Management of a Malignant Hyperthermia Patient During Cardiopulmonary Bypass

MANAGEMENT OF A MALIGNANT HYPERTHERMIA PATIENT DURING CARDIOPULMONARY BYPASS

R.J. BYRICK, D.K. ROSE AND N. RANGANATHAN

ABSTRACT The anaesthetic management of cardiopulmonary bypass (CPB) for a patient with biopsy-proven malignant hyperthermia is reported. Specific changes in the technique used, such as venting the oxygenator before use, monitoring mixed venous Po: and Pco2, as well as the safety of cold hyperkalaemic cardioplegia are described. Controversial aspects of malignant hypet~hermia management such as the safety of calcium and catechol inotropes are discussed in relationship to the successful use of eardio-pulmonary bypass in our patient. We chose to treat left ventricular dysfunction by aggressive vasodilator (nitroglycerine) therapy. We detected no myocardial or respiratory depression secondary to dantrolene therapy either before or after operation.

KEY WORDS" CARDIACSURGERY, COMPLICATIONS,malignant hyperthermia.

MALIGNANT HYPERTHERMIA (MH) is a phar- pulmonary bypass (CPB) for coronary artery macogenetic myopathy I involving both skeletal 2 surgery. and cardiac muscle. 3 Affected patients are susceptible to acute hyperthermia and/or myotonic CASE REPORT reactions triggered by several specific drugs, potent inhalational anaesthetics, some muscle A 54 year old male who had incapacitating relaxants, and the amide type of local anaesthe- angina at rest (Canadian Cardiovascular Society tics. Reactions can be aggravated by sympatho- Class IV) 6 despite medical therapy (proprano- mimetics, parasympatholytics, cardiac glyco- lal 160 mg/day) was admitted for coronary ar- sides and calcium salts. 4 Stressful environmental teriography and elective triple aortocoronary by- situations such as high temperatures, infections, pass grafting. This patient had a strong family muscle injury, exercise and emotional excite- history of hyperthermic anaesthetic catastrophes ment may also precipitate a reaction. The patho- and previously had been studied by muscle physiology of the hyperthermic crisis has been biopsy. The result 7 of both the caffeine contrac- investigated and recently reviewed.4 The clinical ture test and the ATP depletion test on the muscle and laboratory findings of human and porcine biopsy specimen confirmed the diagnosis of MH support the theory that the control of MH. myoplasmic ionized calcium levels is lost, caus- Cardiac catheterization was done using pro- ing an increase in aerobic and anaerobic metabo- caine for local anaesthesia while the patient was lism which characterizes the respiratory and sedated with diazepam given intravenously. metabolic acidosis of this syndrome. Temperature, electrocardiogram and arterial The purpose of this report is to outline the pressure were recorded continuously and pre- anaesthetic implications in a patient with MH cautions were taken to prevent and, if necessary, and coronary artery disease requiring cardio- to treat an MH crisis during the heart catheterization. The selective coronary arteriograms showed severe triple vessel coronary artery R.J. Byrick, M.D., FR.C.P.(C), Assistant Profes- sor, Department of Anaesthesia; D.K. Rose, M.D., disease including a lesion (>90 per cent occlu- F.R.C.P.(C), Lecturer, Department of Anaesthesia; sion) of the left main and right coronary artery. N. Ranganathan, M.D., F.R.C.P.(C), Associate Pro- Left ventricular end diastolic pressure was 1.46 fessor, Department of Medicine; University of Toron- kPa (11 mm Hg) and the left ventricular ejection to and St. Michael's Hospital, Toronto, Ontario. Correspondence to: Dr. R.J. Byrick, Department of fraction was 67 per cent. The patient tolerated Anaesthesia, St. Michael's Hospital, 30 Bond Street, this procedure without any changes in tempera- Toronto, Canada M5B 1WS. ture or cardiac status. 50 Can. Anaesth. Soc. J., vol. 29, no. I, January 1982 BYR1CK, et al.: MALIGNANT HYPERTHERMIA AND CARDIAC SURGERY 51

Before surgical revascularization the possible TABLE I risks were explained to the patient. For two days NON-INVASIVE MEASURES OF VENTRICULAR he was pretreated with dantrolene 50 mg q.i.d. PERFORMANCE (2 mg'kg -l per day), since he noted significant skeletal muscle weakness with a 100 mg dosage. Predicted Pie Post The dose of dantrolene was then gradually normal dantrolene dantrolene increased to 4 mg.kg-t per day for the thirty-six Systolic Time Intervals: hours before the operation. Non-invasive indices PEP (msec) 106 129 131 of left ventricular performance (Table I) were LVET (msec) 308 262 275 measured before dantrolene treatment and again QS2 (msec) 414 391 406 after two days of therapy to evaluate the effects PEPILVET 0.49 0.48 of this drug on ventricular function. Pre- Echocardiogram: operative sedation was achieved with diazepam Shortening fraction 28-46% 41.3% 42.2% 10 mg per os at 0600 hours, followed by intra- muscular morphine 15mg and perphenazine Muga Scan (Tc 99m): Ejection 5 mg one hour later. An oral dose of dantrolene fraction 0.45-0.6 0.58 0.58 100 mg was given with the diazepam two hours before operation. A halothane vaporizer had been removed from cinate were added to promote a diuresis and to the extra-corporeal membrane oxygenator (Tra- enhance membrane stability. venol Teflo) four days before the operation. The Moderate hypothermia (to 30 ~ C) was accom- oxygenator system was continuously vented plished during CPB. Re-warming was started with oxygen for 48 hours before operation. early during the procedure, taking care not to Precautionary measures included ice, cold in- exceed 37~ thus avoiding temperature fluc- travenous solutions and a warming blanket. tuations (high or low) in the peri-operative Intravenous dantrolene sodium, verapamil and period. Vasodilator (nitroglycerine) treatment procainamide were also available. A vapour was used during the re-warming phase to main- free anaesthetic machine was used with fresh tain arterial pressure greater than 7.98 kPa (60 soda lime in the carbon dioxide absorber. mmHg) with increased pump flows (80 Monitors included the electrocardiogram ml.kg-l). Vasodilation during the re-warming (lead Vs), radial artery cannula for pressure phase has been shown to minimize the post CPB monitoring and blood gas sampling as well as a decrease in temperature, s central venous pressure catheter. A left atrial Cardioplegia (induction of electromechanical catheter was inserted before discontinuing CPB. arrest) using a cold solution containing magne- The rectal and oesphogeal temperatures were sium sulphate 1.5 mmol, tromethamine 1 mmol, monitored continuously. Cardiographic leads KC1 10 mmol and sodium chloride 13.5 mmol in for the intra-aortic balloon pump were placed each 500 ml of 5 per cent dextrose in water was before induction of anaesthesia. used. We encountered no difficulty using 1,500 Fentany150 Ixg.kg-1 was used for induction of ml of this solution and electromechanical acti- anaesthesia supplemented with diazepam 10 mg vity returned shortly after the aorta was un- intravenously. Pancuronium was used to provide clamped. The procedure was performed with a muscular relaxation for tracheal intubation and 130 minute pump time and an aortic cross-clamp the patient was ventilated with oxygen (FIo2 = time of 60 minutes. 1.0). Further fentanyl was administered inter- During CPB the acid-base state of the patient mittently to a total dose of 70 ~g.kg -~. No was monitored every 15 minutes by analyzing lidocaine was used either to lubricate the tracheal blood obtained from both the arterial and venous tube or as a local anaesthetic during insertion of cannulae (Table II). No unusual metabolic aci- monitoring catheters. dosis or elevated venous carbon dioxide values The membrane oxygenator was primed with were noted. Serum potassium (K +) levels de- normal saline (2 litres) and potassium chloride creased significantly and supplemental KCI was (KCI 4 mmol. 1-1) and sodium bicarbonate 50 given. This mild acidosis (base excess of -4) is mmol was added. Lactated Ringer's solution not unusual during CPB. was avoided because it contained small amounts The initial attempt to wean from CPB failed of calcium. Mannitol (50 ml of 20 per cent) and when the left atrial pressure increased to 5.32 one gram of methyl prednisolone sodium suc- kPa (40 mmHg) and the systemic blood pressure TABLE II

ARTERIAL SAMPLE VENOUS SAMPLE

CPB Paco2 Pao2 Total [H + Iv Pvco2 PVo~ Total Time [H+] a CO2 CO2 K + Temp rain nmol/I pHa kPa mmHg kPa mmHg mmol/l nmol/l pHv kPa mmHg kPa mmHg mmol/l mmol/I ~

15 39.81 7.40 3.86 29 14.63 110 19 40.74 7.39 4.39 33 4.12 31 20 3.9 29 30 36.02 7.42 4.66 35 16.09 121 24 36.02 7.42 4.92 37 4.92 37 25 3.9 30 45 40.74 7.39 4.66 35 27.93 210 22 43.65 7.36 4.99 37.5 4.39 33 23 5.1 30 60 42.66 7.37 5.32 40 22.74 171 25 39.81 7.40 5.05 38 5.25 39.5 25 5.0 34 75 36.31 7.44 4.12 31 36.18 272 21 36.02 7.42 5.19 39 4.52 34 22 5.6 35 90 39.81 7.40 4.39 33 26.33 198 20 39.81 7.40 4.99 37.5 4.72 35.5 22 5.5 37 Po~ CPB 45.71 7.34 4,79 36 20.75 156 21 -- 4.0 37

Arterial and mixed venous blood samples were analyzed during CPB to detect any increase in carbon dioxide production or metabolic acidosis. The values shown have been temperature corrected. BYRICK, et al.: MALIGNANT HYPERTHERMIA AND CARDIAC SURGERY 53 fell to 9.31/5.32kPa (70/40mmHg). Neither agonists have been shown to trigger an MH intravenous calcium salts nor catecholamine reaction in susceptible swine .4 Although there is infusions were used to assist in discontinuing only one clear report lm of a sympathomimetic CPB. Full flow on CPB was reinstituted for agent (phenylephrine) initiating an MH reaction, fifteen minutes. Using an intravenous nitrogly- the safety of pure beta agonists is not clear. The cerine infusion, we then weaned the patient mechanism of MH activation by alpha agonists easily from CPB, while maintaining left atrial may be secondary to reduced muscle perfusion 4 pressures of 2-2.66kPa (15-20mmHg) and and hypoxia. Thus, when confronted with an systemic arterial pressures of 15.96-18.62/10.64 MH susceptible patient who requires inotropic kPa (120-140/80 mmHg). support unrelated to the MH condition, the The postoperative course was uneventful. anaesthetist may have to accept a significant but Dantrolene sodium 1 mg-kg-~ was given intra- unkown risk when considering the potential venously every six hours for 24 hours following benefits of weaning from CPB. admission to the intensive care unit. Morphine An associated concern was the effect of and diazepam were used for sedation. The dantrolene sodium on the inotropic state of the trachea was extubated without reversal of neuro- diseased heart. ~ There is evidence t2 that dan- muscular block after 12 hours of ventilation. No trolene may depress the myocardium in animals respiratory or cardiovascular depression was but no studies have documented the effect of this noted following extubation. This patient's tem- drug on human cardiac muscle. We noted no perature was monitored in I.C.U. for 48 hours significant change in left ventricular perform- after dantrolene was discontinued and no evi- ance as assessed by systolic time interval mea- dence of MH was noted. surements and radionuclide angiography, during dantrolene treatment with 4mg.kg -~ per day DISCUSSION (Table I). Further study of the effect of this agent on normal and ischaemic human heart muscle is There are several aspects of anaesthesia re- needed before the risk of treatment can be quiring CPB which represent a potential risk to determined. an MH-susceptible patient. One concern pre- Dantrolene frequently causes significant ske- operatively is the possible risk entailed by the letal muscle weakness,'as it did in this patient. avoidance of inotropic agents, 3'4 including di- In the post-operative period, when many patients goxin, calcium salts and catechol infusions. have respiratory complications, the significance Also there are some data which suggest that of this weakness in precipitating respiratory cardiac muscle may be involved in the MH muscle fatigue following tracheal extubation is disease process.3'1~ Episodes of sudden death in unknown. We noted no significant impairment members of known families, unexplained non- of respiratory function while dantrolene was specific cardiomyopathies and abnormal thal- being administered to this patient. However, a lium scans are suggestive of a direct myocardial controlled study of pulmonary function testing involvement in MH patients. 3,4 The dramatic before and after dantrolene therapy could clarify haemodynamic response to aggressive vasbdila- the degree of impairment caused by dantrolene. tor therapy using intravenous nitroglycerine in The initiation of an MH crisis is in proportion this case emphasizes that there are treatment to the susceptibility of the patient and the total modalities which are acceptable for MH pa- dose of triggering agent(s) and other environ- tients. If cardiac failure should persist, in spite of mental stresses. Although triggering drugs and vasodilator therapy, one must consider the re- calcium salts can be avoided, the stress response spective risks of mechanical intra-aortic balloon to CPB can be considerable, resulting in signi- counterpulsation and inotropic support. The use ficant elevation of stress-related hormones (en- of inotropic agents in MH susceptible individu- dogenous cortisol and catecholamines). 13 The als remains controversial. We planned to use use of a technique with pancuronium and "high mechanical support to improve coronary perfu- dose fentanyl ''13 would appear to offer the sion and assist the left ventricle if vasodilator advantage of a reduced endogenous catechol therapy was inadequate. Bradycardia associated response to CPB. with low cardiac output can be treated by One interesting facet of CPB is the ability to pacemaker implantation. monitor the acid-base status in mixed venous When these interventions fail to facilitate blood frequently from the extracorporeal oxy- weaning from CPB the anaesthetist is forced to genator. An acute MH reaction would also be consider the use of inotropic agents. Sympathetic preceded by increasing oxygen consumption 54 CANADIAN ANAESTHETISTS' SOCIETYJOURNAL with a decrease in P%2. One effect of crystal- 2. BRITT, B.A. Malignant hyperthermia: a phar- loid haemodilution on the content of carbon macogenetic disease of skeletal and cardiac muscle. N. Eng. J. Med. 290:1140 (1974). dioxide in the mixed venous blood would be a 3. HUCKELL, V.F., STANILOEF, H.M, BlUrT, reduction in the buffering capacity (protein and B.A., WAXMAN, M.B. & MARCH, J.E. Cardiac haemoglobin) of the blood. Similarly hypother- manifestations of malignant hyperthermia sus- mia would reduce the solubility of carbon ceptibility. Circulation 58:916 (1978). dioxide in blood. Therefore if a patient whose 4. GRONERT, G.A. MalignantHyperthermia. Anes- thesiology .53:395 (1980). blood is diluted and cooled develops an MH 5. RYAN, J.F., DONLON, J.V., MALT, R.A., reaction, one would expect the Pvco2 to rise BLAND, J.H., BUCKLEY, M.J., STRETER, F.A. & rapidly. In this patient there was no evidence of LOWENSTEIN, E. Cardiopulmonary bypass in the either increased lactate production (decrease in treatment of malignant hyperthermia. N. Eng. J. Med. 290: 1121 (1974). bicarbonate) or any rise in mixed venous Pco2 6. CAMPEAU,L. Grading of angina pectoris. Circu- (P~co~) during CPB 4 (Table II). lation 54:522 (1976). In summary, we have successfully managed a 7. BmTT, B.A. Pre-anesthetic diagnosis of malig- patient with biopsy-proven MH during CPB. nant hypertherrnia. Int. Anesth. Clin. 17(4): 77 The anaesthetic management of the potential (1979). 8. NOBACK, C.R. & TINKER, J.H. Hypothermia problems that we considered important is out- after cardiopulmonary bypass in man. Anesthe- lined. Taking these factors into consideration, siology 53:277 (1980). the risk of CPB in patients known to be suscept- 9. KIRKLIN, J.W., CONTI, V.R. & BLACKSTONE, ible to MH may be increased. This serves to E.H. Prevention of myocardial damage during cardiac operations. N. Engl. J. Med. 301:135 emphasize that the diagnosis of malignant hyper- (1979). thermia must not be made indiscriminately. 10. FENOGLIO, J.J., MAJ, M.C. & IREY, N.S. Myo- Precision of the in vitro diagnostic tools used to cardial changes in malignant hyperthermia. An. make this diagnosis is essential to avoid needless J. Pathology 89:51 (1977). concern among patients and physicians who are 11. HALL, G.M., LUCKE, J.N. & LISTER, D. Porcine malignant hyperthermia, V: Fatal hyperthermia contemplating the operative risk of cardiac in the Pietrain pig, associated with the infusion of surgery. More clinical data is necessary to c~-adrenergie agonists. Br. J. Anaesth. 49:855 evaluate the significance of Malignant Hyper- ( 1977). thermia in increasing this operative risk. 12. MEYLER, W.J., WESSELING, H. &ANGOSTON, S. The effects of dantrolene sodium on cardiac and skeletal muscle in rats. Europ. J. Pharmacol. 39: ACKNOWLEDGEMENTS 127 (1976). The assistance of Dr. Beverley Britt in re- 13. STANLEY, T.H., BURMAN, L., GREEN, O. & ROBERTSON, D. Plasma eatecholamine and cor- viewing the manuscript and Mrs. P. Slusarenko tisol responses to fentanyl-oxygen anesthesia for for typing the paper is appreciated by the coronary artery operations. Anesthesiology 53: authors. 250 (1980). 14. MCHARDY,G.T.R. The relationship between the REFERENCES differences in pressure and content of carbon dioxide in arterial and venous blood. Clin. Sci. 1. BRITT, B.A., LOCHER, W.G. d~, KALOW. Heredi- 32:299 (1967). tary aspects of malignant hyperthermia. Can. Anaesth. Soc. J. I6:89 (1969).

RI~SUMI~ Nous rapportons la conduite de l'anesth6sie lors d'une intervention ~ cmur ouvert effectu6e chez un patient susceptible b. l'hyperthermie maligne; la susceptibilit6 ~t rhyperthermie avait 6t~ d~Smontr6e par biopsie musculaire. Du point de vue technique, on cite entre autres, l'enl6vement du vaporisateur d'halothane habituellement fix6 ~t l'appareil co~ur-poumon et la ventilation de l'oxyg6nateur au moyen d'oxyg6ne durant 48 heures avant l'intervention; on cite ~galement les v6rifications des Po2 et des Pco2 veineuses centrales au coups de la circulation extracorporelle. On rapporte l'emploi sans probl6me d'une solution de cardiopl6gie au potassium. L'emploi d'agents inotropes comme le calcium et les cat6cholamines en chirurgie ~ c0eur-ouvert dans un contexte de susceptibilit6 ii l'hyperthermie maligne est comment~. Dans le cas rapport& une d~faillance ventriculaire gauche survenue h la sortie de C.E.C. a pu &re trait~e avec succ~s au moyen de vasodilatateurs (nitroglycerine). Nous n'avons pas observ~ de d6pression respiratoire ou circulatoire ~t la suite de l'administration de dantrol6ne avant et apr~s l'intervention.