MALIGNANT HYPERTHERMIA Greg Gordon MD February 2005

Malignant Hyperthermia Objectives Things to know and do: Participants will: 1. be able to explain the: pathophysiology, clinical presentations, testing for and management of malignant hyperthermia and the MHS patient 2. be able to explain the significance of MMR and its management. 3. keep MH somewhere in mind as they monitor patients, and not hesitate to give dantrolene. 4. easily correctly answer the questions in the MH Quiz.MH Quiz

“If any institution does not feel it can manage the MHS child then they should not be anaesthetising any children at all, since it is not the identified child with a nontriggering technique who will cause grief, but the undiagnosed child given a trigger.” Helen Holtby M.B.,B.S. Director of Cardiovascular Anaesthesia Hospital for Sick Children Toronto, Canada PAC List, 10 Dec 04 Malignant Hyperthermia

pharmacogenetic hypermetabolic state of skeletal muscle induced by inhalational anesthetics or succinylcholine (and maybe stress/exercise)

Drugs + Genes = Pharmacogenetic

Historical MH 1960 Denborough and Lovell 1960’s families and pigs Gordon (?) calls it Malignant Hyperthermia 1975dantrolene saves pigs 1979FDA approves dantrolene 1980’s muscle biopsy for HCCT 1990’sgenetic markers/RYR1

halothane enflurane isoflurane desflurane sevoflurane

200,000 1 (without sux)

SUX

60,000 1 (with sux)

Incidence - Current Concepts Clinically based information: One in 20,000 to 50,000 anesthetics depending on drugs, population Molecular Genetics based information: MH trait in 1 in 2,000-3,000 patients. Low penetrance

Normal excitation-contraction coupling ACh at NMJ depolarizes sarcolemma SR (RYR) releases Ca Ca + troponin actin-myosin slide ATP hydrolyzed SR (RYR?) re-uptake of Ca

RYR1 ryanodine receptor Ca release channel protein (5,032 amino acids) connects SR to T-tubules Ca gate from SR chromosome 19, region 13.1

Excitation-contraction coupling in MH Defective RYR Ca release channel Too much free intracellular calcium

Too much free Ca ATP depletion lactic acidosis VO 2 way up Too much CO 2 myonecrosis/rhabdomyolysis/ ↑↑ K myoglobinemia/uria/renal failure

Diagnosis of MH tachycardia + tachypnea + ETCO 2 increasing + metabolic acidosis = MH = dantrolene IV

HCCT for MH vastus muscle 2-3 months after MH episode nontriggers no dantrolene gentle handling of muscle test within 5 hours About $6,000

Guidelines for Molecular Genetic Testing Determine MHS by HCCT If MH positive, screen for known mutation If mutation positive, test other family members for the mutation If mutation negative, cannot screen family for mutations or determine MH status

Treatment of an acute episode of MH Stop triggers 100% oxygen 10L/min Dantrolene 3 mg/kg To 10 mg/kg Rx metabolic acidosis, HCO 3 Cool, iced NS IV Rx dysrhythmias, hyperkalemia Monitor ETCO 2, ABGs, K, UOP, clotting tests

verapamil + dantrolene = severe hyperkalemia + myocardial depression

dantrolene

5 year-old boy for T&A halothane induction succinylcholine jaw “stiff” for 3 minutes then relaxed

Masseter muscle rigidity (MMR) amyotonic mytonia temporomandibular joint (TMJ) dysfunction not enough succinylcholine not enough time

The stiff jaw subclinical: normal interferes with intubation: 1-3% of children “jaws of steel”: true MMR 50% MHS Kaplan

MMR Rosenberg cancel elective dantrolene 1-2 mg/kg observe overnight (myoglobinuria, fever, hyperkalemia, CPK) muscle biopsy strongly considered

MMR Gordon AVOID SUX

Malignant hyperthermia susceptible (MHS) patient A safe plan prepare to treat MH use safe drugs be happy

preop for T&A needles terrify her history of hernia repair: fever and stiff jaw went for muscle biopsy: normal 7 year-old girl

Malignant hyperthermia susceptible (MHS) patient A safe plan prepare to treat MH use safe drugs be happy

MHAUS Malignant Hyperthermia For more information MetroHealthAnesthesia.com Lesson Quiz