This document provides an overview of malignant hyperthermia (MH), including describing what MH is, its risk factors, etiology, clinical manifestations, diagnosis, management, prevention, and the pharmacology of dantrolene. MH is a rare life-threatening disorder triggered by certain anesthetic agents that causes a rapid rise in body temperature. It results from a genetic mutation affecting the ryanodine receptor in skeletal muscle. Presentation involves muscle rigidity, tachycardia, and a body temperature over 41°C. Diagnosis is based on clinical features and confirmed with in vitro muscle testing. Management involves immediately discontinuing triggers, rapidly cooling the patient, administering dantrolene to reduce calcium levels,

1. Dr.Arun.S
First year Postgraduate
Department of Pharmacology
GMC, Ananthapuramu

2. SPECIFIC LEARNING OBJECTIVES
BY THE END OF THE SESSION THE LEARNER WILL BE ABLE TO
DESCRIBE,
• What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

3. WHAT IS MALIGNANT HYPERTHERMIA?
• Malignant hyperthermia (MH) is a rare and
life-threatening pharmacogenetic disorder
triggered by volatile anesthetics, the
depolarizing muscle relaxant succinylcholine,
and rarely by strenuous exercise or
environmental heat.
• Peak body temp of 41℃ and above or acute
rise of 1-2℃ within 15 mins.
• If not treated immediately patient will go into
multiorgan failure and death.

4. EPIDEMIOLOGY
• Incidence - 1:5000 to 1:50000 during general anaesthesia
• Other causes - 1:100000
• Generally affects in age < 18 years (30-60% cases)
• Male : Female - 4:1 (But in India more female cases are reported).

5. • What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

6. RISK FACTORS
• ANESTHETIC INDUCED:
• GA - Halogenated anesthetics, Ether, Xenon
• LA - Lignocaine, Bupivacaine
• SKELETAL MUSCLE RELAXANTS - Succinylcholine
• NON-ANESTHETIC INDUCED MH:
• Drugs - 5-HT3 antagonists - Ondansetron
• Viral infections - Parainfluenza, HSV-1
• Environmental heat stroke
• Extreme emotions
• Exertional Rhabdomyolysis - Strenuous exercise

7. GENETIC CAUSES
• RyR1 (Ryanodine receptor 1) mutations
• Dihydropyridine receptor (DHPR) - L-type Voltage gated Ca2+
channel mutation.
• Mutations in accessory proteins of Ca2+ channel complex in T-tubules:
1. Calsequestrin
2. FKBP12
3. Triadin
4. Junctophillin
5. Junctate
6. Junctin
7. STAC3

8. • What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

9. ETIOLOGY

10. PATHOGENESIS

11. • What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

12. CLINICAL MANIFESTATIONS
• Early stage
• Progression stage
• Last stage

15. III

16. • What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

17. DIAGNOSIS OF MALIGNANT HYPERTHERMIA
• Medical / Family history
• Clinical presentation
• Biochemical tests
• In vitro caffeine-halothane contracture testing
(IVCT/CHCT)
• Genetic testing
• Minimally invasive tests

18. CLINICAL PRESENTATION
• Muscular spasm or rigidity of a certain part of the body, such as
masseteric spasm or whole-body rigidity.
• Unexplained rapid pulse, fluctuating blood pressure, arrhythmia.
• Body temperature that rises rapidly in a short time (1−2°C over 5−15
minutes) and quickly reaches 38.8°C or even ultrahigh temperatures of
41−42°C.
• Respiratory and circulatory system failure in a short time: cyanosis,
arrhythmia, oliguria & cola colored urine.

19. Score >20 - MH susceptible, > 50 - diagnosed as MH.

20. BIOCHEMICAL TESTS
• Elevated parameters:
1. Glucose, lactate
2. Na+, K+, Mg2+, Ca2+
3. Arterial CO2, ETCO2
4. Phosphate, CPK
5. Serum & urine myoglobin
• Reduced parameters:
1. Arterial pH
2. Arterial O2
3. K+ (at later stages)

21. INVITRO CONTRACTURE TEST

23. GENETICS TESTING
• DNA testing for RYR1 mutations
• AD inheritance - If father or mother affected, test for mutations in
offsprings also.

24. MINIMALLY INVASIVE TESTS
• Nuclear Magnetic Resonance Spectroscopy - detects ATP depletion
during graded exercise (in vivo)
• Capnography - Enhanced release of CO2 is measured by inserting a
microdialysis catheter into muscle and injection of small amount of
caffeine.

25. OTHER MYOPATHIES ASSOCIATED
WITH MUTATIONS IN RYR, DHPR, STAC3

27. All forms of myopathies are diagnosed via genetic testing...

28. DIFFERENTIAL DIAGNOSIS
Mechanical causes: (for raised ETCO2)
• Inadequate fresh gas flow
• Insufficient ventilation
• In-appropriate breathing circuit
• Machine malfunction
Anaesthetic:
• Inadequate anaesthesia and/or analgesia
• Anaphylaxis
• Cerebral ischaemia
• Anesthetic induced rhabdomyolysis

30. DIFFERENTIAL DIAGNOSIS - contd..
Surgical:
• Laparoscopic surgery
• Tourniquet ischaemia
• Thyroid storm
Patient related:
• Phaeochromocytoma
• Neuromuscular disorders
• Pre-existing infection/sepsis
Idiosyncratic:
• Anaphylaxis, serotonin syndrome, neuroleptic malignant syndrome

31. MANAGEMENT GUIDELINES FOR SUSPECTED MH
5 ‘C’ Principles
• Cooling the body with ice packs, infusion with cold saline, cold
immersion of body till chest.
• Convulsion relief: sedation and adequate oxygen supply
• Correcting water and electrolyte imbalance, stabling the cell
membrane
• Calcium supplements and narcotic drugs should be used with caution
• Closely monitoring vital signs, temperature, blood gas indicators, acid-
base balance indicators, and serum ions for at least 24 hours

32. • What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

33. STEP 1
• Stop potent inhalational agents & succinylcholine & shift the patient on Total
Intravenous Anesthesia
STEP 2
• Increase the minute ventilation to lower the ETCO2
STEP 3
• Administer Dantrolene 2.5mg/kg initially, maximum upto 10mg/kg.
• Titrate dantrolene according to tachycardia and hypercarbia
• Dantrolene requires Mg2+ to arrest MH. So check serum Mg2+ and give MgSO4 if
needed.

34. STEP 4
• Begin cooling measures - ice packs to groin, axilla, neck
• Nasogastric lavage with iced saline or infusion of cold NS 2000mL.
• Stop cooling if body temp comes down to 38.5
STEP 5
• Treat arrhythmias with Amiodarone 3mg/kg i.v. Dantrolene also has anti-
arrhythmic action.
STEP 6
• Secure blood for ABG, myoglobin, electrolytes, CK. Urine for myoglobin
• Check coagulation profile every 6-12hrs
℃

35. STEP 7
• Treat hyperkalemia - hyperventilation, bicarbonate and intravenous
glucose and insulin (child - regular insulin 0.1U/kg i.v + 0.5g/kg
dextrose); adult - Regular insulin 10U i.v + 50mL of 50% dextrose.
STEP 8
• Treat acidosis with sodium bicarbonate - 1-2mEq/kg i.v infusion
• Continue dantrolene at 1 mg/kg every 4–8 hours for 24–48 hours
STEP 9
• Ensure urine output of 2 ml/kg/hour with mannitol (1g/kg i.v),
furosemide (0.5-1mg/kg i.v), and fluids as needed.

36. FOLLOW UP
• Tests for DIC should be done - CBC, Prothrombin time, aPTT, D-
dimer, platelet count.
• Patient should be closely monitored for 24-48 hrs after the initial
episode.
• 25 % patients may relapse even on dantrolene treatment.

37. • What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

38. PREVENTION OF MH EPISODES
• Thorough anesthetic history
• Patients with any form of myotonia should not receive
succinylcholine.
• Patients with hypokalemic periodic paralysis, CCD, Duchenne or
Becker muscular dystrophy, paramyotonia, or myotonia fluctuans
should not receive trigger agents.
• All patients receiving more than a brief general anesthetic should have
their core temperature monitored.

39. PREVENTION - contd..
• Young patients (below age 12) should not receive succinylcholine for
elective procedures, in order to avoid the possibility of hyperkalemic
response.
• Advice should be given to patients susceptible to MH to avoid heat
and humid environments.
• Dantrolene 2.5 mg/kg intravenously over one minute, approximately
75 minutes before surgery.

40. • What is Malignant Hyperthermia?
• Risk factors for MH
• Etiopathogenesis of MH
• Clinical manifestations of MH
• Diagnosis of MH
• Management of Acute MH
• Prevention of MH
• Pharmacology of Dantrolene
• Summary

41. PHARMACOLOGY OF DANTROLENE
• It is a directly acting skeletal muscle relaxant
• MOA - Ryanodine receptor 1 antagonist- prevents the receptor from
opening - reduces intracellular calcium.
• T1/2 - 4-8hrs. Metabolized in liver, excreted in urine.
• Available dosage form - Capsules and injection (20mg vial powder) -
to be reconstituted fresh in 60mL distilled water and given as bolus
immediately.
• Adult dosage needed in an acute MH crisis - 10 vials of dantrolene.
• Precautions - Dantrolene + Calcium channel blockers - fatal
hyperkalemia & cardiovascular collapse.

42. OTHER USES OF DANTROLENE
FDAAPPROVED:
• Spasms, cramping, and tightness of muscles caused by multiple sclerosis (MS),
cerebral palsy, stroke, or injury to the spine.
• Dose: Adults - 25 mg/day to max 100mg t.i.d; Children - 0.5 mg/kg twice a day.
OFF LABEL USES:
• Neurolept Malignant syndrome
• Overdose of 2,4-dinitrophenol
• To treat vasospasm following aneurysmal subarachnoid hemorrhage.
• Alzheimers disease (in research)

44. ADVERSE EFFECTS OF DANTROLENE
• Skeletal muscle weakness
• Dyspnea
• Respiratory muscle weakness - decreased inspiratory capacity
• Hepatotoxicity

45. CONTRAINDICATIONS OF DANTROLENE
Oral dantrolene is contraindicated in patients with
• Liver cirrhosis
• Non-alcoholic steatohepatitis
• Hepatitis B or C infections
No contraindications for i.v dantrolene in malignant hyperthermia

46. SUMMARY
• MH - Pharmacogenetic disorder - Body temp > 42℃, Hypermetabolic state.
• M/c with halogenated anesthetics and succinylcholine
• Age < 18 yrs more common
• 3 main mutations - RyR1, DHPR, STAC3
• Emergency condition treated with RyR1 antagonist Dantrolene 2.5mg/kg i.v to
max 10mg/kg i.v.
• Cooling measures till temp reaches 38.5℃.
• Supportive measures with Sodium bicarbonate, Furosemide, mannitol, dextrose,
Insulin (for hyperkalemia).
• Watch for complications of MH- DIC, arrhythmias, CHF.
• Genetic counselling is must in MH susceptible patients.
• Rule out other possible causes of hyperthermia and rhabdomyolysis.

47. REFERENCES
• Rosenberg, H., Davis, M., James, D. et al. Malignant hyperthermia. Orphanet J Rare Dis 2,
21 (2007). https://doi.org/10.1186/1750-1172-2-21
• Malignant Hyperthermia: A Killer If Ignored, Xin Bin, DDS, PhD, Baisheng Wang, DDS,
PhD, Zhangui Tang, DDS, PhD, April 10, 2022. https://doi.org/10.1016/j.jopan.2021.08.018
• Ronald S. Litman, Sarah M. Griggs, James J. Dowling, Sheila Riazi; Malignant
Hyperthermia Susceptibility and Related Diseases. Anesthesiology 2018; 128:159–167 doi:
https://doi.org/10.1097/ALN.0000000000001877
• Yang Lukun, Tautz Timothy, Zhang Shulin, Fomina Alla, Liu Hong. The current status of
malignant hyperthermia[J]. The Journal of Biomedical Research, 2020, 34(2): 75-85. doi:
10.7555/JBR.33.20180089
• Pawan K Gupta , Philip M Hopkins, Diagnosis and management of malignant
hyperthermia, BJA Education, Volume 17, Issue 7, July 2017, Pages 249–254,
https://doi.org/10.1093/bjaed/mkw079

48. THANK YOU!!