Malignant Hyperthermia (MH) is a silent, inherited metabolic disorder of muscle. Affected individuals usually appear perfectly normal and have no functional difficulties in everyday life. However, when these individuals are given a triggering anesthetic this silent disorder may turn deadly. There is an uncontrolled increase in skeletal muscle metabolism and massive release of calcium in the cells when in contact with certain types of anesthetics.

MH is inherited in an autosomal dominant pattern. This means that children, parents and siblings of an MH susceptible person have a 50% chance of inheriting MH susceptibility.  Aunts and uncles of the MH susceptible and grandchildren have a 25% chance. More distant relatives have a lesser chance.  The decision to spend money to determine susceptibility is complex and individual and requires guidance by an expert in genetics and MH.

MH is "triggered" by specific general anesthetics (potent inhalation gas anesthetics and succinylcholine, a muscle relaxant; see complete list below). Preoperative evaluation and screening of those at risk, as well as prompt intraoperative detection of MH by the signs (increased carbon dioxide excretion, muscle rigidity and fever), together with prompt treatment with dantrolene sodium, will eliminate mortality almost entirely.

Diagnosis of MH can only be accurately confirmed by a skeletal muscle biopsy and subjecting the muscle to a Caffeine Halothane Contracture Test (CHCT)*.

However, in December of 2005, a new Molecular genetic testing for susceptibility represented a new era for those interested in and affected by Malignant Hyperthermia.  This is accomplished through a simple blood test.  This test does not replace the CHCT, but is an indicator of the likelihood of the presence of MH in the individual.   This is because not all MH susceptible people will have evidence of the DNA change which indicates MH.  The CHCT is a very sensitive test, and all those with risk and susceptibility for MH will be detected by the contracture test.  The genetic test will detect only about 30% of those at risk.  The CHCT test will detect 100%.  Those with positive genetic (blood) tests are virtually assured of being at risk for MH and through taking this test, if positive, can avoid having to undergo the painful muscle biopsy required for the CHCT.

The molecular genetic testing is only 30% accurate because the investigators have to find all the mutations and DNA changes that predispose to MH.  This is a laborious process since there are several genes that predispose to MH, although changes in the ryanodine receptor gene probably underlie about 70% of cases.  Another gene identified as predisposing to MH is the DHPR gene, also related to muscle function.  In addition, there are probably over 60 mutations in the RYR-1 gene that are causal for MH, although causality has been proven for only about 30 DNA changes.  In order to prove that a DNA is causal, either families must be identified where DNA change pattern is consistent with biopsy proven susceptibility or, in the laboratory, the DNA change must be incorporated in cultured muscle cells, and the calcium release in the cell under the influence of caffeine or halothane must show changes found in MH.

*Caffeine Halothane Contracture Test (CHCT) for Diagnosis of MH:

• The CHCT is the standard for MH diagnostic testing and is used to determine a patient's susceptibility to MH.  (Allen, GC, Larach MG, Kunselman AR, and The North American Malignant Hyperthermia Registry of MHAUS: The sensitivity and specificity of the caffeine-halothane contracture test: A report from the North American Malignant Hyperthermia Registry. Anesthesiology 1998; 88:579-88.  The online reference can be located at the Anesthesiology website: www.anesthesiology.org archive March 1998).
• Patients must be referred to specialized CHCT Centers in order to have the special biopsy for CHCT performed.
• Muscle biopsies for CHCT MUST BE PERFORMED AT one of the designated CHCT Testing Centers because the test MUST be performed on fresh tissue.
• CHCT cannot be performed on muscle samples and SENT VIA THE MAIL.
• A complete list of CHCT testing centres in North America appears here: 

The Ottawa Hospital - Civic 
      Campus, Ottawa, Ontario
      Kevin Nolan, MD, FRCPC
      (613) 761-4169
      This e-mail address is being protected from spambots. You need JavaScript enabled to view it  
      This e-mail address is being protected from spambots. You need JavaScript enabled to view it   

Toronto General Hospital
Toronto, Ontario
Julian Loke, MD, FRCPC
416-340-3128
This e-mail address is being protected from spambots. You need JavaScript enabled to view it

 Uniformed Services University of
      the Health Sciences
      Bethesda, MD
      (Military & Civilian)
      Sheila M. Muldoon, MD
      (301) 295-3532
      This e-mail address is being protected from spambots. You need JavaScript enabled to view it

   University of California
      Davis, CA
      Timothy Tautz, MD
      (530) 752-7805
      This e-mail address is being protected from spambots. You need JavaScript enabled to view it

      University of Minnesota
      Minneapolis, MN
      Paul A. Iaizzo, PhD
      (612) 624-7912 or -3959
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      For more info on this center:
      www.vhlab.umn.edu/mh/index.html

    Wake Forest University
      Winston-Salem, NC
      Joseph R. Tobin, MD
      (336) 716-4498
      This e-mail address is being protected from spambots. You need JavaScript enabled to view it

MHAUS is the only association in the United States dedicated to the control of malignant hyperthermia (MH), a life-threatening genetic disorder. Personal tragedy and unsettling experiences with MH lead four individuals, Suellen Long Gallamore, Owen Davison, Robert Luckritz and George Massik, with the help of Dr. Henry Rosenberg, a researcher in malignant hyperthermia, to establish in 1981 the Malignant Hyperthermia Association of the United States to educate the medical and lay communities about MH and serve as a resource to families affected.

The membership of the association numbers in the thousands today and includes medical professionals from many disciplines as well as MHS individuals and their families, many of whom have had firsthand experience with the devastating impact of an MH episode.

The address for MHAUS is PO Box 1069, Sherburne, New York, 13460.  Telephone:  (607) 674-7901.

Management at ALL Phases of the Perioperative Period:

PreOperative Screening:

• Ask about personal and family past history of Malignant Hyperthermia or adverse anesthesia reactions (unexplained fever or death during anesthesia). Be aware of clinical signs of MH.
• Body temperature monitoring for all patients undergoing general anesthesia for other than brief procedures.
• Capnographic monitoring for all patients undergoing general anesthesia.
• Dantrolene: have dantrolene available wherever MH trigger anesthetics are used.

Intraoperative Observation:

Primary Survey / Clinical Signs:

• Awareness: are you suspecting an MH Crisis?
• Airway: severe masseter spasm (difficult to open the mouth).
• Breathing: difficult to ventilate and/or intubate due to masseter spasm
• Severe Body rigidity after succinylcholine
• Body temperature high (late sign)
• Capnography: elevation of end tidal CO2 despite proper ventilation & adequate fresh gas flows with properly functioning anesthesia ventilating apparatus.
• Circulation: cardiac arrhythmias, tachy/bradycardia, hyper/hypotension
• Drugs: are you using triggering agents (succinylcholine, potent halogens)?
• Exposure/ Examine the patient: skin color, perfusion, temperature, urine colour, extremities, muscle tone.

Emergency Treatment:

• Ask for Help:  ask for the MH cart and for dantrolene.
• Agents/anesthesia: Stop anesthesia triggering agents and the surgery.
• Breathing: hyperventilate with 100% oxygen.
• Cooling, if the patient is hot: insert large intravenous bore catheters.  Give cold intravenous fluids 15 cc/kg IV.  Irrigate the wound, stomach and bladder with cold saline.
• Call MH Hotline: 1-800-644-9737 or 1-315-464-7079
• DANTROLENE:  give dantrolene IV, 2.5 mg/kg, and repeat the dose until the signs are controlled.   See attached Information Sheet for Dantrolene for further information.  Or contact This e-mail address is being protected from spambots. You need JavaScript enabled to view it , official distributors for Dantrolene.
• Check Electrolytes, especially potassium.

Secondary Steps:

• Acidosis? Assess initial and subsequent arterial or venous blood gases.  Is there mixed metabolic and respiratory acidosis?
• Bicarbonate? 1-2 mEq/kg guided by pH, Base deficit.
• Circulation/monitoring: consider arterial line, central venous catheter, laboratories: arterial/venous blood gases, CBC, Coagulation tests, CK, myoglobin levels.
• Dysrhythmias: generally subside with resolution of the hypermetabolic phase of MH.  Arrhythmias can be treated with amiodarone, lidocaine, procainamide, adenosine, or other drugs indicated according to the ACLS protocol. Remember impact of hyperkalemia. Diuresis: assure diuresis greater than 1 ml/kg/h.
• Electrolytes: if hyperkalemic, treat with bicarbonate, glucose/insulin, calcium.
• Follow up: Arterial and venous blood gases, body temperature (core) avoid hyper/hypothermia, end-tidal CO2, CK, Coagulation tests, diuresis (urine output and color), electrolytes.

Postoperative:

Post-Crisis Problems

• Alkalinize urine & diurese, monitor for ARF (acute myoglobinuric renal failure).
• Beware hypothermic, hyperkalemic, hypokalemic, hypervolemic overshoot— serial monitoring of filling pressures, fluid balance, electrolytes, temp, K, Ca, coagulation, and Hematocrit may require recorrection.
• Creatine Kinase (CK) levels track severity of rhabdomyolysis (muscle breakdown): if present, beware of renal failure, which may follow marked rhabdomyolysis. 
• Compartment Syndrome is rare, but requires serial monitoring of extremities and abdominal girth or bladder pressures after severe insults. 
• DIC with coagulopathy, thrombocytopenia, hemolysis, and abnormal bleeding may follow major crises with severe shock and/or severe hyperthermia.
• Elevated liver functions are often observed 12-36 hours post-MH crisis.
• Follow CNS function serially after MH Crisis: magnitude of crisis may or may not correlate with CNS insult.
• Good communication and follow-up is essential among medical specialists in the post-resuscitation and monitoring phase of the MH crisis for prevention of secondary crisis-related organ insults. Care may be transferred from an anesthesia care provider to a pediatric or adult medical or surgical intensivist, provided good information about the MH crisis and post-resuscitation management is maintained.

Post-Acute Phase:

• Be aware of recrudescence signs. Ask the relatives about anesthesia problems/neuromuscular disorders.
• Biopsy: Send the patient to a biopsy center for evaluation.
• Contact MHAUS (or a closer association) for further information/referral of patient.
• Dantrolene 1 mg/kg IV q 4-6h and continued for 24-48h after an episode of Malignant Hyperthermia.
• Documentation: submit forms to the national/international North American MH Registry of MHAUS: www.mhreg.org

Anesthesia for MH-Susceptible Patient:

• Anesthesia machine preparation: change circuits, disable or remove the vaporizers, flush the machine at a rate of 10 L/min for 20 min.
• Anesthesia:  Use local or regional anesthesia but general anesthesia with non-triggering agents is acceptable. Safe drugs include: barbiturates, benzodiazepines, opioids, nondepolarizing neuromuscular blockers and their reversal drugs, and nitrous oxide.
• Body temperature monitoring.
• Capnography: Close monitoring for early signs of MH.
• Dantrolene available.
• Discharge, if no problems, after 2.5 hours.

Anesthetic Agents of Choice for the MH-Susceptible Patient:

The following anesthetic agents are known triggers of MH and are NOT safe for use in the MH-susceptible patients:

 

 

 

 

 

All other anesthetic agents outside of these two categories of Volatile anesthetic agents and depolarizing muscle relaxants are considered safe (see below for samples).

Safe Anesthetic Agents for MH Patients:

MH Crisis: 

Click on this link for your own copy of the MH Crisis Management Poster:  http://medical.mhaus.org/PubData/PDFs/treatmentposter.pdf

Dantrolene prophylaxis is NOT recommended for most MH-susceptible patients.  Dantrolene can worsen muscle weakness in patients with muscle disease and should be used with caution.  For most procedures, including those requiring general anesthesia, dantrolene prophylaxis may be omitted, provided non-triggering anesthetics are used, there is appropriate monitoring and an adequate supply of dantrolene is available.  

Treatment and the Malignant Hyperthermia Cart in the Perioperative Area:

It is iimperative that a cart with appropriate supplies be kept in or near to the Operating Room in case if a "MH Crisis".  The contents of this cart should include, but are not limited to the following:

1. Dantrolene:

• If any potent volatile agents are used, a full supply of Dantrolene (36 vials) should be available on site.  If potent volatile agents are not used, and succinylcholine is available for resuscitation, a minimum of 36 vials of dantrolene should still be available.  If neither potent volatile agents nor succinylcholine are used or available, dantrolene need not be present.
• Research has determined that in a “worse case” scenario of a very large person (i.e., about 100-110 kg or 220 – 250 pounds) having an acute MH incident, as much as 8-10 mg/kg will be needed for treatment.  36 vials of dantrolene will allow for initial stabilization and treatment while more vials are being acquired to continue treatment, as needed. 
• A stock of 36 vials is recommended.  The patient experiencing an MH episode must be stabilized before being transported.  Stabilization of an MH episode may take 30 minutes or more with multiple doses of dantrolene because, in some cases, MH progresses with explosive rapidity.  The full 36 vials of dantrolene is inexpensive insurance against patient injury. The full 36 vials of dantrolene should be available within five minutes of the diagnosis of MH.
• Expired Dantrolene can be sent to the nearest MH Testing Facility (see list above)

   2.  Other Drugs:

• Sterile Water (without bacteriostatic agent) to reconstitute dantrolene (Dantrium),
• Sodium Bicarbonate,
• Furosemide,
• Dextrose,
• Calcium Chloride
• Regular Insulin (refrigerated)
• Antiarrhythmics

Procainamide and Mannitol are no longer used to treat a MH episode since Procainamide was a secondary drug to treat arrhythmias and health care practitioners are not familiar with its use.  Mannitol is no longer used because each vial of Dantrium/dantrolene has 3 grams of mannitol included.

  3. General Equipment:

• Saline for irrigation 4 litres
• Normal Saline IV solution 4 1L bags and 4 250 ml bags
• Micro drip IV set
• Syringes (60 ml x 5) luer lock to dilute the dantrolene
• Intravenous Catheters/cannulas
• Nasogastric tubes
• Foley Catheter trays and 3-way catheters for bladder irrigation with cold solutions
• Irrigation syringes for NG irrigation with cold solutions
• Blood pressure Bag
• Urinometer
• Rectal tube
• Syringes:  3,5,10 ml. and Insulin syringes

   4. Monitoring Equipment:

• CVP kit
• Transducer kits for arterial and central venous lines
• Percutaneous Sheath Introducer Kit (cordis)

   5.  Lab Testing Supplies:

• Blood gas syringes, at least 3
• Urine dip stick for hemoglobin
• Venipuncture supplies vacutainer barrels
• Test Tubes:  for chemistry, hematology, coagulation
• Container for Urine Myoglobin

Waste Anesthetics and susceptible MHS patients: 

There are no cases reported of MHS patients having problems on exposure to waste anesthetic gases while working in the OR.  The usual OR procedures maintain low, trace amounts of the potent volatile anesthetics in the air.  During a mask induction, someone within two feet or so of the face of the patient may be exposed to somewhat greater concentrations, but that is easily avoided.  Further, the volatile agents are heavier than air and drift down to the floor, where the excellent ventilation systems in operating rooms efficiently clear the vapors.  In addition, the data from pigs indicate that very low concentrations of anesthetics do not trigger MH in these highly susceptible animals.  There is only one report of muscle cramps and fatigue in a person who worked in a factory where he was exposed to chemicals whose structure is similar to that of potent inhalation agents.

Ensure that anesthesia vaporizers are disabled by removing or taping in the “OFF” position.  Some consultants recommend changing the CO2 absorbent (soda lime or baralyme).  Flow 10L/min 02 through circuit for at least 20 minutes.  If fresh gas hose is replaced, 10 minutes is adequate.  During this time a disposable, unused breathing bag should be attached to the Y-piece of the circle system and the ventilator set to inflate the bag periodically.  Use a new or disposable breathing circuit.  The expired gas analyzer willl indicate absence of volatile agents in the anesthesia circuit.

Do not attach an anesthetic vaporizer; otherwise, no other changes.

Length of Monitoring MHS patients after uneventful anesthesia:

The patient susceptible to MH undergoing outpatient surgery may be discharged on the day of surgery if the anesthetic has been uneventful.  A minimum period of 1.0 hour in PACU monitoring vital signs at least every 15 minutes and 1.5 hours in phase 2 PACU/step down is recommended.

There should be an adequate supply of ice in a freezer or ice machine in close proximity to the OR. Also, saline solution for central cooling in case of an MH crisis should be kept cooled in the blood or drug refrigerator.

Either calcium gluconate or calcium chloride can be used to treat life-threatening hyperkalemia.  Gluconate is less potent, but is less irritating to peripheral veins.  The higher dosage is more appropriate for the acute situation.

MH cases should be reported to the North American MH Registry of MHAUS.  Forms for data collection can be obtained from the Registry or MHAUS.  Advice regarding acute emergencies can be obtained through the MH Hotline at 800-644-9737 or the nearest MH Testing Facility (listed above).  MHS patients and their families should be put in contact with MHAUS to obtain more detailed information regarding MH and the risks for family members.

Muscle Disease Issues, Heredity & Links:

MH linkage to other serious medical problems:

MH itself is not usually associated with other serious medical problems, such as hypertension, diabetes or similar diseases.  MH or MH-like events however, have occurred in patients with underlying muscle diseases, such as muscular dystrophy and myotonia.  Such patients typically display muscle weakness.  MH has been linked to a rare disorder of muscle called Central Core disease and King Denborough Syndrome, a rarer muscle syndrome.
Additionally, patients with certain forms of muscular dystrophy may develop life-threatening disturbances and muscle destruction on exposure to the triggering agents for MH.  The clinical event may resemble MH in many ways, but is not considered “true” MH.  In patients with Duchenne muscular dystrophy, succinylcholine should always be avoided or rhabdomyolysis may occur.  Potent volatile agents may produce rhabdomyolysis in time, but most believe that brief exposure is a small risk.  Patients with muscle disorders should be carefully evaluated by their anesthesiologist prior to surgery.

Hypokalemic and hyperkalemic periodic paralysis are also associated with risk for MH.  Hyperkalemic cardiac arrest may occur when MH-trigger agents are administered to muscular dystrophy patients.

Patients with osteogenesis imperfecta often develop fever during anesthesia.  Myotonic patients will develop muscle rigidity with succinylcholine.  There have been a few MH cases reported in patients with carnitine palmityl transferase deficiency and it is recommended to stay away from MH triggers in such patients.  Neuroleptic Malignant Syndrome (NMS) is a syndrome that resembles MH but is precipitated by drugs acting centrally on dopaminergic pathways in the brain.

Outpatient Surgery:

MHS patients can safely undergo outpatient surgery using non-triggering anesthetics and may be discharged on the day of surgery if the anesthetic has been uneventful.  A minimum period of 1.0 hour in PACU monitoring vital signs at least every 15 minutes and 1.5 hours in phase 2 PACU/step down is recommended. 

MHS patients discharge from ambulatory facilities after episodes of masseter spasm:

Masseter spasm has a spectrum of severity from mild increase in jaw tension to “jaws of steel.”  A patient who exhibits marked rigidity of the jaw muscles should not be discharged.  Overnight observation for temperature rise, myoglobinuria, elevated CK levels or progression to an MH episode is required.  Patients who experience milder increases in jaw tension should be observed for signs and symptoms of MH for at least 12 hours. If there is evidence of myoglobinuria, dark cola-coloured urine, increase in temperature, pulse rate, and abnormality of acid base balance, the patient should be admitted and observed overnight.

Supplies for a surgicenter:

A surgicenter in which general anesthesia is administered should be equipped to manage MH.  Dantrolene sodium IV (36 vials), sterile water, other drugs and equipment, and a protocol to treat an MH crisis should be available.  The drugs and supplies should be assembled in an MH kit or cart (refer to brochure Managing MH – Drugs, Equipment and Dantrolene for complete details).  Surgicenters that propose to use succinylcholine as an emergency agent should also have 36 vials of dantrolene available and an appropriate MH crisis protocol in place.

There is still much that is not known about MH.  Research is continuing.  Contact the MH Hotline at 1-800-644-9737 for current information. 

Written by Paula Ferguson

References:

http://medical.mhaus.org

Standards of PeriAnesthesia Nursing Practice (OPANA) 5th Edition, 2005