It is clear that malignant hyperthermia (MH) is a collection of diseases that share a final common pathway involving release of intracellular myoplasmic calcium, which causes a hypermetabolic state involving skeletal muscle. In addition, external environmental factors (stress, activity, temperature, drugs) modify the presentation of MH. It is to be expected, therefore, that clinical presentations of MH will vary markedly not only between individuals but also in the same patient.

I. Classic Fulminant Episode: The patient who presents with the classic signs of MH during a triggering anesthetic is rare (approximately 1:200,000 without succinylcholine; 1:50,000 with succinylcholine). These patients are identified quickly with capnography and classic monitors. Aggressive identification and treatment frequently but not always leads to a full recovery. Clinicians, however, should treat MH before all classic signs of MH are evident in order to decrease morbidity and mortality. Physicians are, therefore, often faced with "nonclassic" presentations of MH and must decide quickly on a course of action.

Signs of Malignant Hyperthermia
Tachycardia*	Metabolic acidosis*
Tachypnea*	Respiratory acidosis*
Fever*	Central venous desaturation*
Rigidity*	Central venous hypercardia*
Arrhythmias	+End-tidal CO2*
Cyanosis	Hyperkalemia
Skin mottling	Myoglobinemia
Masseter muscle rigidity	+Creatine kinase
Sweating	Unstable blood pressure
*Classic signs of MH

II. "Nonclassic" Intraoperative Events: MH in its "nonclassic" presentation is a diagnosis of exclusion. Below are descriptions of common clinical intraoperative presentations and appropriate differential diagnoses.

A. Elevation of End-Tidal CO₂:

An elevation of ET CO₂ is the most sensitive clinical sign of MH. A rise of ET CO₂ of 5 mm Hg over an established baseline should be investigated. Causes other than MH should be ruled out [Table 1]. The beginning of some MH episodes may not be associated with ET CO₂ >40 mm Hg. This is due to hyperventilation, inaccuracies in ET CO₂ measurement or large gradients between ET CO₂ and arterial CO₂.

Differential Diagnosis of Increased ET CO₂ >5 mm Hg Above Steady State

1. ⁺CO₂ production - fever, light anesthesia

2. Exogenous CO₂ - Laparoscopy, etc.

3. _-Ventilation (i.e., _-CO₂ elimination)

1. Increased depth of anesthesia (in spontaneously breathing patients)
2. Anesthesia machine - _-fresh gas flow, disconnect, leak
3. Anesthesia ventilator - _-setting, malfunction, _-driving pressure, _-patient lung thorax compliance with decreased VT delivery
4. Breathing circuit
5. Mapleson - _-FGF, leak, disconnect, obstruction
6. Circle - valve malfunction; absorbent (depleted, channeling or bypass); obstruction; leak; disconnection
7. Pulmonary: Upper airway obstruction (mask, soft tissue, endotracheal tube); mainstem intubation; blocked ETT; asthma; CHF; ARDS; aspiration; pneumothorax; hemothorax; pulmonary edema
8. Extrathoracic - ⁺abdominal muscle tone; retractors resulting in _-compliance

4. Monitoring error/inaccurate capnography, e.g., moisture in measuring chamber; calibration drift

B. Rise in Heart Rate or Temperature: A rise in heart rate or temperature (over 2°C per hour or 1°F q 15 min) should also be investigated during anesthesia for possible MH. Causes other than MH should be quickly ruled out and managed.

Differential Diagnosis of Fever and Tachycardia (Rise of >2° C per hour)

1. Excessive covers or ambient temperature
2. Equipment malfunction or misuse/inaccurate T° monitors, heating blanket >40°C, airway warmer >38°C
3. ⁺Heat production-thyrotoxicosis, pheochromocytoma, osteogenesis imperfecta, infection, infected I.V. fluids, transfusion reaction
4. Central nervous system: hypothalamic injury (anoxia, edema, trauma), prostaglandin E₁, ionic contrast into CSF
5. Drug reactions-neuroleptic malignant syndrome (NMS), monoamine oxidase inhibitor, amphetamine, cocaine, tricyclics, atropine, glycopyrrolate, droperidol, metoclopramide, levodopa withdrawal, ketamine, ETOH withdrawal, serotonin syndrome

C. Succinylcholine-Induced Masseter Muscle Rigidity: Incomplete jaw relaxation after succinylcholine and halothane in children is common (±4 percent)¹ and can range from slight difficulty opening the mouth to severe rigidity. Most incomplete jaw relaxation is mild and is a normal response. Masseter muscle rigidity (MMR) should be defined as severe difficulty opening the jaw, which interferes with visualization of the glottis. MMR is associated with abnormal ABGs suggesting MH and a 50-percent incidence of abnormal MH biopsies.² Patients with MMR associated with generalized rigidity are at even higher risk for developing acute MH. Other causes of MMR than MH include TMJ dysfunction, myotonia, muscular dystrophy, multiple sclerosis and polymyositis. In many cases (~ 50 percent) extensive investigation finds no abnormalities. The management of MMR is still controversial, but it is recommended that triggering agents be stopped and the patient monitored closely for signs of MH. MMR patients usually have rises in creatine kinase (CK) within 12 to 24 hours. CK of >20,000 I.U./L are associated with positive MH muscle biopsies (>80 percent).²

D. Postoperative MH Episodes: MH episodes have been reported to the MH Hotline in the immediate postoperative period and several days thereafter. These late episodes raise issues for postoperative surveillance particularly in outpatient settings. Present outpatient recovery guidelines seem adequate in identifying immediate postoperative MH problems but may miss late MH episodes, which may present as postoperative fever or myoglobinuria. Little is known of this area.

III. Hyperkalemic Cardiac Arrest Following Succinylcholine and Other MH Trigger Agents: Another intraoperative catastrophe associated with muscular pathophysiology is sudden hyperkalemic arrest. Sudden cardiac arrest in children and adolescents who were given succinylcholine and/or potent inhalational anesthetics occur about eight times per year with a mortality of 40 percent.³ These apparently healthy children suffered acute hyperkalemia apparently due to a subclinical myopathy. The arrests occurred an average of 17 minutes after induction. One occurred 14 hours after induction! These children usually have Duchenne's muscular dystrophy (DMD). DMD occurs in 1:3,500 live male births and is usually subclinical until age 6-8 years. Other muscle diseases in males and females may cause this response. One report details a child who made a full recovery after five hours of cardiopulmonary resuscitation.⁴

If a child experiences sudden unexplained cardiac arrest, the clinician should suspect hyperkalemia and take all resuscitative efforts for as long as possible to normalize potassium. Since this syndrome is not clearly related to MH, dantrolene is not indicated unless specific signs of MH are also present.

IV. MH or MH-Like Episodes Out of the O.R.

A. Awake MH Episodes: The possibility of awake MH episodes have raised concerns about MH-susceptible (MHS) patients participating in the military, stressful jobs, strenuous activities and travel. Deaths in apparently healthy exercising people due to heat stroke are almost impossible to differentiate from awake MH episodes. It does seem clear that certain MHS patients develop muscle pains, fever and tachycardia that are relieved by dantrolene.⁵ Other MHS patients have died during exercise. It is also clear that these are extremely rare events. Patients and parents should be reassured that unless there are obvious, unexplainable symptoms of awake MH episodes, patients should lead normally active lives without restrictions.

B. Drug-Induced Hypermetabolic States: The expertise of anesthesiologists in MH is being called upon to help intensivists and emergency physicians deal with drug-induced hypermetabolic events occurring outside the operating room. Neuroleptic malignant syndrome (NMS) affects 0.5 percent to 1 percent of patients treated with neuroleptic drugs (e.g., haloperidol, thiothixenes and phenothiazines). It is associated with as much as a 20-percent mortality rate.⁶ NMS has occurred postoperatively due to antiemetic doses of droperidol and metoclopramide.⁷ NMS symptoms progress slowly over 24-72 hours. Patients develop a hypermetabolic state of skeletal muscle and may resemble the MHS patient. The primary disorder appears to be in CNS dopamine receptors. Dantrolene is effective in treating the symptoms of NMS, but high doses (10-20 mg/kg) may be necessary. Although most patients respond to dantrolene, NMS and MHS are not clearly related. MHS patients are not adversely affected by neuroleptic drugs, and NMS patients are not prone to develop MH susceptibility.

Serotonin syndrome is another drug-induced hypermetabolic state that appears clinically similar to MHS and NMS. It is hypermetabolic reaction involving muscles which occurs as a result of treatment with drugs capable of increasing serotonin levels in the central nervous system.⁸ These types of drugs (e.g., Prozac™ and Zoloft™) are becoming extremely popular in the management of certain types of depression. The incidence of serotonin syndrome may become more common with increasing use of these drugs. Dantrolene has been anecdotally beneficial in treating the hypermetabolic state caused by serotonin syndrome.

1. Hannallah RA, Kaplan RF. Jaw relaxation after a halothane/succinylcholine sequence in children. Anesthesiology. 1994; 81:99-103.
2. O'Flynn RP, Shutack JG, Rosenberg H, et al. Masseter muscle rigidity and malignant hyperthermia susceptibility in pediatric patients. An update on management and diagnosis. Anesthesiology. 1994; 80:1228-1233.
3. Larach MG, Rosenberg H, Gronert GA, Allen GC. Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr. 1997; 36(1):9-16.
4. Lee G, Antognini JF, Gronert GA. Complete recovery after prolonged resuscitation and cardiopulmonary bypass for hyperkalemic cardiac arrest. Anesth Analg. 1994; 79:172.
5. Britt BA. Combined anesthetic- and stress-induced malignant hyperthermia in two offspring of malignant hyperthermic-susceptible parents. Anesth Analg. 1988; 67:393-399.
6. Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia. Med Clin North Am. 1993; 77:477-492.
7. Patel P, Bristow G. Postoperative neuroleptic malignant syndrome. A case report. Can J Anaesth. 1987; 34:515-518.
8. Nimmo SM, Kennedy BW, Tullett WM, et al. Drug-induced hyperthermia. Anaesthesia. 1993; 48:892-895.

Richard F. Kaplan, M.D., is an attending anesthesiologist at Children's National Medical Center, Washington, D.C.

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