malignant hyperthermia 2

8/9/2019 Malignant Hyperthermia 2

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MALIGNANTMALIGNANT

HYPERTHERMIAHYPERTHERMIA

Presenter: Dr Fadhli SuhaimiSupervisor: Dr Husaini


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What is it?What is it?

Malignant hyperthermia (MH) is apharmacogenetic hypermetabolicstate of skeletal muscle induced in

susceptible individuals byinhalational anesthetics and/orsuccinylcholine (and maybe by stressor exercise)

Pharmacogenetic? Gene + drug


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In order for this state to occur in an individual, thatindividual must have inherited the appropriateabnormal gene(s) AND then be exposed to inhalationalanesthetic agents and/or succinycholine ("triggeringagents" or "triggers")

Such an individual when not exposed to triggering agentswould not have MH, but rather would be said to bemalignant hyperthermia susceptible or MHS. Exposingan MHS individual to triggers makes MH a possible, butnot a certain, result.

We are unable today to predict which exposures totriggers of which MHS individuals will lead to MH.

Therefore, the safest policy is to always avoidtriggering agents in all MHS individuals .


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1960 : Denborough and Lovell first described"accelerated metabolism under anesthesia" in a21 year old male student undergoing generalanesthesia for repair of a leg fracture.Preoperative evaluation revealed that 10 family

members had died under ether anesthesia! Thepatient was assured that ether would not be usedduring his anesthetic, rather the new and "safer"inhalational agent, halothane, would be used.Fortunately, the patient did survive the resultingMH episode.

1960's : Additional cases in other families weredescribed.Porcine stress syndrome (PSS) found to be anexcellent model for human MH

1975 : dantrolene found to be effective in dealingwith PSS
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1979 : FDA approves dantrolene1980's : caffeine-halothane contracture

testing (CHCT) of biopsied muscledeveloped

(MH Association of the U.S.) formed1985 : Lopez et al : MH myoplasmic calciumlevels lowered by dantrolene

1990's : Genetic markers uncovered2005 : Molecular Genetic Diagnostic Testing

Available2008 : Beginning development of in-vivo

metabolic testing
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MH - Incidence/InheritanceMH - Incidence/Inheritance

Fulminant syndrome: 1 in 200,000anesthetics without succinylcholine vs1 in 60,000 anesthetics that include

succinylcholine. Note that the incidenceof fulminant MH can be reduced 3 to 4fold by avoiding the use of succinylcholine

Human malignant hyperthermia isinherited as an trait with variablepenetrance and expression


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In MHS pigs and in some MHS humans,the disorder seems to be due to aspecific mutation in the ryanodine

receptor (RYR or RYR1) gene, mappedto region q 12-13 of chromosome 19However, at least

29 other specific genetic defects in that g

and in other genes, (including one on17q ) cause MH in other human families.So, MH in humans is a heterogeneousgenetic disorder
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PHYSIOLOGY PHYSIOLOGY

Normal Excitation-ContractionPhysiologyWave of depolarization along motor nerve

causes release of acetylcholine (ACh)from nerve endingsACh traverses neuromuscular junction

(NMJ) and initiates depolarization of muscle cell membrane (sarcolemma)

Wave of depolarization proceedsinternally via transverse tubules (T-tubules) that abut the sarcoplasmicreticuluum (SR)


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SR releases calcium ions (Ca+) through acalcium release channel.Dihydropyridine receptors and

ryanodine receptors (RYRs) are locatedin the area where the T-tubule abutsthe SR and are near or major parts of the calcium release channel. The RYR, a

large protein molecule, is one of (if notthe) largest receptors in the body. RYRsare felt to play an important role intransfer of charge to and, especially,

release of Ca+ from the SR.


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Ca+ in the myoplasm combines withtroponin, releasing troponin's inhibitionof action-myosin interaction

Actin and myosin filaments are thus freeto slide past one another and musclecontraction takes place whileadenosine triphospate (ATP) is used

Subsequent re-uptake of Ca+ by the SR(also an energy-dependent process!)leads to muscle relaxation.


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PathophysiologicPathophysiologicExcitation-Contraction in MHExcitation-Contraction in MH

The abnormality in MH is in or near the SRcalcium release channel, in at least somefamilies involving an abnormal RYR. Thisabnormality leads to too much free

myoplasmic calciumThis calcium ion excess leads to excessive ATPbreakdown ATP depletion lactate production increased CO 2 productionincreased VO 2 myonecrosis andrhabdomyolysis with:

MyoglobinemiaMyoglobinuriaGeneralized stress response

Hyperkalemia


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The effect of the therapeutic agentdantrolene is to decrease the release of Ca+ from the SR and increase re-

uptake of Ca+ by the SR. Sincedantrolene has become available,mortality from MH has declined fromgreater than 50% to less than 10%.


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Clinical PresentationClinical Presentation

Malignant hyperthermia may occur in anMHS patient exposed to triggeringagents. So far, the only known triggers

are:desfluraneenfluranehalothane

isofluranesevoflurane

succinylcholine


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Clinical PresentationClinical Presentation

All other agents are "safe." Safe agentsinclude N 2 O, all intravenousanesthetics, all local anesthetics, and

all nondepolarizing muscle relaxants.


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Clinical PresentationClinical PresentationMalignant hyperthermia may present in a dramatic,

fulminant form or an insidious, relatively mild,"abortive" form

Early detection and prompt treatment are important inminimizing morbidity and mortality

Nonspecific indicators of increased metabolism areseen first. The following may represent the minimalgroup of clinical signs (in a patient not previouslyknown to be MHS) for which a trial of dantrolene isindicated:

tachycardia +tachypnea (or apparent "mechanical

hyper ventilation") +ETCO 2 increasing +metabolic acidosis


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Clinical PresentationClinical PresentationOther clinical events that may develop during an MH

episode:masseter muscle rigidity (MMR) (also referred to as

masseter muscle spasm, MMS)VO2 increasing, sometimes to 8-10 times normal

sweating, mottled and cyanotic skinfever (usually relatively late) perhaps to greater

than 105 degrees Fahrenheitmuscle rigidity (may be severe) of extremities or

entire bodyrhabdomyolysis (with myoglobinemia and

myoglobinuria)hyperkalemiaCardiac arrhythmias (PVC's, ventricular tachycardia

and fibrillation)renal failure , DIC
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Differential diagnisedDifferential diagnised

The differential diagnosis of unexplained increasing ETCO 2 includes hyperthermiaassociated with sepsis, iatrogenicwarming, faulty equipment (e.g., machine

valve malfunction), rebreathingHyperthermia, acidosis, rhabdomyolosis withmyoglobinura, arrhythmias and cardiacarrest may also be features of:cocaine toxicity

exertional heat strokehypoxic encephalopathy


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idiosyncratic drug reaction (e.g., MAOinhibitors and meperidine interaction)

neuroleptic malignant syndrome (NMS)pheochromocytomaserotonin syndromestatus epilepticusthyrotoxicosis

water soluble contrast agents in CSF


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No clinical syndrome is entirely specific formalignant hyperthermia. Increasing ETCO 2 despite apparent in creasing ventilation isvery suggestive of MH

If reasonable suspicion exists , especially inthe presence of an unexplained tachycardia,increasing ETCO 2 plus a moderately severecombined (respiratory and metabolic)acidosis: give dantrolene

A venous blood gas will usually be satisfactoy.Other confirmatory laboratory data wouldinclude elevated CPK, myoglobin, lactate, andpotassium.


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Management of an intraoperative episodeof MH

Initial measuresStop all possible all trigering agents100% O2: increase fresh gas flows and

hyperventilate at 2 -3 times minutevolume

Use a fresh breathing circuit and volatile

anaesthetic free anaesthetic machine if possible

Maintain anaesthesia with IV anaestheticagent and NDMB as needed


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Definite treatment: DANTROLENE


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Dantrolene (Dantrium) 3 mg/kg IV , then1 mg/kg IV Q10 minutes to effect(resolution of acidosis) and continue for 24to 72 hours

Dantrolene should be dissolved in sterilewater (60 ml water plus 20 mgdantrolene - takes 5-10 minutes todissolve). Should injected to large vein orfast running infusion

Each vial of Dantrium also contains 3 GmmannitolDantrolene has a T 1/2 of approximately 6 to 9

hours


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It causes no acute serious toxicity other thanmuscle weakness, although chronic use formonths may result in hepatotoxicity(Dantrolene has a nonspecific, nondiagnosticantipyretic effect.)

Reconsider diagnosis of MH if > 20 mg/kgdantrolene is not succesful

It causes no acute serious toxicity other thanmuscle weakness, although chronic use for

months may result in hepatotoxicity(Dantrolene has a nonspecific, nondiagnosticantipyretic effect.)


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cool the patient if necessaryplastic sheet filled with ice watericed normal saline in body orifices, cavities

and IVCold gastric lavage via NG tubeWithold use of heating devices, remove

garment, reduce OT temperatureconsider: A-line, CVP line, Foley, PACconsider: blood for CPK, K, lactate, blood

gases


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arrhythmias:treat hyperkalemiatreat acidosisprocainamide 15 mg/kg IV slow over 10

minuteslidocaine OK NOT calcium channel blockers (verapamil +

dantrolene has been reported to cause severehyperkalemia and myocardial depression) (

Durbin and Saltzman ).consider: sodium bicarbonate, furosemide,

insulin + glucose
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Management of renal function andcoagulopathy

Urine output > 1 2 mls/kg/hr with IV fluidand diuretic as guided by serial CVPmeasurement

Use NS instead of potassium containing IVfluid

Consider dose of mannitol of frusemide topromote diuresis

Blood product if needed


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ICU ManagementRecrudescence occurs in 25% of cases

need close monitoringAdminister further dose of dantrolene if

rigidity, rhabdomyolysis, elevatedtemperature, hypercarbia persistFuther dose dantrolene may necessary for

at least 24 hours (wacht for muscleweakness)

Patient may be extubated 8 12 hours laterif general condition is satisfactory


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Subsequent managementComplete and through documentation is

essentialInformed the patient and family member

regarding the disorderIf facilities available arrange for muscle biopsyfor the patient 3/12 after the episode.

If the diagnosis of MH-susceptibility is confirmedimmediate family member should be

investigated in the same mannerCounsel regarding future anaesthetics andencourage use of Medic Alert bracelet or anyother form warning


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The Caffeine-Halothane ContractureTest (CHCT)

the current "gold standard" test for MH.recently standardized in North Americathe usual biopsy site is the quadriceps muscle

(vastus lateralis or medialis)Because of the size of the biopsy (2 Grams), it

is recommended that patients weigh at least

20 kg. Most centers will not biopsy patients


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anesthesia for biopsyuse nontriggering agentsregional anesthesia often used (nerve

blocks or neuraxial block)avoid direct infiltration of muscle with local

anestheticdantrolene should be avoidedthe muscle tissue should be handled as

little as possible and not stretched


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the test should be performed within 5hours after the biopsy

costs approximately $6,000 - $10,000

(covered by most US health insurancecompanies) The muscle biopsy and the CHCT should

be performed at

centers with appropriate familiarity and e
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Molecular Genetic Diagnostic TestingNot a screening testAmong patients with postive CHCT , genetic test

sensitivity is 30-40%.Absence of mutation does not rule out MH

Referral for testing should be made only by physician orgenetic counselorBlood sample is all that is needed for testingDoes not replace the CHCT. Those without a mutation

on genetic test should be referred for CHCT todetermine MH susceptibility.

If a known MH mutation is found, other family memberswith that mutation are MH-susceptible for certain andmay bypass the CHCT
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Will presently detect only about 30% of those at risk.However, the genetic test is very specific -- that is,those with a positive test are virtually assured of being at risk for MH

In order to increase the sensitivity of the test, MHAUS

advises that only the following individuals beconsidered for the test:a.Those who have been tested positive by the

contracture test.b.Relatives of those who have been tested positive

by the contracture testc. Those who have been found to have a mutation

causative for MH under a research protocol.d.Relatives of those with a known mutation for MH.e.Those with a very high likelihood of having

experienced an MH episode.


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Cost to assess DNA for presence knownmutations is about $800 (partial test)to $4,000 (full gene sequencing). Costto assess a family member for onespecific mutation is about $200.

Testing centers: Marshfield, WI and Pittsburg
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The Malignant Hyperthermia Susceptible(MHS) Patient

A simple three-step safe plan is suggestedBe prepared to treat a full blown episode. Have

dantrolene available

Safe agents include thiopental, propofol, ketamine,narcotics, benzodiazepines, nondepolarizingmuscle relaxants

even outpatient surgery is acceptable, though somewould extend the postoperative monitoring periodto 2 to 4 hours.


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Myopathies Associated withMalignant Hyperthermia

Two myopathies are clearly associated withMH:

central core disease (CCD) multiminicore disease (MmD) .

Patients with these myopathies should betreated as malignant hyperthermiasusceptible.


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Central core diseaseCentral core disease

Disease characteristics.Central core disease (CCD) is characterized by muscle

weakness ranging from mild to severeMost affected individuals have mild disease with

symmetric proximal muscle weakness and variable

involvement of facial and neck muscles. The extraocular muscles are often sparedMotor development is usually delayed, but in general,

most affected individuals acquire independentambulation. Life span is usually normal

Severe disease is early in onset with profoundhypotonia often accompanied by poor fetalmovement, spinal deformities, hip dislocation, jointcontractures, poor suck, and respiratory insufficiencyrequiring assisted ventilatio

The outcome ranges from death in infancy to survival

beyond age five years. Typically the weakness inCCD is not progressive.


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Diagnosis/testing The diagnosis of CCD is based on clinical

findings of muscle weakness, the

histopathologic findings of characteristic cores on muscle biopsy,and molecular genetic testing

Most CCD is associated with mutations in

RYR1 , the gene encoding the ryanodinereceptor 1

Molecular genetic testing of RYR1 isavailable clinically.


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Management. Treatment of manifestations: physicaltherapy for hypotonia and weakness that mayinclude stretching and mild to moderate low-impact exercise; assistive devices as needed forambulation; orthopedic surgery as needed forscoliosis, congenital hip dislocation, footdeformities; respiratory support, breathingexercises, chest physiotherapy as needed; dietarysupplementation and nasogastric or gastrostomyfeeding as needed

Prevention of secondary complications: interventionas needed to prevent respiratory compromisefrom scoliosis; immunization against influenza;prompt treatment of respiratory infection; mobilityand physical therapy to prevent joint contractures.


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Masseter Muscle Rigidity (Spasm)(MMR, MMS)

MMR is part of a spectrum of responses tointravenous succinylcholine. Some slight,subclinical increase in masseter muscle tonemay be normal. Jaw stiffness that interferes with mouth openingfor direct laryngoscopy and orotrachealintubation occurs in about 2% of children.

This may include an unknown number at riskfor MH.

"True MMR" occurs when "jaws of steel" makemouth opening impossible. This is relativelyrare. In one series of children referred forbiospy, 50% proved to be MHS.


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Differential diagnosis of difficult mouthopening after succinylcholine

not enough timenot enough succinylcholine (use a

peripheral nerve stimulator to test forblock)

temporomandibular joint dysfunction (Couldpatient open mouth before induction?)

amyotonic myotonia


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malignant hyperthermia 2

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