Chuck Magich, CRNA, MS
University of Maryland Medical Center
R Adams Cowley Shock Trauma Center
Baltimore, MD
October 2013
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
Background
 1962 1st MH case described (Denborough)
 1979 Dantrolene FDA approved, greatly
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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%
2002 5 of 9 US testing centers close due to
budget cuts
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.
Pathophysiology
Triggering agents (MH pt)
Calcium: Massive release + Reuptake blocked
Sustained muscle contraction
*Ryanodine Receptor = gatekeeper Calcium release &
reuptake.*
Course of Events in MH
Elevated Calcium
Acidosis
ATP depletion
Muscle contraction
Heat Prod. (peripheral)
Cellular death
Hallmarks of MH:
1. increased CO2 production
2. increased O2 consumption
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).
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.
Incidence
 Adults 1:20,000-1:50,000
 Children 1:15,000
 After puberty, males affected > females 1.5 : 1
 Geographic patterns (states with highest incidence):
 West Virginia
 Michigan
 Wisconsin
 Nebraska
Mortality & Morbidity
North American MH Registry
 291 MH cases (1987-2006)
 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%)
Triggering Agents
(Avoid These!!!)
 All Halogenated
inhalational agents:
 Isoflurane
 Sevoflurane
 Desflurane
 Halothane
 Depolarizing Muscle
Relaxant:
 Succinlycholine
(Anectine)
Non-Triggers (Safe to Use)
 N2O
 Ketamine
 Nondepolarizing MR
 Local anesthetics
 Narcotics
o ester or amide
 Benzodiazepines
o +/- vasoconstrictors
 Propofol
 NMB reversals
 Etomidate
 Vasoactive drugs
 Barbiturates
 Catecholamines
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.
Clinical Presentation
1.
2.
3.
4.
5.
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
Clinical Presentation
Less Common Signs:
6. Masseter muscle rigidity (50%)
7. Tachypnea
8. Rhabdomyolysis
9. PVC’s and VT
10. Exhausted CO2 absorber
11. Labs:


Ca, K, CPK, myoglobin, lactate
mixed venous O2 & pH
12. Marked temperature elevation
More About Temperature…


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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).
Temperature Monitoring
Sites in order of preference:
1) Pulmonary artery
2) Distal esophagus
3) Nasopharynx
4) Tympanic
5) Bladder
6) Axilla
7) Forehead skin
Differential Diagnosis
1.
2.
3.
4.
5.
6.
7.
8.
Thyroid storm
Pheochromocytoma
Sepsis
Light anesthesia
Drug reaction
OD – cocaine, amphetamines, ecstasy
Neuroleptic Malignant Syndrome (NMS)
CO2 insufflation during laparoscopy
1.
Clinical
Management
Discontinue triggers:
• Get HELP –STAT!
• Get MH cart.
• Inform surgeon stop surgery!
2.
Hyperventilate:
• 3-4 x’s normal minute volume.
• 100% O2 @ high flows.
• via “clean” source – ambu
bag.
3.
Dantrolene:
• 2.5 mg/kg rapid IV push.
• repeat Q 5-30 minutes.
• shortcut: approx 1 mg/lb.
Management
4.
5.
6.
7.
8.
9.
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
Management
10. Treat dysrhythmias with usual ACLS drugs:
 Ca Ch blockers absolutely contraindicated if
Dantrolene given!
 Dysrhythmias = tx acidosis + hyperkalemia.
 Dysrhythmias = need more Dantrolene.
11.
Treat hyperkalemia:


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
hyperventilation
bicarb
diuresis
dextrose + insulin(10 units regular insulin /50cc D50)
avoid parenteral potassium (LR)
Calcium chloride
Management
12. D50 + insulin:
• provides quick acting energy substrate.
13. 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.
13. Watch for and treat DIC
 Check coags.
 Replace clotting factors (FFP, plts, cryo).
14. Call MH hotline:
1-800-MH-HYPER (1-800-644-9737)
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)
Post MH Complications
1.
2.
3.
DIC: results from cell destruction + death
Renal failure: myoglobin induced
Recrudescence:
 24-36 hour window
 occurs in 25% of all MH cases
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: 1-800-986-4287.
 Counsel patient &family:
• Potential for MH in other family members.
• Refer for testing.
Dantrolene Sodium
Decreases muscle tone &
metabolism.
Prevents Ca ion release +
increases % bound Ca.
Direct–acting skeletal muscle
relaxant.
Doesn’t work @
neuromuscular junction
(NMB’s).
Dantrolene
 Packaged 20 mg per vial:
 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
Dosing:
Effective does directly related to:
1. Individuals degree of susceptibility.
2. Amount & time of exposure to triggers.
3. 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!
Prevention…food for thought:
 1/2 all MH episodes proceeded by 1 - 13 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.
Screening

Best way to prevent MH:
o detection prior to anesthesia.
 Ask pointed questions:
1. Family /personal history:
•
•
2.
Family history:
•
3.
MH / anesthetic problems?
Muscular / neuromuscular disorders?
Unexpected deaths under anesthesia?
Personal history:
•
•
Dark /tea colored urine after surgery?
High fevers after anesthesia?
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:
1. Anesthesia team was aware of the problem.
2. Appropriate precautions taken.
Planning:
 Have a plan.
 Portable MH cart / kit
available anywhere general
anesthetics administered.
 Minimum: 36 vials of
Dantrolene
• 4 rounds average sized
patient
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.
2. Flush system with 10 lpm O2 via circuit X 20minutes
(using disposable bag on end of circuit).
3. Replace with clean circuit & soda lime after flushing.
1.
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.
Conditions Associated with MH
1.
2.
3.
4.
5.
6.
7.
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!!!
Medical-Legal Issues
Common themes from MH litigation:
1) Failure to obtain a thorough personal history.
2) Failure to monitor temperature.
3) Failure to have adequate supplies of Dantrolene &
management plan.
4) Failure to investigate increased temp, increased
skeletal muscle tone when associated with
tachycardia and dysrhythmias.
1996 Death from MH
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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
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.
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.
CHCT Sites
USA:
1. USUHS-Bethesda, MD
2. UC-Davis, CA
3. University Minnesota,
Minneapolis
4. Wake Forest-WinstonSalem, NC
Canada:
1. Ottawa, Ontario
2. Toronto, Ontario
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:
1) Pittsburg, PA
2) Marshfield, WI
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.
Kids & MMR
•
•
•
•
•
Dantrolene need not be administered:
1. MMR resolves promptly.
2. 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.
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
Kids & Succ
 Sudden cardiac arrest
after succ in kids should
be attributed to
hyperkalemia & treated as
such
 40 cases since 1990
 Mortality 50%
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
•
•
•
•
•
•
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
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
Resources
Malignant Hyperthermia Association
of United States (MHAUS):
PO Box 1069
39 East State Street
Sherburne, NY 13460
1-800-98-MHAUS (non-emergency)
1-800-MH-HYPER (emergency #)
http://www.mhaus.org
Thanks for your attention!!!
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