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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