What is Malignant Hyperthermia? 2019 Update Review
During a general anaesthetic, the anaesthetist remains vigilant at all times, checking the patient's vital signs for anything out of the ordinary. At times a condition presents itself in the operating theatre in which places the patient's life at serious risk. The clock is ticking and time is of the essence to manage these situations. It is during these times the Anaesthetist is able to manage the critical situation and stabilise the patient. A significant example of this is called Malignant Hyperthermia, and quite likely you may not know you have it. During this article, we will explore what Malignant Hyperthermia is, who is at risk and how it is managed.
Table of Contents
What is Malignant Hyperthermia?
Malignant Hyperthermia definition
Malignant hyperthermia (MH) is a life-threatening rare condition that is only triggered in patients that are susceptible to it and have been exposed to specific general anaesthetic medication (halogenated inhalational anaesthetics) or a muscle relaxant (used during general anaesthetics known as succinylcholine).
On exposure to these medications, it triggers the body to produce too much heat. If it is not recognised and managed in its early stages after being triggered, MH can lead to death very quickly. Leading symptoms are muscle rigidity, hypercarbia (high carbon dioxide levels) and metabolic acidosis.
Certain people a predisposed to MH due to a change in the genes within the body (ryanodine 1 gene) that are responsible for controlling the release of calcium in muscle cells.
What is the risk of developing Malignant Hyperthermia?
The risk of a Malignant Hyperthermia (MH) event occurring statistically is about one in every ten thousand general anaesthetics. However only people that are susceptible to the condition will be put at risk. The risk that someone in the population is potentially susceptible is 1 in every 5000 people in the population.
Most people that are susceptible to MH have a mutation in a gene known as the ryanodine 1 gene. This gene is inherited in an autosomal dominant manner. This means your risk is much higher than the average population if your direct family members have the condition. If your parent, sibling or child has MH, your risk of being susceptible to MH is around 50%. Having a more distant relative reduces the risk further. For instance, if your Aunt or Uncle has the condition, your risk is reduced to 25%.
The mortality rate of Malignant Hyperthermia
During the 1960s, the mortality rate of Malignant hyperthermia (MH) was in excess of 70%, predominately due to the limited knowledge of the condition. The condition was described as "malignant" due to the high mortality rate.
Since then our knowledge about the condition has improved tremendously. Anaesthetists have great knowledge in being able to identify susceptible patients early and have the skill set to be able to manage the crisis efficiently. Today the mortality rate in the developed world has been reduced to below 5%.
Pathophysiology of Malignant hyperthermia
Normal muscle contraction (excitation-contraction coupling)
Calcium plays a key role in skeletal muscle contraction. The physiological steps required for a muscle to contract are as follows:
1. Depolarization of the muscle spreads throughout the muscle cell via the transverse tubule system
2. The depolarisation in the transverse tubule system then activates receptor within the t-tubule membrane known as dihydropyridine (DHP) receptors.
3. These receptors are coupled to ryanodine receptors (RYR1). Ryanodine receptors allow the release of calcium from the sarcoplasmic reticulum into the intracellular space.
4. Once calcium is in the intracellular space it combines with troponin to cross-link actin and myosin, resulting in muscle cell contraction.
5. For muscle relaxation to occur calcium is taken back up by the sarcoplasmic reticulum by an active process.
An example of this process may be seen below:
Source: Youtube - StudentHelpAP
Abnormal muscle contraction due to Ryanodine receptor mutation
If there is a mutation in the Ryanodine receptor (RYR1), this can lead to an abnormal physiological response as detailed below:
- Depolarization of the muscle spreads throughout the muscle cell via the transverse tubule system (normal physiology)
- The depolarisation in the transverse tubule system then activates receptor within the t-tubule membrane known as dihydropyridine (DHP) receptors. (normal physiology)
- The receptors are coupled to the mutated RYR1 which results in:
a. leakage of calcium from the sarcoplasmic reticulum resulting in an abnormally high calcium concentration or a stronger calcium signal and delayed closure of the calcium channel causing excessive calcium release.
4. This increased calcium results in a sustained and strong contraction of the skeletal muscle.
5. The sustained contraction requires increased energy requirements which at first is supplied by aerobic metabolism but then is provided by anaerobic metabolism when oxygen supplies are exhausted.
6. This increased metabolism produces heat, carbon dioxide and increasing lactate production. These are what creates the symptoms and signs of Malignant hyperthermia.
What drugs can cause Malignant Hyperthermia?
Malignant hyperthermia may be triggered by exposing a patient to any of the halogenated volatile anaesthetic agents (anaesthetic gas) that anaesthetists generally use for maintenance of anaesthesia or a 'gas induction' (breathing in anaesthetic gas to commence anaesthesia.
The volatile anaesthetic agents that can trigger MH are as follows:
In addition to the volatile anaesthetic agents, the muscle relaxant suxamethonium can trigger MH.
Drugs that do not trigger Malignant Hyperthermia
If a patient is susceptible to MH the following medications have been classed as safe to use:
- Benzodiazepines such as midazolam or diazepam
- Intravenous Anaesthetic agent propofol, methohexital or thiopentone
- Opioid medications such as morphine, fentanyl and oxycodone
- Local Anaesthetic medications
- Non-depolarising muscle relaxants (rocuronium, atracurium, cisatracurium)
How do you diagnose Malignant Hyperthermia?
In vitro contracture test (muscle biopsy test)
The definitive diagnosis of Malignant hyperthermia will require the patient to have a test known as the in vitro contracture test (IVCT). This test requires the patient to have an open muscle biopsy on the quadriceps muscle under local anaesthetic, regional anaesthetic or a trigger-free general anaesthetic (propofol infusion). The procedure is performed in an operating theatre with a result usually obtained within 2-3 hours. Only specialised laboratories are able to perform the IVCT and they require the muscle sample to be freshly excised.
What are the implications of the in vitro contracture test results?
- A negative test will mean the patient is not at risk of having a MH crisis and thus no specific precautions will be needed in the future when coming for an operation. In addition, the patient's children will not need to be tested.
- A positive test will mean that the patient is at risk of a MH crisis. All treating doctors must be informed so that appropriate preparation can be organised prior to the patient having an operation.
Why should a patient have an IVCT?
The three main reasons to obtain an IVCT are:
- The patient has had a reaction during an anaesthetic that is possibly Malignant hyperthermia
- The patient has a family history of MH and there is no genetic test available in the patients family.
- The patient has a family history of MH, a genetic test is available for the patients family but the patient had a negative genetic test.
Another available test is by Genetic screening. This can identify 35 to 40% of true Malignant hyperthermia cases but the test is limited in that it is unable to exclude a person with MH susceptibility. The Genetic screening test provides valuable insight when used together with the IVCT. It is important that Genetic counselling is offered whenever genetic screening is to be performed.
What are the signs and symptoms of Malignant Hyperthermia crisis?
MH may be diagnosed early based on heightened alertness to the early signs and symptoms.
Early signs and symptoms of Malignant Hyperthermia are:
- Masseter muscle may spasm for a prolonged period (more than 2 minutes) after the administration of the muscle relaxant, Suxamethonium. During this time it is often very difficult to intubate the patient because the mouth can not be opened.
- If the patient is being control ventilated, the anaesthetic monitor will show a rising end-tidal carbon dioxide levels.
- If the patient is spontaneously breathing, tachypnea will be displayed by the patient.
- Tachycardia and arrhythmia of the heart, with ventricular ectopic beats being displayed.
Intermediate signs and symptoms of Malignant hyperthermia are:
- Increasing temperature of the patient
- Generalised muscle rigidity
- Metabolic and respiratory acidosis
- Reduced oxygen saturation
Late signs and symptoms of Malignant hyperthermia are:
- ‘Urine brown in colour - 'cola' urine
- Bleeding tendency due to coagulopathy
- Cardiac arrest due to raised potassium levels
- Pathology test will show raised serum CK
What are the symptoms and signs of Malignant hyperthermia in children
The North American Malignant hyperthermia registry shows that approximately 17% of all episodes of MH crisis occur in children under the age of 18. Very young children (under the age of 2) display symptoms of Malignant hyperthermia that is different from adults.
A child that is less than two may present with the following signs and investigations:
- mottled skin
- metabolic acidosis
- high lactate
Of particular note, muscle rigidity was less frequent in this age group.
In older children, signs and symptoms of a Malignant hyperthermia crisis are similar to adults:
- rapid temperature rise
- sinus tachycardia
How do you manage a Malignant Hyperthermia crisis?
In managing a Malignant hyperthermia crisis, it is essential in diagnosing the condition early as this can lead to a substantial decrease in mortality and morbidity. The treatment is quite complex and will require multiple staff to work simultaneously.
Immediate management of Malignant Hyperthermia involves the following tasks:
1. Volatile anaesthetic is to be ceased immediately, the vaporizer removed and an alternative form of anaesthetic administered to the patient such as a propofol infusion.
2. Dantrolene to be administered to the patient as soon as possible. A dose of 2.5mg/kg every 10-15 minutes IV until signs of MH are resolving. Each 20 mg vial of dantrolene needs to be dissolved in 60 mL of water which can be very time-consuming. An 80 kg patient will require 10 vials to be mixed. Thus it is strongly for just preparing the dantrolene dose.
3. Management of hyperkalaemia with:
- Insulin 0.15 units/kg + 0.5 ml/kg 50% dextrose as rapid infusion (10 units
insulin in 50 ml 50% dextrose) in adults
- Calcium Chloride 0.1 ml/kg OR Calcium Gluconate (10%) 0.3 ml/kg
4. Management of cardiac arrhythmia:
- Amiodarone: 3mg/kg slow IV
- Lignocaine: 1mg/kg IV
5. Provide renal protection. The breakdown of muscle predisposes to an acute kidney injury due to the effect of myoglobin on the kidneys. The method that Myoglobin causes renal damage is a combination of stimulating lipid peroxidation and the precipitation of myoglobin in the renal tubules. This it is important to:
- Aim for urine output at least 2ml/kg/hr by increasing intravascular volume with normal saline.
- Mannitol will be given with Dantrolene as there is 3g of mannitol per vial.
6.Management of metabolic and respiratory acidosis
- Increase minute ventilation.
- If pH <7.2 , then consider the administration of sodium bicarbonate at 0.5-1 mmol/kg (8.4% is 1mmol/ml)
7. Cooling of the patient
- Cool IV fluids
Investigations during the Malignant Hyperthermia crisis
The following blood tests are of value during a malignant hyperthermia crisis:
- Urea and electrolytes
- Creatinine Kinase
- Coagulation screen
- Arterial blood gas
Extra monitoring and equipment required to assist in the management of Malignant hyperthermia crisis:
- Arterial line
- Central venous catheter
- Urinary catheter
- Temperature probe
What is Dantrolene?
Malignant Hyperthermia currently only has one medication that is specific to the treatment of a crisis being the medication Dantrolene.
The medication Dantrolene is poorly soluble in water due to being highly lipophilic. It comes prepared for intravenous use in vials containing 20 mg lyophilized dantrolene sodium with 3g of mannitol added to improve its water solubility.
To prepare Dantrolene, the contents of the vials have to be dissolved in 60 ml water, which can be very time consuming and will require a dedicated staff member to execute.
The mechanism of action of Dantrolene is by blocking calcium release from the intracellular storage of calcium in the sarcoplasmic reticulum with skeletal muscle. The effect is skeletal muscle contraction is reduced. It does not affect the action potential patterns of the neuromuscular junction.
Can someone that is susceptible to Malignant Hyperthermia have an anaesthetic?
Patients that are susceptible to Malignant Hyperthermia can safely have an anaesthetic provided the anaesthetist is well aware of the patient's susceptibility and the Anaesthetist takes appropriate measures to prevent a crisis for being triggered.
If at all possible a regional anaesthetic should be strongly preferred to eliminate the need to utilise general anaesthetic medications.
If a general anaesthetic is required, the following steps are advisable to avoid triggering a crisis:
- A clean anaesthetic machine and the circuit should be utilised (no residual anaesthetic agents in the circuit from previous operations.
- Dantrolene is not required prophylactically
- Strictly no use of volatile anaesthetic agents of suxamethonium
- The ideal general anaesthetic is to use a 'total intravenous anaesthetic' (TIVA) with propofol.