Diagnostic Evaluation Diagnostic Evaluation of Perioperative of Perioperative Anaphylaxis Anaphylaxis David A. Khan, MD Professor of Medicine and Pediatrics Southwestern Medical Center Allergy & Immunology Program Director Division of Allergy & Immunology 1
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Diagnostic Evaluation of Perioperative Anaphylaxis David A. Khan, MD Professor of Medicine and Pediatrics Southwestern Medical Center Allergy & Immunology.
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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
• 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
Propofol and Egg AllergyPropofol 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 AllergyPropofol 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
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
• 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
Diagnostic Approach Diagnostic Approach to Perioperative to Perioperative
AnaphylaxisAnaphylaxis
49
Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53.
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
• 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
Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51.
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
Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53.
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