Chuck Magich, CRNA, MSUniversity of Maryland Medical CenterR Adams Cowley Shock Trauma Center

Baltimore, MDOctober 2013

Definition of MHInherited skeletal muscles disorder triggered in

susceptible individuals when exposed to certain anesthetic agents resulting in:

• hypermetabolism• skeletal muscle damage

• hyperthermia• eventual death if untreated

Background1962 1st MH case described

(Denborough)1979 Dantrolene FDA approved, greatly

reduces mortality1980’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.

PathophysiologyTriggering 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

Hallmarks of MH: 1.increased CO2 production 2.increased O2 consumption

Muscle contractionHeat Prod. (peripheral)Cellular death

Causes of MHRyanodine 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 TransmissionAutosomal 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.

IncidenceAdults 1:20,000-1:50,000Children 1:15,000 After puberty, males affected > females 1.5 : 1Geographic patterns (states with highest

incidence):West VirginiaMichigan WisconsinNebraska

Mortality & MorbidityNorth 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)N2ONondepolarizing

MRNarcoticsBenzodiazepinesPropofolEtomidateBarbiturates

KetamineLocal anesthetics

o ester or amideo +/-

vasoconstrictorsNMB reversalsVasoactive drugsCatecholamines

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. Unexplained

tachycardia (earliest, most consistent sign, seen in 96% of cases)

2. Suddenly increased & rising ETCO2 (2-3X’s normal, despite adequate MV)

3. Muscle rigidity (75-80%)

4. Cyanosis (70%)5. Hemodynamic

instability (85%), BP initially then

Clinical Presentation

Less Common Signs:6. Masseter muscle rigidity (50%)7. Tachypnea8. Rhabdomyolysis9. PVC’s and VT10. Exhausted CO2 absorber11. Labs:

Ca, K, CPK, myoglobin, lactate

mixed venous O2 & pH12. Marked temperature elevation

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).

Temperature MonitoringSites in order of

preference:1) Pulmonary artery2) Distal esophagus3) Nasopharynx4) Tympanic5) Bladder6) Axilla7) Forehead skin

Differential Diagnosis

1. Thyroid storm2. Pheochromocytoma3. Sepsis4. Light anesthesia5. Drug reaction6. OD – cocaine, amphetamines, ecstasy7. Neuroleptic Malignant Syndrome (NMS)8. CO2 insufflation during laparoscopy

Clinical Management1. 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.

Management4. Multiple large bore IV’s (central line)5. Foley (3-way): monitor urine + active

cooling6. A-line to monitor BP and serial lab draws.7. Monitor core temp continuously. 8. Bicarb 1-2 mEq/kg given empirically.9. 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: hyperventilation bicarb diuresis dextrose + insulin(10 units regular insulin /50cc

D50) avoid parenteral potassium (LR) Calcium chloride

Management12. 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: HRtemp PaCO2 (ETCO2)

Post MH Complications1. DIC: results from cell destruction +

death2. Renal failure: myoglobin induced3. Recrudescence:

24-36 hour windowoccurs in 25% of all MH cases

Follow-upICU 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).

DantrolenePackaged 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 = 188mg188mg / 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: • MH / anesthetic problems?• Muscular / neuromuscular disorders?

2. Family history:• Unexpected deaths under anesthesia?

3. 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:

1. 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.

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 MH1. Central Core disease

2. Duchene’s muscular dystrophy

3. Becker’s or other forms of muscular dystrophy

4. Schwartz-Jampel syndrome

5. King-Denborough syndrome

6. Myotonia Congenita

7. Neuroleptic Malignant Syndrome

*Patients with any of the above should not receive triggering agents!!!

Medical-Legal IssuesCommon 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 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

TestingThe 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 SitesUSA:1. USUHS-Bethesda,

MD2. UC-Davis, CA3. University

Minnesota, Minneapolis

4. Wake Forest-Winston-Salem, NC

Canada:1. Ottawa, Ontario2. Toronto, Ontario

Genetic testingBlood 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, PA2) 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 & SuccSudden cardiac

arrest after succ in kids should be attributed to hyperkalemia & treated as such

40 cases since 1990Mortality 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 SyndromeVery similar presentation as MHOnset 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 MH74 y/o male for AAA repairFamily hx of MH, confirmed by CHCTTrigger agents usedMH episode at end of caseTreated with DantroleneDied 2 days post-op from DIC, renal failure

and ischemic bowel

ResourcesMalignant Hyperthermia Association

of United States (MHAUS):

PO Box 106939 East State Street

Sherburne, NY 134601-800-98-MHAUS (non-

emergency)1-800-MH-HYPER (emergency #)

http://www.mhaus.org

Thanks for your attention!!!

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