), and sodium patient had given informed consent, muscle biopsy was performed bicarbonate, and 5,000 IU unfractionated heparin (Heparin Braun; using regional anesthesia. The muscle bundle was excised carefully Braun Melsungen, Melsungen, Germany) and aprotinin (Antagosan; from the vastus lateralis muscle, and an additional small muscle sample Behringwerke AG, Marburg, Germany). Standard CPB was established was obtained for evaluation of histomorphologic changes. ⅐ Ϫ1 ⅐ Ϫ2 with a flow rate of 2.5 l min m , which was reduced during The in vitro contracture tests (IVCTs) with halothane and caffeine ⅐ Ϫ1 ⅐ Ϫ2 hypothermia to 2.0 1 min m at 34.2°C (rectal temperature). were performed according to the protocol of the European Malignant Hyperthermia Group (EMHG).2 The muscle bundle was dissected into eight strips. Only viable muscle samples (twitch response to supra- * Associate Professor of Cardiac Surgery, ‡ Resident, ʈ Professor and Head, maximal electrical stimulation Ͼ 10 mN) were used. Two samples Department of Cardiac Surgery, § Staff Anesthesiologist, Department of Anesthe- were tested with each drug. The muscle specimens of this patient siology, # Anesthesiologist and Head, Department of Cardiac Anesthesiology, Albertinen-Hospital. † Staff Anesthesiologist, †† Associate Professor of Anesthe- developed abnormal contracture responses to 0.44 mM halothane and siology, Department of Anesthesiology, University-Hospital Eppendorf. 2.0 mM caffeine, indicating susceptibility to MH. After administration of ␮ Received from the Departments of Cardiac Surgery, Anesthesiology, and Cardiac 1 M ryanodine, an accelerated and increased contracture develop- Anesthesiology, Albertinen-Hospital, Hamburg, Germany, and the Department of ment was observed.3 The contracture test results are presented in Anesthesiology, University-Hospital Eppendorf, Hamburg, Germany. Submitted for table 1. publication December 28, 1999. Accepted for publication May 24, 2000. Support Two additional muscle samples were tested using enoximone. The was provided solely from institutional and/or departmental sources. IVCTs were performed with cumulative administration of enoximone Address reprint requests to Dr. Riess: Department of Cardiac Surgery, in concentrations of 0.2, 0.4, 0.6, 0.8, 1.2, and 1.6 mM, and as a bolus Albertinen-Hospital, Suentelstrasse 11 a, 22457 Hamburg, Germany. Address 4 electronic mail to: [email protected]. Individual article reprints may administration of 0.6 mM enoximone, as described previously. The be purchased through the Journal Web site, www.anesthesiology.org. original tracings of the enoximone–IVCTs are shown in figure 1. In the Anesthesiology, V 94, No 2, Feb 2001 355 356 CASE REPORTS Table 1. Results of the In Vitro Contracture Tests with Halothane, Caffeine, and Enoximone in the MHS Patient and Normal Results in MHS and MHN Patients Normal Values: Substance Concentration (Contracture Ն 2 mN) Muscle Twitch at Substance Concentration (mM) Concentrations Start (Contracture Ն 2 mN) Test Substance (mM) (mN) (mM) MHS MHN Halothane (1) 0.11, 0.22, 0.44 208 0.44 Յ 0.44 Ͼ 0.44 Halothane (2) 0.11, 0.22, 0.44 80 0.44 Յ 0.44 Ͼ 0.44 Caffeine (1) 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 32.0 202 2.0 Յ 2.0 Ͼ 2.0 Caffeine (2) 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 32.0 104 3.0 Յ 2.0 Ͼ 2.0 Enoximone 0.2, 0.4, 0.6, 0.8, 1.2, 1.6 84 0.6 Յ 0.6 Ͼ 0.6 (cumulative) Enoximone 0.6 85 Contracture maximum Contracture Contracture Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 (bolus) 23.4 mN Ն 2mN Ͻ 2mN MHS ϭ malignant hyperthermia–susceptible; MHN ϭ malignant hyperthermia–normal. IVCTs with cumulative enoximone administration, the muscle sample glycine in position 2433, which was shown to be associated with 6 showed contracture development at a concentration of 0.6 mM enoxi- malignant hyperthermia. mone. Moreover, a single bolus administration of 0.6 mM enoximone induced a contracture maximum of 23.4 mN. Both results are compa- rable with findings from MH-susceptible muscle fascicles in the differ- Discussion ent IVCTs with enoximone.5 Histomorphologic evaluation was per- formed for the additional muscle sample; all investigations of this In this unusual case, two MH-like episodes developed muscle specimen (e.g., morphometry, immunohistochemistry, fiber in a patient after cardiac operation with CPB and con- size, and ratio analysis) showed normal findings. comitantly after the administration of the phosphodies- Preparation of DNA and oligonucleotides, genotyping, and detection terase-III (PDE-III) inhibitor enoximone. The patient was of mutations in the ryanodine receptor gene were performed as de- scribed previously.6 Mutation screening led to the discovery of a not administered any of the known trigger substances of 1 substitution of A for G7297. The patient was heterozygous for this MH, such as volatile anesthetics or succinylcholine. mutation. This mutation results in the substitution of arginine for None of the substances administered to the patient con- Fig. 1. Effects of cumulative administration (upper, 0.2–0.4–0.6–0.8–1.2–1.6 mM) and bolus administration (lower, 0.6 mM)of enoximone on contracture development in two skeletal muscle specimens of this malignant hyperthermia–susceptible patient. For normal values, see table 1.