diagnostic evaluation of perioperative anaphylaxis david a. khan, md professor of medicine and...

Diagnostic Evaluation of Diagnostic Evaluation of Perioperative AnaphylaxisPerioperative Anaphylaxis

David A. Khan, MDProfessor of Medicine and Pediatrics

Southwestern Medical CenterAllergy & Immunology Program Director

Division of Allergy & Immunology

1

OutlineOutline

• Epidemiology

• Anesthetic Drugs

• Clinical Features

• Causal Agents

• Diagnostic Testing

2

EpidemiologyEpidemiology

Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429-51.

CountryIncidence 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

3

EpidemiologyEpidemiology

• 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 DrugsAnesthetic Drugs

Thong BYH et al. Ann Allergy Asthma Immunol 2004;92:619–28.

Perioperative Period

Medications Used

PreoperativeAntibiotics, opioids, latex, chlorhexidine, blood/colloids, benzodiazepines

Intraoperative

Neuromuscular blocking agents (NMBA), hypnotics, opioids, neuroleptics, benzodiazepines, local anesthetics, dyes, contrast, latex, aprotinin, chlorhexidine, blood/colloid

PostoperativeOpioids, NSAIDs, neostigmine, atropine/glycopyrrolate

5

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

fluamzenil6

Causal Agents of Perioperative Causal Agents of Perioperative Reactions in FranceReactions in France

Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51.

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 0.5 4.6 5.0 3.1 2.7 4.0 2.8

Antibiotics 2.0 2.6 3.1 8.3 8.0 15.1 14.7

Other 2.0 2.8 2.2 2.6 2.9 1.3 3.0

Total 100 100 100 100 100 100 100

7

Perioperative Anaphylaxis:Perioperative Anaphylaxis:Mayo Clinic ExperienceMayo 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 FeaturesClinical 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 Clinical Features of Perioperative AnaphylaxisPerioperative 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

• 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

Clinical Features of Clinical Features of Perioperative AnaphylaxisPerioperative Anaphylaxis

11

Perioperative Anaphylaxis: IgE vs. non-IgEPerioperative Anaphylaxis: IgE vs. non-IgE


Clinical Signs Observed in IgE-Mediated Reactions Compared withNon–IgE-Mediated Reactions

Clinical SignsIgE-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 50

Cardiovascular collapse 249 12

Cardiac arrest 29 ––

Bronchospasm 129 (39.9) 43 (19.5)

12

Differential Diagnosis of Differential Diagnosis of Perioperative AnaphylaxisPerioperative 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 urticaria13

High Risk PatientsHigh 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

Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 14

High Risk PatientsHigh 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


Severity Grading of PerioperativeSeverity Grading of PerioperativeAllergic ReactionsAllergic Reactions

Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53.

Grade of Severity for Quantification of ImmediateHypersensitivity Reactions

Grade Symptoms

ICutaneous signs: generalized erythema,urticaria, angioedema

IIMeasurable but not life-threatening symptomsCutaneous signs, hypotension, tachycardiaRespiratory disturbances: cough, difficulty inflating

IIILife-threatening symptoms: collapse, tachycardiaor bradycardia, arrhythmias, bronchospasm

IV Cardiac and/or respiratory arrest

16

Causal AgentsCausal Agentsof Perioperative of Perioperative

AnaphylaxisAnaphylaxis

17

Neuromuscular Blocking Agents Neuromuscular Blocking Agents (NMBA)(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 FlexibilityDivalency and Flexibilityof NMBAsof 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

Didier A et al. J Allergy Clin Immunol 1987;79:578-84. 19

Neuromuscular BlockingNeuromuscular BlockingAgents (NMBA)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 HypothesisPholcodine 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 Pholcodine Consumption Correlated with Sensitization to SuxamethoniumSensitization to Suxamethonium

Johansson SGO et al. Allergy 2010;65:498–502.

PHO

MOR

SUX

PAPPC

0.037

0.035

0.015

–0.001

RegressionCoefficient R 2

0.767

0.843

0.633

0.004

22

IgE Sensitization to Suxamethonium HighIgE Sensitization to Suxamethonium Highin US Despite Lack of Pholcodinein US Despite Lack of Pholcodine

Johansson SGO et al. Allergy 2010;65:498–502.

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 CityNumber of

SeraPHO

%SUX

%MOR

%PAPPC

%

Sweden Stockholm 213 0 0 0.5 0.9

Denmark Copenhagen 179 0.6 0 1.1 0.6

USA Lenexa 200 2.0 2.5 5.0 2.0

Germany Freiburg 211 0 0.5 0.9 2.4

The Netherlands

Rotterdam 184 4.9 0 6.0 1.6

Finland Helsinki 209 1.0 0 1.0 1.4

Norway Bergen 199 7.0 1.0 5.5 0.5

UK Manchester 209 2.4 0 2.4 0

France Nancy 214 6.5 3.7 7.5 1.9

23

NMBAs and Non-IgE Mediated NMBAs and Non-IgE Mediated ReactionsReactions

• 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

LatexLatex• 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

AntibioticsAntibiotics

• 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

BacitracinBacitracin• 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

HypnoticsHypnotics

• 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

ThiopentalThiopental

• 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 AllergyPropofol 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 g

• Few case reports of suspected allergic reactions to propofol in egg-allergic patients

• Warning labels for propofol vary by country despite same manufacturer

30


• 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


• 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

OpioidsOpioids

• 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 AnestheticsLocal 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

ColloidsColloids

• All synthetic colloids used for volume replacement have been reported to cause anaphylaxis

• Dextrans and gelatins more common causes than albumin or hetastarch

Laxenaire MC et al. Ann Fr Anesth Reanim 1994;13:301-10.

Colloid Volume Expander

Gelatins Dextrans Albumin Starches

Frequency of anaphylactic reactions

0.35% 0.27% 0.10% 0.06%

35

DextranDextran• 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

Gedin H et al. Int Arch Allergy Appl Immunol 1976;52(1-4):145-59. 36

Hapten inhibition Reduces Hapten inhibition Reduces Dextran AnaphylaxisDextran 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

Ljungstrom KG et al. Anaesthesia 1988;43:729-32. 37

Vital Blue DyesVital 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

Scherer K et al. Ann Allergy Asthma Immunol 2006;96:497-500.38

Vital Blue DyesVital 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 AnaphylaxisClinical 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 requiringcontinuous epinephrine infusion

– Skin tests were positive in all cases• 8 on prick testing alone

Mertes PM et al. J Allergy Clin Immunol 2008;122(2):348-52. 40

Blue UrticariaBlue Urticaria

Parvaiz MA et al. Anaesthesia 2012;67:1275–89.41

Vital Blue DyesVital 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

ProtamineProtamine• 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 AllergyProtamine 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

AntisepticsAntiseptics

• 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

ChlorhexidineChlorhexidine• 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-Povidone- IodineIodine

• Multiple case reports of anaphylaxis to topical povidone-iodine including during surgery

• Positive skin tests have been reported

Chong YY et al. Singapore Med J 2008;49(6):483-7. 47

Miscellaneous Causes of Miscellaneous Causes of Perioperative AnaphylaxisPerioperative 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 Diagnostic Approach to Perioperative to Perioperative

AnaphylaxisAnaphylaxis

49


Decisional Algorithm for a Patient Reporting a Hypersensitivity Reaction During Decisional Algorithm for a Patient Reporting a Hypersensitivity Reaction During Previous Anesthesia and Who Has Not Undergone an Allergy WorkupPrevious Anesthesia and Who Has Not Undergone an Allergy Workup

50

Practical Steps to ConsiderPractical 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 Laboratory Confirmation of AnaphylaxisAnaphylaxis

• 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 Laboratory Confirmation of AnaphylaxisAnaphylaxis

• 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


Assessing Tryptase in Assessing Tryptase in AnaphylaxisAnaphylaxis

• 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 Histamine and Tryptase in Perioperative ReactionsPerioperative Reactions

• French survey 2005-2007 of 1253 patients with perioperative allergic reactions

• Histamine and tryptase measured in 599 cases

Dong SW et al. Minerva Anestesiol 2012;78:868-78.

Histamine(% elevated)

Tryptase(% elevated)

IgE-mediated 78.2% 60.5%

Non-IgE-mediated 42.0% 10.6%

55

Practical Steps to ConsiderPractical 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 ConsiderPractical 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 Skin Testing in Perioperative AnaphylaxisAnaphylaxis

• 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 TestingAccuracy 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%

• -lactam sensitivity also good

• Other agents vary

Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51. 59

Concentrations for TestingConcentrations 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 ControlsNMBA Skin Tests in Healthy Controls

Mertes PM et al. Anesthesiology 2007;107:245–52.

Ro

curo

niu

m

Ra

pa

curo

niu

m

Ve

curo

niu

m

Pa

ncu

ron

ium

Atr

acu

riu

m

Cis

-atr

acu

riu

m

Miv

acu

riu

m

250

Pe

rce

nt

Ch

an

ge

Fo

rea

rm

ppd

10-7

10-6

10-5

10-4

10-2

200

150

100

50

0

–50

Forearm

Su

ccin

ylch

olin

e

61


Concentrations of Anesthetic Agents Normally NonreactiveConcentrations of Anesthetic Agents Normally Nonreactivein Practice of Skin Tests in Practice of Skin Tests

62

Positive Rocuronium Skin TestPositive Rocuronium Skin Test

63

Concentrations for DyesConcentrations for Dyesand Antisepticsand Antiseptics


Concentrations of Antiseptic and Dyes that Are Normally Nonreactive in Skin Tests

AvailableAgents

Skin Prick Tests Intradermal Tests

Dilution mg/mL Dilution g/mL

Chlorhexidine Undiluted 0.5 1 / 100 5

Povidone iodine Undiluted 100 1 / 10 10000

Patent blue Undiluted 25 1 / 10 2500

Methylene blue Undiluted 10 1 / 100 100

64

Positive Isosulfan BluePositive Isosulfan BlueSkin TestSkin Test

Negative Control Patient

65

In Vitro In Vitro Specific IgE TestsSpecific 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 TestsBasophil 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 TestsChallenge Tests

• Limited to few agents– Local anesthetics

– -lactams

– Latex

• Should only be considered if other diagnostic tests negative

68

Subsequent Anesthesia afterSubsequent Anesthesia after Perioperative Anaphylaxis 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

procedureMoscicki RA et al. K Allergy Clin Immunol 1990;86:325-32. 69


• 19 patients from Belgium with NMBA anaphylaxis and positive skin tests

• Underwent 26 surgeries with skin test negative NMBAs

• No reactions occurred

Soetens FM et al. Acta Anesthesiol Belg 2003;54:59-63. 70


• 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

Fisher MM, Doig GS. Drug Safety 2004;26:393-410. 71

Diagnostic Testing ConclusionsDiagnostic 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 StrategiesPreventive 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 possible73

ConclusionsConclusions• 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

diagnostic evaluation of perioperative anaphylaxis david a. khan, md professor of medicine and...

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