Difficult Cases: Perioperative Anaphylaxis Joel M. Hartman, MD Phillip L. Lieberman, MD FAAAAI Presented February 28th, 2014 AAAAI Annual Meeting San Diego, CA Objectives • Appreciate common medications associated with perioperative anaphylaxis and the complexity of available testing • Appreciate an uncommon cause of perioperative anaphylaxis Case 1 Park YC et al HPI – 34 year old female, 55 kg – Scheduled to have elective endovenous laser surgery and varicosectomy – No underlying medical disorder – No past surgeries – Preoperative evaluation unremarkable including exam, 12 lead ECG, Chest X-ray, Complete blood count Case 1 Pre-operative – 30 minutes prior to the Operating Room (OR) she received 2 mg midazolam and 0.2 mg glycopyrolate intramuscular – In the OR, pre-anaesthetic vitals: • Blood Pressure 110/70 mmHg • Heart Rate 75 bpm • Pulse oximetry 99% Case 1 Induction Anesthesia Administered: – 110 mg propofol mixed with 2% lidocaine injected intravenously – Loss of consciousness verified and patient ventilated using a mask with 3L/min O2, nitro oxide 3L/min and sevoflurane 3 vol% – Endotracheal intubation occurred 1 to 2 minutes after 40 mg rocuronium provided Case 1 Intraoperative Course – 3 minutes after intubation HR and BP were 135/min and 75/35 mmHg, respectively – Anesthetic agent discontinued (vitals suspected to be related to inhalation anesthetic) – HR increased and BP decreased to 60/30 mmHg – Slight flushing of face and chest – Angioedema around eyes RECOGNIZING ANAPHYLAXIS (next slide) Recognize Perioperative Anaphylaxis • Prompt recognition may be challenging: – Side effects from anesthetic agents may mask or simulate findings – Verbal communication by the patient is limited – Visual inspection may be compromised by sterile drapes • Skin manifestations are less common compared to other causes of anaphylaxis Case 1 Intraoperative Course – Patient developed generalized urticaria with elevated end tidal CO2 consistent with obstructive pattern – Oxygen was increased to 6L/min, crystalloid and colloid provided, ephedrine 4 mg was administered – Improvement in BP and HR to 110/65 mmHg and 100 bpm, respectively – The urticaria, flushing and angioedema progressed Question #1 At this point her physicians are concerned about an allergic reaction. Which of the following labs might be helpful? A.) Serum Tryptase B.) Urine metanephrines C.) Serum glucose D.) Cardiac Biomarkers ANSWER on next slide Answer: Serum Tryptase • Can be detected as soon as 30 minutes but recommended 60-120 minutes after symptom onset • Serum tryptase is increased in 68% of IgEdependent perianesthetic anaphylaxis • Approx 4% of non-IgE reactions are associated with increased serum tryptase • False negatives levels may be seen in basophil mediated reactions • False positive levels may be seen in hypoxia and major trauma Ebo DG et al. Allergy 2007 Laroche D et al. Anesthesiology 1991 Mertes PM et al. J Investig Allergol Clin Immunol 2011 Case 1 Intraoperative Course – Patient was given hydrocortisone 250 mg, pipirinhydrinate 3 mg intravenously followed by midazolam 3 mg to prevent emergence – Vitals stabilized within 20 minutes and urticaria/angioedema resolved within 40 minutes – Physicians, in discussion with family, decided to proceed with the planned procedure – A serum tryptase was sent Question #2 Which of the following agents is most likely responsible for our patient’s symptoms? A.) Propofol B.) Midazolam C.) Rocuronium D.) Latex ANSWER on next slide Perioperative Anaphylaxis: Answer: Rocuronium • Anaphylaxis is more common with general anesthesia compared to local or spinal • Most common overall cause: Neuromuscular Blocking Agents (NMBA) – 3 most common causative agents in both adults and children include NMBA, antibiotics, latex • Prevalence varies with geographic area: – Antibiotics likely more common in U.S. (approx 50% of cases) – Neuromuscular blocking agents are the most common cause in Europe (approx 70% of cases) Harboe T et al. Anesthesiology 2005 Simmons FE et al. Curr Opin Allergy Clin Immunol 2012. Gurrieri C et al. Anesth Analg 2011 Suspected Agents: Timing of symptoms is important Symptoms within First 30 Minutes of Anesthesia – Antibiotics – Neuromuscular blocking agents – Hypnotic inducing agents Symptoms After 30 Minutes of Anesthesia – – – – – Latex Protamine Supravital dyes (ex. Isosulfan blue) Plasma expanders Blood products Laxenaire MC. Ann Fr Anesth Reanim 1999 Case 1 Intra- and Postoperative – No additional muscle relaxants during the remaining 2 hour procedure – Operation completed without further complications – Successfully extubated with normal recovery in the post-anesthesia care unit – serum tryptase was elevated at 42 Question #3 Which of the following is an appropriate next step in the diagnosis of this patient? A.) Skin testing to agents used during the case B.) Bone marrow biopsy C.) Office based open challenge to rocuronium D.) Perform a methacholine challenge ANSWER on next slide Testing Answer: Skin testing to agents used • Few culprit drugs have reliable or standardized testing available • 72% of perioperative anaphylaxis is due to specific IgE – Understanding underlying mechanisms helps with choosing appropriate testing Mertes PM et al. J Investig Allergol Immunol 2005 Mertes PM et al. J Allergy Clin Immunol 2011 Testing: Understanding Mechanisms Proposed Mechanism Direct Mast Cell/Basophil Degranulation Ig-E Mediated Immunologic Non-IgE due to immune complexes Example Agent Radiocontrast agents ● Opioids ● Some neuromuscular blocking agents ● Antibiotics ● Latex ● Neuromuscular blocking agents ● Blood transfusion ● Agents with Probable IgE Mediated Mechanism Antibiotics Latex Neuromuscular Blocking Agents Protamine Chlorhexidine Blood transfusions containing IgA in IgA deficient subjects Barbiturates Isosulfan blue (sentinel node dissection) Testing • In vitro testing for allergen-specific IgE is reported for latex, succinylcholine, thiopental and penicillin – In vitro testing is generally less sensitive compared to skin testing • Skin testing can be performed for agents commonly associated with IgE-mediated reactions – Commercial preparations for latex are not available Ebo et al. Allergy 2007 Suggested skin testing concentrations Agents Skin Prick Tests Intradermal Tests mg/mL Dilution mg/mL Dilution µg/mL Atracurium 10 1/10 1 1/1000 10 Cisatracurium 2 Undiluted 2 1/100 20 Mivacurium 2 1/10 0.2 1/1000 2 Rocuronium 10 Undiluted 10 1/200 50 Suxamethonium 50 1/5 10 1/500 100 Pancuronium 2 Undiluted 2 1/10 200 Vecuronium 4 Undiluted 4 1/10 400 Thiopental 25 Undiluted 25 1/10 2500 Etomidate 2 Undiluted 2 1/10 200 Midazolam 5 Undiluted 5 1/10 500 Propofol 10 Undiluted 10 1/10 1000 Adapted from PM Mertes et al. J Investig Allergol Clinic Immunol 2011. Why Some Agents Need Dilution? (next slide) Some Agents Require Dilution • Some agents, such as succinylcholine, atracurium, and mevacurium, may cause direct mast cell degranulation – Must dilute such agents for initial prick • May start with concentrate with other agents Caveat: “Perfect” skin testing concentrations not known • Additional references for suggested testing concentrations are available • Appendix WEB Supplement. Mayo Clinic Allergy Division protocol for assessment of medications/substances http://links.lww.com/AA/A314 Screening Testing • Screening subjects without a prior history of allergic drug reaction is not recommended – Data suggests a discrepancy between skin prick test results and clinical outcomes – One study screening anesthesia-naïve subjects reports that 9.3% had either a positive test to one or more NMBAs or the presence of specific IgE to quaternary ammonium ions Lexenaire MC et al. Ann Fr Anesth Reanim 2002 Porri F et al. Clin Exp Allergy 1999. Back to Case 1 Postoperative Testing performed several weeks later – Rocuronium showed positivity at 1/100 dilution with intradermal testing – All other agents used during surgery were tested and negative – Serum tryptase was normal Case 1 Postoperative Testing – Vecuronium was tested and also positive at 1/100 dilution with intradermal testing Question #4 Which of the following statements regarding neuromuscular blocking agents is correct? A.) Skin testing is recommended for preanesthesia screening of subjects without a history of anaphylaxis. B.) The adamantium core is responsible for crossreactivity among neuromuscular blocking agents. C.) Neuromuscular blocking agents cause only IgEdependent reactions. D.) Neuromuscular blocking agent reactions are more common in women. Answer on next slide Neuromuscular blocking agents Answer: Reactions are more common in women • Agents are responsible for both IgEdependent and IgE-independent reactions – Direct histamine release from mast cells and basophils is implicated • 3 out of 4 reactions occur in women – Suggesting cross-reactions with ammonium compounds in make-up and personal care products Baldo BA et al. Ann Fr Anesth Reanim 1993 Birnbaum J et al. Clin Exp Allergy 1994 Neuromuscular blocking agents: Cross Reactivity • The tertiary or quaternary ammonium structure likely responsible for cross reactivity – Estimated 65% by skin tests – 80% by radioimmuno assay inhibition • Patterns of cross-reactivity vary between subjects – Most consistent between vecuronium and pancuronium Ebo et al. Allergy 2007 Leynadier F et al. Br J Anesth 1987 Cross reactivity and testing (next slide) Variable Pattern of Cross Reactivity • Given the variable pattern of cross reactivity it is advised to: – Perform testing to suspect agent – Perform testing to any agent that may be used in future planned procedures • General agreement that succinylcholine carries the highest risk for anaphylaxis • Diagnostic management of anaphylaxis from NMBA rests upon an evocative history corroborated by appropriate skin tests Ebo et al. Allergy 2007 Case 1 Conclusion – Rocuronium was identified as the causative agent for this patient’s anaphylaxis – Patient and family also informed about positive result to vecuronium – Recommend avoiding both rocuronium and vecuronium, AND testing to potential neuromuscular agents prior to future planned procedures Risk Mitigation • Primary Prevention – Screening subjects without a prior history of allergic drug reactions is not recommended • Secondary Prevention – Accurate documentation of prior reactions – Make every effort to identify the responsible trigger – Avoid the culprit drug Next Case… Case 2 • HPI – A 52 year-old male seen in the office as a new patient for consultation for ‘shock’ occurring during lumbar laminectomy 2 years ago – He now has spinal stenosis and requires semielective laminectomy with spinal fusion Case 2 • Past History – Status post tonsillectomy and adenoidectomy at age 3 years (reportedly uneventful) – Hospitalized for dehydration with gastroenteritis at age 13 years – Takes omeprazole for gastroesophageal reflux – Carries an epipen due to several allergic reactions from bee stings • Physical exam, including vitals, all normal Case 2 • Review of Anesthesia Records – Prior to entering the Operating Room, he was given intravenous Rocephin and Versed – In the OR he was given succinylcholine – Within 30 minutes he developed profound hypotension requiring intravenous epinephrine and fluid replacement Case 2 • Skin testing was performed to each agent used during his procedure and these were all negative • A baseline serum tryptase was sent: 18 ng/mL Question # 5 Based on these results what would you advise the patient? A.) No further work-up is indicated and he may proceed with planned surgery. B.) Mastocytosis is unlikely. C.) Further work-up for mastocytosis is indicated. Answer on next slide Answer: Further Evaluation Threshold for further Work-up • Baseline total serum tryptase levels greater than 20 ng/mL are highly suggestive of systemic mastocytosis • One study evaluating the incidence of mast cell disorders in subjects with systemic reactions to Hymenoptera stings shows higher frequency of systemic mastocytosis diagnosis when a baseline serum tryptase cut off of 11.4 ng/mL was used • Given the clinical history in our patient, proceeding with further work-up for clonal mast cell disease would be indicated despite baseline serum tryptase less than 20 ng/mL Valent P et al. Int Arch Allergy Immunol 2012. Bonadonna et al J Allergy Clin Immunol 2009. Case 2: 816V Analysis • 816V mutational blood analysis showed a ckit 816V mutation – Can be performed on peripheral white blood cells, bone marrow or cells from skin or other organs – Bone marrow yields most sensitive results Sporadic vs. Familial occurrence of Mastocytosis (next slide) 816V KIT Mutation in a Case of Familial Mastocytosis • Most clustered cases of mastocytosis are pediatric, without KIT mutations • May also present with uncommon KIT lesions • Generally accepted that adult patients with sporadic mastocytosis express activating mutations in D816V • A recent case was reported describing familial systemic mastocytosis in two adults, a mother and her son, both carrying the D816V mutation Zanotti R et al. J Allergy Clin Immunol 2013. Case 2: Bone Marrow Biopsy was Performed • Bone marrow sampling revealed the following: – Multifocal aggregates of spindle-shaped mast cells with 15 mast cells per aggregate – Mutational analysis revealed presence of 816V KIT mutation Question # 6 In a patient with mastocytosis which of the following statements is correct? A.) Increasing serum tryptase levels are not associated with an increased risk for anaphylaxis. B.) Minor procedures such as endoscopy are not associated with an increased risk for anaphylaxis. C.) Inhalation agents are generally preferred during surgery. Answer on next slide ANSWER: C.) Inhalation agents are generally preferred during surgery. Mastocytosis and Surgery • Patients with mastocytosis are at increased risk for adverse events • The stress of surgery and perioperative medications are potentially fatal triggers • Shock has been reported in minor procedures such as upper endoscopy Schwab et al Gastrointest Endosc 1999. Serum Tryptase and Anaphylaxis • Baseline serum tryptase levels are higher in mastocytosis subjects with anaphylaxis compared to those without anaphylaxis Brockow et al Allergy 2008. Medication use in Mastocytosis • Medications may cause mast cell activation in subjects with either cutaneous or systemic mastocytosis – Specific medications may have varying effect on histamine release – Dermal mast cells express opioid receptors that stimulate mediator release without specific IgE. • Generally recommended to avoid higher risk medications • Volatile (inhalation) anesthetics are generally safe – Inhalation agents generally do not cause histamine release Ochoa Chaar C. The American Surgeon 2009 List of Medications and Risk (next slide) Higher Risk Meds Category Analgesics Hypnotics Muscle Relaxants Local Anesthetics Konrad FM Acta Anesthesiol Scand 2009. Examples Morphine NSAIDs Thiopental Succinylcholine Mivacurium Rocuronium Atracurium Lidocaine Bupivocaine Lower Risk Meds Category Analgesics Hypnotics Muscle Relaxants Local Anesthetics Examples Fentanyl Acetaminophen Benzodiazepines Propofol Etomidate Ketamine Cis-Atracurium Pancuronium Ropivacaine Konrad FM Acta Anesthesiol Scand 2009. Ochoa Chaar C. The American Surgeon 2009. Bains S. Ann Allergy Asthma Immunol 2010. Question # 7 Which of the following has been shown to improve safety in subjects with mastocytosis undergoing surgery? A.) Using NSAIDs as premedication prior to surgery. B.) Preoperative skin testing. C.) Preoperative exercise echocardiogram. D.) Administration of H1 and H2 blockers 30 minutes prior to surgery. Answer on next slide Management: Data is Case-based • Combination of H1, H2 blockers and steroids have been shown to be successful – Provided 30 minutes prior to surgery • Anxiolytics have also been used with success • There are varying reports with preoperative skin testing Possible Management Strategies (next slide) Ochoa Chaar C. et al The American Surgeon 2009. Potential Recommendations Recommended one hour prior to procedure Diphenhydramine 25 to 50 mg orally or IV Ranitidine 150 mg orally, or 50 mg IV Optional one hour prior to procedure Anxiolytic to minimize stress and emotional factors Montelukast 10 mg orally Prednisone 25 to 50 mg orally, 12 hours and 2 hours prior to procedure (or equivalent of other systemic steroid) Comment on Preoperative NSAID Use (next slide) Adapted from Ochoa Chaar C. et al The American Surgeon 2009. Non-Steroidal Anti-inflammatory (NSAID) Agents Prior to Surgery • Prostaglandin D2 levels shown to be increased in patients with systemic mastocytosis • Few reports exist using aspirin or NSAIDs for pre-treatment to prevent formation of prostaglandin D2 – Use of NSAIDs can be considered though data for preoperative use is limited and there may be an increased bleeding risk Roberts LJ et al. N Engl J Med 1980. Potential Recommendations in our Patient Case • Avoid high risk meds if possible – Advise use of inhalation agents • Continue combination H1 and H2 blockers until after patient is fully recovered • Close monitoring throughout the perioperative period, including until after patient has fully recovered References • • • • • • • • • • Laroche D, Vergnaud MC, Sillard B, et al. Biochemical markers of anaphylactoid reactions to drugs. Comparison of plasma histamine and tryptase. Anesthesiology 1991; 75:945-49. Mertes PM, Malinovsky JM, Jouffroy L, et al. 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Bonadonna P, Perbellini O, Passalacqua G, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol 2009; 123:680-6. Zanotti R, Simioni L, Garcia-Montero AC, Perbellini O, Caruso B, Jara-Acevedo, Bonaficio M, Matteis G. Somatic D816V KIT mutation in a case of adult-onset familial mastocytosis. J Allergy Clin Immunol 2013; 131(2):605-607. References • Akin C, Valent P, Metcalfe D. Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126:1099-104. • Schwab D, Raithel M, Ell C, et al. Severe shock during GI endoscopy in a patient with systemic mastocytosis. Gastrointest Endosc 1999; 50:264-7. • Bains SN, Hseih FH. Current approaches to the diagnosis and treatment of systemic mastocytosis. Ann Allergy Asthma Immunol 2010; 104:1-10. • Ochoa Chaar C, Bell RL, Duffy TP, et al. Guidelines for safe surgery in patients with systemic mastocytosis. 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