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Local Anesthetic Systemic Toxicity

Morgan Morrow, DNAP, CRNA

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Objectives

Describe and list the chemical structure of local anesthetics

Describe and list

Describe the mechanism of sodium channel blockade and the mechanism for toxicity, as well as risk factors

Describe

Summarize the toxic nature of potent local anesthetics

Summarize

State why it is important to prepare of a local anesthetic toxicity event

State

Describe the steps that should be taken to prevent local anesthetic toxicity

Describe

State the intervention for local anesthetic toxicity

State

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Incidence

0.08-0.98/1000 between 2003-2013 in peripheral nerve blocks

0.1/1000 in 2003 for epidural anesthesia

The occurrence of local anesthetic toxicity has dropped significantly since the 1990s. Epidural analgesia and peripheral nerve blocks are the most commonly performed procedures requiring volumes of local anesthetics high enough to increase the risk for toxicity. However, toxicity can occur in other fashions as well. The reported incidence is mainly for cardiovascular toxicity. Likely, neurologic toxicity is underreported because symptoms may be more mild-including perioral numbness, tinnitus, and agitation, and or sedatives and anesthetic agents mask these symptoms. Local anesthetic toxicity outside of anesthesia may also be underreported in fields such as ENT, dental, or ophthalmologic surgery. One thing to note about the number included in this slide is that ultrasound use has exploded since these studies were concluded. Ultrasound use is associated with increased safety, and the incidence is currently likely lower. A 2018 study by El-Boghadly reported LAST occurring at about 0.27 per 1,000 cases with peripheral nerve blocks.

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Chemical structure of local anesthetics

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Toxic nature of local anesthetics

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Mechanism of sodium channel blockade

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Mechanism of cardiac toxicity

Depression of the maximal depolarization rate of cardiac action potential by inhibiting sodium influx

If enough local anesthetic is absorbed or administered intravascularly, free local anesthetic that is not protein bound can diffuse to the cardiac conducting tissue in the heart. All local anesthetics depress the maximal depolarization rate of the cardiac action potential by inhibiting sodium to influx into cells. Blockade of cardiac ion channels affects initiation and propagation of contraction and repolarization. Local anesthetics also block calcium channels and at high concentrations, they can inhibit other channels, enzymes, and receptors. Cardiac toxicity is likely caused by a combination of electrophysiologic and contractile dysfunction. This results in slowing conduction of the cardiac action potential, which will appear as a prolonged PR and QRS intervals, as well as reentry ventricular dysrhythmias. Ventricular fibrillation is the most serious of the arrythmias seen.

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Toxicity risk factors

Local anesthetic (type and concentration)

Toxicity risk factors involve the type and dose of local anesthetic administered, factors related to the specific procedure, and patient-related factors. Related to local anesthetics, the lowest possible dose should be utilized to produce a satisfactory block. I have included generalized recommendations on the next slide. However, it is crucial to consider that systemic blood levels of a local anesthetic depend on the area of the block related to vascular uptake, the technique of the provider, and the specific type of local anesthetic utilized. Bupivacaine has a high lipid solubility and high affinity for sodium channels, making bupivacaine-induced LAST associated with high morbidity and mortality. Bupivacaine in peripheral nerve blocks should be used at lower concentrations, 0.5% compared to 0.75%, because of the risk of toxicity. Ropivacaine was invented because of concerns related to bupivacaine cardiotoxicity. Ropivacaine does have a similar clinical profile, but it can be administered in large quantities before signs of toxicity develop. Sometimes drugs are reported in a cardiovascular collapse/CNS ratio, where the drug dose required to cause catastrophic cardiovascular collapse is compared to the drug dose required to produce seizures. A low CC/CNS ratio is associated with more cardiotoxic agents, and a lower ratio is considered to have higher safety margins.

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Recommended maximum dosages

	Max dose without epinephrine (mg/kg)	Max dose with epinephrine (mg/kg)
Lidocaine	3-4	7
Bupivacaine	2-2.5	2-2.5
Ropivacaine	3	3
Prilocaine	6-8	-

Here I have listed some commonly accepted maximum dosages for local anesthetics with and without vasoconstrictors. One way that I learned to calculate these dosages fast is to memorize the maximum dose for bupivacaine and ropivacaine as 2.5 mg/kg. Because quarter percent (0.25%) of both drugs is 2.5 mg/mL, a patient can have 1 mL per kg of body weight. Half percent (0.5%) is 5 mg/mL, they can have ½ as much, or .5 mL per kg of body weight. These dosages need to be calculated based on a patient's ideal body weight, rather than total though. It is not uncommon in anesthesia to have performed a peripheral nerve block and a surgeon asks if they can locally infiltrate. For a 70 kg, ideal body weight patient, they can have 70 mL of 0.25% or 35 mL of 0.5%. Likely, if we did a nerve block, we would use something between 10-30 mL of 0.5%-leaving the surgeon very little volume to inject. Luckily, we will likely be administering high quality nerve blocks with ultrasound guidance and the need for them to administer more will be less. However, if you have block failure, this is something to consider and plan for. The utilization of ultrasonography for peripheral nerve blockade has made anesthesia safer because we do not need to administer the higher volumes we did when blocks were performed with landmark/nerve stimulator techniques.

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Toxicity risk factors: type of block

IV

Tracheal

Intercostal

Caudal

Paracervical

Lumbar Epidural

Brachial Plexus

Sciatic

Subcutaneous

Topical

•Knowing that toxicity occurs when local anesthetics reach plasma concentrations, it only makes sense that blocks in highly vascular areas are associated with LAST more commonly than blocks performed in areas with poor blood supply. Once local anesthetic reaches the plasma, it can be distributed to well-perfused tissues like the brain and the heart. This free drug exerts toxic effects. Intravenous regional anesthesia, like a Bier Block, is associated with a significant risk of LAST. Seizures have been reported with doses as low as 1.4 mg/kg of lidocaine and cardiac arrest at doses of 2.5 mg/kg. LAST can occur even with an inflated tourniquet in a Bier block technique or up to 30 minutes after tourniquet deflation. While I did perform Bier blocks in the early 2010s, this technique has seemed to fall out of favor. Anesthesia for the airway is also associated with LAST-whether it is for TEE, bronchoscopy, endoscopy, or for performing awake intubation. It is important to consider the total dose of local anesthetic administered-especially if given in multiple different techniques, such as nebulization and injection techniques. A significant portion of drug can be lost to the atmosphere and swallowed with nebulization. Some evidence suggests up to 9 mg/kg can be nebulized. Intercostal blocks, and now I think we could add truncal blocks into this category, as they seem to be replacing intercostal blocks, have a high risk of LAST. Skeletal muscle can act as a depot for systemically absorbed local anesthetic, and those will less muscle mass-like the elderly will have more free drug. Additionally, because the blocks require the spread of local anesthetic, in the form of high volume, a higher amount of drug is utilized. The purpose of this slide is not meant to scare anyone from utilizing nerve blocks in clinical practice; the opposite, in fact. It is important to be aware of the risks and which procedures carry higher risks. The use of ultrasound has been shown to reduce the risk of LAST by 60%-65%. The addition of ultrasonography to peripheral nerve blockade increases safety by allowing increased precision of local anesthetic depositing, which lowers doses needed to achieve adequate anesthesia and or analgesia and allows the provider vascular cues of IV injection, like vascular puncture and needle identification.

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Toxicity risk factors: patient characteristics

Extremes of age

Pregnancy

Renal disease

Hepatic disease

Cardiac disease

Patients at extremes of age are at a greater risk for LAST. Neonates have reduced plasma concentrations of alpha1-acid glycoprotein and immature hepatic enzymes; therefore, if being given a local anesthetic, the dose should be reduced by about 15% in patients less than 4 months of age. Geriatric populations are also at increased risk because of their reduction in muscle mass and decreased organ function, reducing metabolism. Because of their increased incidence of comorbidities, they are more susceptible to systemic effects. Geriatric patients should also have a reduced dose of local anesthetics, by about 10%-20%. Pregnant patients also see a reduction in alfa1-acid glycoprotein and increased cardiac output. This manifests as accelerated perfusion to injection sites, rapid local anesthetic absorption, and high peak free local anesthetic concentrations. Parturients may be likely to receive epidural anesthesia during labor and delivery may have increased drug absorption because of epidural venous engorgement. Patients with renal disease are known to have hyperdynamic circulation and reduced clearance of local anesthetics. However, they have increased alfa1-acid glycoprotein concentrations, so doses might not necessarily need to be adjusted unless the patient is acidotic or uremic. Patients with hepatic dysfunction will have difficulty metabolizing local anesthetics. However, because they likely have a large volume of distribution and maintenance of alpha1-acid glycoprotein synthesis, single-shot doses do not necessarily need to be adjusted, but continual infusions will need to be. Finally, patients with cardiac dysfunction are susceptible to local-anesthetic induced myocardial depression and arrhythmias. Dose reduction is recommended in patients with heart failure.

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Presentation of symptoms

Although LAST presents atypically in 40% of cases, CNS symptoms occur in 89% of cases. Likely, CNS symptoms are underreported or may not be acknowledged by the anesthesia provider. Note here on the charge the escalation of symptoms prior to seizures or cardiovascular symptoms. LAST usually beings with symptoms like perioral numbness, tinnitus, agitation, dysarthria, and confusion. Cardiovascular symptoms usually appear as hypertension and tachycardia. A colleague of mine, Dr. Pauline Zelaya, noted in her facility, monitoring and oxygen administration only occurred in about 2% of peripheral nerve block placements. Her quality improvement included education which increased monitor and oxygen use during peripheral nerve block placement to 100%. Patient monitoring is a standard of care and should be a top priority of the CRNA.

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Timing of LAST

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Preparation

MONITORS

RESUSCITATION EQUIPMENT

LAST RESCUE KIT

LAST MANAGEMENT CHECKLIST

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Prevention

Risk reduction

Frequent syringe aspiration

Ultrasound guidance

There is not necessarily a surefire method to prevent LAST but hypervigilance is imperative. A CRNA can consider risk reduction by utilizing the lowest possible local anesthetic dose possible to achieve the best results for their specific patient, based on the anesthetic and analgesic needs of that patient and their co-morbidities. Incrementally administering local anesthetics-3-5 mL at a time and pausing for 15 seconds between injections while monitoring the patient for neurological and cardiovascular changes should be employed. An intravascular marker can be added to local anesthetic solution-such as epinephrine to increase heart rate and blood pressure, or fentanyl to produce sedation in laboring patients. These are imperfect markers and intravascular injection of either medications carries their own inherent risk, so risk versus benefits should be weighed. Lastly, ultrasound guidance likely reduces LAST, although no current available studies confirm this.

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Intervention

STOP

Call for help

ABCs

IV lipid therapy

Initial focus of a LAST event is ceasing administration of a local anesthetic if the procedure is currently being employed and getting help. Maintence oxygenation/ventilation/ and hemodynamic support of the patient, as well as seizure suppression with benzodiazepines. Life support measure can be based off currently BLS/ACLS protocols but adjustments need to be made appropriately to adjust medications administered as well as time frame for resuscitative efforts. Chest compressions should be immediately started but epinephrine doses should be lowered to 1 mcg/kg to avoid impaired pulmonary gas exchanged and increased afterload. Vasopressin should be avoided because of adverse outcomes in animal studies as should beta blockers and calcium channel blockers, or lidocaine for arrythmias. Amiodarone is the preferred drug for ventricular arrythmias. Early consideration should be given to cardiopulmonary bypass and the facility should be notified about this possibility. Lipid resuscitation works by capturing local anesthetic in the blood, increases fatty acid uptake by the mitochondria, interfering with local anesthetic binding of sodium channels, activating serine/threonine kinase leading to cytoprotection, promoting calcium entry into voltage-depending calcium channels to create more inotropy, and accelerated pharmacokinetic effects. Lipid emulsion can be given in the parturient as well.

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Lipid Emulsion Therapy

Patients > 70 kg (LBW)

100 mL over 2-3 minutes
Infusion 200-250 mL over 10-15 minutes

Patients <70 kg (LBW)

1.5 mL/kg over 2-3 minutes
Infusion 0.25 mL/kg/min

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Propofol

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Is regional anesthesia safe in a patient under general anesthesia?

Marhofer (https://journals.lww.com/co-anesthesiology/Fulltext/2017/10000/Regional_blocks_carried_out_during_general.18.aspx) reviewed the safety of peripheral nerve blocks and determined that more patients would likely consent to regional anesthesia if the procedures were performed with sedation or general anesthesia, regional anesthesia is generally extremely well tolerated and rarely causes permanent neurological complications, high-resolution ultrasound improves safety by avoiding need-to-nerve contact, LAST can be immediately detected in an awake patients, but general anesthesia reduces the seizure-inducing potency of local anesthetics and expedites cardiopulmonary resuscitation-which will include inducing anesthesia and securing an airway. Additionally, hemodynamic signs of local anesthetic systemic toxicity are detectable in an anesthetized patient. Marhofer does note that American Society for Regional Anesthesia recommends that blocks of the brachial plexus be done awake but for most truncal blocks, blocks of the lower extremity, and neuraxial anesthesia can be performed in anesthetized patients. Regional anesthesia under general anesthesia has been more common in the pediatric population, with the consideration that movement could be catastrophic, and the patients would not tolerate the procedures. Taenzer (https://rapm.bmj.com/content/39/4/279) noted that in a study of over 50,000 pediatric patients, the incidence of LAST was 0.08/1000 in the GA population versus 0.34/1000 in the sedated or awake population. Something to consider about the pediatric population is the wide variety of appropriateness. Meaning, about a third of the blocks placed were in patients 10-18 years old, who are more likely to tolerate sedation and more likely to be cooperative than younger populations. In the infant population, 91% of blocks were placed with general anesthesia. The takeaway message is that nerve blocks can be safely performed under general anesthesia and or heavy sedation if the anesthesia provider remains hypervigilant and skilled in regional anesthesia.

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Math break!

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Block failure ☹

Patient Mr. Smith comes in for a THA and receives a SAB with 1.5 mL of 0.75% bupivacaine and an adductor canal block with 20 mL of 0.5% ropivacaine and complains of knee pain 3 hours after surgery. Can (or should!) I repeat the block?

Unfortunately, block failure happens, although it is becoming rarer with the advances in ultrasonography but let's look at this case where a patient has a spinal for surgical anesthesia and had an adductor canal block that does not appear to providing adequate postoperative analgesia. A lot of providers would probably not calculate the spinal Marcaine into the equation for a few reasons-1. it is such a small volume that it does not necessarily provide clinically altering results, and 2. we have passed the half-life and we know the spinal has worn off because of the patient complaints of pain. Let's calculate both ways. We will assume Mr. Smith has an ideal body weight of 60 kg, meaning he can receive a total volume of 30 mL of ½% or 60 mL of ¼%, or a total mg of 150mg. If we assume Mr. Smith has had no metabolism of drug at all-maybe he is getting a new knee in fulminant liver and renal failure, we need to subtract the total mg he has received from 150. He received 11.25 mg in the SAB and 100 mg in the block, leaving us with 38.75 mg, assume 0 metabolism has occurred. This could be given in a repeat adduct block in 7.75 mL of ½% Marcaine, or 15.5 mL of ¼% Marcaine. Because it is unlikely that Mr. Smith has both liver and renal failure, and we know the half life of the Marcaine is 3 hours, we can assume ½ of the total drug has decreased via metabolism, meaning we can assume he still has approximately 56 mg of the drug in his system, leaving us with about 94 mg to administer, which equates to 19 mL of 0.5% or 38 mL of 0.25%. Clinically speaking, we would likely repeat the block knowing we are keeping Mr. Smith safe and comfortable.

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Can I TAP block an OB epidural to CS?

Epidural @10 mL/hr of 0.2% ropivacaine

TAP block with 40 mL of 0.2% ropivacaine

Recently, a colleague asked me why our OB patient don’t get local anesthetic toxicity from the high volume of local anesthetic given when we covert from labor epidural to surgical anesthesia with a post-operative block, so let's break down the math in this situation.

We know that the half-life of ropivacaine is about 4 hours. So, lets assume no local anesthetic has been metabolized for 4 hours, even though that is not realistic and local anesthetic is consistently being metabolized and replaced from the epidural infusion. But, for 4 hours at 10 mL per hour, we have 80 mg of ropivacaine have been given. If we add the TAP block, that is another 80 mg of ropivacaine, for a total of 160 mg. Knowing the toxic dose of ropivacaine is approximately 3 mg/kg, we will need our patient to weigh over 53 kg before reaching toxic levels. We also need to consider the volume of local we give to convert the epidural for CS anesthesia but this calculation, not accounting for any metabolism, does demonstrate that for a normal sized patient, we are within our acceptable ranges.

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Post-lecture Test

Post-lecture Evaluation

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Thank you!

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Refences

Di Gregorio, G., Neal, J. M., Rosenquist, R. W., & Weinberg, G. L. (2010). Clinical presentation of Local Anesthetic Systemic Toxicity: A review of published cases, 1979 to 2009. Regional Anesthesia and Pain Medicine, 35(2), 181-187.
El-Boghdadly, K., Pawa, A., & Jinn Chinn, K., Local anesthetic systemic toxicity: current perspectives. Local and Regional Anesthesia, 11, 35-
Gitman, M., Fettiplace, M., & Weinberg G. (n.d.). Local Anesthetic Systemic Toxicity. NYSORA. https://www.nysora.com/foundations-of-regional-anesthesia/complications/local-anesthetic-systemic-toxicity/
Hadzic, A. (2017). Hadzic’s Textbook of Regional Anesthesia and Acute Pain Management. McGraw Hill.
Hemmings, H. C. & Egan, T. D. (2019) Pharmacology and Physiology for Anesthesia. Elsevier.
Hines, R. L. & Marschall, K. E. (2018). Stoelting’s anesthesia and co-�existing disease (7th ed.). Philadelphia, PA: Elsevier
Marhofer, P. (2017). Regional blocks carried out during general anesthesia or deep sedations: myths and facts. Current Opinions in Anesthesiology, 30(5), 621-626.
Nagelhout, J. J. & Plaus, K. L. (2014). Local anesthetics. In Nurse anesthesia (5th ed., pp. 125-144). Elsevier Health Sciences.
Taenzer, A. H., Walker, B. J., Bosenberg, A. T., Martin, L., Suresh, S., Polaner, D. M., Wolf, C., & Krane, E. J. (2014). Asleep versus awake: Does it matter? Regional Anesthesia & Pain Medicine, 39(4), 279-283.
Zelaya, P. (2021). Perioperative peripheral nerve block safety education: a quality improvement project. Journal of Perianesthesia Nursing, 36(4), 359-366.