1. Malignant Hyperthermia
Barbara Robertson, MD, FRCPC
Dept of Anesthesia, PAH
Cue music!
So that was Peggy Lee singing “Fever” to get us in the mood.
Thank you very much for inviting me to participate in this PANBC education day. When Ingrid first gave me the topic title “Too Hot to Handle” I thought she was asking me to talk about my menopause symptoms!

2. Overview What is it? Why is it? Who gets it? How do you recognize it?
How do you treat it?
What to do if patient is susceptible?
I am sure all of you are aware of the syndrome of malignant hyperthermia so during this talk I am going to review this topic by asking the following questions:
What is it – the classic definition
Why does it happen – the pathophysiology
Who gets it – epidemiology & genetics
How do you recognize it – symptoms & signs, lab abnormalities
How do you treat it
And what kind of anesthesia can a MH susceptible patient have
And there will be lots of time at the end for discussion and sharing of stories – although as my bio states, I have yet to encounter an MH crisis in 30 years of anesthesia practice but I am sure there are a few people here who have had a patient who is “too hot to handle”.
I’ll just mention now that research is going on in an effort to elucidate more of the molecular genetic aspects of MH which will perhaps eventually provide an easy diagnostic test, and maybe even a screening test – but that’s a long way into the future!

3. Inherited component suggested 1960’s
First case described
1962
Inherited component suggested
1960’s
Toronto and Wisconsin MH families identified / similarity to PSS recognized
1971
International symposium Toronto
CHCT muscle biopsy described
1975
Dantrolene found to be specific treatment (FDA approved 1979)
Patient advocacy groups formed
1980’s
Use of intraoperative capnography helps early detection
1990’s
RYR1 gene mutation discovered (100% PSS, 50% MH)
2000’s
Genetic testing available
This slide shows a brief outline of the history of MH. If there are any ex Toronto folk here, they will know that a Cdn anesthesiologist Dr Beverley Britt at U of T was one of the initial investigators & researchers of MH, and helped develop the CHCT which is now the standard test for MH
Go through chart
1960: 1st case described
1962 : inherited component suggested
1960’s: research into the clusters of MH families & recognition of animal model
1971: international symposium / description of CHCT
1975: use of dantrolene as specific treatment / FDA approval granted 1979
1980”s: MHAUS, adoption of intraoperative capnography
1990’s: RYR1 gene mutation discovered
2000’s: genetic testing becomes available

4. Resources at hand MH hotline: 1-800-644-9737
Outside USA:
Website:
Wall flow chart from MHAUS
There’s an app for that (ePocrates, Gas Guide, MHapp)
There are plenty of resources available for dealing with an MH event and I’m sure every OR has the MHAUS flow chart stuck on the wall. If you have a smartphone, there is an app for that too.
The MHAUS online shop stocks Crisis management supplies like wall charts, Education packs, Patient supplies, books & pamphlets, videos & DVDs for in service and mock drills, procedure manuals, & info on a syndrome that looks like MH but isn’t called Neurolept Malignant Syndrome

5. What is MH? Potentially fatal inherited disease
Fever, rigidity, acidosis
Hypermetabolic state of skeletal muscles with high intracellular calcium levels
Triggered by exposure to volatile anesthetics and / or succinylcholine
MH is a pharmacogenetic disorder inherited as autosomal dominant with variable penetrance
Overall characteristic is hypermetabolism, which if left to run its course, ends up killing the patient
Does not affect other muscle like cardiac, only skeletal

6. Why is it? It’s complicated!
Uncontrolled release of calcium by the ryanodine receptor in the terminal cisternae of the sarcoplasmic reticulum
The simple answer is that people with MH have a disturbance of calcium homeostasis in skeletal muscle on exposure to triggering agents.
The next slide shows the complicated sequence of events leading to muscle contraction in the normal state

7. Action potential opens sodium channels
Action potential travels down t tubules
And arrives at dihydropyridine receptors [voltage sensor] (1% of MHS have mutation in the CACNA1S gene that codes for this protein)
Calcium release channels open (this is a large protein called the type one ryanodine receptor or RYR1) and this is where it has been discovered that variants of this RYR1 can be responsible for MH in 50 % of cases
Stored calcium in terminal cisternae released
Calcium interacts with actin myosin to move the muscles
ATP driven calcium pump pumps calcium back into sarcoplasmic reticulum
Sarc retic stores calcium in terminal cisternae
Sodium that entered cell thru channel pumped in exchange for K
Or exchanged for calcium
Fatty acids & triglycerides supply energy for cellular ATP ion pumps

8. Intracellular hypercalcemia
Increased calcium release
Decreased calcium uptake
Defect in the muscle membrane
Altered function / structure of proteins & fatty acids
One of the causes of MH appears to be a mutation in the gene encoding RYR1 which is the calcium channel receptor at the terminal cisternae. However there must be other causes because not everyone who tests positive on muscle biopsy testing carries one of the 30 or so RYR1 mutations known to be related to MH
Other factors that might be involved in MH are listed on the slide such as decreased calcium uptake into the SR, defects in the muscle cell membrane, and alterations in other proteins and fatty acids.
New research reveals that alterations in extracellular calcium entry play a role in maintaining the MH reaction in MHS.

9. Trigger agents Volatile anesthetic gases (sevo, des, etc)
Succinylcholine
Why are these particular agents triggers? Refer to article in BJA 2011 describing the pharmacology of triggering. In MHS volatile anesthetics appear to overcome the inhibitory regulatory effect of magnesium ions on the ryanodine receptor
New evidence casts doubt on ability of sux WITHOUT volatile gas to trigger MH!
An interesting aside, besides pigs, horses & dogs can also exhibit MH. In dogs the MH susceptibility is inherited as autosomal recessive

10. Safe drugs in MH
N20
Nondepolarizing relaxants (roc, vec, atracurium etc)
Local anesthetics
Narcotics
Sedative hypnotics (midaz, propofol etc)
Everything that’s not a trigger is safe

11. Who gets it? 1:50,000 adult GAs 1:15,000 pediatric GAs
Incidence rising due to better awareness but mortality declining (overall 10%)
Inherited as autosomal dominant with variable penetrance
Clusters of MHS families exist (Toronto, Ottawa, Quebec, Wisconsin)
Autosomal dominant means that 50% of offspring (1st degree relatives) will have the syndrome, 25% of 2nd degree (aunts, uncles, grandparents)
Variable penetrance means that not all MHS will demonstrate the classic signs & symptoms of MH when exposed to triggers

12. Conditions associated with MH
Central core disease
Myotonia flutuans
King or King-Denborough myopathy
Osteogenesis imperfecta
Heat / exercise syndromes?
Periodic paralysis (hypo & hyper kalemic) types considered MHS
Carnitine palmityl transferase deficiency patients MHS
Recent CJA article from the UofT MH group found that 22% of MHS have range of non specific changes in their skeletal muscle cells on microscopic examination
RYR1 mutations are associated with MHS as well as subclinical & overt myopathies
Recommended now that confirmation of MHS by CHCT or molecular genetic testing should also include a thorough neuro musc exam & histologic studies
Spectrum of clinical manifestations of mutations & DNA variants of RYR1 gene is varied & extensive
Some patients with myalgia & exercise induced rhabdomyolysis have RYR1 variants & could be MHS

13. Other conditions
Muscular dystrophy (hyperkalemia after sux but not MH)
Pheochromocytoma & thyrotoxicosis show hypermetabolism but not MH
Neuroleptic malignant syndrome (related to phenothiazine exposure over long term causing dopamine depletion)
Sudden cardiac arrest in a young man after sux most likely due to hyperkalemia (responds to treatment with gluc insulin, calcium, hypervent’n) and may be the 1st sign of a myopathy like musc dystrophy. Refer pt to neurologist after recovery

14. How to recognize it? Classically presents in OR Tachycardia Tachypnea
Hypertension
Arrhythmias
Rigidity
Hyperthermia
Hypermetabolism results in increased CO2 production & causes stimulation of sympathetic nervous system
ATP energy stores become depleted and cell membranes break down
Clinical presentation can be fulminant as in the slide or insidious with “mild” symptoms & signs that occur much later even after the anesthesia is over

15. As the crisis develops….
Rising ET CO2
CO2 absorbent gets hot
Skin colour mottled or cyanotic
Sweating
Mixed respiratory & metabolic acidosis
Elevated K, lactate, myoglobin, CK
With ETCO2 monitoring as standard procedure for all GAs, rising ETCO2 is one of the 1st signs of MH
Muscle destruction or rhabdomyolysis releases myoglobin protein into the blood stream – can be damaging to kidney

16. Later….. Myoglobinuric renal failure DIC Death
If MH continues without treatment, very high mortality (80%) – which gave rise to the name “malignant” when it was 1st recognized

17. Variable presentations
Delay in onset until emergence, PAR or ward
Masseter muscle rigidity
Several uneventful GA’s in the past, then MH occurs during current GA
MMR commonest in children & young adults (incidence 1:100 with halothane & sux combo?)
Typically inhalational induction then sux resulting in rigidity of jaw muscles, with tachycardia & dysrhythmias
MH usually develops after 20 minutes if triggering anesthetics continued. Recommended to cancel the case. Can be associated with myoglobinuria & increased CK. May need MH treatment and may have occult myopathy (refer to neurologist). Check CK and observe in ICU -
Why uneventful GAs then MH happens?? Thought to be dose dependent exposure or the co administration of drugs that “protect “ against MH (IV induction agents, non depolarizing NMBs)

18. Diagnostic tests
Caffeine halothane contracture test is the gold standard (muscle biopsy)
5 centres in North America perform the accepted protocol (Toronto is only one in Canada listed on MHAUS website)
Genetic testing (2 centres in USA listed on MHAUS website)
For muscle biopsy, patient has to travel to the centre & have an anesthetic in order to obtain the specimen which must be prepared “fresh” according to protocol. Patient must be older than 10 (minimum amount of muscle needed)
Could be a muscle biopsy testing centre in Ottawa according to a google search
Muscle biopsy & genetic test centres in Europe, Australia & NZ
North America vs European standards slightly different to diagnose person as MH susceptible depending on results of CHCT & genetics
UofT website states genetic testing is available at their MH clinical investigation unit
Genetic testing blood samples can be mailed to test centres but incur a cost ?

19. Problems with testing False negative (had MH after testing negative)
More than one gene mutation may cause MH because only 50% to 80% of MH susceptible patients have RYR 1 variant or mutation
False negative after muscle biopsy is rare but can happen because patient results fall outside the standard cutoff
Genetic testing useful for family members of MH patients tested positive with muscle bx & who have the mutation (family members don’t have to be biopsied)
False negative rates higher with genetic testing (have MH but not the particular gene mutation)
50% of children of MH susceptible at risk for having MH, 25% of aunts, uncles, grandchildren

20. How to treat?
Early diagnosis and treatment result in very low mortality
Any location where anesthetics are administered should have MH plan & sufficient dantrolene
MH cart, practice drills, wall chart with hotline number

21. MH treatment memory aid
Some
Hot
Dude
Better
Give
Iced
Fluids
Fast
Some: Stop triggering agents
Hot: Hyperventilate 100% O2 high flow
Dude: dantrolene
Better: bicarb for metabolic acidosis
Give: glucose & insulin for hyperkalemia
Iced: cool IV fluids / external cooling / lavage
Fluids: furosemide for urine output
Fast: fast HR / arrhythmias

22. Acute phase Call for help & get the MH cart / crash cart
Declare an emergency
Stop the triggering agents
Hyperventilate with high flow 100% O2
Switch to non triggering anesthesia to finish the surgery if needed / change circuit?
Dantrolene
Follow MHAUS wall chart guidelines and ask for expert help by calling the hotline
If high flow 10 lpm O2 ventilation provided, don’t waste time changing the anesthesia circuit
Secure AW with ETT if not already intubated (use nondepolarizing drugs)

23. Dantrolene Need help to mix Initial dose 2.5 mg/kg (175 mg)
Each bottle is 20 mg = 9 bottles for first dose
Each bottle mixed with 60 ml H2O = 540 ml water for 9 bottles
Acts by reducing intracellular calcium in skeletal muscles
Max dose is 10 mg/kg
Dantrolene dosing until signs of MH start to normalize by following ETCO2, acidosis, temp
Dantrolene acts on ryanodine receptor to prevent release of calcium
Rapid dissolve preparation available said to dissolve in 20 sec, 4 times faster than old
Found an abstract from 2010 pediatric anes mtg testing solubility of the new & old types of dantrolene:
warm diluent at 40 deg increased the rate of dissolution most for the new (4 sec) compared to the old but at room temp 23 deg old dissolved faster than new!
Warm the sterile water? Warming affects effectiveness?
Analogue of dantrolene called azumolene (30 times more soluble) not yet tested in humans

24. Acute Episode (cont’d)
Cool patient (goal = 38)
ABG, lytes results guide further treatment for metab & resp acidosis, hyperkalemia
Arrhythmias respond to correction of hypercapnia, hyperkalemia & acidosis
CK level, myoglobin
No calcium channel blockers like verapamil
No procainamide or lidocaine for wide complex QRS from hyperkalemia – risk of asystole
Treat hyperkalemia with hyperventilation, glucose & insulin, calcium
Each dantrolene vial contains 3 grams mannitol (promoting kidney flushout of myoglobin)
Avoid Ringers Lactate which contains potassium

25. Afterwards, monitor for….
Recrudescence (25% of patients)
DIC
Myoglobinuric renal failure
When patient is stable, transfer to ICU

26. In ICU: Dantrolene 1mg/kg q6hr x 24-36 hours then orally?
EKG, art line, urinary catheter, temperature, 2nd IV line
CVC?, capnography?
Monitor & treatment for specific abnormalities
Continue the dantrolene
Invasive monitoring as guided by patient’s condition

27. ICU care (cont’d) Refer patient & family to MH centre for testing
Recommend registry in MHAUS data base
Recommend Medic Alert bracelet

28. ABC’s A: Aware of recrudescence
Ask relatives anesthesia / neuromusc disease history B:
Biopsy C:
Contact MHAUS
Here’s an easy way to remember what to do after the acute phase is over: ABC + D
Clinical scoring system to describe severity of MH reaction (on MH app)

29. ABC’s + D D: Dantrolene 1 mg/kg IV q6h x 24 -36 hrs
Documentation to MHAUS registry
MHAUS registry was established in 1987 & is located in Pittsburgh's Children’s Hospital.
Database
epidemiologic studies
Standardize & validate MH testing procedures
Website for patients as well as health professionals with online forms for documenting & registering, FAQ’s, quizzes for continued professional development

30. Management of MH susceptible patient
Refer to anesthesia consult clinic
Prophylaxis with dantrolene?
Hospital setting vs private clinic?
GA vs local / regional?
So up to now we have talked about the MH crisis situation. What happens if a patient is coming for surgery or is a maternity case and already is labeled as MHS?
Reassurance vital!
Prophylaxis generally not recommended since dantrolene can make people feel weak
Clinic? Only if all the anesthetics are non triggers, or if capable of handling an MH crisis with enough dantrolene & lab & critical care backup
Opt for local or regional if possible

31. GA in MH susceptible
Flush gas machine / remove vaporizers / new circuit & CO2 absorber
Monitor ETCO2 & temp
MH cart ready & nearby
TIVA with propofol +/- N2O +/-nondepolarizing NMB + narcotics = non trigger anesthesia
Use high fresh gas flow
Flushing of gas machine acc to manufacturer – may take 10 to 90 min. MHAUS recommends 20 min with ventilator on and breathing bag “lung”
Check expired anes gas analyzer to confirm absence of gas
FGF should be 10 lpm during case
Use of charcoal filters on insp limb of circuit effective within 10 min – duration of action? May need to replace intra op
Vapor Clean brand claims to reduce gas conc to < 5 ppm in < 2 min for at least 90 min (extent of testing) although website states good for 12 hours!
Other charcoal filter brand is QED-100 effective for 6 hours
Vapour free machine: not cost effective for most hospitals now, due to maintenance concerns
Safe limit of volatile gas is < 5 ppm halothane acc to testing in MHS pigs
Rebound phenomenon can happen after flushing with high gas flows 10 lpm then using low gas flow 1 or 2 lpm for anesthesia

32. MH cart Dantrolene Sterile water (in warming cupboard?)
Bicarb, dextrose, CaCl2, lidocaine
Insulin (in fridge)
NS IV bags (in fridge)
Other stuff
Use of sterile water in 500 ml bags? Risk of accidental IV use? MHAUS recommends 100 ml vials of sterile water
Syringes, IV catheters, NG tubes & toomey syringe, temp probe, CVC kit, art line kits, urometer, Steridrape for surgical wound, irrigation tray with syringe, bags for ice (large & small), bucket for ice, urine chem strips, ABG kits, lab test tubes, urine spec containers for myoglobin
Cart should be available within 10 min
36 vials of dantrolene cost USD 3000 good for 30 months

33. PAR care for MH susceptible
Observe for 4 – 6 hours
May be appropriate for day surgery if GA was uneventful
North American standards: minimum 1 hour in PAR, additional hour in step down
Now I hope we have time for some discussion before lunch!
Thank you again for inviting me and now I’ll close with a photo of one of the grandbabies…..asleep in her daddy’s firefighter gear

34. Thank you!
Cue music!
The Doors: Light My Fire