Diagnostic Evaluation of Perioperative Anaphylaxis David A. Khan, MD Professor of Medicine and Pediatrics Southwestern Medical Center Allergy & Immunology Program Director Division of Allergy & Immunology 1 1

Outline Epidemiology Anesthetic Drugs Clinical Features Causal Agents Diagnostic Testing 2

Incidence of Perioperative Epidemiology Country Incidence of Perioperative Anaphylaxis France 1 in 4600 Australia 1 in 5000-13,000 Thailand 1 in 5000 New Zealand 1 in 1250-5000 England 1 in 3500 Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429-51. 3

Epidemiology Incidence remains poorly defined Few prospective studies Uncertainty in accuracy and completeness of reports Immune-mediated reactions account for > 60% reactions Mortality ~3-9% 4

Anesthetic Drugs Perioperative Medications Used Period Preoperative Antibiotics, opioids, latex, chlorhexidine, blood/colloids, benzodiazepines Intraoperative Neuromuscular blocking agents (NMBA), hypnotics, opioids, neuroleptics, benzodiazepines, local anesthetics, dyes, contrast, latex, aprotinin, chlorhexidine, blood/colloid Postoperative Opioids, NSAIDs, neostigmine, atropine/glycopyrrolate 5 Thong BYH et al. Ann Allergy Asthma Immunol 2004;92:619–28.

fentanyl, sufentanil, morphine pancuronium, rocuronium, vecuronium Class of Drug Name Intravenous anesthetic Induction agents: thiopental, etomidate, propofol, ketamine Inhalational anesthetic Volatile liquid anesthetics: halothane, enflurane, isoflurane, desflurane, sevoflurane Antimuscarinic Atropine, hyoscine, glycopyrronnium Sedative and analgesics Class Example(s) Benzodiazepine midazolam NSAIDs ketorolac Opioids fentanyl, sufentanil, morphine NMBA nondepolarizing (aminosteroid) pancuronium, rocuronium, vecuronium NMBA nondepolarizing (benzylisoquinolinium) atracurium, mivacurium NMBA depolarizing) succinylcholine Opioid antagonist naloxone Benzodiazepine antagonist fluamzenil 6

Causal Agents of Perioperative Reactions in France Substances Responsible for IgE-Mediated Hypersensitivity Reactions in France: Results from Seven Consecutive Surveys Substance 1984-1989 (n=821) (%) 1990-1991 (n=813) 1992-1994 (n=1030) 1994-1996 (n=734) 1997-1998 (n=486) 1999-2000 (n=518) 2001-2002 (n=502) NMBAs 81.0 70.2 59.2 61.6 69.2 58.2 54.0 Latex 0.5 12.5 19.0 16.6 12.1 16.7 22.3 Hypnotics 11.0 5.6 8.0 5.1 3.7 3.4 0.8 Opioids 3.0 1.7 3.5 2.7 1.4 1.3 2.4 Colloids 4.6 5.0 3.1 4.0 2.8 Antibiotics 2.0 2.6 8.3 15.1 14.7 Other 2.2 2.9 Total 100 Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51. 7

Perioperative Anaphylaxis: Mayo Clinic Experience From 1992 to 2010, identified 38 patients with perioperative anaphylaxis 18 patients had likely IgE-mediated reactions Antibiotics most common identified agent (50%) 7/9 cases due to cefazolin Induction agents (16.7%) Latex (16.7%) NMBA (11%) Others Chlorhexidine, isosulfan blue, protamine, flumazenil Gurrieri C et al. Anesth Analg 2011;113:1202–12. 8

Clinical Features Clinical presentation of anaphylaxis differs somewhat in anesthetized patients vs. conscious patients Perioperative anaphylaxis No early warning subjective symptoms Pruritus, dizziness, dyspnea, and malaise absent Cutaneous findings not easily recognized No pruritus Patient is draped 9

Clinical Features of Perioperative Anaphylaxis Changes in vitals signs or airway resistance may be attributed to affects from anesthesia medications Due to all of these features, anaphylaxis may not be recognized early in the anesthetized patient 10

Clinical Features of Perioperative Anaphylaxis Cannot differentiate IgE vs. Non-IgE mediated reactions on clinical features alone Timing of anaphylaxis may suggest etiology 90% reactions within minutes of induction NMBA, antibiotic, induction agent Maintenance of anesthesia Latex, volume expanders, dyes, contrast 11

Perioperative Anaphylaxis: IgE vs. non-IgE Clinical Signs Observed in IgE-Mediated Reactions Compared with Non–IgE-Mediated Reactions Clinical Signs IgE-Mediated Reactions (%) Non–IgE-Mediated Reactions Cutaneous symptoms 326 (66.4) 206 (93.6) Erythema 209 151 Urticaria 101 177 Edema 50 60 Cardiovascular symptoms 386 (78.6) 70 (31.7) Hypotension 127 Cardiovascular collapse 249 12 Cardiac arrest 29 –– Bronchospasm 129 (39.9) 43 (19.5) Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51. 12

Differential Diagnosis of Perioperative Anaphylaxis Cardiovascular Arrhythmia, myocardial infarction, pericardial tamponade Pulmonary edema, pulmonary embolism Overdose of vasoreactive drug Pulmonary Asthma, tension pneumothorax Sepsis Allergy and immunology HAE, mastocytosis, cold urticaria 13

High Risk Patients History of perioperative drug allergy Patients allergic to drugs or agents likely to be used during anesthesia Patients with prior allergic reactions during anesthesia Recommendations from a panel of experts from the European Network for Drug Allergy (ENDA) and the European Academy of Allergy and Clinical Immunology (EAACI) interest group on drug allergy Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 14

High Risk Patients Latex allergy Patients with clinical signs of latex allergy Children who have undergone several surgical interventions (e.g., spina bifida, myelomeningocoele) Patients with food allergy to avocado, kiwi, banana, chestnut, and buckwheat Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 15

Severity Grading of Perioperative Allergic Reactions Grade of Severity for Quantification of Immediate Hypersensitivity Reactions Grade Symptoms I Cutaneous signs: generalized erythema, urticaria, angioedema II Measurable but not life-threatening symptoms Cutaneous signs, hypotension, tachycardia Respiratory disturbances: cough, difficulty inflating III Life-threatening symptoms: collapse, tachycardia or bradycardia, arrhythmias, bronchospasm IV Cardiac and/or respiratory arrest Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 16

Causal Agents of Perioperative Anaphylaxis 17

Neuromuscular Blocking Agents (NMBA) Most common causal agent worldwide May not be as common in US Most reactions are IgE-mediated Quaternary and tertiary ammonium ions main component of allergic epitopes Cross-sensitization is frequent amongst NMBAs ~60-70% Higher with amino-steroid NMBAs Sensitization to all NMBAs rare Monosensitization frequent with succinylcholine 18

Divalency and Flexibility of NMBAs NMBAs have 2 substituted ammonium ions per molecule (divalent) Divalency allows bridging of IgE molecules by a single NMBA molecule Suxamethonium (succinylcholine) is the NMBA associated wit highest frequency of anaphylaxis when adjusted for use Longer molecules and more flexible backbones enhance mediator release characteristic of suxamethonium 19 Didier A et al. J Allergy Clin Immunol 1987;79:578-84.

Neuromuscular Blocking Agents (NMBA) 15-50% cases NMBA anaphylaxis occurs with first contact with an NMBA Theories on cross-reactive antibodies Exposure to substituted ammonium groups in foods, cosmetics, disinfectants, industrial material Pholcodine hypothesis 20

Pholcodine Hypothesis Pholcodine is a cough suppressant containing quaternary ammonium ion epitopes and is available in certain countries International study compared pholcodine consumption and IgE to suxamethonium Johansson SGO et al. Allergy 2010;65:498–502. 21

Pholcodine Consumption Correlated with Sensitization to Suxamethonium Regression Coefficient R 2 PHO MOR SUX PAPPC 0.037 0.035 0.015 –0.001 0.767 0.843 0.633 0.004 Johansson SGO et al. Allergy 2010;65:498–502. 22

IgE Sensitization to Suxamethonium High in US Despite Lack of Pholcodine Number of Sera Collected from the Participating Countries and the Respective Percentages of Sera with IgE Antibody Levels of 3.5 kUA/I or Higher to PHO, MOR, SUX and PAPPC Country City Number of Sera PHO % SUX % MOR % PAPPC % Sweden Stockholm 213 0.5 0.9 Denmark Copenhagen 179 0.6 1.1 USA Lenexa 200 2.0 2.5 5.0 Germany Freiburg 211 2.4 The Netherlands Rotterdam 184 4.9 6.0 1.6 Finland Helsinki 209 1.0 1.4 Norway Bergen 199 7.0 5.5 UK Manchester France Nancy 214 6.5 3.7 7.5 1.9 The results also indicate that other, yet unknown, substances may lead to IgE-sensitization towards NMBAs. 23 Johansson SGO et al. Allergy 2010;65:498–502.

NMBAs and Non-IgE Mediated Reactions Non-IgE mediated reactions to NMBA occur with similar frequency as IgE mediated Presumed to be due to direct nonspecific mast cell/basophil activation Generally less severe NMBAs associated with greatest histamine release D-tubocurarine, atracurium, mivacurium Rapacuronium (withdrawn from US) 24

Latex Often cited as the second most common cause in large surveys but less common in U.S. and other countries Study from Norway of anesthetic anaphylaxis from 1996-2001 found only 3% cases due to latex Noted systematic reduction of latex use in Norway Latex is the primary cause of anaphylaxis in children with spina bifida who have frequent surgeries Harboe T et al. Anesthesiology 2005;102:897-903. 25

Antibiotics May be highest causative agent in the U.S. with cefazolin being most common Beta-lactams most common overall Vancomycin a frequent cause of non-IgE-mediated reactions which may manifest with urticaria and even hypotension 26

Bacitracin Bacitracin anaphylaxis has been reported with topical antibiotics Most reports of intraoperative anaphylaxis from bacitracin are with irrigation during surgery Skin testing may be positive with local application only (without puncture) Bacitracin specific IgE has been detected in some cases Sharif S et al. Ann Allergy Asthma Immunol 2007;98:563–6. 27

Hypnotics Commonly used hypnotics include: Propofol, midazolam, thiopental, etomidate, ketamine, and inhalational agents Allergic reactions to hypnotics are relatively rare No immune-mediated reactions to inhalational agents has been reported 28

Thiopental Most common barbiturate implicated in perioperative anaphylaxis Women more likely than men to react Reactions thought to be IgE-mediated Skin testing has been shown to be helpful in diagnosis 29

Propofol and Egg Allergy Propofol preparations are lipid suspensions containing egg lecithin/phosphatide and soy oil Egg lecithin contains residual egg yolk but no egg white proteins Estimated to be 5 mg Few case reports of suspected allergic reactions to propofol in egg-allergic patients Warning labels for propofol vary by country despite same manufacturer 30

Propofol and Egg Allergy Retrospective study of 32 egg-allergic patients who received propofol at a Children’s Hospital in Sydney IgE egg sensitization determined by Egg SPT ≥ 7 mm or egg spIgE > 7kUA/L without a clinical history of egg allergy Egg SPT ≥ 3 mm or egg spIgE > 0.35kUA/L with a clinical history of egg allergy N=19, 2 with anaphylaxis Murphy A et al. Anesth Analg 2011;113:140-4. 31

Propofol and Egg Allergy Only 1 child had a reaction to propofol (erythema and urticaria 15 minutes after 2nd dose) History of egg anaphylaxis after sucking on candy with egg albumin Propofol likely to be safe in majority of egg-allergic children without egg anaphylaxis Authors recommend avoidance of propofol in those with histories of egg anaphylaxis Murphy A et al. Anesth Analg 2011;113:140-4. 32

Opioids Allergic reactions to opiates uncommon with anesthesia Morphine, fentanyl, sufentanil most commonly used Morphine more likely to cause non-IgE mediated (pseudoallergic) reactions Rare reports of IgE-mediated reactions to opiates 33

Local Anesthetics Extremely rare cause of perioperative anaphylaxis Most adverse reactions related to inadvertent intravascular injection with resultant systemic effects from Local anesthetic (e.g. arrhythmias) epinephrine 34

Colloids All synthetic colloids used for volume replacement have been reported to cause anaphylaxis Dextrans and gelatins more common causes than albumin or hetastarch Colloid Volume Expander Gelatins Dextrans Albumin Starches Frequency of anaphylactic reactions 0.35% 0.27% 0.10% 0.06% Laxenaire MC et al. Ann Fr Anesth Reanim 1994;13:301-10. 35

Dextran Most common hypothesis for severe anaphylactoid reactions to dextran is related to dextran reactive antibodies High titer dextran reactive antibodies have been correlated with severe reactions Immune complexes generate anaphylatoxins stimulating mast cell/basophil activation 36 Gedin H et al. Int Arch Allergy Appl Immunol 1976;52(1-4):145-59.

Hapten inhibition Reduces Dextran Anaphylaxis Very low molecular weight dextran (dextran 1) has been infused prior to clinical dextran injections to prevent anaphylactoid reactions Study from Sweden compared dextran use between 1975-1979 and dextran use with dextran 1 between 1983-1985 Reduced severe reactions from 22/100,000 to 1.2/100,000 units Reduced fatal reactions from 23 to 1 37 Ljungstrom KG et al. Anaesthesia 1988;43:729-32.

Vital Blue Dyes Vital dyes have been used for many years in a variety of settings Use for lymphatic mapping in the context of sentinel lymph node biopsy in cancer surgery has increased along with increasing reports of anaphylactic reactions Montgomery et al (2002) performed a meta-analysis of 2,392 patients, and calculated the incidence of allergic reactions to vital blue dyes: Patent blue: 1.8% Isosulfan blue (lymphazurin): 1.4% Most reactions were mild 38 Scherer K et al. Ann Allergy Asthma Immunol 2006;96:497-500.

Vital Blue Dyes Most anaphylactic reactions occur with first exposure to the dye An unproven hypothesis states sensitization against vital dyes is facilitated by the common use of patent blue and other structurally closely related triarylmethane dyes in everyday life color textiles, cosmetics, detergents, paints, inks, antifreeze, cold remedies, laxatives, and suppositories Scherer K et al. Ann Allergy Asthma Immunol 2006;96:497-500. 39

Clinical Features of Dye Anaphylaxis Review of 14 cases of perioperative anaphylaxis to patent blue V dye use in lymphatic mapping Reactions characteristics Relatively severe 6/14 grade 3 reactions Average of 30 minutes to onset of symptoms 65% cases reactions prolonged requiring continuous epinephrine infusion Skin tests were positive in all cases 8 on prick testing alone 40 Mertes PM et al. J Allergy Clin Immunol 2008;122(2):348-52.

Blue Urticaria 41 Parvaiz MA et al. Anaesthesia 2012;67:1275–89.

Vital Blue Dyes Isosulfan blue and patent blue V are structurally similar and have highest rates of reaction Methylene blue rare cause of anaphylaxis Some patients exhibit positive skin tests to patent blue and methylene blue suggesting potential for cross-reactivity Keller B et al. Am J Surgery 2007;193:122-4. 42

Protamine Agent used to reverse heparin anticoagulation Rare cause of anaphylaxis Incidence 0.19-0.69% Mechanisms unclear IgE, IgG, complement Multiple proposed risk factors Diabetics on NPH insulin Fish allergy, vasectomized men, other drug allergy Bivalirudin is an alternative for protamine allergic patients Park KW. Int Anesth Clin 2004;42:135-45. Koster A et al. Ann Thorac Surg 2010;90:276-7. 43

Protamine and Fish Allergy Protamine prepared from sperm of salmon or related species Case reports of fish allergic patients and protamine anaphylaxis In vitro studies by Greenberger found no evidence for cross-reactivity between IgE to salmon and protamine Prospective evaluation of 6 fish allergic patients found none had adverse reaction to protamine Greenberger PA et al. Am J Med Sci 1989;298(2):104-8. Levy JH et al. J Thorac Cardiovasc Surg 1989;98(2):200-4. 44

Antiseptics Chlorhexidine digluconate is a common disinfectant Home uses: mouthwash toothpaste, ointments, suppositories Medical uses: swabs for disinfection prior to epidural/spinal anesthesia, surgical incisions, urinary catheterization Chlorhexidine is becoming more recognized as a cause of perioperative anaphylaxis Garvey LH et al. J Allergy Clin Immunol 2007;120:409-15. 45

Chlorhexidine Retrospective study of 22 Danish patients with history of chlorhexidine allergy 12/22 positive skin tests 11/22 positive chlorhexidine sp IgE Clinical characteristics Most patients males Most had previous mild reactions on prior exposure Hypotension common Urologic procedures common precipitant Garvey LH et al. J Allergy Clin Immunol 2007;120:409-15. 46

Povidone- Iodine Multiple case reports of anaphylaxis to topical povidone-iodine including during surgery Positive skin tests have been reported Betadine Chong YY et al. Singapore Med J 2008;49(6):483-7. 47

Miscellaneous Causes of Perioperative Anaphylaxis Numerous other agents have been reported to cause perioperative anaphylaxis Hydroxyzine Oxytocin Aprotinin Pantoprazole Hydrocortisone NSAIDs Neostigmine Radiocontrast media Blood products Hydatid cyst rupture 48

Diagnostic Approach to Perioperative Anaphylaxis 49

Decisional Algorithm for a Patient Reporting a Hypersensitivity Reaction During Previous Anesthesia and Who Has Not Undergone an Allergy Workup 50 Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53.

Practical Steps to Consider Patient history focused on prior known drug allergies or other unexplained reactions Comorbid factors Prior anesthetic history If recent reaction, serum tryptase from stored sera may be helpful to confirm anaphylaxis 51

Laboratory Confirmation of Anaphylaxis Plasma histamine Peak observed within minutes of reaction Elimination t ½ ~ 15-30 minutes False positives Spontaneous lysis Pregnancy > 6 months Placental synthesis of diamine oxidase Heparin Increased diamine oxidase 52

Laboratory Confirmation of Anaphylaxis Serum tryptase Optimal sampling time varies by severity 15-60 minutes for Grade 1 and 2 30 minutes to 2 hours for Grade 3 and 4 May remain positive > 6 hrs in severe cases Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 53

Assessing Tryptase in Anaphylaxis Commercial labs measure total tryptase One can have anaphylaxis with a normal total tryptase (< 11.4 ng/mL) Best to compare baseline to acute tryptase (with anaphylaxis) an increase of >135% of baseline indicates mast cell activation Example: baseline 5 ng/mL; with anaphylaxis 7 ng/mL Borer-Reinhold M et al. Clin Exp Allergy 2011;41:1777-83. 54

Histamine and Tryptase in Perioperative Reactions French survey 2005-2007 of 1253 patients with perioperative allergic reactions Histamine and tryptase measured in 599 cases Histamine (% elevated) Tryptase IgE-mediated 78.2% 60.5% Non-IgE-mediated 42.0% 10.6% Dong SW et al. Minerva Anestesiol 2012;78:868-78. 55

Practical Steps to Consider Obtain anesthesia and surgery record including pre-op medications May need to contact anesthesiologist to interpret Identify any suspect medications Don’t forget about antiseptics Consider lab work Baseline tryptase, latex-specific IgE 56

Practical Steps to Consider Obtain medications needed for testing If a neuromuscular blocking agent is suspected, obtain other NMBAs to test Skin testing typically done after 4-6 weeks to avoid “refractory” period of false negatives No data exist on this for perioperative anaphylaxis Inform patient of expectations for testing Prolonged, multiple skin tests 57

Skin Testing in Perioperative Anaphylaxis Skin testing in association with history remains mainstay for diagnosis of IgE-mediated reactions Prick testing followed by intradermal testing recommended Positive prick if ≥ 3mm than negative control Positive intradermal definition varies ≥ twice initial wheal We recommend initial 5 mm wheal and look for increase of ≥ 3mm 58

Accuracy of Skin Testing True negative predictive value unknown Many drugs cannot be challenged with safety in an office setting (e.g. NMBAs) Sensitivity for NMBAs estimated to be 94-97% b-lactam sensitivity also good Other agents vary Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51. 59

Concentrations for Testing Some controversy as to what is optimal concentration for testing as well as site forearm vs. back Certain agents such as NMBAs will cause positive reactions at higher concentrations Largest data from French Society of Allergology (Societe Francaise d’Allergologie et d’Immunologie Clinique) 60

NMBA Skin Tests in Healthy Controls Forearm ppd 10-7 10-6 10-5 10-4 10-2 250 200 150 Percent Change Forearm 100 50 120 healthy volunteers underwent skin tests with varying concentrations of all commercially available NMBAs; 100% change would be considered positive –50 Rocuronium Atracurium Rapacuronium Vecuronium Mivacurium Pancuronium Cis-atracurium Succinylcholine Mertes PM et al. Anesthesiology 2007;107:245–52. 61

Concentrations of Anesthetic Agents Normally Nonreactive in Practice of Skin Tests 62 Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51.

Positive Rocuronium Skin Test 63

Concentrations for Dyes and Antiseptics Concentrations of Antiseptic and Dyes that Are Normally Nonreactive in Skin Tests Available Agents Skin Prick Tests Intradermal Tests Dilution mg/mL Chlorhexidine Undiluted 0.5 1 / 100 5 Povidone iodine 100 1 / 10 10000 Patent blue 25 2500 Methylene blue 10 Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 64

Positive Isosulfan Blue Skin Test Negative Control Patient 65

In Vitro Specific IgE Tests Several studies with specific assays for IgE to various anesthetic agents have been published Best results with NMBAs, latex, and thiopental Important to realize that performance characteristics of these published assays likely differ from commercially available assays in the U.S. Sensitivity of latex CAP assay may be as low as 35%* *Accetta Pedersen DJ et al. Ann Allergy Asthma Immunol 2012;108:94–7. 66

Basophil Activation Tests Few studies with NMBAs and beta-lactams Not recommended as a routine diagnostic tests even in Europe Commercially available tests in U.S, have not been studied 67

Challenge Tests Limited to few agents Local anesthetics b-lactams Latex Should only be considered if other diagnostic tests negative 68

Subsequent Anesthesia after Perioperative Anaphylaxis 11 patients from Boston evaluated for perioperative anaphylaxis had subsequent surgeries 7/11 had positive skin tests and agent avoided All premedicated using typical radiocontrast media protocol No anaphylaxis 1 patient had urticaria and angioedema after procedure 69 Moscicki RA et al. K Allergy Clin Immunol 1990;86:325-32.

Subsequent Anesthesia after Perioperative Anaphylaxis 19 patients from Belgium with NMBA anaphylaxis and positive skin tests Underwent 26 surgeries with skin test negative NMBAs No reactions occurred 70 Soetens FM et al. Acta Anesthesiol Belg 2003;54:59-63.

Subsequent Anesthesia after Perioperative Anaphylaxis Data from Sydney reported largest experience of follow up of perioperative anaphylaxis patients 52 patients with negative skin and in vitro tests 1/52 had a reaction likely due to latex which was not tested at the time 301 patients with positive skin tests 295 had no reaction 6/301 (2%) had 2nd anaphylactic reaction 2 NMBA not tested 4 NMBA with false-negative reaction 71 Fisher MM, Doig GS. Drug Safety 2004;26:393-410.

Diagnostic Testing Conclusions Skin testing and history is most useful tool to identify causal agent 2/3 cases a causal agent can be identified by skin testing 1/3 cases the causal agent is unclear Referred to as non-IgE-mediated reactions in literature After diagnostic evaluation, majority of patients undergo anesthesia safely 72

Preventive Strategies Latex safe environments for latex allergy Premedication Antihistamine +/- corticosteroids will not reliably prevent IgE-mediated anaphylaxis May be considered in cases where causal agent cannot be found Choice of NMBA Cisatracurium appears to have lowest risk of anaphylaxis of NMBAs Avoidance of NMBAs if possible 73

Conclusions Perioperative anaphylaxis remains underestimated due to underreporting Antibiotics, NMBAs, latex remain common causes but numerous causes exist Chlorhexidine reactions often unrecognized Systematic evaluation with comprehensive skin testing can identify causal agents in 2/3 cases After diagnostic evaluation, majority of patients can undergo anesthesia safely 74