Anaphylaxis and Anesthesia: A Case-based Discussion of Fundamental Principles

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1 Anaphylaxis and Anesthesia: A Case-based Discussion of Fundamental Principles Stephanie Keller, MD Resident in Anesthesia and Critical Care University of Pennsylvania, Philadelphia PA Joshua H. Atkins, MD,PhD Assistant Professor of Anesthesiology and Critical Care Assistant Professor of Otorhinolaryngology: Head and Neck Surgery University of Pennsylvania, Philadelphia, PA A 32-year-old female (5 5, 136 lbs) with a past medical history significant for mild asthma presents for functional endoscopic sinus surgery. The patient has no previous history of anesthesia, no drug allergies and uses an albuterol inhaler as needed for asthma flares with no recent use. An IV induction is planned followed by endotracheal intubation and maintenance with sevoflurane. During induction, the patient receives fentanyl, propofol, vecuronium and cefazolin. Several minutes after securing the endotracheal tube, the anesthesiologist notices a precipitous drop in the arterial blood pressure to systolic pressures of 60s-70s with sinus tachycardia and a heart rate in the 130s. The blood pressure is unresponsive to multiple boluses of phenylephrine and ephedrine. Several boluses of epinephrine 16 mcg and 1.5 L of normal saline solution are administered with an improvement in the arterial blood pressure. An epinephrine infusion of 2mcg/min is begun. The chest is examined under the gown and the skin appears mottled. Mild wheezing is auscultated bilaterally and peak ventilatory pressures are moderately elevated. Hydrocortisone 50mg, diphenhydramine 25mg, and ranitidine 50mg are administered intravenously. Ten puffs of albuterol are administered via the endotracheal tube. The patient s hemodynamics stabilize and surgery commences. The surgery proceeds smoothly and the epinephrine infusion is slowly weaned. The patient is extubated at the end of the case and sent to the ICU, where she experiences an uneventful 48-hour recovery and is discharged home for outpatient follow-up. Although the outcome was positive, the anesthesiologist and surgical team are left with questions regarding the potential causes of the hemodynamic instability, the information the patient should receive regarding the safety of future anesthetics and what if any follow up care should be recommended. What is anaphylaxis and how may a patient clinically present under general anesthesia? Anaphylaxis is a systemic, inflammatory mediated response to an offending agent which via an Ig-E mediated response causes the release of multiple inflammatory mediators. Similar to an anaphylactic reaction, patients may also experience an anaphylactoid reaction. An anaphylactoid reaction produces an identical clinical picture as anaphylaxis, but it does not involve an Ig-E mediated pathway for release of inflammatory mediators but rather direct stimulation of immune cells by the offending agent.

2 Whether it is an anaphylactic or anaphylactoid reaction, both reactions result in the release of inflammatory mediators that produce multiple clinical and physiological alterations in different organ systems of varying clinical severity. Responses can range from mild cutaneous symptoms to complete cardiovascular collapse. Often, the typical initial presentation of rash and erythema will not be immediately recognized. This may be due to multiple factors unique to the operating room environment. The patient is often covered in surgical drapes and the skin is not readily observed. Also, many of the physiological changes attributed to anaphylaxis may be masked by general anesthesia. Frequently, the anesthesiologist s first sign of an anaphylactic reaction will be the cardiovascular symptoms including hypotension, tachycardia, bradycardia, cardiac arrhythmias and cardiovascular instability 1, 5. The time course of these events can be quite rapid and if not recognized, cardiac arrest can result within minutes of the inciting event. Other commonly reported presentations under general anesthesia include the respiratory manifestations of bronchospasm 1, 5. These respiratory manifestations can present as increased peak airway pressures, decreased tidal volumes, and wheezing on auscultation. Airway swelling and edema are frequent sequelae. Because anaphylaxis can present with different symptoms of varying clinical severity, making the diagnosis can be extremely difficult. The initial diagnosis of anaphylaxis is presumptive based on presenting clinical symptoms in temporal relationship to possible triggering agents. Most anaphylactic reactions occur within 5-10 minutes of introduction of the inciting agent 8 with many reactions occurring within minutes of anesthesia induction 1. Important to note, however, anaphylactic reactions to latex and medications administered via enteral routes may present with a delayed response 5. What are some of the changes in physiology occurring during an anaphylactic reaction? Anaphylaxis is an antibody-mediated response. On an initial exposure to an allergen, susceptible individuals develop Ig-E antibodies to that allergen. When these susceptible individuals are reexposed to that allergen, Ig-E antibodies are cross-linked, and they activate a cascade of inflammatory mediators including histamine, proteases, prostaglandins, and leukotrienes. These inflammatory mediators are responsible for the clinical signs and symptoms of anaphylaxis, including the hypotension, bronchospasm, and edema. What is the incidence of anaphylaxis and what are the common triggering agents? The incidence of perioperative anaphylaxis is estimated at 1 in 10,000-20,000 anesthetics 1. While these reactions are rare, the overall incidence may be underreported secondary to the difficulty in making and confirming the diagnosis. Even if the diagnosis of anaphylaxis is made, discerning the causative agent is difficult. Very frequently multiple medications are administered in close temporal proximity to one another. Two retrospective studies examined cases of anaphylaxis and found the most common triggering agents to be neuromuscular blockers with both rocuronium and succinylcholine most commonly implicated 3. Latex and antibiotics were the second and third most common cause of anaphylaxis respectively 2, 3. Seventy percent of the cases of anaphylaxis to antibiotics were attributed to beta lactams 4. Important to note is the frequency in which antibiotics are used throughout the OR such as antibiotic coated central lines and antibiotic irrigation solutions.

3 Although rare, case reports of anaphylactic reactions many common drugs in the OR have been reported. These cases include induction agents/hypnotics, colloids, opioids, aprotinin, protamine, heparin, blood products and radiocontrast dye 3, 4. There is very little evidence to suggest patients with an egg or soy allergy should avoid propofol 4. There have been no documented case reports of anaphylaxis to halogenated inhalation agents 4. What should you do if you suspect an anaphylactic reaction? The diagnosis of anaphylaxis is based on a high index of clinical suspicion. If you suspect anaphylaxis, withdraw the suspected triggering agent, secure the airway if not already secured and administer 100 percent oxygen. Early epinephrine and aggressive fluid resuscitation are the foundations of treatment and should be administered as soon as the diagnosis is made. There is no contraindication for administration of epinephrine and adverse clinical outcomes have been associated with cases in which epinephrine administration was absent or delayed 1. A recent retrospective review of anaphylaxis cases suggests that treatment of anaphylaxis with epinephrine is frequently delayed 10. The study authors postulate this delay in administration of epinephrine is likely due to difficulties in diagnoses and a lack of knowledge regarding dosage, timing and route of administration 10. There is currently no established IV dosing regimen for epinephrine 6. Several sources suggest that epinephrine should be bolused in small increments ( mcg boluses depending on severity of reaction) and titrated in incremental doses to achieve hemodynamic stability 1, 4. An epinephrine infusion should be strongly considered, starting with a low dose infusion (1-2ug/min) with titration as needed for control of clinical symptoms and hemodynamic stability 1. Intramuscular epinephrine (500mcg in adults, mcg in children) can be used in patients without intravenous access. Inflammatory mediators released during anaphylaxis induce systemic vasodilatation and increased vascular permeability promoting large fluid shifts to the interstitial space. Fluid therapy with crystalloid or colloid solution is paramount to maintaining intravascular volume and cardiovascular stability. After administration of epinephrine, other therapy modalities can be considered, including 2 agonists, corticosteroids, and H1/H2 antagonists. These therapies are second line treatment and should only be considered only after initiation of epinephrine therapy. Bronchospasm can be treated with an inhaled/nebulized agonist 2 such as albuterol. Persistent bronchospasm may respond to an IV injection of salbutamol ( ug) (1). Corticosteroids can be administered, but they will not improve the acute course of anaphylaxis. They may play a role in the treatment of angioedema and protracted anaphylaxis, but their roll has never been evaluated in any placebo-controlled trial 1. There is also no one corticosteroid that is recommended in the treatment of anaphylaxis although hydrocortisone (0.5-2mg/kg) is frequently employed. Intravenous methylprednisolone (1-2mg/kg) and dexamethasone are alternative agents. H1/H2 antagonists routinely are administered for anaphylaxis. Diphenhydramine (H1+H2) 25-50mg IV or ranitidine 50mg/cimetidine (H2) 4mg/kg can be considered 6. A few studies suggest

4 that the combination of H2 and H1 blockers may improve the cutaneous symptoms 7 however; controversy exists to the best regimen. Are there any tests that can be performed at the time of a suspected anaphylactic reaction to help support your clinical diagnosis? At the time of a suspected anaphylactic reaction, blood histamine and tryptase levels may be drawn. Histamine has an exceptionally short half-life and is rarely useful. Histamine levels should ideally be drawn within 30 minutes and tryptase within an hour of the reaction 1. Followup tryptase levels are recommended at 3-6 hours and after 24 hours to trend the relationship of the tryptase level to the timing of the event. Elevations in these values may aid in supporting the diagnosis of anaphylaxis and determining the severity of the reaction, but they provide no evidence to the casual agent 1. A negative test dose not exclude anaphylaxis. Should the patient be extubated and discharged home as planned? The decision to extubate must be based on both clinical and patient factors. Clinically, the patient should be stable from a pulmonary and cardiovascular standpoint. The patient should be free of wheezing and have normal pulmonary mechanics. Anaphylaxis may cause significant swelling and edema of the airway, which should be assessed prior to extubation. Additional patient comorbidities such as history of severe asthma, COPD, or cardiovascular disease may also weigh into the decision on when to extubate. Many sources recommend keeping patients for a period of observation after a suspected anaphylactic reaction 12. The patient should be kept for a minimum of six hours, however, longer observation may be warranted. Factors that contribute to increased length of observation include: a severe reaction, an idiopathic reaction, the risk of continued absorption of the antigen, a patient with co- morbid conditions such as asthma, or a history of a biphasic anaphylactic reaction 12. After an anaphylactic reaction, there is a rare risk that patients may develop symptoms of another anaphylactic response hours after the initial insult. Studies quote a risk ranging from 1-20 percent of developing this biphasic anaphylactic reaction 12. It is unclear why or which patients will have a relapse in symptoms of anaphylaxis, but because of this some sources suggest a full 24-hour observation period with patient education on discharge regarding the signs and symptoms of a recurring reaction 12. Clearly the management will be specific to the patient, the clinical severity of the reaction, the clinical circumstances, and the response to management. After a suspected anaphylactic reaction, what information should the patient receive regarding follow-up and further anesthetics? After a suspected anaphylactic reaction, questions arise regarding the identity of the triggering agent. The patient should be informed that they had an allergic reaction to a medication during surgery. It should be stressed that in order to avoid re-exposure to that agent and potential future reactions, identification of a potential causal agent is important. Identification of a causal agent can help future anesthesiologists develop a safe anesthetic plan. A referral to an allergist/immunologist can be made to do testing to help identify this agent. Referrals should be scheduled 4-6 weeks after the suspected anaphylactic reaction in order to avoid false negative tests due to mast cell depletion 5.

5 For identification of a causal agent for Ig-E mediated anaphylaxis, skin testing is the gold standard 1. Agents chosen for the skin testing should be linked to the clinical context of the anaphylactic reaction. Skin tests for the various potential causal substances vary in their sensitivity and specificity 1. For the most common causal agents, neuromuscular blockers, the sensitivity of the skin test approaches 95 percent 1. There is percent cross-reactivity among neuromuscular blockers, so recommendations suggest all skin tests for neuromuscular blockers should be performed to identify safe options 1. Skin tests for antibiotics are limited to beta lactam antibiotics and vancomycin 1,8. There are no commercially available skin tests for latex, although glove extracts are often used 1. Skin tests are available for most induction agents, opioids, local anesthetics, colloids, antiseptics and protamine. There is a chance that immunological testing may yield unknown results. In a study examining the causal agents of anaphylaxis, about 30 percent of examined cases found no identifiable casual agent 2. This study postulates that these unknown cases may be due to an anaphylactoid response to drugs rather than Ig-E mediated anaphylaxis 2. A 30-year-old female pharmacist with no prior medical history presents to an outpatient surgery center for routine excision of a benign lesion from her arm. The patient has no history of anesthetic problems or drug allergies, but is concerned because she develops a rash at work when she uses latex gloves. She questions if she has a latex allergy. Who is at risk to develop a latex allergy? Several groups of individuals are susceptible to developing a latex allergy. As suggested in the case scenario, health care workers are at risk secondary to repeated contact with latex products as well exposure to inhalation of the latex glove powder. About 5-17 percent of health care employees have a form of latex allergy. Patients may be reluctant to reveal an allergy to latex for fear that it could impede employability in the acute care setting. For the anesthesiologist, the operating room can have many hidden sources of latex exposure, including sterile gloves, latex tourniquets, PA catheter balloons, and the breathing bag on the anesthesia circuit 11. Latex is present in the stoppers of anesthetic medication vials. Large bore needles and repeat passes through a stopper may increase the potential for latex antigens to be transferred into administration syringes but in general the risk is considered to be minimal. Children with a history of multiple surgeries on the mucous membranes (genitourinary and bowel) as well as spina bifida are susceptible to developing an allergy secondary to multiple exposures to latex containing products. Patients with a history of food allergies to bananas, avocado, passion fruit, kiwi, and peaches may be susceptible because of the cross reactivity between latex and these tropical fruits. How may a latex allergy present? A latex allergy can range in severity from a contact dermatitis to a systemic anaphylactic reaction. The contact dermatitis may develop hours after exposure and manifest as localized erythema, edema, and a rash. Systemic anaphylaxis secondary to latex is the third most common cause of anaphylaxis and manifests similar to other presentations of anaphylaxis with the exception that symptoms may be delayed minutes after latex exposure.

6 How do you diagnosis a latex allergy? If a latex allergy is suspected, a patient can receive skin testing toward the latex proteins. Latex glove extracts are used, but the amount of latex proteins used is not standardized 1. The results of the Ig-E tests can be equivocal 8 and the results must be taken in context with the clinical scenario and patient risk factors. What is the treatment? The treatment for a suspected anaphylactic reaction to latex is the same as for any other suspected anaphylactic reaction. The suspected offending agent should be removed and epinephrine should be administered. The only treatment to prevent further reactions is avoidance of latex. How do you make an operative environment latex safe? Many health care facilities have moved toward a latex-safe environment in the operating room or the hospital as a whole. Hospitals have approached the latex allergy from two approaches. The first involves identifying all the latex products in the operative suite and switching to latex-safe alternatives so the work environment is latex free. The operating room is filled with latex products and it can be very difficult to identify all the products involving latex. The second approach involves having a supply of latex-free products stocked and readily available to care for a latex allergic patient.

7 Clinical evidence suggestive of an anaphylactic reaction? Search for other causes of symptoms Immediate Response: -Administer epinephrine (10-200mcg) - Repeat and titrate as necessary -Aggressive fluid administration (20-40ml/kg of crystalloid) -Discontinue suspected agent(s) -Early intubation and 100% oxygen - Initiate epinephrine infusion -Call for help Improvement/Cardiovascular stability Continued hemodynamic instability Can consider: -β2 agonists for bronchospasm -H1/H2 receptor antagonists (diphenhydramine 25-50mg IV; ranitidine 50mg IV) -Intravenous corticosteroids -Histamine, tryptase level during reaction -Observation post procedure - Prolonged PACU stay (6 hours) - ICU observation recommended for 24 hours (risk of delayed recrudescence) in severe cases -Consider continued oral corticosteroids & antihistamines (H2) -Consult with allergist/immunologist for further workup Improved clinical picture Cardiovascular collapse: ACLS Reference 1 Detacher P, Mouton-Faivre C, Emala CW: Anaphylaxis and Anesthesia: Controversies and New Insights. Anesthesiology 2009; 111: Harboe, T, Guttormsen AB, Irgens A, Dybendal T, Florvaag E: Anaphylaxis during Anesthesia in Norway: A 6-Year Single-center Follow-up Study. Anesthesiology 2005; 102: Mertes PM, Laxenaire MC, Alla F: Anaphylactic and Anaphylactoid Reactions Occurring during Anesthesia in France in Anesthesiology 2003; 99: Harper NJ, Dixon T, Dugue P, Edgar DM, Fay A, Gooi HC, Herriot R, Hopkins P, Hunter JM, Mirakian R, Pumphrey RS, Seneviratne SL, Walls AF, Williams P, Wildsmith JA, Wood P, Nasser AS, Powell RK, Mirakhur R, Soar J: Suspected anaphylactic reactions associated with anaesthesia. Anaesthesia 2009; 64:

8 5 Dewachter P, Mouton-Faivre C: What investigation after an anaphylactic reaction during anaesthesia? Curr Opin Anaesthesiology 2008; 21: Practice Parameters of the Joint Task Force on Practice Parameters for Allergy and Immunology : The diagnosis and management of anaphylaxis-an updated practice parameter. J Allergy Clin Immunol 2005; 115: S Lin RY, Curry A, Pesola GR, Knight RJ, Lee HS, Bakalchuk L, Tenenbaum C, Westfal RE: Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med 2000; 35(5): Ebo DG, Fisher MM, Hagendorens MM, Bridts CH, Stevens WJ: Anaphylaxis during aneasthesia: diagnostic approach. Allergy 2007; 62: Pasquarierella CA: Latex Allergy What the Anesthesiologist should know! Garvey LH, Belhage B, Kroigaard M, Husum B, Malling HJ, Mosbech H: Treatment with Epinephrine (Adrenaline) in Suspected Anaphylaxis during Anesthesia in Denmark. Anesthesiology 2011;115: ; Gurrieri C, Weingarten,TN, Martin DP, Babovic N, Narr, BJ, Sprung N, Volcheck GW. Allergic Reactions During General Anesthesia at A Large United States Referral Center. Anesth. Analg. 2011; 113(5): Pennsylvania Patient Safety Authority: Hidden Sources of Latex in Healthcare Products. Pa- PSRS Patient Safety Advisory 2004; 1(2). 12 Resuscitation Counsels (UK): Emergency treatment of anaphylactic reactions: Guidelines for healthcare providers