Episode #39 Perioperative Hypersensitivity and Patient Safety

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. A big threat to patient safety during anesthesia care includes reactions to medications. We need to remain vigilant when administering medications taking into consideration correct medication, dose, route and then our job is not done because we need to monitor for the response to the medication and be on the look-out for any adverse effects or reactions.

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, we are going to be talking about a specific medication and potential reaction. The featured article is from the February 2021 APSF Newsletter and is called, “Perioperative Hypersensitivity: Recognition and Evaluation to Optimize Patient Safety” by David Khan, Kimberly Blumenthal, and Elizabeth Philips. To follow along online, head over to APSF.org and click on the Newsletter heading. First one down is the current issue. Then, scroll down on the right under the Featured Articles heading until you see this article. What you will not see on the website is the exclusive content from the author David Khan. We will be hearing from him shortly, but first let’s start with a summary.

The authors highlight the scope of the problem. Cefazolin is a first generation cephalosporin that is used for prophylaxis to prevent surgical site infections. It is also a rather common cause of anaphylaxis in the United States with an anaphylactic reaction occurring once for every 10,000 surgeries. Have you seen this while providing anesthesia care? Correct diagnosis may be challenging, but serum tryptase levels within 2 hours can provide vital information. Keep in mind that Cefazolin has different R1 and R2 side chain groups than other beta-lactam antibiotics so that if you have a patient with a history of anaphylaxis to Cefazolin, your patient may be able to receive Penicillin and other cephalosporins safely.

Before we get more into the article, I want to introduce one of the authors, David Khan.

[Khan] Hello, my name is Dr. David Khan. I am professor of medicine and pediatrics in the division of allergy and immunology at UT Southwestern in Dallas.

[Bechtel] I asked David Khan why he wrote this article. Let’s take a listen to what he had to say.

[Khan] My colleagues, Dr. Elizabeth Philips and Kim Blumenthal and I wrote this article for 2 main reasons. First, this was an opportunity to increase awareness on the topic of perioperative sensitivity and highlight the fact that Cefazolin is the leading culprit in the US. We also hope this article provides practical advice regarding the approach to surgical prophylaxis in patients labeled as being allergic to penicillin. The second reason was to hopefully foster increased collaboration between anesthesia specialists and allergists regarding both patients with perioperative hypersensitivity and those with antibiotic allergy. Our specialty can certainly assist in helping identify the culprit in perioperative hypersensitivity reactions and also help de-label the thousands of patients with penicillin and other beta-lactam allergies n order to improve outcomes for your patients.

[Bechtel] What a great way to start the show. Thank you to David Khan and we are looking forward to hearing more from you at the end of the show. Let’s jump into the article as the authors take us through a case of a Cefazolin Anaphylactic reaction. A 50 year-old African American woman was evaluated at the Allergy and Immunology clinic for outpatient follow-up 2 months after 2 anaphylaxis events that occurred when she was administered antibiotics just before undergoing a hip replacement. The patient did not have any other medical co-morbidities and her home medications included Rosuvastatin 20mg daily and Acetaminophen as needed, and prior to these episodes, she had no known drug allergies.

For the first event, the patient received Vancomycin 2g and Cefazolin 1g preoperatively before receiving any sedation or anesthetic medications. Minutes after receiving Cefazolin, the patient developed skin flushing, facial and lip swelling, and hypotension. Treatment included Epinephrine 0.3mg IM, Diphenhydramine 50mg IV, and Hydrocortisone 125mg IV. Instead of proceeding with her planned hip replacement, she was observed in the ICU overnight. She returned to the preoperative holding area 10 days later for her hip replacement. Antibiotic administration included Cefazolin 2 g and this time Vancomycin was held given her recent reaction. Unfortunately, once again, minutes after receiving Cefazolin, the patient again developed facial swelling and flushing. Treatment included epinephrine 0.3mg IM as well as diphenhydramine 50mg IV and the patient was observed for several hours and remained stable. At the allergy clinic, the patient was tested with skin prick testing to Cefazolin as well as intradermal testing to Penicillin, Cefazolin, and Ceftriaxone. The results revealed weakly positive skin tests to Cefazolin and strongly positive intradermal testing to Cefazolin and negative to the other medications. She did well with Amoxicillin and Cephalexin 250mg PO challenges. This complete allergy workup allowed the patient to be correctly diagnosed with a Cefazolin anaphylaxis with the advice that it would be safe for her to take Penicillin and other cephalosporins as well as Vancomycin in the future. The recommendation was for Cefazolin to be documented in her medical and pharmacy records as a severe anaphylactic reaction and that she should wear a medic alert bracelet.

We are going to talk more about Cefazolin reactions, but let’s take a step back and discuss Perioperative Hypersensitivity. These are important reactions to be prepared for in the perioperative period. This is a frequently tested topic for anesthesia and healthcare professionals as well. Perioperative Hypersensitivity encompasses a wide range of reaction types from mild reactions to severe anaphylaxis which may even be fatal. There is a wide range for the incidence of these reactions as well, but recent studies report an incidence of 1 in 10,000. These reactions are thought to be usually the result of an allergic reaction with IgE-mediated mast cell activation. It is important to remember that there may be non-Ig-E dependent mechanisms that can activate mast cells following administration of certain medications. One of these mechanisms is related to the Mas-related G-protein-coupled receptor X2 which has been implicated in reactions to neuromuscular blocking medications, vancomycin, fluroquinolones, and opioids. Reactions to radiocontrast dyes may be due to non-IgE-mediated mast cell activation as well.

Have you taken care of a patient who developed a Perioperative Hypersensitivity reaction? Patients may present with cardiovascular and respiratory signs and symptoms including hypotension, tachycardia, bronchospasm, and cardiac arrest. Be on the lookout for erythema, urticaria, and angioedema especially because these mucocutaneous reactions may be hidden under the drapes. Of course, there are other reasons why patients may develop similar cardiovascular and respiratory changes especially shortly after induction of anesthesia and intubation due to medications, hypovolemia, heart failure, pre-existing respiratory disease, and difficult intubation. But help is on the way because an expert panel of anesthesia and allergy professionals developed a clinical scoring system for suspected perioperative hypersensitivity reactions. The authors include this table in the article, so head over to the website and check it out. The scoring system includes a weighted scale with points for or against perioperative hypersensitivity based on clinical parameters leading to a score for the likelihood of an immediate hypersensitivity reaction. The score is determined by cardiovascular, respiratory, and dermal/mucosal symptoms minus points for confounders in these categories as well as points for certain combinations of the above symptoms and depending on the timing of symptoms. The total score greater than 21 reveals an almost certain likelihood of an immediate hypersensitivity reaction. A score of less than 8 means it is unlikely that the reaction was due to an immediate hypersensitivity reaction. The authors note that this scoring system is new and has gone through content, criterion, and discriminant validity, but not independent external validation at this time.

Laboratory evaluation following suspected hypersensitivity reaction includes a serum Tryptase level. Remember, tryptase is a protease that is released by mast cells when they are activated. This lab test should be drawn within 2 hours of the reaction and the results will not be affected by the medications used to treat anaphylactic reactions. When tryptase levels are high, there is a high positive predictive value to this test for anaphylaxis ranging from 82-99%, but patients may have anaphylaxis and not have tryptase levels greater than 11.4ng/ml. In patients with more significant reactions including cardiac arrest, serum tryptase levels greater than 7.35 ng/ml have a 99% positive predictive value for hypersensitivity reaction. Another way to use elevated serum tryptase levels for anaphylaxis confirmation includes levels that are greater than 1.2 times the serum baseline tryptase +2. This level has a positive predictive value of 94%. We may also see elevated tryptase levels in cases of non-IgE mediated mast cell activation which occurs in about 10% of cases.

The most common causes of perioperative hypersensitivity reactions include the following: antibiotics, neuromuscular blocking medications, and disinfectants. In the United States, Cefazolin is the most common cause of perioperative hypersensitivity reactions with over 50% of the cases. These reactions may occur following the first exposure to Cefazolin, but the pathway of sensitization is still unknown. Another interesting point about cephalosporin reactions is that it is usually due to the R1 side chains. Cefazolin contains unique R1 and R2 side chains that all other beta-lactams in North America do not have. This is good news though since patients with Cefazolin allergy usually do not have allergic reactions to Penicillin or other cephalosporins.

While anesthesia and healthcare professionals are aware of the risks for perioperative hypersensitivity reactions and the presentation and timely treatment, the authors highlight the importance of laboratory testing to identify the culprit medication for suspected perioperative hypersensitivity reactions for the following reasons.

1. The patient may have had their surgery or procedure aborted due to the reaction, but they will likely need to undergo the surgery in the future.
2. To help keep patients safe when they need surgery and anesthesia in the future.

The international consensus recommendations include a comprehensive allergy evaluation in collaboration with anesthesia and allergy professionals for all patients who have a perioperative hypersensitivity reaction. This evaluation should occur 4 weeks after the event, but the information can be helpful as long as it is completed within 6 months. A timely evaluation is important since the majority of patients with anaphylaxis to cephalosporins will by negative on skin prick testing after 5 years.

The collaboration between anesthesia and allergy professionals is vital by providing information from the anesthesia record and operative note including time of drug administration and timing for other potential exposures including disinfectants, latex, lubricants, contrast dyes, gelatin sponges used for hemostasis, foreign devices, and local anesthetics. The outpatient allergy evaluation includes skin testing, followed by observed challenges with medications that tested negative on the skin testing. Keep in mind that most outpatient allergy clinics do not do IV medication challenges and do not complete challenges with opioids, benzodiazepines, neuromuscular blocking drugs, and propofol. For these medications that have a negative skin test, it may be helpful to administer a test dose prior to anesthesia induction. The good news is that 90% of patients who are formally evaluated by an allergist will be able to safely have anesthesia without a recurrent allergic reaction.

Anesthesia professionals often see patients in preop who have a reported history of allergy to penicillin or cefazolin, but have never seen an allergist. This may lead to alternative antibiotic administration in order to avoid the potential allergic reaction. This is not without other risks though. Alternative antibiotics may not be as effective for prophylaxis leading to increased risk for  infection. Plus, common alternatives such as clindamycin and vancomycin have an increased risk for Clostridium difficile colitis and acute kidney injury. Patients with cefazolin allergy may be able to receive other beta-lactam antibiotics safely when this is confirmed with allergy testing instead of just avoiding all beta-lactams in the future.

What about our patients with reported penicillin allergies which are often benign rashes, remote reaction in childhood, or unknown reactions? These patients with history of low-risk reactions can safely receive cefazolin. Emory University has a simple algorithm for perioperative antibiotic administration in patients with a history of penicillin allergy. Basically, patients were given Cefazolin or Cefuroxime unless their reported reaction included the following: Stevens-Johnson syndrome or toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, liver or kidney injury, anemia, fever, or arthritis following penicillin. Implementation of this algorithm led to increased cephalosporin administration with no immediate hypersensitivity reactions. Another important statistic is that for patients with documented anaphylaxis to penicillin, the risk of a cefazolin allergy is less than 1%.

The authors conclude with a simple standard approach for patients with perioperative hypersensitivity reactions that includes collaborating with allergists to identify the culprit and develop a plan for future anesthesia and surgery that minimizes the risk of repeat reactions. I will include a link to the allergists professional society in the show notes which may be helpful to connect anesthesia and allergy professionals. This may also be a time when an allergy telemedicine appointment can be useful for triage and risk stratification before sending patients for the skin testing.

Before we wrap up for today, I asked David Khan what’s next for his research and projects. I am so excited to share with you his response. Spoiler alert, it is very exciting in terms of increased patient safety going forward. Here we go.

[Khan] We are part of a multicenter drug allergy group interested in determining the optimal diagnostic testing strategy for patients with immediate reactions to cephalosporins particularly those with Cefazolin anaphylaxis. We are planning to conduct an NIH-sponsored study to recruit patients with anaphylaxis to cephalosporins and determine the optimal testing strategy in order to confirm the diagnosis and identify alternative cephalosporins these patients may safely receive in the future. We also hope to use nano-allergen technology to improve our understanding of cephalosporin allergy and potentially develop new diagnostic tools. Lastly, we plan to explore if there is a genetic basis for cephalosporin anaphylaxis.

[Bechtel] Thank you so much to David Khan for his contributions to the show today. We are looking forward to finding out the results from your studies and projects. Don’t forget that perioperative hypersensitivity reactions are rare events so it is important that we continue to learn about them so that we are prepared when they occur. Keep your eye on Cefazolin which is the most common cause of perioperative hypersensitivity reaction in the US. It may be beneficial to partner with allergy specialists to help with the diagnosis as well as determine which antibiotics can be safely administered and for further collaboration, you may include the surgery team in this as well. Finally, this article highlights that many patients will present to the OR with a penicillin allergy, but when this is unverified it may not represent a true allergy and many of these patients can receive cefazolin safely.

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. Please keep in mind that the information in this show is provided for informational purposes only and does not constitute medical or legal advice. If you have not done so already, we hope that you will rate us and leave a review on iTunes or where ever you get your podcasts.  Thanks for listening.

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

© 2021, The Anesthesia Patient Safety Foundation