Malignant hyperthermia

Malignant hyperthermia Report of two cases F. J. Urukowiak, D.D.S.,“: .I. .J. Vutrd, D.D.S.. M.S..“;” R. c’. Moot-~. A. B. Pickett, B.S.. D.M.D., M.S., **** J E. Nylunder, D.D.S., ***** F. c’. Gdlett, B.S.. x’i’*‘k*i’ Fort Beming. Go.

Jr.. M.D.. uncl

B.S..“‘-““,

A dentist using local or general anesthetics must be cognizant of the possibility of mallgnant hyperthermia presenting as a catastrophic emergency. The purpose of this article IS to describe the syndrome of malignant hyperthermia, to emphasize its early clinical symptoms, and to outline definitive treatment. Two cases of malignant hyperthermia in pediatric dental patients illustrate the clinlcal and laboratory features and the appropriate therapy.

M

alignant hyperthermia is one of the most intense and life-threatening complications of general anesthesia and, although rare, it occurs in patients in whom no anesthetic complications are expected. The syndrome is characterized by tachycardia, fever. tachypnea, cyanosis, and death. A 64 to 73 percent mortality rate indicates the need for early recognition and aggressive treatment. The incidence of this complication has been reported to be one in 15,000 anesthetized children and one in 50,000 anesthetized adults.’ Familial genetic transmission is by an autosomal dominant gene. Reduced penetrance and variable expressivity also characterize its genetic transmission.’ Males are affected more frequently than females, and this predominance increases with age. The youngest patient reported was 3 months of age and the oldest was 78 years.” Most episodes of malignant hyperthermia occur during the first general anesthetic experience, but it has been reported in patients who have undergone previous uncomplicated anesthetic procedures. Most potent anesthetic agents, local anesthetics of the amide type. and muscle relaxants of both depolarizing and nondepolarizing types have been associated with malignant hyperthermia. (Table I).“-” Neuroleptanalgesia (ketamine) or ;I combination of ‘Chiet. Pedodontic Service. Dental Ac‘~l\~t\ “Yhirt’. Oral Surgery Service; Director. Genrral Pracr~cr Reals dent). Dental Actlvit) ‘“*Supervisor, Anesthcaiology Servrc. Martin Army Hospital >‘:‘:**Chief. Oral Pa!hology. Dental Actiwt!. “““*.‘;Gencral Practice Redent. Dental Actl\lr) **xs4*Staff Nurse. Anerthesia Nursing Servvx. Martm Arm! Ho\pa.d

218

barbiturates, nitrous oxide, and narcotics have been used safely in about 500 susceptible patients.” Ketamine has also been reported as a weak triggering agent .‘; Dantrolene. a hydantoin derivative. has been administered orally for control of muscle spasticity. Its action may be related to inhibition of calcium release into the muscle cell. In malignant hyperthermia susceptible Landrace pigs, dantrolene will relax spasticit): and lower temperature.’ Dantrolene has been successfully in a limited number of cases of malignant hyperthermia in man.’ Britt and Kalow.!’ at the University c~t“l‘oronto. have established an international registry of reported casej. Two syndromes of malignant hyperthermia have been described from this registry. a rigid and it nonrigid type.” Rigidity may occur subsequent to succinylcholine administration. making laryngoscopy and intubation difficult.” and it may also develop later during inhalation anesthesia. Both rigid and nonrigid forms 01 the syndrome have been found in the \ame family. Some patients with the condition had pre-existing localized skeletal muscle weakness manifested hq ptosis, strabismus, kyphoscoliosis, spontaneous muscle cramps, or hernias.‘” izlso reported is the association ot malignant hyperthermia with myotonia congenita (Thornsen’s disease). The latter ih a muscular disease possibly caused bq defective potassium transfer in the sarcoplasm. Both diseases are transmitted by autosomal dominant genes.” Malignant hyperthermia has been ahsoclated with ;1 preexisting subclinical or overt muscular defect denonstrated by elevated serum creatine phosphokinasc

Volume 47

Number 3

(CPK)levek3.I* Normal levelsforCPK are 0to80

Table I,Anesthetic agents associated with malignant

international units.l3 The creatine phosphokinaseis

hyperthermia3

composed of threeisoenzyme fractions-isoenzymes arising from skeletal muscle, cardiac muscle, and brain’ Testing for elevated CPK levels in asymptomatic relatives has been used for pre-anesthetic screening to help identify susceptible persons when a family history of malignant hyperthermia exists. 12*I4 Serum creatine phosphokinase levels have not proved to be diagnostic,, since one third of patients susceptible to malignant hy.. penhermia have normal levels. When the CPK level is greatly elevated, it may be of diagnostic value; when it is normal, it is of no value. Factors unrelated to the syndrome, such as exercise, emotional stress, certain drugs. sampling technique, method of measurement, and any recent muscle injury, will elevate the CPK levels.:’ Preoperative muscle biopsy for determination of caffeine-induced contracture response may be of diagnostic value. Another useful test may be one in which contracture of muscle biopsy material from susceptible patients can be induced by bathing the tissues in halothane.” With the use of markedly elevated CPK levels and in vitro muscle tension studies using caffeine and/or halothane, a better means of identifying susceptible members of known families may be developed. The onset may be insidious and the syndrome may suddenly become apparent, with rapid progression after administration of a “triggering agent.” Succinylcholine is the most commonly involved agent, although a11common potent inhalation anesthetics and muscle relaxants are known “triggering agents.” When the inhalation agent alone initiates the onset of the syndrome, the clinical signs do not appear as rapidly as when a muscle relaxant triggers the episode. The amide type of local anesthetic (lidocaine, mepivicaine, prilocaine) appears to be a weak triggering agent and is contraindicated in the treatment of a patient with malignant hyperthermia.“, I6 PATHOPHYSIOLOGY

The exact cause of malignant hyperthermia is unknown, although research has been directed toward abnormal muscle cell function.“, Ix The sustained muscle contraction and the requirement for continued energy production result in excessive liberation of heat. There appears to be a defect in calcium ion metabolism in the muscle cells of the susceptible patient.‘” In the rigid type of syndrome, there appears to be a genetic defect in the ceil membrane that allows an abnormally large concentration of calcium ions to be released from the sarcoplasmic reticulum or permits a blocking of the

Halothane- 60percentof allcases Succinyfcholine- 77percentof all cases N,O - meperidine Methoxyflurane Ether Ethyl chloride

Trichlorethylene Cyclopropane Ethylene Gallamine D-tubocurarine Isoflurane

Enflurane Lidocaine* Carbocaine*

*It is of significantimportanceto all dentiststhat two commonly usedlocal anestheticagentshave been implicatedwith this syndrome

transport of the calcium ions back into the storage sites in the sarcoplasmic reticulum. This sustained increase in muscle cytoplasmic calcium ions tends to explain the prolonged contracture of skeletal muscle and the resultant hypermetabolic state. Secondarily, mitochondria take up the excessively available calcium ions and uncoupling of oxidative phosphorylation occurs, resulting in an increase in aerobic and anaerobic metabolism.“* ” Other suggested mechanisms postulate sarcolemmal dysfunction, rather than depressed sarcoplasmic reticulum, as the cause of calcium accumulation. The cause of malignant hyperthermia without rigidity still remains obscure.” CLINICAL

FEATURES

The signs of malignant hyperthermia include those that signal the oncoming catastrophe and those that represent the onset of the syndrome itself.” If, after administration of succinylcholine, active rigidity of the masseter muscle develops, a presumptive diagnosis of malignant hyperthermia can be made.“’ Administration of anesthesia should be discontinued and preparations made to cope with the possible onset of the syndrome. Other early indicators are increased heart and respiratory rates due to intense metabolic and respiratory acidosis. A change of pulse rate from 90 per minute or less to more than 140 over a short period of time without clear cause is rarely due to light anesthesia, and before more anesthesia is administered it is essential that an explanation be found for the tachycardia. Dark, venous blood may become apparent in the operative field as a result of the increase in oxygen extraction by the tissues in the hypermetabolic state. Ventricular arrythmias may arise from an increase in potassium ion

concentration.” Rigidity may or may not be present. Fever is a late sign since the underlying metabolic problem that results in increased heat production has been triggered well before any noticeable increase in tenperature develops. I7 Early laboratory findings include acidosis. hypoxemia, hyperkalemia. hypermagnesemia, myoglobinemia. and elevated lactate and pyruvate level>. An incrcasc in temperature of I” F. or greater III ;I patient with other early signs of malignant hyperthermia should be noted and all preparations made to avoid ;I catastrophe. ” Immediate and aggressive treatment will be required.” Late complications may occur despite successful inltial therap). They include consumptive coagulopathq necessitating heparinization. acute renal failure resulting from myoglobinemia, inadvertent hypothermia with resulting arrythmia, pulmonary edema secondary to cardiac arrest. skeletal muscle swelling from local hypoxia and acidosis, and such neurologic sequelae as paraplegia and dccerebration. TREATMENT Following diagnosis of hyperthermia. the patient’s electrocardiogram, temperature. blood gases. electrolytes. and urinary output must be monitored closely. Symptomatic therapy consists of: I. Discontinuation of anesthesia, including the changing of any anesthesia rubber tubing because of the solubility of inhalation agents in rubber. All traces of the inhalation anesthetic that triggered the episode must be removed. -.’ Hyperventilation with 100 percent oxygen. 3. Monitoring of arterial blood gases and pH for a correct evaluation of the patient’s acidosis which is always present. 1. Intravenous administration of sodium bicarbonate for rapid blood alkalinization. 5. Intravenous administration of chloroprocainc or procainamide as soon as possible after diagnosis. Electrocardiographic monitoring is necessary, since large doses of these agents may produce cardiovascular colidpse. A loading dose of 1 mg./kg./minute is given until slowing of the pulse is observed. Procaine and chloroprocaine increase calcium ion transfer from the sarcolemma of the striated muscle cell into the storage sites of the sarcoplasmic reticulum. Local anesthetics of the amide type (lidocaine. mepivacaine, and prilocaine) do not reverse the calcium ion flow and are contraindicatcd in the treatment of the primary metabolic problem or the ventricular arrythmias that may be associated with the syndrome. 6. Initiation of cooling. Pediatric patients may be

packed

III ICC LGth successful

perature.

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tempcraturcs.

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Volume 47

Malignanthyperthermia221

Number 3

hyperventilation with100percent oxygen, Thecreatine phos- highmortality rateassociated withthissyndrome phokinase valuewas I X0 1.U. necessitates continuous temperature monitoring during Thepatient wascatheterized, andthecollected urinewas administration of generalanesthesia. Sincefevermay found to be free of myoglobin but positive for hemoglobin. Within an hour, the patient’s rectal temperature returned to 100” F. At this time, she was taken to the intensive care unit. The following day, the creatine phosphokinase level rose to 3.870. Electrophoresis of the creatine phosphokinase indicated that the isoenzyme fraction present was primarily of skeletal muscle origin. The patient remained in the intensive care unit for 48 hours. She was transferred to the pediatric ward, where she remained afebrile and was dischargedin good condition after

a hospital stab of 7 days. CASE 2 The 642.year-old brother of the girl described in Case 1 was admitted to MatTin Army Hospital, Fort Benning, Georgia, on the same day as his sister. The diagnosis on admission was “multiple abscessed and carious teeth.” The results of a

physical examination. complete blood count, and urinalysis were normal. The patient was given 45 mg. Demerol and 0.2 mg. atropine as preoperative medication with no adverse reactions. After the episode of malignant hyperthermia in the sister. it was decided to postponegeneral anesthesiafor this

patient until il later date. A blood sample for creatine phos.. phokinase analysis was drawn prior to discharge and was reported as 580 I.U. Electrophoresis of the isoenzymes indicated that the creatine phosphokinase was almost entirely of skeletal mu\clc origin. The boq was readmitted 6 weeks later. The creatine phosphokinase balue was 35’3 I.U., consisting almost entirely of skeletal muscle origin. Electrolytes were as follows: sodium,

132: potassium. 4.7: chloride, 109; and carbon dioxide, 33. The complete blood count and urinalysis were normal. The patient was premcdicated with 45 mg. Demerol and 0.7 mg. atropine. Under ketamine induction. the patient was intubated nasoendotracheally and carried on nitrous oxide, oxygen, and halothane. The patient’s rectal temperature rosz from 08.6” F. to 100.1” F. immediately after the intramuscular injection of the 350 mg. ketamine. It returned to 98.6” F. with a continuous slow intravenous drip of 60 C.C. Z percent chlomprocaine in 500 C.C. saline solution. The pulse rate was I40 per minute at the beginning of the procedure and dropped to I20 per minute upon administration of the chloroprocaine. Postoperative urinalysis was normal. with no myoplobin present. The rectal temperature remained at 98.6” F. throughout the 1% hour procedure. The patient remained in the inten\i\,e care unit for 48 hours and w’as then transferred to the pediatric ward. His temperature remained stable. and he bias discharged after a hospital stay of 7 days. The parents of the two patients described ignored all requests to ;allow determination of their own creatine phosphokinase Icvels. DISCUSSION

Malignant hyperthermia is a most intense and lifethreatening complication of general anesthesia. The

be a late sign during the potentially catastrophic episode, early signs must be recognized. Prompt and aggressive management is essential. A presumptive diagnosis of malignant hyperthermia can be made if masseter muscle contraction occurs after administration of muscle relaxants. Careful attention to the patient’s past medical history, history of complications in previous anesthetic experiences, postoperative course, family history of malignant hyperthermia, history of musculoskeletal disease, and abnormal creatine phosphokinase levels in the patient or a relative should be screened carefully to determine possible susceptibility to the syndrome. Two case reports involving young siblings show these points of diagnosis and successful management. REFERENCES I. Tsang, H. S., and Schoenfeld, F. G.: Malignant Hyperthermia, Med. J. 149: 471-473. 1976. 2. Britt, B. A., Lecher, W. G., and Kalow, W.: Hereditary Aspects of Malignant Hyperthermia, Can. Anaesth. Sot. J. 16: 89-98. 1969. 3. Ryan, J. F.: Refresher Course in Anesthesiology. Chapter 8. Malignant Hyperthermia, The American Society of Anesthesiologists. Inc., Philadelphia, 1976, J. B. Lippincott Company. Vol. 4. 4. Gronert, G. A., Milde, J. H., and Theye. R. A.: Porcine Malignant Hyperthermia Induced by Halothdne and Succinylcholine. Anesthesiology 44: I24- I3 I, 1976. .5. Byrd, B. F.. Daniel, R. A., Jr., and Vasudec, P.: Serious Sequelae of General Anesthesia, Ann. Surg. 175: 673-683, 1972. 6. Roervik, S., and Stovner, J.: Ketamine-Induced Acidosis. Fever, and Creatinine-KinaseRise, Lancet 2: 1384.1385. 1974. 7. Gronert, G. A., Milde, J. H., and Theye, R. A.: Dantrolene in Porcine Malignant Hyperthermia, Anesthesiology 44: 488-495, 1976. 8. Harrison, G. G.: Control of Malignant Hyperthermia Syndrome by Dantrolene Sodium, Br. J. Anaesth. 47: 66-67. 1975. 9. Britt, B. A., and Kalow, W.: Malignant Hyperthermia: A Statistical Review, Can. Anaesth. Sot. J. 17: 293-315, 1970. IO. Kent, J. N., and Winslow. J. R.: Correction of Severe Dentofacial Deformity Associated with Myotonia Congenlta, J. Oral Surg. 36: 129-134, 1978. II Neal, H. A., Peterson, L. J., and Devore. M.: Sul-viva1of an Oral Surgery Patient With Malignant Hyprthermla, J. Oral Surg. 33: 953.960, 1975. 12 Britt, B. A., Endrenyi, L., Peters, P. L., Kwang. F. H-F.. and Kadijevic. L.: Screeningof Malignant Hyperthermia Susceptible Families by Creatine PhosphokinaseMeasurement and Other Clinical Investigations. Can. Anaesth. Sot. J. 23: 263-382, 1976. 13 Katz, J. D., and Krich, L. B.: Acute Febrile Reaction Complicating Spinal Anesthesia in a Survivor of MalIgnant Hyperthermia, Can. Anaesth. Sot. J. 23: 285-289, 1976. 14 Innes, R. K. R., and Stromme, J. H.: Rise in Serum Crcatine PhosphkinaseAssociatedWith Agents Used in Anesthesia, Br. J. Anaesth. 45: 185, 1975. I5 Goupil, M. T., and Roche, W. C.: Pre-operative and Operative Considerationsin Malignant Hyperpyrexia. J. Am. Dent. Assoc. 96: 1033-1036, 1978. 16I. Bloom, D. A., Fonkalsrud,E. W.. and Reynolds, R C.: Malig-

I?.

Beldavs. J.. Small. V.. Cooper. I>. ,A, ef al. Posroperati\e Malignant Hyperthermia.: A Case Report. Can. Anaesth. Sot. J. 18: 1@-~12. 1971. IX Gronerl. G. A.. and They. R. A : Halothane-Induced Porcmr Malignant Hyperthermia. Anesthesiology. 44: 36-33. IC)7h. 19. Britt. B. A.. Kalow. W.. and Gordan. R. A.: Malignant H\perrhernria: An Investigation of Five Patient\. Can. Anaecth. sot. J 20: ?iI-467. 1973

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