MH & Dantrolene

Question 1

What area of the brain regulates temperature?

Answer 1

Hypothalamus

most improtant area for temp regulation

Gain center: posterior hypothalamus

Loss center: anterior hypothalamus

Question 2

For each 1 degree fahrenheit change, basal metabolic rate will change how much?

Answer 2

7%

Question 3

Routes of heat loss - in %

Answer 3

Radiation 40%

Convection 30%

Evaporation (burn pt)

Conduction

Question 4

MH incidence?

Answer 4

1:8,000 to 1:50,000 adults (depending on the source cited)

Higher in children

Question 5

How does someone get MH?

Answer 5

Genetic susceptibility;

autosomal dominant RYR mutations are common in MH patients

Question 6

MH pathophysiology (generalized)?

Answer 6

It is a syndrome

a chain of clinical responses to muscle hypermetabolism (“decoupling”; ATP needed for Ca release)

issue with innapropriate Ca^{<strong>++</strong>} release

Question 7

4 earliest signs of MH and other s/s?

Answer 7

4 earliest:

1. hypercarbia
2. tachycardia
3. tachypnea
4. masseter spasm

Other:

1. hyperthermia (inc 1-2°C every 5 min)
2. hypertension
3. dysrhythmias (r/t acid/base imbalance, hyperkalemia)
4. metabolic acidosis
5. hyperkalemia
6. myoblobinuria
7. hypoxemia
8. elevated CPK with rhabdo
9. coke-colored urine

**Most common to be noted 1^st in clinical practice - hyperthermia**

Question 8

What are triggers of MH?

Answer 8

Inhalational agents (probably excluding nitrous oxide)

Succinylcholine

Mild MH triggers: exercise in hot conditions, neuroleptic drugs (haldol, dopamine), alcohol, infections

Question 9

How does someone get tested for MH?

Answer 9

1 gram of muscle is tested with the halothane -caffeine contracture test

Question 10

How does dantrolene work?

Answer 10

Reduces muscle tone and metabolism

Prevents ongoing release of Ca⁺⁺ from muscle (SR)

Blocks external entry of Ca⁺⁺ into sarcoplasm

**Stabilizes calcium induced calcium release and stabilizes the negative feedback**

Question 11

dantrolene

Side effects

Answer 11

Significant muscle weakness

• can last long → ICU for 36h

Phlebitis - especially through peripheral IV

• watch it

Question 12

Dantrolene interaction?

Answer 12

CCB will cause life thretening hyperkalemia and myocardial depression

Question 13

You want the place you work to have how much dantrolene?

Answer 13

36 vials

Also lots of sterile water to mix with

Question 14

Sequence of events the second you realize your patient has MH

Answer 14

Call for help

get MH cart

D/C volatile agent, sux

Change circuit and soda, use highest flow possible of O2 through the machine or ideally change to new dedicated MH safe machine

hyperventilate 100% oxygen and switch to TIVA

Dantrolene

Tx acidosis with sodium bicarb

• Monitor with capnography & q 15 minute ABG

Monitor core temperature & Cooling to 38°C

Maintain urine output with diuretics and fluids (NOT LR)

• U/O >2 ml/kg/hr

Tx dysrhythmias

• give lidocaine or procainamide 15mg/kg IV (NOT CCB)

Tx hyperkalemia

• 1mL/kg D₅₀ glucose and 0.15 units/kg regular insulin
• calcium chloride 5-10 mg/kg IV

Continue dantrolene sodium for at least 72 hours after control of episode (≈1 mg/kg q 6 hours)

Question 15

Dantrolene dose?

Answer 15

Bolus 2.5 mg/kg

Then maintenance dose 2 mg/kg IV q5min up to 10 mg/kg

Then 1 mg/kg q6h for 72h

Each vial of dantrole contains 20 mg dantrolene and 3g mannitol; needs to be diluted with 60 mL sterile water

Question 16

What lab tests do you want to get for someone having an MH episode?

Answer 16

ABG CK myoglobin Electrolytes thyroid

LDH PT/PTT fibrinogen FSP CBC

lactic acid Urine for myoglobin/hemoglobin

Question 17

What muscle diseases are definitely associated with MH (predispose MH reactions)

Answer 17

• Central core disease
• King-Denborough syndrome
• Evan’s myopathy

Direct association with muscle dystrophy is not likely

• however, can still develop rhabdomylosis & hyperkalemia without hypermetabolic issues so avoid triggering agents anyway

Question 18

Neuroleptic malignant syndrome presentation?

Answer 18

Mimics MH

Presents with muscle rigidity, fever (cardinal sign), autonomic instability, delirium & cognitive changes, elevated CPK

relieved by NMB (as opposed to MH)

pt population at risk: those on antipsychotics (haldol, prolixin, thorazine)

Question 19

What is the presentation of occult myopathy in young males having surgery?

Answer 19

Mimics MH

Sudden cardiac arrest, especially soon after use of sux,

muscle rigidity

hyperkalemia

Question 20

How does basal metabolic rate (oxidative metabolic consumption) chnage in regards to change in °C?

Answer 20

1°C = 11.2% change in BMR

Question 21

Radiation

Answer 21

Electromagnetic waves that directly transport ENERGY through space

50% of heat loss

Question 22

Convection

Answer 22

Transfer of heat from one place to another by the actual movement of fluids (warmed matter, either liquids or gases)

Heat transfer in a gas or liquid by the circulation of currents from one region to another

30% heat loss

Question 23

Evaporation

Answer 23

In a liquid the particles have a range of energies. At the surface of the liquid some particles will have enough energy to escape from the liquid and overcome the attraction of the other liquid particles. This leaves the less energetic particles still in the liquid and so the liquid is cooler.

H2O is transferred from the surface to the atmosphere, the process by which water changes from a liquid to a gas

Question 24

How do burn patients lose most H₂O?

Answer 24

Through evaporation

Question 25

Conduction

Answer 25

Is the movement of thermal energy through a material without the particles in the material moving. Transfer of energy through matter from particle to particle

Question 26

MH mutations

Answer 26

Ryanodine receptor 1 (**RYR-1**) - on **chromosome 19** **CACNA1S** gene - provides instructions for making calcium channels - on **chromosome 1** **STAC3 gene** - protein encoded by this gene is a component of the excitation-contraction coupling machinery of muscles- on **chromosome 12**

Question 27

MH pathophysiology - cascade of events

Answer 27

1. membrane depolarization 2. Ca⁺⁺ release 3. failure of negative feedback (that would otherwise decrease subsequant Ca⁺⁺ release) 4. increased myoplasmic Ca⁺⁺ release 5. hypoxemia and cell death and other events ## Footnote Lots of ATP needed and used up for Ca++ release, reuptake into SR, and troponin “decoupling” (hypermetabolism) Aerobic metabolism replaces ATP with heat and CO2 → lactic acidosis Excess Ca⁺⁺​ also signals cell death Myoglobin released causes rhabdo, hyperkalemia When ATP is depleted = CV collapse

Question 28

what is the key event in MH pathophysiology

Answer 28

uncontrolled myoplasmic Ca⁺⁺ release

Question 29

how does Succinylcholine trigger MH?

Answer 29

succinylcholine acts **indirectly** by activating the nicotinergic acetylcholine receptor (nAChR), a nonspecific cation channel, resulting in continuous local depolarization The depolarization can trigger propagated action potentials and will further activate the dihydropyridine receptors (DHPR, CaV1.1) this leads to the gating of both Ca⁺⁺ release from the SR via RyR1 and L-type Ca⁺⁺ current from the extracellular space

Question 30

how do inhalational agents trigger MH?

Answer 30

inhalational agents **dirrectly on RYR1** they stimulate Ca⁺⁺ release via RYR1

Question 31

MH treatment besides Dantrolene

Answer 31

Fluids and Mannitol - kidney protection Oxygen PPV & hyperventialtion - to remove CO₂ Bicarb (HCO₃) - for acidosis Insulin & Glucose, Calcium - hyperkalemia Ice packs AVOID Ca⁺⁺ channel blockers in dysrhythmias

Question 32

What other conditions might look like MH?

Answer 32

Neuroleptic Malignant Syndrome Light Anesthesia Pain Thyroid storm (Hyperthyroid) Pheochromocytoma (esp if doing a bowel resection) occult myopathy

Question 33

Isolated Trismus

Answer 33

May be early sign usually can still open the mouth for airway instrumentation Stiff jaw but still can open –need to get airway secured incase something happens Don't cancel the case, but be extra vigilent

Question 34

Masseter muscle rigidity (MMR)

Answer 34

sustained contracture of the jaw muscles following succinylcholine disallowing mouth opening → may be a forewarning of MH * A mild ↑ in masseter muscle tone following succinylcholine with limb flaccidity may be a normal response * **Immediately check K⁺ & ABG** * Clinical signs of MH occur in about 20% of cases of MMR Not possible to determine, clinically, whether that ↑ in tone represents an MH reaction or not If generalized rigidity also occurs → then MH is highly likely

Question 35

CPK levels in MH

Answer 35

↑ \>20,000 During episode - Very high, up to 100,000 May be elevated up to 2 weeks after the event Elevation correlates * Best with rhabdomyolysis * Less well with fever & acidosis

Question 36

Rapid rhabdomyolysis vs. slow rhabdomyolysis

Answer 36

Rapidly developing rhabdomyolysis includes rapid ↑ in K+ → leading to dysrhythmias Slowly developing rhabdomyolysis is safer → K+ is redistributed before blood levels can ↑

Question 37

Myoglobinuria in MH

Answer 37

Myoglobin "leaked" from damaged cells → urine may occur within a few hours should be anticipated & treated to prevent acute tubular necrosis * Mannitol, diuresis, & ↑ fluids

Question 38

Acidosis in MH

Answer 38

High lactate & acidosis with very low pH * may be \<7 Cardiac contractility falls at low pH * the response to NE and epi are GREATLY reduced

Question 39

MH Compensatory mechanisms

Answer 39

Heat loss * Sweating * Cutaneous vasodilatation Sympathetic hyperactivity: * ↑ circulating catecholamines * ↑ HR, ↑ SVR, ↑ CO * Cutaneous vasoconstriction ↑ ventilation * as the CO₂ increases, minute ventilation goes up * may be masked by fentanyl

Question 40

Dantrolene class & MOA

Answer 40

postsynaptic muscle relaxant antagonizes ryanodine receptors inhibits Ca2+ ions release from sarcoplasmic reticulum → depresses excitation-contraction coupling in skeletal muscle

Question 41

how much Dantrolene should you have in the cart

Answer 41

36 vials (720 mg) sufficient for a 70-kg person each vial = 20 mg Needed if succinylcholine is available for resuscitation even if it's a facility in which volatile anesthetics are not used

Question 42

Dantrolene E½t Redosing

Answer 42

E½t 10-15h Redosing Q 6hrs

Question 43

Dantrolene and NMB

Answer 43

Dantrolene **does not** significantly potentiate effects of nondepolarizing relaxants or interfere with reversal of muscle relaxants May cause significant muscle weakness in patients with pre-existing muscle disease (MS, MD ect.) * still **give** with extreme caution

Question 44

what sould Dantrolene be mixed with?

Answer 44

Sterile water (without bacteriostatic agent)

Question 45

Drugs needed in the MH cart/kit

Answer 45

1. Dantrolene 36 vials 2. Sterile water to reconstitute dantrolene: 1,000 ml x 2 3. Sodium bicarbonate (8.4%): 50 ml x 5 4. Furosemide: 40 mg/amp x 4 ampules 5. D₅₀: 50 ml vials x 2 6. CaCl (10%): 20 ml vial x 2 7. Regular insulin: 100 units/ml x 1 (refrigerated) 8. Lidocaine HCl (2%): 1 box = 2 grams or 10 ml/100 mg preloaded vial

Question 46

general equipment needed in the MH cart/kit

Answer 46

1. Syringes (60 ml x 5) to dilute dantrolene 2. Mini-spike® IV additive pins x 2 & Multi-Ad fluid transfer sets x 2 (to reconstitute dantrolene) 3. Angiocaths: (4 ea.) (for IV access and arterial line – need to start an artline and more IVs) 4. 20G, 2-inch; 22G, 1-inch; 24G, ¾-inch 5. D5W 250 ml x 1 6. Micro Drip IV set x 1 7. NG tubes (Size appropriate for patient population) 8. Irrigation tray with piston syringe (x1) for NG irrigation 9. Toomey irrigation syringes (60 ml x 2) for NG irrigation

Question 47

MH monitor equipment

Answer 47

1. Esophageal or other core temperature probes 2. CVP kits: size appropriate to patient population 3. Transducer kits for arterial & central venous cannulation

Question 48

MH kit - other supplies needed

Answer 48

1. Large sterile Steri-Drape (for rapid drape of wound) – you may need to start CPR 2. Three-way irrigating foley catheters → size appropriate for patient population 3. Urine meter x 1 4. Irrigation tray with piston syringe 5. Rectal tubes [Sizes (Malecot Drain) 14F, 16F, 32F, 34F] 6. Large clear plastic bags for ice x 4 7. Small plastic bags for ice x 4 8. Bucket for ice

Question 49

How is the Anesthesia Machine Prepared for MHS Patients?

Answer 49

1. Ensure anesthetic vaporizers disabled by removing them from the machine 2. Change CO2 absorbent (soda lime/baralyme) 3. Flow 10 L/m O2 though circuit via ventilator for the amount of time specified by machine manufacturer (20-100 minutes) 4. During this time a disposable unused breathing bag should be attached to the Y-piece of the circle system & the ventilator set to inflate the bag periodically 5. Use new or disposable breathing circuit

Question 50

Pre-treatement with Dantrolene

Answer 50

Prophylaxis treatment is not recommended

Question 51

patient susceptible to MH - uneventful surgery

Answer 51

may be discharged on the day of surgery Minimum of 4 hours observation is strongly suggested

Question 52

MH - laryngospasm treatment

Answer 52

rocuronium positive pressure propofol

Question 53

Occult Myopathy therapy

Answer 53

Therapy should be directed at treatment of hyperkalemia: * Calcium chloride * Bicarbonate * Insulin * Glucose * Hyperventilation * Dialysis & cardiopulmonary bypass may be required