Malignant Hyperthermia

Dr. Naveen Kumar Gaur

2nd Year Resident

Dept.of Anaesthesiology, Govt. Medical College & Sir T. Hospital,

Bhavnagar(Gujarat)

Definition

• Uncommon, life-threatening, pharmacogenetic, hypermetabolic disorder of the skeletal muscle triggered by inhalation agents and succinylcholine.

Genetics

• Its an autosomal dominant trait.• Gene located on19th chromosome (19q11.2-13.2).• In most cases(>50%) MH is caused by defect in

the ryanodine receptor(RyR1).

(Release of calcium from SR)• Other chromosomes involved are –

- 17q11.2-q24 – altered Na channel functioning.

- 7q21.1 – altered Dihydropyridine receptors(DHPR) – voltage sensors for RyR1.

Epidemiology• Usually occurs in children & young adults.

(incidence highest in 1st three decades of life, but cases reported at extremes of ages)

• Overall incidence rate during GA-

1 in 3000 – 15,000 children

1 in 50,000 – 100,000 adults• Geographical variation- more prevalent in certain

areas of North America.• Male = Female• Mortality reduced from 70% to <5%(after dantrolene)

Definite association: central core disease- autosomal dominant congenital myopathy.

(common gene RyR1 mutation)

Possible association: Duchene, Becker, King-Denborough, other myopathies.

(Pts with Duchene's or Becker’s dystrophy are at risk for hyperkalemic cardiac arrest with succinylcholine or other MH triggering agents, but this is not MH.

Coincidental association: Neuroleptic Malignant Syndrome, Heat Stroke, etc

Porcine Stress Syndrome

• MH like syndrome in certain breeds of swine.• Presentation - ↑ metabolism, acidosis, fever, rigidity

& death.• Triggered by – separation, shipping condition,

weaning, fighting, coitus, preparation for slaughter, etc.

• This can be induced in stress susceptible swine by administering halothane & succinylcholine.

• Cause – single mutation in RyR1.

Pathophysiology

• MH is an inherited disorder of the skeletal muscle system in which a defect in the calcium regulation is expressed by exposure to triggering anesthetic agents → intracellular hypercalcemia.

• The ryanodine receptors(RyR1) modulate calcium release from the channels in the SR.

• ↑ in concentration of calcium in cells (upto 500 folds)

- Actomysin cross-bridging - Sustained muscle contraction - Rigidity

↓

- ↑ oxygen consumption

- ↑ CO2 and heat production(hyperthermia)

- depletion of ATP stores

- lactic acid(Acidosis)

- marked increase in - myoglobin

- creatine kinase

- potassium. • Cells damaged due to membrane instability.

Identifying Susceptible PatientsMuscle Contracture Test• Caffeine Halothane Contracture Test(CHCT)• For patients having H/O MMR.• Gold Standard.• Requires 3-4 inch muscle biopsy taken from

thigh(vastus muscle) under GA or LA.• Protocols – 1. North American MH group – abnormal contracture

to either Halothane or Caffeine labels pt. as MH susceptible.

2. European MH group – abnormal contracture to both Halothane & Caffeine labels pt. as MH susceptible.

• 97-99% sensitivity, false negatives are rare. • 78-94% specificity.

Genetic Testing

• Involves isolation of DNA from patient (blood, muscle cells, or other tissue sample)

• RYRI (ryanodine receptor) found, there are currently 29 MH causative RYRI mutations.

• Presence of causative mutation in RYRI gene is diagnostic for MH susceptibility.

• Sensitivity based on population selected and methodology of testing utilized.

MH Triggers• Volatile anesthetics

- Ether

- Halothane

- Sevoflurane

- Desflurane- Isoflurane

- Enflurane

• Depolarizing muscle relaxants

- Succinylcholine

Nontriggering drugs for MH

• Barbiturates• Propofol• Benzodiezepins• Opioids• Nitrous oxide• Non depolarizing muscle relaxants• Anticholinergics• Anticholinesterases• Sympathomimetics• Local anaesthetics• Clonidine,dexmedetomidine

Clinical Features

• Early –

- Clinical signs –

- Masseter spasm.

- Tachypnea(in spontaneously ventilating pt).

- Tachycardia.

- Rapid exhaustion of soda lime.

- Irregular pulse.

- Change in monitored variables –

- ↑ in minute ventilation.

- ↑ in EtCO2

- Dysrythmia with peak T wave.

- Biochemical changes –

- ↑ in PaCO2 (100-200 mmHg)

- Acidosis(pH 7.15-6.8)

- Hyperkalemia.

• Intermediate –

- Clinical signs –

- Warm skin(temp↑ @ 0.5°C every 15 minutes and reaching levels as high as 46°C.)

- Cyanosis.

- Dark blood on surgical site.

- Dysrythmia.

- Change in monitored variables –

- ↑ in core body temp.

- ↓ Hb saturation.

• Late -

- Clinical signs –

- Generalized skeletal muscle rigidity.

- Prolonged bleeding.

- Dark urine.

- Irregular heart rate.

- Biochemical changes –

- ↑ in s. creatine kinase level.

- Myoglobinuria.

- Hyperkalemia.

• Late complications(if MH untreated)

- DIC(due to release of thromboplastin secondary to cellular destruction)

- Pulmonary edema.

- ARF.

- CNS damage – Blindness

- Seizures

- Coma

- Paralysis

Treatment

• Etiologic treatment –

- Inj. Dantrolene 2-3 mg/kg iv bolus, followed with repeat dose every 5-10 min to maximum dose upto 10mg/kg.

- To prevent recrudescence – Inj. dantolene 1mg/kg every 6 hrs for 48-72 hrs.

• Symtomatic treatment –

- Immediate termination of inhaled anaesthetic & conclude surgery.

- Hyperventilation with 100% oxygen.

- Initiate active cooling –

- surface cooling.

- gastric & bladder lavage with iced saline.

- iced saline 15 mg/kg iv every 10 minutes.

(discontinue cooling when temp falls to 38°C)

- Correct metabolic acidosis –Inj. Soda bicarb 1-2 mEq/kg iv according to blood pH.

- Maintain UOP – Hydration

- Mannitol(0.25 mg/kg)

- Furosemide(1mg/kg)

- Treat cardiac dysrythmia(Loxicard 1.5mg/kg)

- Monitoring of UOP, ABG, S.electrolytes.

Anaesthetic management• Regional anaesthesia-

- Acceptable choice(both esters and amides can be used)

• Dantrolene prophylaxis –

- if past H/O MH – Inj. Dantrolene 2-4mg/kg iv over 10-30 min. just prior to induction.

- Catheterize patient, as drug contains mannitol (to make drug isotonic).

- Large doses may cause –

nausea, vomiting, diarrhea, blurred vision, skeletal muscle weakness(post op monitoring is must)

• Drug selection –

- Keep preparations to treat MH.

- Good sedation.

- Avoid triggering agents.

- Avoid CCB with dantrolene, may cause hyperkalemia and myocardial depression.

• Anaesthesia machine –

- “Dedicated” anaesthesia machine preferred(never been used to deliver volatile anaesthetics).

- Conventional machine with –

- disposable breathing circuits.

- fresh soda lime.

- no vaporizers.

- continues flow of O2 @ 10 L/min for 10-60 minutes before using for MH susceptible patient.

Differential Diagnosis

1. Hyperthyroidism- similar symptoms, but blood gas abnormality occurs gradually.

2. Pheochromocytoma – marked BP swings.

3. Malignant neuroleptic syndrome – usually associated with use of neuroleptic/antipsychotic drugs.

4. Cocaine intoxicity – similar to MNS.

5. Heat stroke – outside the OT.

6. Metastatic carcinoid – similar to Pheochromocytoma.

7. Sepsis – usually ABG normal.

Dantrolene• A skeletal muscle relaxant(hydantoin derivative)• Blocks RyR1 receptors, thus block the calcium

release.

• T1/2 = 4-8 hrs.

• Metabolized in liver.• Side effects – weakness, dizziness.• Each vial of dantrolene contains –

- 20 mg dantrolene sodium.

- 3000 mg mannitol(to make solution isotonic.

- Sodium hydroxide(to keep pH near 9.5)

Thank you…