Malignant Hyperthermia

Malignant Hyperthermia

Review and Case StudiesReview and Case StudiesHolly Price, CRNAHolly Price, CRNA

ObjectivesObjectives• Review of normal muscle physiology• Physiology impairment associated with Malignant

Hyperthermia• Treatment of Malignant Hyperthermia• Case Studies/Discussion

Structure and Organization of Skeletal Structure and Organization of Skeletal MuscleMuscle

Propagation of Muscle Contraction

Action Potential

Nicotinic Acetylcholine Receptor

Muscle Fiber AnatomyMuscle Fiber Anatomy

SarcomereSarcomere

Muscle Fiber AnatomyMuscle Fiber Anatomy

Cross Bridge Cycle = Muscle Cross Bridge Cycle = Muscle ContractionContraction

Calcium's involvement in muscle Calcium's involvement in muscle contractioncontraction

The cycle repeats as long as calcium is bound to Troponin C.

How does contraction stop? How does contraction stop? • Relaxation occurs when Calcium is reaccumulated by

the sarcoplasmic reticulum. When intracelluar Calcium is low, the crossbridge cycle can not occur.

• Ca is needed in every muscle type to function, smooth muscle, cardiac and skeletal muscle.

• In the neuromuscular junction, (synaptic space) acetylcholine is broken by acetylcholinesterase. The rapid removal prevents continued re-excitation after the muscle has recovered from its initial action potential.

What are the products of muscle What are the products of muscle contraction?contraction?

• Heat• Carbon

dioxide• Lactate

What is the dysfunction in What is the dysfunction in Malignant Hyperthermia?Malignant Hyperthermia?

TreatmentTreatment• Dantrolene Sodium—a hydantion

derivative is the drug of choice for reversing the symptoms of malignant hyperthermia.

• Vials contain 20mg and must be dissolved with at least 60ml of sterile preservative free water

• Treatment for acute MH is 2.5mg/kg as a rapid bolus, repeating at 5 minute intervals until symptoms are reversed.

• Manage associated symptoms

Where is the MH cart located?Where is the MH cart located?

Malignant HyperthermiaMalignant Hyperthermia• MH is an inherited skeletal muscle disorder.• Linked with the ryanodine receptor type I gene

(RYR1). • Susceptibility to MH is based on an altered release of

Calcium from the sarcoplasmic reticulum.• Patients may undergo multiple anesthetics before MH

is triggered.• Prevalence is between 1:5,000 to 1:100,000, the trend

is increasing in recent years.• MH can be triggered by emotional stress, heatstroke,

strenuous exercise and trauma.

Case Scenario: Increased End-Tidal Carbon Case Scenario: Increased End-Tidal Carbon DioxideDioxide

Case: 55 yo male was scheduled to have I & D of a large thigh abscess with general anesthesia.

Medical History: Admission to extensive substance abuse, including ETOH, tobacco, methamphetamines and cocaine. No reported history of anesthetic complications, no reported medications. No cardiac or pulmonary disease history.

Preop VS: Weight 77Kg, 189cm tall. BP 125/85, HR 85, temp 37.8 Tympanic membrane.


Anesthetic Regime:• 200mg Propofol, 50mg

Rocuronium. • 8.0 OETT, +Bilat BS,

mechanical ventilation started at 12min with TV 600ml.

• Sevo vaporizer on at 2.5%• 30 min after induction and

after the surgery began the ETCO2 was 35mmHg and ET Sevo at 2.2%.

• Over the next 30 minutes the ETCO2 increased from 35-45mmHg, accompanied by a slight increase in HR from 95-105/min.

• Nasopharyngeal temp was 38.9 C

• The ventilation was increased to RR 15/min, the ETCO2 continued to increase to 60mmHg over a 5 minute period. HR 110.


• ETCO2 continued to increase to 65mmHg despite an increase in minute Ve (TV 900, RR 20/min).

• The EKG showed sinus tachycardia with normal T waves.

• No muscle rigidity was observed.

• Urinary catheter placement urine was dark. Dipstick + for hgb or myoglobin.

ABG• pH: 7.13• PaCO2: 73mmHg• PaO2: 225mmHg• O2 sat: 99%• HCO3: 19mEq/L• K: 5.0mEq/L-ETCO2 was 67 at time of

draw.-CK 1200 IU/L

Differential Diagnosis of Increased ETCO2Differential Diagnosis of Increased ETCO2

Causes of increased ETCO2: Inadequate Excretion and Increased Production• Inadequate ventilation• Iatrogenic causes• Malfunction of monitor, calibration error or gas supply switch.• Anesthesia machine malfunction• Exhausted soda lime• Bronchospasm• Sepsis• Recent substance abuse• Surgical stress• Seizures• Hyperthyroidism• Burns• Neuroleptic malignant syndrome, Pheochromocytoma

Determining the cause.Determining the cause.1. Inspired CO2 was not observed on the capnograph.2. Ventilation pressures and breath sounds were normal.3. Inadequate anesthesia can increase metabolic production of CO2.

ET Sevo levels were 2.2%.4. Antibiotics were given (1Gm Ancef and 100mg Gent) for the

possibility of seeding into the blood.5. Recent history of substance abuse increases the likelihood of toxic

drug reactions.6. Physiologic response to surgical stress will cause an increase in

metabolism.7. Seizure activity, especially if there is marked tonic-clonic activity will

markedly increase CO2 production. 8. Rarer causes are undiagnosed hyperthyroidism or

pheochromocytoma, which can cause an increased metabolic rate.

Quickly determine the causeQuickly determine the cause• MH looks like the cause of the patients clinical

presentation, particularly because of the progressive increase of CO2.

• The treatment efficacy is dependant on timely initiation.

Intraoperative ManagementIntraoperative Management1. Sevo was discontinued, anesthesia was maintained

with remifentanil and propofol.2. Dantolene 2.5mg/kg was given over more than 15

minutes.3. Cooling measures were initiated—iced towels on the

torso. 4. Rapid administration of IVF to cool the patient and

prevent renal damage from rhabdomyolysis.

ResultsResults• Rapid resolution of hypercarbia (ETCO2 25mmHg)• Ventilation was decreased TV 700ml RR 8/min• Nasopharyngeal temp 37.4C• Serial blood tests: no hyperkalemia, CK peaked at 25,000IU w/in 24

hours

After the surgery was finished the patient was awakened and extubated.

Postop management: frequent monitoring of VS, urine, electrolytes and ABG help guide treatment. Any increases in K levels, worsening acidosis or resumption of hypermetabolism should be treated w/dantrolene. Coagulation can be impaired as a result of shock state, PT, PTT, INR and D-dimer should be monitored. The urine should be alkalized to help clear myoglobin that might have deposited in the renal tubules. CK must be monitored until values fall and serial serum electrolytes.

Differential Diagnosis of Differential Diagnosis of Malignant Hyperthermia: Case Malignant Hyperthermia: Case

Report. Report. Case: 17 year old, 71Kg male was admitted for an

arthroscopy and anterior cruciate ligament repair of the knee.

Medical History: Manic depressive d/o, asthma, cigarette use. Past surgical history: cystoscopy, right inguinal repair and closed reduction of leg fracture. No previous reported problems with anesthesia. Allergy to Tylenol.

Medications: Albuterol inhalor, lithium carbonate and Zoloft


Report. Report. OR Course• The patient was premedicated with versed and glycopyrrolate and

versed.• All appropriate monitors were applied (NIBP, pulse ox, EKG,

temperature and gas analyzer). General anesthesia was induced uneventfully with propofol, nitrous oxide, oxygen and Isoflurane. Muscle relaxants were avoided due to the possible interaction with lithium. After 10 minutes of IA induction, the patient was easily intubated and surgery started shortly thereafter.

• For the next 90 minutes VS remained stable, ETCO2 remained 36-38mmHg despite a change in Ve. Morphine was given in response to a slight increase in HR, which returned to baseline.

• Esophageal temp maintained 36 C, HR 80’s and ETCO2 35-40mmHg.


ReportReport• Approximately 1hour and 40 minutes into the case, the

patients temp abruptly rose to 37.4 C, ETCO2 increased to 60mmHg and HR rose from 80’s-125.

• The minute volume was 12-15L and the patient was initiating spontaneous RR.

• The new soda canister was warm to touch.• MH was suspected.• The surgeon requested to stop the procedure, all

anesthestic agents were discontinued.

Exhausted Soda LimeExhausted Soda Lime

Rebreathing CO2 from Exhausted Absorber

TreatmentTreatment• Ventilation with 100% oxygen was initiated.• Dantrolene 2.5mg/kg, sodium bicarbonate and

mannitol were given.• Arterial line, urinary catheter were placed and cooling

measures instituted. • Iced 0.9% NS IVF were given and the patient was

packed with ice. Labs were sent.• ABG: 7.31/38/119/19/-6. • 10 minutes after dantrolene was given, the patients

HR decreased to 100’s, temperature ↓ from 38-36.8C and ETCO2 to 39mmHg.

• Electrolytes and CPK remained normal, urine myoglobin was negative.

• The highest ETCO2 was 62mmHg and K 5.6. Temp max was 38 C by esophageal probe.

• Differential Diagnosis: undisclosed preop drug ingestion, hyperthyroidism—both ruled out. Neuroleptic Malignant Syndrome due to use of lithium and zoloft was ruled out. The patient had persistent hypercarbia, which isn’t present with NMS along with significant tachycardia and hyperpyrexia.

• 2 weeks from the original surgery date the patient returned for completion of the knee surgery. Medications: lithium, Zoloft and motrin. Anesthetic: tetracaine spinal w/o complications.

Sevoflurane-induced malignant hyperthermia Sevoflurane-induced malignant hyperthermia during cardiopulmonary bypass and moderate during cardiopulmonary bypass and moderate

hypothermiahypothermiaCase:56 yo male, 100kg, 185cm admitted for CABG and

MVR due to unstable angina and moderate MR.

Medical History: 3 vessel CAD, EF 40%, s/p MI several years prior, non Q wave MI 1 month prior to this admission, ETOH abuse, HTN and COPD. No reported history of MH. No previous anesthetics.

Medications: ASA, atorvastatin, isosorbide formoterol inhaler and ramipril.

Sevoflurane-induced malignant hyperthermia Sevoflurane-induced malignant hyperthermia during cardiopulmonary bypass and during cardiopulmonary bypass and

moderate hypothermiamoderate hypothermiaOR Course: Premedication with 15mg morphine and

skopolaminbromide 0.6 IM• Uncomplicated induction: diazepam 10mg,

pentobarbital 350mg, fentanyl 500mcg, and cisatracurium 16mg.

• Monitors: ABG analysis, invasive blood pressure, CVP, pulsox, capnography, urinary output and TEE.

• Endotracheal anesthesia was maintained with Sevoflurane ET 1.6-2.3% and O2/N2O 30/70. No events were noted in the first 20 minutes.

Sevoflurane-induced malignant Sevoflurane-induced malignant hyperthermia during cardiopulmonary hyperthermia during cardiopulmonary

bypass and moderate hypothermiabypass and moderate hypothermiaFirst ABG:-7.29/56/-0.6/26.5 ETCO2 46, rectal temp 36 C-Ventilation increased from 8-10L/min-Hypotension gradually developed (MAP ~45mmHg),

repeated boluses of phenylephrine and epi were ineffective

-Epi was started .01mcg/kg/min and continued until CPB.-During CPB blood flow was 2.4L/min/m2 and gas flow

3.8L/min, Sevo was delivered through CPB circuit. Active cooling was initiated.

-Hypotension continued on CPB, norepi was started at 0.2mcg/kg/min

Sevoflurane-induced malignant hyperthermia Sevoflurane-induced malignant hyperthermia during cardiopulmonary bypass and moderate during cardiopulmonary bypass and moderate

hypothermiahypothermia• First ABG after initiation of CPB:

-7.22/50/-6.9-19.9/lactate 4.3, rectal temp 35.9 C• Methylprednisolon 2G and milrinone 50mcg/kg bolus

were given. No improvements were noted.• It was determined that the patient had an increased

metabolism, probably due to MH. • Sevo was stopped, propofol infusion started to maintain

anesthesia. • Dantolene 2.5mg/kg was given during CPB and a second

dose during termination of CPB• Rewarming stopped at 36 C• Oliguria and hypotension were treated

Sevoflurane-induced malignant hyperthermia Sevoflurane-induced malignant hyperthermia during cardiopulmonary bypass and during cardiopulmonary bypass and

moderate hypothermiamoderate hypothermia• Soon after weaning from CPB metabolic acidosis developed

again (pH 7.26 and BE -2.6), rectal temp increased to 38.2. PA catheter was placed CI 4.9, SVRI 525 and PCWP 16mmHg.

• The first ABG in the ICU: 7.14, pCO2 55, BE -3.5, HCO3 23.8– Dantrolene was given (150mg over 3 hours)– CK increased to 38,000 and serum myoglobin increased

to 23,353– The patient was exbubated on POD 11 and was

discharged to a local hospital after 2 weeks– The patient fully covered from the operation and MH

incident.

• The diagnosis of MH was complicated by CPB and hypothermia.

• Tachycardia is a common response to increased metabolism in MH, this patients HR changed from 67-75/min in the pre-CPB period.

• After arriving to the ICU the HR was 105/min and decreased to 80 during the dantrolene infusion.

• Hypertension is often a early symptom, this patient presented w/hypotension.

• Combined metabolic and respiratory acidosis is the most typical symptom, which lead to the diagnosis.

• Differential diagnosis considered: anaphylatic reaction, circulatory disturbance of abdominal organs, drug abuse and thyrotoxic crisis, there were no signs of preoperative infection.

• Relapse of the syndrome post-op is not uncommon.

Exertional Heat Illness, Exertional Exertional Heat Illness, Exertional Rhabdomyolysis and Malignant Rhabdomyolysis and Malignant

Hyperthermia: Is there a link?Hyperthermia: Is there a link?• Exertional Heat Illness (EHI) is a disorder of excessive

heat production, coupled with insufficient heat dissipation.

• Often serious heat illness events are associated with adverse health conditions, medications and environmental factors, many people with EHI are normal and otherwise healthy before their EHI episodes.

• EHI can progress to exertional heat stroke.• US Army reports 994 hospitalizations for EHS between

1980-2002, 37 deaths.

Exertional Heat Illness, Exertional Exertional Heat Illness, Exertional Rhabdomyolysis and Malignant Hyperthermia: Rhabdomyolysis and Malignant Hyperthermia:

Is there a link?Is there a link?• Extertional rhabdomyolysis (ER) is a syndrome

characterized by destruction of the skeletal muscle cell membrane resulting in massive release of intracellular creatine kinase (CK), potassium, myoglobin and other intracellular contents.

• ER can result in response to strenuous physical activity, particularly exercise eccentric in nature when mechanical or metabolic stress damages muscle fibers.

• CK level > or = 5x normal and urine positive for myoglobinuria. Musculoskeletal pain typically occurs 24-48 hours after extreme or non-familiar exercise.

• ER can occur in both cool or warm environments.

Similarities between EHI and MHSimilarities between EHI and MH

• Excessive heat production that exceeds dissipation capacity and rhabdomyolysis.

• Both syndromes can occur in otherwise healthy individuals over a wide range of ages.

• Some persons who present with signs and symptoms of EHI have later been shown to be MHS.

• Much of the knowledge regarding a link is from case reports.

• Italian investigators described 45 patients with Exertional heat stroke (EHS) who had in vitro contracture test (IVCT) at least three months after their EHS.

• 42% were diagnosed as MH susceptible (19 out of 45) • Histological studies revealed various muscle

abnormalities including rhabdomylysis, mitochondrial myopathy, denervation type II atrophy and other non-specific findings.

• Ryan et describes a 23 year old male police recruit whose family has a history of MHS.

• The recruit was in excellent physical condition but developed rigidity and cardiac arrest during moderate exercise on a cool/dry day 54 degrees and 54% humidity.

• Following a brief warm up period of calisthenics and stretching, he began a 3 mile run at 8.5 min/mile.

• Cardiopulmonary arrest occurred and he was transferred to the local hospital. Resuscitation efforts were unsuccessful.

• Family history of MHS, brother had a positive CHCT and nephew with clinical MH episode.

• It is of interest to note that one study did show that MHS individuals who were exercised at 120% VO2max exhibited delayed recovery in muscle energy metabolism.

• Functional testing may be the best approach to differentiate between MH, EHI and ER.

• Heat tolerance testing has been shown to discriminate between heat tolerant and intolerant soldiers. It is used in Israel to determine whether EHI victims can be retained or need to be discharged from the military.

Recovery from MH, EHI and ER• Complete recovery from a fulminant MH episode: normalization of

electrolytes, CK, creatinine and LFTs.-6-12 months of rest is recommended before resuming strenuous exercise program.

• Recovery from EHI: determined by normalization of serum electrolytes, CK, creatinine, liver function tests and normal mental status.

• ER recovery is similar to EHI. Time to recovery will vary depending on the factors that precipitated ER and risk. – High risk individuals: delayed recovery, persistently elevated

CK, acute renal failure, personal or family history of similar symptoms, MH or sickle cell trait, personal history of severe muscle pain with activity or heat injury, complications of drug/supplement use or CK >100,000.

Evidence based patient safety Evidence based patient safety advisory: Malignant Hyperthermiaadvisory: Malignant Hyperthermia

• Hypermetabolic responses in swine have been documented after exposure to heat, exercise, anoxia and excitement.

• The role of stress in triggering MH in humans is still controversial.

• There is some evidence in literature that patients who have experience heat stress in the past are more likely to have MH positive in vitro-contracture tests.

• Clinical studies have shown no clear evidence between duration or type of surgery and risk of an episode in susceptible patients.

Putting it all togetherPutting it all together• Patients may have been exposed to several previous

anesthetics prior to a MH episode.• Presentation of MH may mimic other conditions,• Requirements for the surgery may mask symptoms

and/or make diagnosis difficult (CPB, etc).• Consider additional associated conditions when

screening patients for potential complications, (previous heat stroke, concurrent drug use)

Malignant Hyperthermia

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