Episode #33: Not the LAST Word on Anesthesia Patient Safety

February 23, 2021

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Welcome to the next installment of the Anesthesia Patient Safety podcast hosted by Alli Bechtel.  This podcast will be an exciting journey towards improved anesthesia patient safety.

Recently, we dove back into our archives to talk about local anesthetic toxicity and intralipid treatment with an article from the APSF Spring 2009 Newsletter by Pete Stiles and Richard Prielipp called, “Intralipid Treatment of Bupivacaine Toxicity.”  This article is one of the most frequently visited pages on our website and you can find it here. https://www.apsf.org/article/intralipid-treatment-of-bupicavaine-toxicity/

Check out podcast episode #32.

Today, we are discussing “Local Anesthetic Systemic Toxicity (LAST) Revisited: A Paradigm in Evolution” by Guy Weinberg, Barbara Rupnik, Nitish Aggarwal, Michael Fettiplace, and Marina from the APSF February 2020 article. This is a special two part series on Local Anesthetic Systemic Toxicity.  We are going to review incidence, risk factors, presentation, and treatment.


Risk Factors
  • Hypoxia or acidosis
  • Extremes of age
  • Small patient size or muscle mass
  • Frailty
  • Heart disease:
    • Coronary artery disease, low cardiac output, arrhythmias, bundle branch blocks
  • Mitochondrial dysfunction
  • Liver or kidney disease
  • Carnitine deficiency
  • Use of lowest effective dose
  • Use of vascular marker (e.g., epi)
  • Adequate monitoring
  • Incremental injection
  • Intermittent aspiration
  • Individualized dosing
  • System safety (e.g., preparedness)
  • Educating doctors and nurses
  • Assessing patient risk factors
Presenting Symptoms and Signs
Prodrome Major CNS Major CV
  • Tinnitus
  • Metallic taste
  • Hypertension
  • Tachycardia
  • Agitation/ confusion
  • Obtundation
  • Seizure
  • Coma
  • Bradycardia/ heart block
  • Hypotension
  • Ventricular tachycardia or fibrillation
  • Asystole
Treatment of Local Anesthetic Systemic Toxicity
  1. Stop administering local anesthetic/call for help
  2. Manage airway
  3. Control seizures with benzodiazepine
  4. CPR as needed
  5. 20% lipid emulsion 1.5 mL/kg (bolus given over 2–3 min)

Check out http://www.lipidrescue.org/ for more information and case reports of LAST.

After listening to the show, check out the newest APSF Newsletter for February 2021. You can find the Newsletter here: https://www.apsf.org/newsletter/february-2021/ We are so excited to review these articles on future show.

Be sure to check out the APSF website at https://www.apsf.org/
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© 2021, The Anesthesia Patient Safety Foundation

Hello and welcome back to the Anesthesia Patient Safety Podcast.  My name is Alli Bechtel and I am your host. Thank you for joining us for another show.

We have a great show for you today as we take a look at local anesthetic toxicity and treatment once again…this time through the lens of the more recent article from the APSF February 2020 Newsletter which was released last year. And speaking of February APSF Newsletters, the APSF February 2021 Newsletter is now available at www.APSF.org. Have you seen it yet? If not, as soon as this show is over, I hope that you will check it out. We will be reviewing some of the articles on an upcoming show. There is so much to talk great content to talk about.

Before we dive into today’s episode, we’d like to recognize Fresenius Kabi, a major corporate supporter of APSF. Fresenius Kabi has generously provided unrestricted support as well as research and educational grants to further our vision that “no one shall be harmed by anesthesia care”. Thank you, Fresenius Kabi – we wouldn’t be able to do all that we do without you!”

Today on the show, we are continuing a series on Local Anesthetic toxicity. This is a very important consideration for anesthesia patient safety and APSF has several articles on the topic. Recently, we explored the APSF Newsletter archives from Spring 2009 to look at the article by Pete Stiles and Richard Prielipp called, “Intralipid Treatment of Bupivacaine Toxicity.” That was episode #32. Research and protocols related to local anesthetic toxicity have changed a lot since, so today, I am so excited to talk about the article, “Local Anesthetic Systemic Toxicity (LAST) Revisited: A Paradigm in Evolution” by Weinberg and colleagues from the APSF February 2020 article.

You can find the article by clicking on the Newsletter heading, 4th one down is the Newsletter archives. Then, just scroll down a little bit and click on February 2020. Right at the very top is our featured article today.

This is such an important topic since Local Anesthetic Systemic Toxicity or LAST falls under several of the APSF Patient Safety Priorities include the first priority: preventing, detecting, and mitigating clinical deterioration in the perioperative period since appropriate patient monitoring and safe procedure techniques during peripheral nerve block and epidural placement is crucial. The second priority is Safety in non-operating room locations such as endoscopy and interventional radiology suites. Peripheral nerve blocks and epidural procedures are often performed in non-operating room locations including the preoperative holding areas or in a patient room on the OB floor. The 4th priority involves medication safety and we need to be careful with local anesthetic administration to help keep our patients safe.

Now, let’s get into the article. The authors re-introduce this topic by highlighting the clinical and basic science efforts that have led to the discovery of the clinical presentation of LAST as well as treatment options and techniques for monitoring and prevention as well as the role that the APSF Newsletter has had in bringing this vital information to anesthesia professionals who perform peripheral nerve blocks and epidural procedures or administer local anesthetic medications. Over the past decade, the area of regional anesthesia has expanded greatly to include ultrasound guidance for procedures, catheter placement, IV infusions of Lidocaine for pain relief, local infiltration, new local anesthetic medication options such as Exparel or liposomal bupivacaine. Regional anesthesia is often the starring role in Enhanced Recovery After Surgery or ERAS protocols, for multimodal anesthesia plans, and to possibly decrease cancer risk.

Has the incidence of LAST changed over the years? It is hard to say for sure since the reported estimates for the incidence of LAST vary with single-site studies at academic institutions reporting very low rates of LAST while larger studies from registry and administrative databases report an incidence of 1 in 1,000 peripheral nerve blocks. But this is not the time to let down our guard since the incidence may be higher since LAST events are often under-reported and may be misdiagnosed. What does the literature tell us? Morwald and colleagues report an incidence of events with LAST clinical signs and symptoms of about 1.8 out of 1,000 peripheral nerve blocks during joint replacement surgery. When the authors looked at the same population during 2014 of patients undergoing knee replacement surgery, they discovered the rate of lipid emulsion administration to be about 2.6 out of every 1,000 peripheral nerve blocks…in other words LAST may occur as often as once out of every 384 surgeries. Wow!! This is such an important area for anesthesia professionals to continue to stay alert to help keep their patients safe.

So, what are the risk factors for the development of LAST? Historically, we have recognized that hypoxia and acidosis are risk factors that increase the risk for LAST. Other risk factors include the following:

  • Pre-existing heart disease including myocardial ischemia, arrhythmias, conduction abnormalities, and reduced ejection fraction
  • Extremes of age
  • Frailty
  • Conditions that cause mitochondrial dysfunction such as carnitine deficiency
  • Liver disease and Kidney disease since these patients are at risk for delayed presentation of LAST due to decreased local anesthetic metabolism or disposition.

Barrington and Kruger reported on 25,000 peripheral nerve blocks performed in Australia between January 2007 and May 2012 with 22 cases of LAST for an incidence of 0.87 in 1000 blocks. This study revealed that ultrasound guidance decreased the risk of LAST likely due to less intravascular injections and lower drug volume administration for the ultrasound guided blocks. Even with ultrasound guidance though LAST can still occur. This study also found that small patient size was an additional risk factor for LAST which may be due to skeletal muscle acting as a large reservoir for local anesthetic. Fettiplace and colleagues conducted a study with a rat model that showed this finding as well. This may be an area where anesthesia professionals can take action to decrease the risk for LAST by decreasing the dose of local anesthetic administered for patients with risk factors.

The authors reports on 3 large scale studies of case reports on LAST events including DiGregorio and colleagues from October 1979 to October 2009, Vasques and colleagues from March 2010 to March 2014, and Gitman and Barrington from January 2014 to November 2016. In the first and oldest study, there were more events associated with epidurals and brachial plexus blocks. This has changed though in the past 10 years with findings from the more recent studies where neuraxial procedures with LAST represented only 15% of the LAST events and extremity blocks accounting for 20% of the published cases with additional cases due to penile blocks and local infiltration which each make up about 20% of the cases. The studies also revealed that LAST events may be associated with continuous IV infusions, paravertebral, peribulbar, transabdominis plane, and maxillary nerve blocks, topical gel local anesthetics, and following oral, esophageal, or tracheal mucosal administration. LAST can even occur following submucosal nasal injection of 120mg of lidocaine leading to cardiac arrest which was reported in the literature. Do not let down your guard. The studies have also highlighted where last occurs with 80% of cases in the hospital, 10% of cases in an office setting, and the last 10% in the ER or at home. About 60% of cases occurred with anesthesia professionals or trainees involved in the patient care and 30% occurred with surgeons involved in the local anesthetic administration and the following 10% of cases occurred with dentists, ER physicians, pediatricians, cardiologists, and dermatologists. This is an important area where anesthesia professionals need to continue to provide education about safe local anesthetic administration and recognizing and treating LAST for all other physicians and specialties who use local anesthetics.

Get your stop watches out because next up we are going to talk about when LAST occurs. We are sticking with the three large studies that I mentioned earlier which have shown a trend towards more of a delay in the onset of clinical signs and symptoms of LAST and this is thought to be due to ultrasound use and catheter-based techniques. The use of ultrasound can decrease the risk of intravascular injection and immediate-onset LAST which also helps to explain why we are seeing more delayed presentations with 40% of the LAST cases presenting over 10 minutes after the local anesthetic administration. Back in 2009, delayed presentation was much less common and only occurred about 12% of the time. Additional cases of delayed presentations occur following catheter placement or IV infusions. Anytime there is a time gap between local anesthetic administration and the development of LAST it can make correct diagnosis and management difficult and this is especially true for our of the OR locations.

So far, we have reviewed incidence, risk factors, and timing of presentation. It’s time to discuss the clinical signs and symptoms of LAST so we know what to be on the look-out for. There is a table in the article that I hope you will check out and I will include it in the show notes as well. There is a range for the clinical presentation of LAST from mild to severe central nervous system and/or cardiovascular symptoms. Actually, half of the cases only have CNS symptoms while about 20% have only cardiovascular symptoms and about 30% have a combination. Keep in mind that the cases with only cardiovascular symptoms were often under general anesthesia or sedation which may mask the CNS symptoms. 50% of patients will preset with a seizure and the other mild CNS symptoms occur about 30% of the time in the 2 most recent studies. These CNS symptoms include tinnitus, metallic taste, hallucinations, slurred speech, limb twitching, extremity paresthesia, intention tremor, facial sensorimotor and eye movement abnormalities. For the cardiovascular symptoms, the most common presentation included arrhythmias such as bradycardia, tachycardia, and VT or VF, conduction disturbances including bundle branch block, AV conduction block, and widened QRS, hypotension, and cardiac arrest which includes non-shockable rhythms, PEA, and asystole. A common presentation appears to be progression of symptoms from hypotension and bradycardia to complete cardiovascular collapse within minutes. At this time, we don’t know which patients will progress to cardiac arrest, but we do know that early treatment can delay or prevent the progression and decline. The authors leave us with a call to action to be prepared to treat early for patients with signs and symptoms of LAST following local anesthetic administration.

Before we get to the treatment, we need to talk about a new local anesthetic medication that hit the scene in 2011. Do you use liposomal bupivacaine at your institution? Liposomal bupivacaine or Exparel   maintains the local anesthetic within a nanoparticle carrier matrix in order to prolong the action with a slow release. It is available in 20ml vials with 266mg of 1.3% bupivacaine and this is the manufacturer’s maximum recommended dose for an adult patient. In 2011, it received FDA approval for local infiltration at the surgical incision site and in 2018 it was approved for interscalene brachial plexus nerve block. This is a very interesting medication. 3% of the bupivacaine is free and available to start working to provide analgesia immediately and bupivacaine will remain in circulation of up to 96 hours following injection. This is yet another subset of patients at risk for delayed presentation. Another important risk for patients receiving liposomal bupivacaine is immediate release of the liposomal bupivacaine leading to increased free plasma bupivacaine concentrations and a big risk of LAST. This can happen if non-bupivacaine local anesthetics are given within 20 minutes. Communication for the use of liposomal bupivacaine is imperative. Safe use of this drug should include education for operating room staff and a time-out prior to use so that other other local anesthetics are not given within 20 minutes. The risk for LAST is a big concern with liposomal bupivacaine which is evident since an adverse event signal was detected for increased rates of LAST with the use of liposomal bupivacaine in the FDA Adverse Event Reporting System Database between January 2012 and March 2019.

The authors point out that there is a clearly a need for improved reporting on LAST events especially in any clinical trials that study local anesthetics especially with some of the newer techniques including catheter placement and IV lidocaine infusions so that delayed or out of OR events are not missed. The authors write, “Until this occurs, understanding the associated risks will remain hampered by reliance on anecdotal reports and personal experience.”

Finally, let’s review the treatment for LAST so that if and when it occurs, we will be ready. We first saw recommendations for treatment published in 2010 which highlighted the importance of airway management, treatment for the seizure, and administration of intralipid. In the past decade, the recommendations have been updated to include a treatment checklist to make sure important steps are not missed and an easier way to give the lipid emulsion. Remember, the lipid emulsion is coming to the rescue by redistribution of the local anesthetic, direct inotropic effects, and shuttling the lipid away from the brain and heart to the liver and skeletal muscle so it is important to give a big dose quickly of about 1.5mkl/kg over the first 2 minutes followed by either repeat bolus or infusion. A study in a rat model by Liu and colleagues suggests that repeating the bolus dose may be superior to the initial bolus followed by infusion method. In addition, don’t forget to keep the total dose administered to less than 10-12 ml/kg ideal body weight. Another important part of LAST resuscitation is cardiovascular resuscitation by treating the underlying pathology with intralipid, while taking care to decrease the dose of epinephrine to about 1 mcg/kg. There does not appear to be a role for Vasopressin for LAST resuscitation due to no benefit from the increased afterload and worse outcomes in animal models. Other medications to avoid is local anesthetic anti-arrhythmic, beta-blockers, calcium channel blockers, This is the time to alert the ECMO team at your institution since extracorporeal circulatory support may be required.

Do you administer local anesthetics? Have you taken care of a patient with LAST? Unfortunately, we will likely continue to see this since there is an increasing role for regional anesthesia and IV lidocaine infusions as we strive to provide multimodal analgesia and minimize opioid administration. But there are some steps that we can take to improve safety including appropriate local anesthetic dosing, safe technique, recognizing risk factors, and working on safety protocols. It is imperative to keep LAST at the top of your differential diagnosis and make sure that any healthcare professional who administers local anesthetic medications can recognize LAST and treat quickly when needed.

There are some simple and very informative charts that accompany this article. I encourage you to check them out and I will include the link to the article in the show notes as well.

If you have any questions or comments from today’s show, please email us at [email protected]. Visit APSF.org for detailed information and check out the show notes for links to all the topics we discussed today.

And remember, the February 2021 APSF newsletter is out and you can find it on the APSF website. That’s right, the wait is over and you can spread the news to your friends and colleagues. I will include a link in the show notes and I am so excited to talk about some of these articles and introduce some of these authors on future shows. Thanks for listening.

Until next time, stay vigilant so that no one shall be harmed by anesthesia care.

© 2021, The Anesthesia Patient Safety Foundation