Malignant Hyperthermia

What occurs after depolarization that causes MH to occur?

When does rigidity occur in MH?

when unbound Ca reaches contractile threshold

What causes the fever and acidosis associated with MH?

• Oxidative phosphorylation (synthesis of ATP - aerobic metabolism)

• But, excess Ca is absorbed into mitochondria ⇢causes toxic concentrations that uncouples oxidative phosphorylation from electron transport chain ⇢leading to decreased ATP production

• This causes lactate acid and heat production

• anaerobic metabolism accelerated O2 consumption and heat

Once ATP is depleted, what occurs?

the pumping systems fail, so ions/molecules follow their concentration gradients, and cell death can occur

When ATP pumps fail, what moves in and out of the cell and what are some results?

• Movement into cells:

  • Na⁺ with H₂O - swelling

  • Ca²⁺ - worsening the intracellular derangement

• Movement out of cells:

  • K⁺

  • Phosphorylase

  • Magnesium

  • Later: Enzymes and myoglobin

    • Obstructs renal tubules ®ARF

• Cell death

Initial heat production probably is due to increased _____________, and later it is due to___________ production

aerobic metabolism; lactate (anaerobic)

what is Tismus Masseter Spasm or Masseter Muscle Rigidity (MMR)?

a condition that occurs most often with succs or in children after inhalation induction

• normally pathologic, but may be benign bc it does occur in non-MHS people

What will a peripheral nerve stimulator show if it is Masseter Muscle Rigidity?

flaccid paralysis (usually)

What are differential diagnoses for Masseter Muscle Rigidity?

• Myotonic syndrome

• TMJ

• Underdosing of SCh (in true MMR, repeat succs will not relieve issue)

• Not allowing sufficient time for SCh to work prior to intubation

Treatment options for MMR?

• cancel elective surgeries and treat s/s

• in a hospital, you can d/c triggers, treat s/s, and consider dantrolene (should NOT be done in surgery centers or where ICU is not available)

Which labs should be checked if MMR occurs?

• Obtain creatine kinase levels at 6, 12 and 24 hrs after episode

  • Levels >20,000 IU → MH is more likely cause

• Check myoglobin

  • Serum (>170 mcg/L)

  • Urine (>60 mcg/L)

Early signs of MH

hypercarbia, MMR, tachycardia, and fever(fever use to be a later sign, but is now considered an early sign)

Why does hypercarbia occur in MH?

the increased metabolism increases O2 consumption and CO2 production resulting in metabolic acidosis (can lead to tissue hypoxia- increases temp and potassium)

What is a good sign of MH that anesthesia can monitor for?

increase in EtCO2 that is resistant to changes in MV (any unexplained rise in CO2 should be investigated)

What is often the first recognized sing of MH?

tachycardia

Other signs of MH

• HTN

• Hyperkalemia (>6)

• cyanosis

What is the clinical hallmark sign of MH

fever (can climb 1-2C per 5 mins)

How does succs influence muscle rigidity from MH?

• Will make rigidity occur faster

• Repeat doses will worsen the stiffness

What does muscle rigidity eventually cause?

• Rhabdomyolysis / Myoglobin release ®ARF

  • Monitor for compartment syndrome

  • Cases exist that this was only sign (postop)

• K⁺ release ®cardiac arrest

• CK release

How does MH effect the pulm system

• Acidosis and hypoxemia

• Tachypnea due to acidosis

• Pulmonary edema can result with overzealous fluid administration

how does MH effect the renal system

• Low output (oliguria, anuria) secondary to shock

• Myoglobinuria will block renal tubules ®ARF

• ARF is a problem with hyperkalemia

How does MH effect the CNS

• Extreme: coma, areflexia, unresponsiveness

• ­ICP due to systemic manifestation i.e. ­temp, acidosis, ­K⁺, hypoxia, cell membrane dysfunction

How can MH impair coagulation?

• DIC due to release of tissue thromboplastin during high temp, acidosis, hypoxia, and hypoperfusion

• Impaired coag associated with hemolysis, marked decrease in platelets, fibrinogen, and factor VIII

How can MH result in mortality?

• Ventricular arrhythmias (hyperkalemia)

• Acute pulmonary edema

• Brain death (edema, temp, acidosis)

• Acute DIC

• ARF

Differential diagnoses from MH

• Neuroleptic Malignant Syndrome (NMS)

• Hyperkalemic cardiac arrest

  • Sudden unexpected cardiac arrest, exposed tocertain meds (mainly succs), assume Hyperkalemia

• Pheochromocytoma (­HR, HTN and fever, but lacks the metabolic changes / response)

• Thyroid storm (lacks acid-base abnormality)

• Elevated ETCO₂

  • Lap cases, faulty humidifier or CO₂ exhausted

• Septicemia - fevers

• Blood product reactions

• Light anesthesia

• Cocaine or other drug toxicity

• Seizure disorder

• CNS bleed

s/s of neuroleptic malignant syndrome

• Fever, tachycardia, HTN, rhabdomyolysis, tachypnea, diaphoresis, muscle rigidity and acidosis (extrapyramidal effects, pulmonary congestion, dyspnea, stupor, LOC)

• Mortality is about 20%

Which drugs are associaated with NMS?

• Virtually all classes of drugs (in therapeutic range) that induce dopamine-2 receptor blockade have been associated with NMS

  • Haloperidol, phenothiazines, butyrophenones, lithium, and MAO inhibitors

  • Antiemetics (prochlorperazine), pro-peristaltic agents (metoclopramide), anesthetics (droperidol), and sedatives (promethazine)

• Sudden withdrawal from meds treating Parkinson’s also may trigger NMS

treatment for NMS

• Bromocriptine, amantadine (dopamine agonists)

• Benzodiazepines and dantrolene

How does NMS compare to MH

• NMS has slow onset / patient need not be MH susceptible 

  • MH is acute

• NMS is not inherited (problem with drugs affecting the brain)

  • MH is inherited (problem with skeletal muscle receptors & Ca control)

• Can relax patient with NDMR

  • MH patients may have break-through rigidity

Who is most at risk for developing hyperkalemic cardiac arrest post succs?

pts suffering from undiagnosed subclinical myopathy like muscular dystrophy (more common in boys under 10)

How do you treat cardiac arrest due to hyperkalemia?

• Rule out hypoxia and ventilatory problems first, then treat hyperkalemia:

  • CaCl₂, bicarb, insulin, glucose, hyperventilate

• Resuscitation may be prolonged and difficult

• This reaction is usually not MH

  • However, it is described on MH posters as cautionary

Which non-MH disease can result in life threatening hyperkalemia and rhabdo when triggering agents are given?

• Dystrophinopathies 

• Duchene’s and Becker muscular dystrophies

  • Genetic mutation is on X chromosome (MH is chromosome 19)

Diseases/conditions associated with or related to MH (Predisposing – from high to low)

• Central core disease (CCD) & MultiminiCore disease (MmD) with RYR1 mutation

  • Rare familial polymyopathyies characterized by hypotonia, delay in walking, muscle weakness

  • (core: bx is stained and a central area of muscle fiber doesn't stain)

• King-Denborough Syndrome (KDS)

• Periodic Paralysis

• History of unexplained fevers without diagnosis

• Previous episode of rhabdomyolysis without diagnosis

• History of dark-colored urine

• EHI / ER

Which gene mutations have been linked with MH?

• Chromosome 19- Ryanodine (RYR1)

  • over 50% of cases

• CACNA13

  • codes for DHP and is directly coupled with RYR1

  • CaV1.1

• STAC 3 (SH3)

What is CaV1.1?

AKA DHP Receptor that controls voltage gated Ca channel

What does a mutation of CaV1.1 cause?

causes a gain of function that makes RyR1 hypersensitive to caffeine and anesthetics in MHS causing excessive release of Ca into cytosol

Which MH gene mutation has been linked to Native american myopathy?

STAC3

WHat is the gold standard lab test for diagnosis of MH?

a muscle biopsy with Caffeine Halothane Contracture (CHCT) Test

How is a caffeine halothane contracture test performed?

A muscle biopsy is taken from the vastus lateralis muscle. The fiber are suspended in a Kreb’s solution. Halothane is bubbled through, caffeine and Ryanodine are added and contraction is measured

How accurate is the CHCT test?

97% sensitivity and 78% specific (false positives like 20% of the time with other myopathies that are not MH)

Indications for a CHCT test

• Patient with known MHS relative (tested positive by muscle biopsy)

• Patient with MHS relative (suspicious episode)

• Patient  with past suspected MH event

• Patient with severe MMR

• Patient with mild to moderate MMR + rhabdomyolysis

• Patient with unexplained rhabdomyolysis during or after surgery or with exercised-induced rhabdo

• Signs suggestive of MH, but not definitive

• If military service is desired, patients with suspicion of MHS are required to undergo CHCT

What test, other than CHCT, can be done for diagnosis of MH?

• creatinine kinase- must be elevated in 3 different occasion and is not specific to MH (>20,000 IU after MMR indicates an ~80% likelihood the patient will have positive contracture test, but CK is often higher if SCH was used)

• genetic testing- does not replace the muscle biopsy bc not all mutations are Id’d

How do you prepare dantrolene?

it comes as a lyophilized yellow/orange substance with 20 mg Dantrolene and 3000mg Mannitol/NaOH. it is reconstituted in 60 ml of sterile water w/o bacteriostatic agent. It can be warmed to 37-39C for faster mixing. shake for 20 secs or until solution is clear (20mg/60mL)

Dantrolene dosing

• Initial dose of 2.5 mg/kg and a total dose of 10 mg/kg

  • titrated to HR, PaCO2, and rigidity

  • if not subsided after 10-30 mg/kg, probs not MH

• Post-op: 1mg/kg IV q 6hrs for 24 hrs and PO for 24 hrs or more after

There is a new formulation of Dantrolene called Ryanodex, how does preparation of this formulation differ?

it is reconstituted with 5mL sterile water and is ready in 1 min (250mg/5mL = 50 mg/mL)

requires a LOT less vials and overall fluids than other preparations (3 bottles=35 bottles)

does not contain large doses of mannitol, like other preparations

Why can dantrolene not be reconstituted with NS?

it causes precipitate and results in a hypertonic solution (526mOsm/L) almost double what it is when reconstituted with sterile saline (261 mOsm/L)

MOA of Dantrolene

acts in the SR of skeletal muscle (little efefct on heart and smooth muscle) and acts by reducing Ca release by the SR or inhibiting excitation contractures at the transverse tubules

does NOT effect Ca reuptake, electrical activity, or rate of ACH synthesis

Cons of dantrolene

• Drowsiness, nausea, weakness

• Potentiates NDMR

• Placental transfer

  • Can cause fetal weakness

  • Also can cause uterine atony →bleeding

• can alter liver function when used long-term

What other conditions can dantrolene be used in?

• Management of spasticity resulting from upper motor neuron disorders:

  • MS, cerebral palsy, spinal cord injury, CVA

• Muscle breakdown from

  • Heat strokes, cocaine & MDMA (ecstasy)

If MH occurs, call for help… then what? (step 1 of the process)

• Discontinue triggers

• Hyperventilate – lower CO₂

• 100% O₂ high flow rates at > 10 L/m

• Place charcoal filters (replace each hour in crisis event)

• Halt surgery when possible and/or continue with non triggering agents

• Do not waste time changing circle system & absorbent

• Consider more vascular access

• Foley

• Switch to core temperature monitoring

What are the steps 1-7 on the Malignant Hyperthermia Card?

1-Callfor help, get dantrolene, notify surgeon, and call MH hotline

2- give dantrolene

3- Treat acidosis

4-cool the pt

5- dysrhythmias

6- hyperkalemia

7- follow

How should acidosis be treated (step 3)?

give 1-2 mEq/kg of bicarb until blood gas is available

How should pt be cooled (step 4)?

• cool to 38C (COOL, BUT DON”T OVERCOOL)

• give cool IV of Plyte or NS

• lavage open cavities with cool saline

• ice packs

• pharmacological cooling

• can use invasive techniques

If dysrhythmias occur (step 5), dantrolene should correct it, but if not uses standard drug therapies, but avoid the following drugs:

• Ca channel blockers- can worsen hyperkalemia and cause cardiac arrest in the presence of Dantrolene (do not withhold dantrolene if pts are on these drugs)

• lidocaine and procainamide- avoid if hyperkalemic can cause wide QRS

How to treat hyperkalemia (step 6)?

• Bicarb 1-2 mEq/kg

• Reg insulin 10 units with 50 mL of 50% dextrose – adults

• Reg insulin 0.1 units/kg with 2mL/kg of 25% dextrose – peds

• CaCl 10 mg/kg IV (Cal gluconate 10-50 mg/kg) - for life-threatening K

• Albuterol or B2 agonist nebulized can lower K

• Check glucose hourly

What steps are included in step 7: Follow?

• ETCO₂ & minute vent

• Blood work

  • ABGs, lytes, BG, CK

  • Venous gases may show hypermetabolism before arterial

  • Coags

  • DIC treatment

    • Heparin, FFP, PLT, and clotting factors

• Core temp

• Urine – amount and color and prevent rhabdomyolysis

  • Fluids greater than 2 mL/kg/hr

  • Diuretics

How long should pt be monitored post-op with MH attack?

at least 24 hrs (continue dantrolene for 24 hrs) and check CK q 6 hrs

Where should pts be referred after an event of MH?

MHAUS- have resources and counseling

call hotline and fill out a adverse metabolic or muskuloskeletal reaction to anesthesia form so it can be documented for pt anaonymously (even if they do not want the referral)

For pts with known MH, where can providers get a thorough history of the pt?

North American MH registry in Fl will have the pt database which contains:

• Adverse anesthetic events

• Family MH history

• Muscle biopsy result

• Subsequent anesthesia course

• Patient info can be anonymous (will need pt signed consent to receive info and must give th ept’s name, BD, and mom’s maiden name)

If a pt has known MH, how should anesthesia be given?

• Avoid triggers

• Monitoring and labs

  • Routine monitoring including temp

  • Labs: maybe ABGs with electrolytes / coags / CPK / myoglobin

  • Postop:  keep 4-6 hours before discharge

• Dantrolene should be accessible within ten minutes of the first signs of MH

  • Should have the capacity to administer at least 10 mg/kg of dantrolene in the event of an acute MH episode

• prepare AGM prior to surgery

How can the GAM be adjusted for an MH case?

• use a charcoal filter

• Physically disconnect vaporizers from the workstation

• Tape message over ones that cannot be removed

• Use a new, disposable breathing circuit

• Replace absorbent

• Follow AGM manufacturer recommendations for flushing

What anesthetic can be used for a muscle biopsy for suspected MH>?

• Adults: lateral femoral cutaneous nerve block

• Children:  GA with safe agents

How is a charcoal filter used?

• used to remove unwanted anesthetics from breathing circuit

• Setup: flush oxygen 10 L/m for 90 sec - then place filters

  • they are labeled insp and exp (do not switch them)

• Keep gas flow at least greater than 3 L/m during case

• Filters are good for up to 12 hours once placed – change q 12 hrs

• However, during a crisis change every hour

How much does a charcoal filter improve care?

• Without the activated charcoal filters it took

  • Took 55 min to reach less than 5 ppm of isoflurane

• With the activated charcoal filters

  • Inspired iso concentration was quickly less than 5 ppm

    • Charcoal filters: elective and during crisis

What can be done to the GAM if charcoal filters are not available?

• flush the workstation (may take 10-90mins

• during the case, FGF may need to be >10L/m to avoid rebound phenomenon

• use a dedicated vapor free machine (unusual to have spare machine)

• use an ICU vent that has never been exposed to volatile agents

What is rebound phenomenon?

increased release of residual volatile anesthetic agent when fresh gas flow is reduced after a set period of flushing