1. Malignant Hyperthermia More than just… “Quick, get the ice!”
Chuck Magich, CRNA, MS
University of Maryland Medical Center
R Adams Cowley Shock Trauma Center
Baltimore, MD
October 2013
Many pics from trauma to keep your interest, not necessarily related to MH.

2. Definition of MH
Inherited skeletal muscles disorder triggered in susceptible individuals when exposed to certain anesthetic agents resulting in:
hypermetabolism
skeletal muscle damage
hyperthermia
eventual death if untreated

3. Background 1962 1st MH case described (Denborough)
1979 Dantrolene FDA approved, greatly reduces mortality
1980’s susceptible swine prove to be most reliable animal models in study of MH
1990’s Focus on genetics to isolate responsible gene
2000 Properly treated, mortality still approx 10%
of 9 US testing centers close due to budget cuts
Rare condition but today still has a high mortality even when treated properly – can strike young healthy people and result in death.

4. Basic Physiology Actin & myosin filaments
slide across each other
causes muscle shortening & contraction.
Calcium controls muscle contraction:
Contraction: Calcium released (stored in sarcoplasmic reticulum).
Relaxation: calcium’s reuptake.

5. Pathophysiology Sustained muscle contraction Triggering agents (MH pt)
Calcium: Massive release + Reuptake blocked
Sustained muscle contraction
*Ryanodine Receptor = gatekeeper Calcium release & reuptake.*

6. Course of Events in MH Elevated Calcium Acidosis ATP depletion
Hallmarks of MH:
increased CO2 production
increased O2 consumption
Muscle contraction Heat Prod. (peripheral) Cellular death
All of our interventions aimed at treating either or both of theses problems.

7. Causes of MH
Ryanodine receptor (RYR1) mutations responsible for majority of MH cases.
However, as many as 30 (or more 80) different mutations may be responsible for MH = (inconsistent presentation).
A lot of these pics have nothing to do with MH but are purely for entertainment.

8. Mode of Transmission Autosomal dominant inheritance.
"Dominant" = only 1 mutated gene of a pair needed to posses trait.
Offspring of patient with MH have a 50% chance of inheriting the gene for MH.
Someone has a suspected episode, they need to be tested and blood relatives need to be made aware that they might also have the condition.

9. Incidence Adults 1:20,000-1:50,000 Children 1:15,000
After puberty, males affected > females : 1
Geographic patterns (states with highest incidence):
West Virginia
Michigan
Wisconsin
Nebraska
Higher incidence in children thought to be because that is there first exposure to anesthetics and this often unmasks an undiagnosed myopathy. Hopefully this would have been picked up on by adulthood, thus explaining the lower incidence in adults.

10. North American MH Registry
Mortality & Morbidity
North American MH Registry
291 MH cases ( )
8 cardiac arrests (2.7%)
4 died (1.4%)
Mean age = 20 y/o
Mortality higher in ambulatory setting (21%) compared to hospital cases (7%)
Limited resources / supplies in outpt setting.

11. Triggering Agents (Avoid These!!!)
All Halogenated inhalational agents:
Isoflurane
Sevoflurane
Desflurane
Halothane
Depolarizing Muscle Relaxant:
Succinlycholine (Anectine)

12. Non-Triggers (Safe to Use)
Nondepolarizing MR
Narcotics
Benzodiazepines
Propofol
Etomidate
Barbiturates
Ketamine
Local anesthetics
ester or amide
+/- vasoconstrictors
NMB reversals
Vasoactive drugs
Catecholamines
Amide (lido & marcaine), ester (tetracaine) – 2 “e”s in name.

13. Food For Thought… MH can occur anywhere triggers are given (ED, ICU).
MH can have delayed onset, usually presenting within 2* after triggers (PACU).
Only use triggers like succ when clearly indicated.
I have had 2 hyperkalemic arrest from succ in my14 year career.

14. Clinical Presentation
Unexplained tachycardia (earliest, most consistent sign, seen in 96% of cases)
Suddenly increased & rising ETCO2 (2-3X’s normal, despite adequate MV)
Muscle rigidity (75-80%)
Cyanosis (70%)
Hemodynamic instability (85%), BP initially then
Sometimes shown as step-like pattern where each breath it goes higher and higher.
Cyanosis from increased O2 consumption, unable to keep up with demand.
Given a drug to paralyze yet muscles remain contracted.
Cyanosis comes from inability to meet the high O2 demand, system is revved up.
5. Initial HTN stress response from excess CO2, then hypotension as patient becomes more acidotic.

15. Clinical Presentation
Less Common Signs:
Masseter muscle rigidity (50%)
Tachypnea
Rhabdomyolysis
PVC’s and VT
Exhausted CO2 absorber
Labs:
Ca, K, CPK, myoglobin, lactate
mixed venous O2 & pH
Marked temperature elevation
MMR or trismus, clenched jaws – will discuss later
Burning thru MR or trying to over-breath the vent if paralyzed
Tea or cola colored urine
2*to electrolyte abnormalities
Kitty litter changes to purple from absorbing all excess CO2 produced
Most accurate lab test to gauge resusc is mixed venous gas – shows total CO2 production prior to elimination by lungs, and shows increased O2 consumption despite what may seem like an adequate SaO2. High potassium (K) is the one that will kill the patient, causes lethal cardiac dysrhythmias.
If you wait to see this, u missed something!!! Even though the condition is called malignant hyperthermia this is a VERY LATE sign, though it is very specific if it is in fact present.

16. More About Temperature…
Hyperthermia is a late & inconsistent sign!!!
If present, very specific sign!
Skin temp doesn’t adequately reflect core temp.
Can rise 1* Celsius Q 5 mins, may reach 43*C (110*F).
Cold environments may mask temp rise (large field, cold room, CPB).

17. Temperature Monitoring
Sites in order of preference:
Pulmonary artery
Distal esophagus
Nasopharynx
Tympanic
Bladder
Axilla
Forehead skin
Ask SRNA’s if they know what standard is for temp monitoring.
Must monitor core temp on any GA lasting greater than 30mins
Why not monitor on every GA

18. Differential Diagnosis
Thyroid storm
Pheochromocytoma
Sepsis
Light anesthesia
Drug reaction
OD – cocaine, amphetamines, ecstasy
Neuroleptic Malignant Syndrome (NMS)
CO2 insufflation during laparoscopy
NMS will cover later
laparoscopic case can serve as a good drill for what you would see in MH…insufflate abdomen with CO2, ETCO2 rises, become tachycardic & hypertensive.

19. Clinical Management Discontinue triggers: Hyperventilate: Dantrolene:
Get HELP –STAT!
Get MH cart.
Inform surgeon stop surgery!
Hyperventilate:
3-4 x’s normal minute volume.
100% high flows.
via “clean” source – ambu bag.
Dantrolene:
2.5 mg/kg rapid IV push.
repeat Q 5-30 minutes.
shortcut: approx 1 mg/lb.
Refer to pocket reference cards I passed out earlier.
These 3 steps are what will save a patient, the rest is kind of fine tuning.
Not always possible to rapidly abort surgery (CABG on pump)
Clean source Ambu bag. Gases are dissolved in the circuit and the kitty litter so not gone as soon as we switch the vaporizer off and so and subsequent exposure to these gases can potentially make the crisis worse.
Will see in a few minutes how many vials needed in first round of treatment.

20. Management Multiple large bore IV’s (central line)
Foley (3-way): monitor urine + active cooling
A-line to monitor BP and serial lab draws.
Monitor core temp continuously.
Bicarb 1-2 mEq/kg given empirically.
Active core cooling measures:
gastric lavage
foley irrigation
ice packs
iced (or room temp) IVF
hypothermia blanket
cold irrigation of surgical field
Push fluids to prevent renal failure. Central line not immediate priority.
Don’t have to wait for ABG’s just give it empirically.

21. Management Treat dysrhythmias with usual ACLS drugs:
Ca Ch blockers absolutely contraindicated if Dantrolene given!
Dysrhythmias = tx acidosis + hyperkalemia.
Dysrhythmias = need more Dantrolene.
Treat hyperkalemia:
hyperventilation
bicarb
diuresis
dextrose + insulin(10 units regular insulin /50cc D50)
avoid parenteral potassium (LR)
Calcium chloride
Calcium channel blockers (Verapamil, Cardiazem) with Dantrolene maybe lethal.

22. Management D50 + insulin: Prevent myglobin induced renal failure:
provides quick acting energy substrate.
Prevent myglobin induced renal failure:
non-K IVF: (cold NSS 15 ml/kg Q15 min X3).
Mannitol / Lasix: keep U/O >2 ml/kg/hr.
Alkalinize urine w/Bicarb.
Watch for and treat DIC
Check coags.
Replace clotting factors (FFP, plts, cryo).
Call MH hotline:
1-800-MH-HYPER ( )
Use up all energy (ATP) cells begin to die
Diuretics after adequately hydrated
Stickers on each of phones in OR + PACU

23. Additional management points:
Treatment is labor intensive,
need lots of help fast!
Objective of cooling:
decrease O2 consumption
CO2 production
Core cooling superior to surface cooling.
Titrate Dantrolene and Bicarb: HR
temp
PaCO2 (ETCO2)
Just like in this pic, need a lot of help and fast. Doesn’t have to be only anesthesia help, can be PACU or OR nurses, ICU nurses in the middle of the night – mixing Dantrolene is labor intensive and takes a lot of people.

24. Post MH Complications DIC: results from cell destruction + death
Renal failure: myoglobin induced
Recrudescence:
24-36 hour window
occurs in 25% of all MH cases
Tissue thromboplastin released which sets off DIC cascade.
Myoglobin from muscle breakdown gets clogged up in kidneys causing them to shutdown.
Reemerge.

25. Follow-up ICU monitoring X 24-36*.
Dantrolene 1mg/kg IV Q4-6hrs x 24-36*.
Next oral Dantrolene X3 days.
Dantrolene continued 2* to recrudescence.
Register patient:
North American MH Registry:
Counsel patient &family:
Potential for MH in other family members.
Refer for testing.

26. Dantrolene Sodium Decreases muscle tone & metabolism.
Prevents Ca ion release + increases % bound Ca.
Direct–acting skeletal muscle relaxant.
Doesn’t neuromuscular junction (NMB’s).

27. Dantrolene Packaged 20 mg per vial: Warming medication /sterile water:
Reconstitute: 60 ml sterile water (injection).
Shake vigorously until clear.
Each vial contains 3 gms Mannitol:
increases solubility of drug.
Warming medication /sterile water:
Helps dissolve drug.
Dose 2.5 mg/kg rapid IV push,
Repeat Q5-30 mins (HR, ETCO2, temp).
Total dose usually <10 mg/kg (4 rounds).
One year supply costs approx $2,400
Important slide
Sterile H2O not saline (from IV bags for infusion, not for irrigation).

28. Dosing: Effective does directly related to:
Individuals degree of susceptibility.
Amount & time of exposure to triggers.
Time elapsed between onset of crisis & start of Dantrolene.
Example: Initial dose for 75 kg patient:
75kg x 2.5mg/kg = 188mg
188mg / 20mg per vial= 9 vials first 5 minutes of crisis!
Weight in lbs divided by 20.

29. Prevention…food for thought:
1/2 all MH episodes proceeded by uneventful anesthetics!
Succinlycholine only on indication:
RSI, difficult airway, full stomach, laryngospasm.
Increased suspicion with history:
muscle cramps, heat stroke, caffeine sensitivity.
Blood relatives of MH patient should be considered MH susceptible, unless tested & negative.
MH patients should carry some form of ID
Med Alert bracelet, wallet card, etc.
That is the meat & potatoes of the talk…rest is the “nice to know” stuff
Inconsistent presentation because of multiple (rather than just one simple) gene mutation.
Even though asking screening questions doesn’t mean we are out of the woods, we are still obligated to ask them.

30. Screening Best way to prevent MH: detection prior to anesthesia.
Ask pointed questions:
Family /personal history:
MH / anesthetic problems?
Muscular / neuromuscular disorders?
Family history:
Unexpected deaths under anesthesia?
Personal history:
Dark /tea colored urine after surgery?
High fevers after anesthesia?
We tend to ask general questions “any problems” that don’t give us the answers we are seeking.

31. Planning: Training of OR + PACU personnel.
Periodic dry-runs of MH crisis.
Monitor core temp on any GA.
No reported deaths from MH in previously diagnosed MH-susceptible patients when:
Anesthesia team was aware of the problem.
Appropriate precautions taken.
Going to see examples of what happens when appropriate precautions are not taken. Your going to see some examples of what happens when the appropriate precautions weren’t taken.

32. Planning:
Have a plan.
Portable MH cart / kit available anywhere general anesthetics administered.
Minimum: 36 vials of Dantrolene
4 rounds average sized patient

33. Management of the MH Susceptible Patient (MHS)
1st case of day.
MH cart readily available & Dantrolene not expired.
Continuous monitoring: HR, ETCO2 + temp.
Prep gas machine:
Remove vaporizers & change soda lime.
Flush system with 10 lpm O2 via circuit X 20minutes (using disposable bag on end of circuit).
Replace with clean circuit & soda lime after flushing.
Don’t just tape vaporizers off, may be a small leak in the system that allows trace amount of gas into the circuit which can harm the patient.

34. MH Susceptible Dantrolene pretreatment no longer routine.
+/- if documented fulminant episode.
Well planned non-trigger anesthetic more advantageous than prophylactic Dantrolene.
Nontrigger technique, 3 options:
TIVA (G/A).
Regional (spinal / epidural).
Local + sedation.
Minimum 2.5 hour PACU.
Can cause significant muscle weakness, don’t want to mask MH or delay its onset if it is going to happen, don’t want to use up drug on pretx then not have enough to tx crisis.

35. Conditions Associated with MH
Central Core disease
Duchene’s muscular dystrophy
Becker’s or other forms of muscular dystrophy
Schwartz-Jampel syndrome
King-Denborough syndrome
Myotonia Congenita
Neuroleptic Malignant Syndrome
*Patients with any of the above should not receive triggering agents!!!

36. Medical-Legal Issues Common themes from MH litigation:
Failure to obtain a thorough personal history.
Failure to monitor temperature.
Failure to have adequate supplies of Dantrolene & management plan.
Failure to investigate increased temp, increased skeletal muscle tone when associated with tachycardia and dysrhythmias.

37. 1996 Death from MH 16 year old female 4 hour TMJ surgery
Temperature was not monitored during the case
Precipitous rise in ETCO2 at end of case
Dysrhythmias and cardiac arrest
Temp noted to be >106*F
Dantrolene 10 mg/kg
Died 2 days later from DIC

38. Testing
The caffeine halothane contracture test (CHCT) is the gold standard of MH diagnosis.
CHCT:
Small piece skeletal (thigh) muscle obtained (local anes).
Muscle exposed to:
caffeine & halothane separately.
Rate & force of muscle contraction recorded electronically.
MH susceptible muscle more sensitive & contracts with greater sustained force than normal muscle.
Shakes after too much coffee? Caffeine activates same mechanism seen in MH – Ca is locked out and causes involuntary skeletal muscle contractions.

39. CHCT
Top graph: positive for MH, showing muscle contraction after exposure to 3% Halothane.
Normal muscle (bottom).
MH + have exaggerated response to caffeine.
Cost approx $6,000-10,000.
CK not a reliable test.
Sensitivity 100% (false negative rare)
Specificity 80% (20% false positive)

40. CHCT Sites USA: USUHS-Bethesda, MD UC-Davis, CA
University Minnesota, Minneapolis
Wake Forest-Winston-Salem, NC
Canada:
Ottawa, Ontario
Toronto, Ontario

41. Genetic testing Blood test for genetic markers.
Less expensive $800-$4,000.
Insurance may not cover.
Less invasive.
Sensitivity 25-30% since only a few of the known mutations have been isolated.
Very specific if positive for one of the known mutations.
Only 2 centers in US:
Pittsburg, PA
Marshfield, WI
Patient has an MH episode and gets CHCT which is positive. Can then have genetic testing and if marker is identified, offspring of that patient can undergo genetic testing instead of CHCT to see if they also possess the mutation.
Many false negative (bad), no false positives.
Downfall of genetic testing is that it is only able to detect a handful of the possible mutations responsible for causing this condition.
Most useful for family members of MH positive individual whose mutation can be isolated.

42. Kids & MMR Masseter muscle rigidity (MMR) / trismus:
Occurs after succinlycholine administration.
Forceful contraction of jaw musculature.
Prevents full mouth opening.
Extremities remain flaccid.
1% of children receiving succinlycholine develop MMR
50% of these have been shown to
be MHsusceptible by
muscle biopsy.
Most common in children
Special scenario.
Other causes: IV not in, didn’t wait long enough, not enough drug (worst thing is to give more).
When this happens red flags should go up, bells and whistles should go off in your head because there is a chance this kid is MH susceptible.

43. Kids & MMR Dantrolene need not be administered: MMR resolves promptly.
No other clinical signs of MH.
Clinical signs of MH occur in about 20%.
What to do next???
MMR with MH 3X’s more common in males.
MMR mostly in age ranges 4-12 y/o.
Describe how to proceed in elective (cancel) vs emergency (TIVA), & Dantrolene vs no Dantrolene.

44. Appendectomy in a 35kg, 10y/o – case study (Feb’92)
10:30 atropine 0.3mg, Fentanyl 50 mcg premed
10:40 Propofol 80 mg, Succ 40 mg – MMR, tachycardia, generalized rigidity
10:55 Isoflurane 2%, Propofol 20, Atracurium 10mg – persistent spasm and tachycardia
12:23 pH6.78, pCO2-158, pO2-414, BE-16, continued rigidity, HR180, Temp 38.4
13:05 pH6.88, pCO2-85, pO2-365, BE-20, temp 40.4, HR 220, cardiac arrest

45. Kids & Succ
Sudden cardiac arrest after succ in kids should be attributed to hyperkalemia & treated as such
40 cases since 1990
Mortality 50%
1993 FDA considered banning routine use of succ in kids

46. Sudden Cardiac Arrest in a Child – Case History
5y/o male, apparently healthy
8:00 mask induction with Halothane
8:05 Succinlycholine 40mg
Intubated with 5.0 ET – leak
Reintubated with #5.5
8:06 HR 130, then v-fib, then asystole (CPR, atropine, epi, lidocaine, bretylium, shock)
8:26 pH 6.81, pCO2 74, pO2 22, BE-21
11:15 dead despite 2+hour resuscitation
Autopsy:
Nectrotizing myopathy (gastroc)
CK >63,000
Myoglobin in kidney

47. Neuroleptic Malignant Syndrome
Very similar presentation as MH
Onset much slower (days to weeks)
Cause: typically antipsychotic & dopamine blockers: (Thorazine, Haldol, Inapsine, Reglan, Phenergan)
Problem is central in nature, MH is peripheral.
Management is drug withdrawal & symptomatic treatment.
Dantrolene can be considered.
NMS patients should not receive MH triggers

48. 1997 Death from MH 74 y/o male for AAA repair
Family hx of MH, confirmed by CHCT
Trigger agents used
MH episode at end of case
Treated with Dantrolene
Died 2 days post-op from DIC, renal failure and ischemic bowel
With all that we know, it still happens.

49. Resources
Malignant Hyperthermia Association of United States (MHAUS): PO Box East State Street Sherburne, NY MHAUS (non-emergency) MH-HYPER (emergency #)

50. Thanks for your attention!!!
Any questions?

51. References
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