Sep 25, 2020
This podcast presents, Dr. Nate Beerling, a Ridgeview Medical Center anesthesiologist, who discusses two rare but life threatening events - malignant hyperthermia (MH) and local anesthetic systemic toxicity (LAST). Dr. Beerling will discuss how they occur and how to treat these conditions.
Enjoy the podcast!
Upon completion of this podcast, participants should be able to:
CME credit is only offered to Ridgeview Providers & Allied Health Staff for this podcast activity. Complete and submit the online evaluation form, after viewing the activity. Upon successful completion of the evaluation, you will be e-mailed a certificate of completion within approximately 2 weeks. You may contact the accredited provider with questions regarding this program at firstname.lastname@example.org.
To receive continuing education credit for this activity - click the link below, to complete the activity's evaluation.
you are listening to the podcasts through iTunes on your laptop or
desktop, it is not possible to link directly with the CME
Evaluation for unclear reasons. We are trying to remedy this. You
can, however, link to the survey through the Podcasts app on your
Apple and other smart devices, as well as through Spotify, Stitcher
and other podcast directory apps and on your computer browser at
these websites. We apologize for the inconvenience.)
The information provided through this and all Ridgeview podcasts as well as any and all accompanying files, images, videos and documents is/are for CME/CE and other institutional learning and communication purposes only and is/are not meant to substitute for the independent medical judgment of a physician, healthcare provider or other healthcare personnel relative to diagnostic and treatment options of a specific patient's medical condition; and are property/rights of Ridgeview Medical Center & Clinics. Any re-reproduction of any of the materials presented would be infringement of copyright laws.
It is Ridgeview's intent that any potential conflict should be identified openly so that the listeners may form their own judgments about the presentation with the full disclosure of the facts. It is not assumed any potential conflicts will have an adverse impact on these presentations. It remains for the audience to determine whether the speaker’s outside interest may reflect a possible bias, either the exposition or the conclusions presented.
Ridgeview's CME planning committee members and presenter(s) have disclosed they have no significant financial relationship with a pharmaceutical company and have disclosed that no conflict of interest exists with the presentation/educational event.
Malignant hyperthermia first appeared in letters written between anesthesiologists who noticed patients having "ether convulsions" in surgery.
It was formally discovered in the 1960s by Dr. Michael Denborough, in Australia. One of his patients' required surgery for a tibia fracture, and the patient was terrified about having surgery because 10 of his family members had died during surgery. This patient did actually have a malignant hyperthermia event, but survived.
Pathophysiology is of course complex, but remember 2 things: calcium release and ryanodine receptors.
First, let's trace the normal pathway for muscle reaction. Signal generates from the brain, travels down the nerve pathway till it synapses with a motor neuron. here acetylcholine is released and triggers a voltage. That voltage is sodium channels opening and causing depolarization and generating action potential, aka, the electrical signal. This signal travels down the muscle cell to the T-tubules where a dihydropyridine receptor is mechanically linked to an organelle called the sarcoplasmic reticulum where calcium lives. When that voltage travels down and sets off the dihydropyridine receptor, that then opens the ryanodine receptor, calcium is released into the cell which sets off the muscle contraction cycle.
Calcium binds to troponin, attracts it to the myosin. The myosin then contracts and shortens, causing an overall muscle contraction. ATP, the energy unit of the cell, has already been broken apart to cause the contraction. In order for the muscle cell to relax, a new ATP must attach to the myosin. That process will repeat as long as calcium is around.
In malignant hyperthermia, there is a double hit phenomenon. The patient has mutated ryanodine receptors and exposure to an induction agent (which we'll talk about later). The agent binds to the mutated ryanodine receptor and doesn't allow it to close. Calcium continues to leak which sets off this cycle of muscle contraction, release, contraction.
As new ATP is required to relax the muscle, ATP is quickly depleted. When ATP is gone, there is muscle contraction without ATP to release it. That's what causes the rigidity in malignant hyperthermia. The cell will now try to make energy in any way possible and reverts to anaerobic metabolism, with lactic acid production.
The clinical effects are hypoxia, increase in CO2 or hypercapnia, and lactic acidosis.
Let's use an example. Let's say there is a patient who is going to undergo a laparoscopic appendectomy. The induction agents that would be used include propofol, a neuromuscular blocking agent, fentanyl, versed, and lidocaine. In addition, the patient will receive an inhalation agent like cevoflorine, desflurane or isolflurane via a ventilator. It's these agents as well as the neuromuscular blocking agent, succinylcholine, that can cause a malignant hyperthermia event.
In a situation where malignant hyperthermia would develop, the obvious sign would be a rise in end tidal CO2. Though in this case example, which is laparoscopic, CO2 is used to insufflate the abdomen, and thus is part of your differential diagnosis. Look for rise in end tidal CO2 that does not respond to ventilation, arrhythmias, and hyperthermia. Rigidity in a patient is a pathognomonic sign of malignant hyperthermia.
What are the clinical
A rise in end tidal CO2 and tachycardia. Hypoxia if they're using up all their oxygen. Hypertension in the presence of a huge catecholamine dump as a compensatory mechanism, and arrhythmias due to hyperkalemia. To drag it back to pathophysiology, all the energy or ATP has been used up in the cells, and they can't support normal metabolic processes. The cell dies, and potassium which mainly lives in the cell, gets released in the bloodstream causing hyperkalemia.
We mentioned the differential diagnosis earlier when talking about surgical insufflation of CO2, but other rule outs would be a rise in CO2 due to hypoventilation or hypermetabolic processes, like neuroleptic malignant syndrome or serotonin syndrome. Arrhythmias could be the result of a primary cardiac event.
When intubating the emergent patient with unknown past medical history, can succinylcholine be used? In general, succinylcholine is a "nice, safe drug". However, there is another neuromuscular blocking agent, Rocuronium, which has a reversal agent, sugammadex, that would work faster than succinylcholine would wear off, and also is not a malignant hyperthermia triggering agent. Always consider whether or not any neuromuscular blocking agent is actually appropriate for that particular patient and situation.
The first step when treating malignant hyperthermia, is to recognize it, then treat the life-threats. Treat the hyperkalemia, ventilate with 100% oxygen to replace what's being used up and most importantly - dantrolene.
In this case, dantrolene is the life-saving drug, the gold standard that has significantly decreased the mortality of malignant hyperthermia events. Discovered in the 1970s, it works by attaching to the ryanodine receptor and disengages the triggering agent from the ryanodine receptor and allows it to function normally again. Bolus dose for dantrolene is 2.5 mg/kg bolus that can be repeated. This is a change, as it used to be recommended that a bolus dose plus a drip be administered, but a new formulation has made reconstituting the drug easier. Thus, the recommendation is a bolus, with repeated boluses, if required.
The malignant hyperthermia kit should include: dantrolene (obviously), but also ACLS drugs. For treatment of hyperkalemia - insulin/dextrose and albuterol. Bicarbonate, which treats low pH, hyperkalemia, and helps alkalize the kidneys in light of muscle breakdown. Calcium is extremely important for myocardial stabilization.
Cooling in the OR could involve lavage of an open cavity, but also cold IV saline, and or ice packs to the axillary and groin areas. Once the body temperature has dropped below 38o C, cooling should be terminated to avoid hypothermia.
Ongoing care would include transfer to a tertiary care facility, where the patient can undergo continued monitoring. Dantrolene can be given intermittently every 4-6 hours for 24-hours, because malignant hyperthermia recrudescence can occur. Watch for kidney failure due to rhabdomyolysis, DIC, and if recrudescence occurs, hyperkalemia.
Malignant hyperthermia is an inherited autosomal dominant trait. When assessing for risk, a thorough history and physical is required to look for individual problems, as well as looking for a lethal family history from anesthesia. If there is a family history, it's best to avoid triggering agents.
If a patient has a malignant hyperthermia event, they don't need any further testing, they are confirmed. However, they may want genetic testing. There are 30 mutations of both the ryanodine and dihydropyridine receptors that have been linked to malignant hyperthermia. Those results can be used to help identify family members with the same mutations. Unlike the caffeine/halothane test, genetic testing doesn't require a muscle biopsy. The caffeine/halothane test is another way to confirm patients with malignant hyperthermia. It's done by applying caffeine and halothane to a fresh muscle biopsy. If a certain amount of contraction is achieved, it is diagnosed for malignant hyperthermia. However, to complete the test, the patient must be physically present at the institution performing it, and there are only 5 such institutions in North America. It would be best to refer these patients to a specialized institution before a scheduled surgery.
MHAUS.org is a great resource for information on malignant hyperthermia. There is also a hotline that can bel called during an event. It's staffed 24/7 by anesthesiologists that are highly trained in malignant hyperthermia. It's important to remember that these events are rare, and it's important to have all the resources and help possible during an event.
LAST is local anesthetic systemic toxicity. Much like MH, it is a life threatening reaction that is almost completely preventable when care is take while injecting local anesthetics. It is also managed differently than a normal cardiac arrest.
There are 2 types of symptoms of LAST, cardiac and neurological. Most of the time it is felt that the neurologic symptoms precede the cardiac ones.
These anesthetic agents work by blocking the sodium channels, and thereby block the depolarization of the nerves, both cerebral and cardiac. These agents are not always specific to sodium channels and can block other channels.
What predisposes cardiac effects depends on the agent, bupivacaine is most likely to cause cardiac issues; followed by ropivacaine, then lidocaine. This is related to the properties of the individual agents. The more lipophilic the agent, the more potent it is. Each anesthetic has a ratio of where it's most likely to be toxic at. Lidocaine is more likely to be toxic in the brain, than the heart. Bupivacaine is more likely to affect the heart at the same time it affects the brain. So, for example, if lidocaine were injected, there would be neurologic symptoms, but bupivacaine, if injected, because it's ration is lower, would have both cardiac and neurologic effects.
Safety of local anesthetics administered IV is due to dosage. For example, before almost every surgical case, a 1 to 1.5mg/kg bolus is given IV because it helps some of the sympathetic response i.e. the cardiac response to laryngoscopy and intubation, bronchospasms etc. Lidocaine is an antiarrhythmic, as well and probably one of the safest legal anesthetics to give IV. It's used as IV infusion for enhanced recovery after surgery for colorectal surgeries, and it's also used for renal colic in the emergency room setting. Giving IV lidocaine within that range of 1 to 1.15 mg/kg has been shown to be safe with almost zero chance of LAST. LAST can also occur when high doses are given and absorbed into the bloodstream.
It can get confusing looking at different percentages of drugs, and mixes. Lidocaine with epinephrine tends to depot the drug. The max dose of local anesthetic are based on the mass of the dose, the mg/kg, not the volume of the dose. For example, a fascia iliaca block is a volume block. You want to get a large volume of the medication to get a good coverage. A large volume of a dilute anesthetic is safe if it remains within the normal dose ranges.
Max doses for local anesthetics
- Lidocaine: 4mg/kg
- Lidocaine with Epi: 7mg.kg
- Bupivacaine: 3mg/kg
- Ropivacaine: 3mg/kg
For quick dosing, if using 25% bupivacaine, the max dose is the patient's weight in mls. For example, a patient that is 70kg, their max dose would be 70mls of 25% bupivacaine. If using 50% bupivacaine, the max dose is half their weight. For the same 70kg patient, the dose would be 35 mls. This same quick dosing can be used for ropivacaine.
Predisposition of patients for LAST include extremes of age, low muscle mass, the very end stages of liver or renal disease along with low-protein binding states.
Areas where LAST has a higher prevalence, is due to the vascularity of the tissue being injected, and how quickly it can be absorbed. This list of highest absorption to lowest is as follows: IV, tracheal, intercostal, paravertebral, epidural, abdominal wall, tap blocks and brachial plexus blocks, sciate, femoral, and then subcutaneous.
LAST presentation can be variable, but the classic presentation of LAST is first neurologic symptoms: excitatory, circumoral numbness, ringing in the ears, agitation, and just "not feeling right". This then can lead to delirium, sedation, coma and/or seizures. Then cardiac toxicity can develop. This can also be quite variable resulting in tachycardia to bradycardia, widening of the QRS, elongation of the QT, and/or flat out Vtach/Vfib.
In the event of LAST, treatment depends on the variable presentation. Mild symptoms require 1:1 monitoring of Spo2, cardiac rhythms and blood pressures to make sure it doesn't advance. If severe signs develop, in particular seizures, treatment must be aggressive and intralipid infusion should be started. Intralipid or lipid emulsion therapy is the first line drug in LAST; and works by affecting the agent through lipophilicity. It helps shift the diffusion gradient, and pull the anesthetic agents like bupivacaine off the sodium channels in the cardiac myocytes, and shuttle them away from the heart to the skeletal muscle and to the liver. A secondary mechanism is that it helps limit ischemia reperfusion syndrome and acts as a fluid bolus. It generally works fast - within minutes.
In a LAST event, ACLS doses are different. EPI doses should remain under a 100mcgs or a 1mcg/kg. EPI is arrhythmogenic and standard ACLS doses contribute to local anesthetic induces arrhythmias. Sodium channel blockers like lidocaine or procainamide should not be used. Other aspects of the ACLS protocol: CPR, defibrillation, and airway management remain unchanged. It is recommended that in this event that transfer to a facility that has ECMO should be considered.
Lipid emulsion dosing for adults over 70kg, is 200mls for the first bolus, with repeat doses of 100mls every few minutes. If under 70kg, the dosing returns to the old formulation of 1.5ml/kg bolus, and then an infusion of 0.25ml/kg/min. If rebolusing, increase the rate or the drip. Max dose is 12ml/kg. If reaching the max dose, consider that this event may not be LAST.
Is ultrasound or nerve stimulator better at reducing the risk of LAST when injecting anesthetic? It depends on who you ask. Ultrasound is like "turning the lights on". It allows you to see the spread of the anesthetic being injected.
Thanks for listening.