This is an inheritable (Autosomal Dominant with genomic imprinting) "fulminant hyper metabolic state" of skeletal muscles triggered when a genetically susceptible person is exposed, in a stressful situation, to a triggering agent. The genotypic variation and the environmental variability contribute to the lack of uniformity in the clinical response. The classic MHS crisis may manifest immediately on exposure to a triggering agent or may only manifest at some stage within the 24-36 hours following exposure to a triggering agent, or it may not manifest at all.

Triggering agents that are currently un-contested are all depolarising muscle relaxants (including succinyldicholine), all volatile anaesthetic agents (halothane, enflurane, isoflurane, sevoflurane and desflurane), caffeine and all halogenated X-ray contrast materials.
The associated "stressful" environmental factors are surgery, pregnancy, infection and psychological stress

The controversial drugs are the phenothiazines.

Drugs which are unquestionably not triggering agents are antibiotics, antihistamines, antipyretics, benzodiazepines (midazolam, diazepam, lorazepam), barbiturates (thiopental, methohexital), propofol, ketamine^*, Non depolarising muscle relaxants (atracurium, cisatracurium, pancuronium^*, vecuronium), droperidol, nitrous oxide, opioids, propanolol, the vasoactive^* drugs, amide and ester local anaesthetics (Lignocaine, bupivacaine). The drugs marked ^* have inherent circulatory effects that may mimic the MHS.

1. Masseter muscle rigidity.
   • This is defined as difficulty in opening the mouth after an intubating dose of succinylcholine, with loss of twitches on neuromuscular stimulation.
   • These patients may be susceptible to MHS: A full blown episode typically occurs 20-30 minutes after the onset of the MMR. It is controversial as whether to proceed with the anaesthetic using a non-triggering technique or to cancel the elective procedure.
   • The incidence of MMR is 1% in children induced with halothane and given succinylcholine to aid intubation, and 2,8% in children for strabismus surgery. These patients are prone to an increase in creatinine kinase MM, myoglobinuria, tachycardia and dysrhythmias independent of the MHS.

2. A rise in end tidal CO₂ of >5mmHg/hour over an established baseline is the most sensitive, but not specific clinical sign of an impending MHS crisis.

   Differential diagnosis of a rise in end tidal CO2 >5mmHg/hour above steady state
   1. Decreased CO2 elimination	Airway obstruction Upper - mask, tongue, pharynx, secretions, blood ETT - lumen, mainstem intubation, Lower - asthma, oedema, haemo/pneumothorax
   	Respiratory depression in spontaneously breathing patients
   	Breathing circuit malfunction Mapleson - low FGF, obstruction, leak, disconnection Circle - valve / absorbent malfunc, obstr, leak, discon.
   	Ventilator malfunction Setting low, low driving pressure, changed pt compliance.
   2. Increased CO2 production	Light anaesthesia Fever TPN Thyrotoxic Crisis
   3. Exogenous CO2	NaHCO3 administration Laparoscopy
   4. Inaccurate measurement	Calibration drift Moisture
   5. Malignant hyperthermia

   3. Hyperthermia is often a late sign in MHS but when it occurs it correlates well with the severity of the attack.

   Differential diagnosis of fever (>2oC/hour) and tachycardia
   1. Decreased To gradient	Excessive covers Excessive ambient temperature
   2. Exogenous To	Heating blanket Bair hugger Airway warmer
   3. Endogenous To general	Thyrotoxicosis Phaeochromocytoma Osteogenesis imperfecta Infection Infected intravenous fluids Transfusion reactions
   4. CNS dysfunction	Hypothalamic injury - anoxia, oedema, trauma Prostaglandin E1 Serotonin
   5. Drugs	Neurolept malignant syndrome (­ dopamine) Serotonin syndrome (Prozac) Cocaine MAOI Amphetamine TAD Phenothiazines Atropine Droperidol Metoclopramide Ketamine
   6. Malignant hyperthermia

   4. Decrease in arterial oxygen saturation and cyanosis
   5. Tachycardia - an unexplained tachycardia is usually the first sign
   6. Dysrhythmias
   7. Rigidity - despite the use of muscle relaxants.
   8. Tachypnoea is spontaneously breathing patients.
   9. Laboratory examination
      • Myoglobinuria
      • arterial blood gas - metabolic acidosis
      • Venous blood gas - excessive carbon dioxide production
      • Hyperkalaemia
      • Hypercalcaemia
      • Hyperphosphataemia
      • Increased creatinine kinase fraction MM levels

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   Treatment of the acute phase of a MHS crisis.

   As with all flow diagrams the following is presented in a step wise fashion, help should be sent for immediately and as many of the steps as possible should be performed simultaneously, .

   1. HELP
   2. Stop all triggering agents immediately. Surgery must be terminated as soon as feasible.
   3. Sedate the patient. Midazolam or Propofol infusion.
   4. Hyperventilate (>12L/min) the lungs with 100% O₂.
   5. Give Dantrolene 2.5mg/kg intravenously in repeated boluses until PaCO₂, heart rate and body temperature have normalised. If 20mg/Kg has been given and nothing has happened it is not a MHS crisis and management and diagnosis must be reviewed.
   6. Actively correct the metabolic acidosis with NaHCO₃ 1mmol/Kg.
   7. Correct hyperkalaemia by hyperventilation, treatment of metabolic acidosis and a glucose (0.5g/Kg) and rapid acting insulin (0.15 units/Kg = 0.3 units/g glucose) infusion. Add CaCl₂ 2-5mg/Kg to stabilise the myocardium if K⁺ >7.0 mmol/L
   8. Monitor end tidal CO₂ , pulse oximeter saturation and T^o continuously, ABG and mixed venous blood gases, CVP, K⁺ and glucose, urine output and blood pressure levels every 10 minutes.
   9. Maintain urine output >2ml/Kg/hour. Push intravenous fluids and give Mannitol (0.25mg/Kg NB Mannitol 3g per vial of Dantrolene) and Lasix 1mg/Kg when an adequate CVP is insufficient to maintain urine output.
   10. Actively cool patient with iced saline at 15ml/Kg every 15 minutes through at least three large bore indwelling intravenous cannulae, lavage body cavities with iced saline (PNGT and rectal catheter irrigation) and place ice over the neck, in the axilla and in the groin.
   11. Arrhythmias that do not respond to the treatment of the acidosis, hypoxia, hypercarbia and hyperkalaemia, must be treated with standard antiarrhythmic agents. Procainamide is the drug of choice as it inhibits multiple dysrythmias and inhibits abnormal drug induced contraction in MHS muscle in vitro, calcium chloride 2-5mg/Kg must be used to stabilise the myocardium during hyperkalaemia. Avoid Ca²⁺ channel blockers as they will precipitate an acute cardiovascular collapse when used in combination with Dantrolene.

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   Treatment after the acute phase of the MHS has settled.

   1. The patient must be nursed in an intensive care setting, with dedicated doctor and nursing staff. Appropriate sedation and pain relief must be given on an hourly basis.
   2. Give Dantrolene 1mg/Kg intravenously every 6 hours for 48-72 hours.
   3. Monitor for
      1. Recrudescence: ABG and VBG to calculate oxygen extraction ratio, Core body T^o, end tidal CO₂, pulse oximetry and muscle tone.
      2. DIC: Repeat clotting studies six hourly until fully stabilised.
      3. Myoglobinuric renal failure: Urine and serum myoglobulin and urine output
      4. Electrolyte abnormalities: Measure K⁺ and Ca²⁺ hourly until patient stabilised.
      5. Skeletal muscle weakness: Creatinine kinase - MB fraction is a crude marker of muscle breakdown. Keep the patient sedated and intubated until airway protection is assured.
   4. Ensure the patient attains and wears a medic alert bracelet for future reference.
   5. Ensure the patient's relatives are given proper counselling and testing for MHS.

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   Diagnosis

   Increased awareness of the MHS and of the clinical signs have allowed the anaesthetist to take early evasive action and prevent the full blown acute syndrome. This has created a population of uncertain clinical probands who place an even larger population of relatives in a diagnostic conundrum.

   A patient who was thought to have had a MHS crisis, and responded well to treatment with Dantrolene, should be regarded as MHS. Family members of these patients should be counselled and after informed consent is obtained, should be subjected to a diagnostic procedure. No unequivocal test is possible because of the genetic heterogeneity of the disease coupled with the intrinsic fallibility of diagnostic tests (normal biological variability (age and sex), environmental influences and the normal overlap of normal and diseased populations).

   A muscle biopsy is currently the only possible test for MHS. The vastus lateralis, anaesthetised by a Winnie 3 in 1 femoral block, {xref please} is the best source for the large piece of muscle required.

   This muscle is then exposed to halothane and / or caffeine and / or ryanodine. The isometric contracture tension weight is compared to predetermined diagnostic cut-off limits.

   	European group protocol	North American protocol
   Halothane	1, 2, 3% baths	3% bath
   Caffeine	0.5, 1, 2, 3, 4mM	0.5, 1, 2, 4, 8, 32mM
   Groups	MH Susceptible MH Negative MH Equivocal	Guideline selection criteria Sensitivity 100% Specificity 79%
   Comment:	False negatives in RSA

   Ryanodine a plant alkaloid toxic to insects and mammals has a slow onset and slow offset to cause irreversible muscle contraction

   1. The isometric contracture tension is taken at 60min after the myofibril has been exposed to concentrations varying from 0.75 - 2.5mm of ryanodine
   2. Ryanodine is added at three minute intervals to a bath and the threshold concentration is noted that initiates contraction.

   All patients with abnormal contracture responses have a much greater chance than normal of developing a fulminant MHS when administered a triggering anaesthetic. It is not possible to predict the response to a triggering anaesthetic based on the contracture response.

   Central core disease is the only disease certainly related to the MHS, it is a sarcoplasmic myopathy characterised by proximal muscle weakness.

   The myopathies may possibly be related to the MHS

   Duchenne's muscular dystrophy (X linked), King-Denborough syndrome (short stature, musculoskeletal abnormalities and mental retardation), Becker's muscular dystrophy, myotonia congenita, Fukuyama's muscular dystrophy and myoadenylate deaminase deficiency.

   Sudden Infant Death Syndrome, the Neuroleptic Malignant Syndrome , Lymphomas, Osteogenesis imperfecta and the glycogen storage disease are probably not related to the MHS.

   NMS which may be confused with MHS may appear 24-72 hours after the administration of a psychotropic agent (haloperidol, droperidol fluphenazine, clozapine, perphenazine, thioridazine). The cause of the NMS is related to dopamine receptor blockade in the hypothalamus and the basal ganglia. NMS is characterised by akinesia, muscle rigidity, hyperthermia, tachycardia, cyanosis, autonomic dysfunction, sensorium changes, diaphoresis and elevated levels of creatinine kinase MM. NMS has a mortality of 10%, treatment is with dantrolene, bromocriptine or biperiden.

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   General principles in anaesthetising a probable MHS susceptible patient.
   1. Standard preoperative medication.

   2. Prophylactic Dantrolene 2.5 mg/Kg intravenous bolus 15-30 minutes before induction of anaesthesia is only indicated in three situations
      • The patient has an underlying condition that will not tolerate any additional physiological stress e. g. Ischaemic heart disease
      • The operation will be longer and more stressful than average
      • The patient has a history of a stress induced MHS episode.

      The controversy exists because pre-treatment may only mask or delay the onset of a MHS crisis, depletes the store of the agent and may induce or worsen muscle weakness.

   3. Capnography and constant end tidal CO₂ monitoring

   4. Constant core body T^o monitoring

   5. Regional anaesthesia and intravenous sedation is the anaesthetic of choice.

   6. General anaesthesia.
      • Clean anaesthetic machine. 100% O₂ @ 8L/min for 10 minutes to clear volatile anaesthetics.
      • Vaporiser removed
      • New breathing system and circle absorber
      • Ready availability of the MHS cart containing all possible medications for an acute event

        Drugs	Equipment	Extra
        Dantrolene 36 vials	To probe	Blood collection tubes
        Sterile water 3 litres	NG tubes	Refrigerated saline 6 litres
        Sodium Bicarbonate 12 amps	Rectal catheters
        5% Dextrose 3 litres	IV catheters
        20% Mannitol 1 litre	IA catheters
        Furosemide	Urinary catheters
        Anti-arryhthmic agents	50ml syringes

      • Induction: Propofol
      • Intubation: Vecuronium ED₉₅ 0.05mg/Kg can be used in 3-4 times ED₉₅ to facilitate a rapid sequence induction and intubation.
      • Maintenance: N₂O:O₂ 70:30% + total intravenous anaesthesia.

        One possible TIVA routine (with a muscle relaxant of choice)
        Time		Sufentanil	Propofol
        Induction		0.35-0.7 micog/Kg	0.8-1.2mg/Kg 1-2 min post sufentanil
        Maint	0-10min	None	0.1-0.2mg/Kg/min
        	10-25min	None	0.07-0.1mg/Kg/min
        	25min-2hrs	0.6microg/Kg/hour	0.07-0.1mg/Kg/min
        	2-4hrs	0.5microg/Kg/hour	0.04-0.07mg/Kg/min
        	>4hours	0.35microg/Kg/hour	0.04-0.07mg/Kg/min
        Reversal		End 15-30min prior to finish	End 5-10 min prior to finish

      • Post operative: The patient must be monitored closely for 6 hours after a non triggering anaesthetic. They can be discharged home after 24 hours if no sign of the MHS have developed.

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   Dantrolene.

   Action:

   Direct acting skeletal muscle relaxant. Dissociates excitation-contraction coupling, probably by interfering with the release of Ca²⁺ from the sarcoplasmic reticulum.

   Biokinetics:

   Absorption- Intravenous injection only possible with the lyophilised formulation mixed with Mannitol to improve water solubility. Therapeutic plasma levels within 5 minutes.

   Absorbed ~20% after oral administration, peak plasma level at 6 hours.

   Distribution- Vd_ss 0.54L/Kg. t_1/2b varies between 4 to 12 hours

   Metabolism- Not fully elucidated, known to occur in the liver. Major metabolites are 5-hydroxydantrolene and an acetylamino metabolite.

   Excretion- Renal

   Chemistry:

   Lipid soluble hydantion as the hydrated imidazolidinedione sodium salt.

   Dose:

   Acute MHS crisis

   2-3mg/Kg given as a rapid intravenous bolus, repeated every five minutes until the MHS crisis has been aborted. If 20mg/Kg has been given and no effect has been seen it is not a MHS crisis that is causing the symptoms.

   Prophylaxis.

   2.5mg/kg intravenous bolus 15-30min prior to induction.

   Effects-

   Respiratory and airway - muscle weakness causing dysarthria in the awake, non intubated patient.

   Development of pulmonary oedema because of the large volume of fluid needed to administer the therapeutic dose of Dantrolene is a theoretical possibility.

   CNS- Lethargy, dizziness and drowsiness. Acts at GABA receptors centrally and peripherally.

   Antipyretic.

   CVS- Dantrolene by itself is cardiostable. MHS crisis is not.

   Muscle- Addition of Dantrolene to the "triggered" MH muscle cell re-establishes a normal level of ionised calcium in the myoplasm. Inhibition of Ca²⁺ release from the sarcoplasmic reticulum by Dantrolene re-establishes the myoplasmic calcium equilibrium by increasing the percentage of bound calcium. This attenuates and reversed the physiological, metabolic and biochemical changes associated with a MHS crisis.

   Other- Hepatic dysfunction, K⁺ elevation

   Formulation: Dantrium intravenous, 70ml vials containing

   • 20mg Dantrolene sodium
   • 3g Mannitol
   • NaOH to yield a pH of ~9.5 when reconstituted with
   • 60 mls sterile water for injection with no bacteriostatic agent.
     • 5% Dextrose, 0.9% sodium chloride and other acidic solutions are not compatible.
   • To give Dantrolene 0.33mg/ml and Mannitol 50mg/ml

   Indications:

   MHS crisis along with appropriate supportive measures. It should be given by a continuous, rapid intravenous push in as soon as the MHS crisis is suspected.

   Prophylactically to prevent or attenuate the development of clinical and laboratory signs of the MHS in individuals judged to be MHS susceptible.

   Chronic spastic conditions - cerebral palsy, cerebrovascular accidents and spinal cord injury.

   Contra-indications: None

   Precautions:

   Avoid extravasation because it confuses actual dosage given and the pH of 9.5 is incredibly irritating to the vascular endothelium.

   3g of Mannitol is present with every 20mg of Dantrolene.

   Ca²⁺ channel blockers (e.g. verapamil) and Dantrolene administered together during a MHS crisis have resulted in ventricular fibrillation, marked hyperkalaemia and profound cardiovascular collapse.

   A newer water soluble analogue of Dantrolene, Azumolene is available. It is less irritant and needs a smaller volume for dilution. The short shelf half life of six months compared to 4 years is the most compelling reason for its failure to take over from dantrolene

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   Web References

   There are several Web references worth a brief peek:
   
   • There is a fair amount at Yale, including
     • Stuff on managing MH;
     • A clinical update;
     • Basic information about dantrolene;
     • Simple info on drugs & equipment;
     • Preventing MH;
   • All of the above are produced by MALIGNANT HYPERTHERMIA ASSOCIATION OF THE UNITED STATES (MHAUS), who have a medical FAQ , as well as posters, brochures, etc. There is also a 340K list of references.
     
     
   • Policy document for muscle biopsy, at University of Minnesota.
   • An MH protocol.
   • and yet another!
     
     
   • Some Japanese MH stuff is so-so, but the pictures with Japanese annotations at Hiroshima are cute. There is a basic Japanese/English Q&A page too.
   • The chaps in Basel have provided a brief tutorial and they are intimately associated with the European MH Hyperpyrexia group.
   • The Cardiff Institute of Medical Genetics has lots on the ryanodine receptor
     
     Besides this:
     
   • Did you know that the famous nematode worm C. elegans gets MH?
   • There is also some information for patients scattered about the web.
   • There is a poorly constructed page with lots of broken links (when viewed on 10/2/98) at the Canadian MH Association site.

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   We are still busy adding to this page.
   
   If you have any topical information about MH, please mail us!

   Flames

   Web page author: lara@anaesthetist.com

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