Malignant Hyperthermia

OVERVIEW

• Malignant Hyperthermia = pharmacogenetic disease of skeletal muscle induced by exposure to certain anaesthetic agents. Occasionally exercise, heat or illness induced.
• incidence 1:5,000 -> 1:65,000 anaesthetics (suspected)
• mutation in the gene coding for the ryanodine receptor
• RYR1 pathogenic variant confers autosomal dominant malignant hyperthermia susceptibility (see detailed genetics at end of article).
• Most at-risk individuals have no known family history of MH

PATHOPHYSIOLOGY

• excess Ca2+ release during muscle contraction -> increased musle metabolism + heat production.
• prolonged and intensified interation between actin and myosin.
• enhanced aerobic metabolism -> lactic acidosis -> accumulation of intra-mitochondrial calicum -> deconjugation of oxidative phosphorylation -> cytolysis.

TRIGGERS

• Suxamethonium
  -> potent trigger of MHS e.g. with first exposure
  • these all either enhance Ca2+ influx or slowing its efflux
  •  potent trigger (first exposure)
• All volatile agents (except N₂O)
  • -> may have tolerated the same agents previously
  • Rare in barbiturate-N₂O-opiate-tranquiliser-non-depolarising muscle relaxants
  • Exercise, heat or illness (uncommon trigger)

CLINICAL

• in lower North Island of NZ
• history of Central Core Disease

(1) increased ETCO2
(2) tachycardia
(3) tachypnoea
(4) masseter spasm (if develops this convert to a MH safe anaesthetic)
(5) muscle rigidity
(6) temp increase (late) – 1 C\15min

• intra-op & 4\24 post op
• tachyarrhythmia
• difficulty ventilation
• hypertension
• sweating
• DIC
• hyperkalaemia
• cardiac arrest

INVESTIGATIONS

• PaCO2 >60mmHg
• PvCO2 >90mmHg and increasing
• BE -5 and falling
• metabolic acidosis
• CK >50,000 IU/L
• K+ increases
• Na+ increases
• myoglobinuria

ACUTE MANAGEMENT

• call for help
• discontinue all anesthetic agents
• maintain anaesthesia with hypnotics and opioids.
• muscle relaxation with NDNMBD
• terminate surgery
• hyperventilate
• 100% O2
• cool (N/S stomach lavage)
• maintain urine output
• inotropes as needed
• HCO3 2-4mEq/kg
• Dantrolene 2.5mg/kg every 5min (total dose 10mg/kg/day – continuous infusion or treat recurrence (25%))
• cardiac arrhythmias -> beta blockers & lignocaine.
• high K+ -> glucose-insulin & frusemide
• watch for DICCK Q6hrly

PROGNOSIS

• mortality without dantrolene = 70%
• mortality with dantrolene = 5%

DEFINITIVE DIAGNOSIS

• All suspected cases warrant referral to an MH centre
• National Specialist Referral Centre – Australia and NZ (MDT clinics) e.g. https://malignanthyperthermia.org.au
• Warn patient and family of impending consequences
• Letter to patient
• Medical Alerts on EMR
• Letter to at-risk family members (usually by genetics clinics)

In the MH clinic

• Genetic testing – small gene panel e.g. RYR1, CACNA1S, STAC3 (See table below for further details)
• Muscle biopsy for in vitro contracture test (IVCT) = definitive diagnosis
• Distinguishing pathogenic variants from variants of uncertain significance (VUS) in MHS can be very challenging
• If a genetic diagnosis confirmed i.e. likely pathogenic or pathogenic variant (LP/PV_
  • Can offer predictive genetic testing to at risk relatives
  • Genetic counselling and informed consent are essential
• If no genetic diagnosis (or VUS)
  • Muscle biopsy/IVCT is required for diagnosis
  • 40% of MHS patients have no identifiable genetic diagnosis 
• Genotype alone does not equal a diagnosis: IVCT/CHCT and clinical context are essential considerations.
  • Diagnostic genetic testing is best ordered by a MH specialist or geneticist.
• At-risk family members who choose not undergo predictive genetic testing or IVCT must be assumed to carry the MHS

PROPHYLACTIC MANAGEMENT

• take history
• decrease anxiety with midazolam
• machine -> remove vapourisers, flush with O2 @ 10 L\min for 20min
• new circuit and airway devices
• ETCO2 monitoring
• nasal temp probe
• dantrolene available

OBSTETRIC PATIENTS

• baby = 50% chance of having MH
• planned delivery with early anaesthetic advice
• anticipate airway problems -> AFOI
• RA safe and preferred
• MH safe drugs
• sux doesn’t cross the placenta

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Genetics

• Malignant hyperthermia susceptibility (MHS) is primarily a disorder of sarcoplasmic reticulum Ca²⁺ release in skeletal muscle. The genes associated with MHS lead to decoupling of depolarisation of the transverse tubule and opening of the ryanodine receptor. 
• CACNA1S (DHPR) in the T‑tubule normally controls RYR1-dependent channel opening in the adjacent SR; STAC3 couples DHPR to RYR1
• All three converge to regulate SR Ca²⁺ release. This explains why volatile/sux triggers MHS and why dantrolene is efficacious – as an RYR1 antagonist.

Gene	Chromosomal locus	Encoded protein / role	Inheritance	Example variant(s) (HGVS)	Practical notes
RYR1	19q13.2	Ryanodine receptor 1; SR Ca²⁺ release channel central to excitation–contraction coupling	Autosomal dominant	c.1840C>T, p.Arg614Cys (classic MH variant; historically “Arg615Cys”)	Major gene. Many families lack a single hotspot; coverage of exon 91 can be poor on some NGS panels.
CACNA1S	1q32.1	Dihydropyridine receptor α1S (skeletal L‑type Ca²⁺ channel) that mechanically gates RYR1	Autosomal dominant	Multiple rare variants reported	Some variants overlap with hypokalaemic periodic paralysis/myopathy.
STAC3	12q13.3	Adaptor linking DHPR to RYR1 for depolarisation‑mediated Ca²⁺ release	Autosomal recessive (classically in STAC3‑related myopathy)	Pathogenic variants described	Primarily a congenital myopathy gene; MH‑like crises reported under anaesthesia.
Linked / unknown loci	17q11.2–q24; 3q13.1; 5p; 7q21–q22	—	—	—	Several linkage regions described; no additional proven MH genes yet.

References and Links

• Cadogan M. Michael Denborough (1929-2014). Eponymictionary