2014B03 Briefly outline the acute management of malignant hyperthermia (during a relaxant general anaesthetic).
Describe the important aspects of dantrolene pharmacology relevant to treating malignant hyperthermia.

Definition

·  Rare, life-threatening hypermetabolic reaction to volatile anaesthetics or suxamethonium

Aetiology

·  Autosomal dominant mutation RYR1 gene encoding the skeletal muscle ryanodine receptor (RR) and ion channel

·  1 in 200,000

Pathophysiology

·  Continuous, excessive Ca²⁺ release

·  Continuous skeletal muscle contraction

·  ↑↑VO₂, ↑↑VCO₂

·  ↑HR, ↑etCO₂, ↑temp

Complications

·  Rhabdomyolysis

·  Acidosis

·  Arrhythmia

·  Death (80% mortality if untreated)

Basics

·  Call for help, need many hands

·  Abandon surgery

·  Stop the offending agent(s) ASAP

o Cease volatile, FGF >10L/min to flush circuit, ↑FiO₂ to 100%

o No more suxamethonium

·  Start IV sedation e.g. propofol 30mL/h

ABC

·  A: insert ETT

·  B: IPPV, note ↑↑MV required

·  C: ensure BP within safe limits, insert arterial line

·  D: sedate e.g.propofol 200mg/h

Dantrolene ASAP

·  Bolus dose: 2.5mg/kg rapidly ± repeat; may require >10mg/kg

·  Infusion for up to 24h: 1mg/kg/h

Cool to 37C

·  Remove clothing and blankets

·  Cold IV saline

·  Cold bladder or intraperitoneal irrigation

Treat complications

·  e.g. hyperkalemia

Take to ICU

·  Observation ~24 hours

·  +/- dantrolene infusion

Physicochemical

·  Glass vial, orange powder

·  20mg dantrolene, 3mg mannitol (solubiliser), NaOH

·  Add to 60mL H₂O

·  Needs mixing +++ (poorly water soluble)

·  ± thrombophlebitis

·  ± necrosis if extravasated

Pharmacokinetic

·  IV or oral

·  Low V_D 0.6L/kg

·  90% plasma protein bound

·  Hepatic metabolism Phase 1; active metabolite 5-OH-dantrolene

·  Renal excretion of metabolites

·  t_1/2β 9 hours

Pharmacodynamic

·  Competitive antagonist at the skeletal muscle RR -> ↓Ca²⁺ release -> post-junctional relaxation

·  Effects: skeletal muscle relaxation, resp paralysis

·  No effect on cardiac or CNS ryanodine receptor

·  Side effects rare:

o ↑LFTs

o APO from IV fluid +++