Diagnostic Evaluation of Perioperative Anaphylaxis

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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

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Outline

• Epidemiology
• Anesthetic Drugs
• Clinical Features
• Causal Agents
• Diagnostic Testing

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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
200929429-51.
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Epidemiology

• Incidence remains poorly defined
• Few prospective studies
• Uncertainty in accuracy and completeness of
  reports
• Immune-mediated reactions account forgt 60
  reactions
• Mortality
• 3-9

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Anesthetic Drugs
Perioperative Period Medications Used
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
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Thong BYH et al. Ann Allergy Asthma Immunol
20049261928.
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Class of Drug Name Name
Intravenous anesthetic Induction agents thiopental, etomidate, propofol, ketamine Induction agents thiopental, etomidate, propofol, ketamine
Inhalational anesthetic Volatile liquid anesthetics halothane, enflurane, isoflurane, desflurane, sevoflurane Volatile liquid anesthetics halothane, enflurane, isoflurane, desflurane, sevoflurane
Antimuscarinic Atropine, hyoscine, glycopyrronnium Atropine, hyoscine, glycopyrronnium
Sedative and analgesics Class Example(s)
Sedative and analgesics Benzodiazepine midazolam
Sedative and analgesics NSAIDs ketorolac
Sedative and analgesics Opioids fentanyl, sufentanil, morphine
Sedative and analgesics NMBA nondepolarizing (aminosteroid) pancuronium, rocuronium, vecuronium
Sedative and analgesics NMBA nondepolarizing (benzylisoquinolinium) atracurium, mivacurium
Sedative and analgesics NMBA depolarizing) succinylcholine
Opioid antagonist naloxone naloxone
Benzodiazepine antagonist fluamzenil fluamzenil
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Causal Agents of Perioperative Reactions in France
Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys Substances Responsible for IgE-Mediated Hypersensitivity Reactions in FranceResults from Seven Consecutive Surveys
Substance 1984-1989 (n821) () 1990-1991 (n813) () 1992-1994 (n1030) () 1994-1996 (n734) () 1997-1998 (n486) () 1999-2000 (n518) () 2001-2002 (n502) ()
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
Mertes PM et al. Immunol Allergy Clin N Am
20092942951.
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Perioperative AnaphylaxisMayo 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 2011113120212.
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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

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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

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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

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Perioperative Anaphylaxis IgE vs. non-IgE
Clinical Signs Observed in IgE-Mediated Reactions Compared withNonIgE-Mediated Reactions Clinical Signs Observed in IgE-Mediated Reactions Compared withNonIgE-Mediated Reactions Clinical Signs Observed in IgE-Mediated Reactions Compared withNonIgE-Mediated Reactions
Clinical Signs IgE-Mediated Reactions () NonIgE-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)
Mertes PM et al. Immunol Allergy Clin N Am
20092942951.
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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

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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

Mertes PM et al. J Investig Allergol Clin Immunol
201121(6)442-53.
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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
201121(6)442-53.
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Severity Grading of PerioperativeAllergic
Reactions
Grade of Severity for Quantification of ImmediateHypersensitivity Reactions Grade of Severity for Quantification of ImmediateHypersensitivity Reactions
Grade Symptoms
I Cutaneous signs generalized erythema,urticaria, angioedema
II Measurable but not life-threatening symptomsCutaneous signs, hypotension, tachycardiaRespiratory disturbances cough, difficulty inflating
III Life-threatening symptoms collapse, tachycardiaor bradycardia, arrhythmias, bronchospasm
IV Cardiac and/or respiratory arrest
Mertes PM et al. J Investig Allergol Clin Immunol
201121(6)442-53.
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Causal Agentsof Perioperative Anaphylaxis
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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

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Divalency and Flexibilityof 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

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Didier A et al. J Allergy Clin Immunol
198779578-84.
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Neuromuscular BlockingAgents (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

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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 201065498502.
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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 201065498502.
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IgE Sensitization to Suxamethonium Highin 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 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 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 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 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 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 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 ofSera PHO 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
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Johansson SGO et al. Allergy 201065498502.
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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)

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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 2005102897-903.
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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

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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
2007985636.
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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

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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

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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

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Propofol and Egg Allergy

• Retrospective study of 32 egg-allergic patients
  who received propofol at a Childrens Hospital in
  Sydney
• IgE egg sensitization determined by
• Egg SPT 7 mm or egg spIgE gt 7kUA/L without a
  clinical history of egg allergy
• Egg SPT 3 mm or egg spIgE gt 0.35kUA/L with a
  clinical history of egg allergy
• N19, 2 with anaphylaxis

Murphy A et al. Anesth Analg 2011113140-4.
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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 2011113140-4.
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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

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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

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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
199413301-10.
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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

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Gedin H et al. Int Arch Allergy Appl Immunol
197652(1-4)145-59.
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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

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Ljungstrom KG et al. Anaesthesia 198843729-32.
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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

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Scherer K et al. Ann Allergy Asthma Immunol
200696497-500.
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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
200696497-500.
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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 requiringcontinuous
  epinephrine infusion
• Skin tests were positive in all cases
• 8 on prick testing alone

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Mertes PM et al. J Allergy Clin Immunol
2008122(2)348-52.
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Blue Urticaria
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Parvaiz MA et al. Anaesthesia 201267127589.
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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 2007193122-4.
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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 200442135-45. Koster A
et al. Ann Thorac Surg 201090276-7.
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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
1989298(2)104-8. Levy JH et al. J Thorac
Cardiovasc Surg 198998(2)200-4.
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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
2007120409-15.
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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
2007120409-15.
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Povidone- Iodine

• 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 200849(6)483-7.
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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

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Diagnostic Approach to Perioperative Anaphylaxis
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Decisional Algorithm for a Patient Reporting a
Hypersensitivity Reaction During Previous
Anesthesia and Who Has Not Undergone an Allergy
Workup
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Mertes PM et al. J Investig Allergol Clin Immunol
201121(6)442-53.
51
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

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Laboratory Confirmation of Anaphylaxis

• Plasma histamine
• Peak observed within minutes of reaction
• Elimination t ½ 15-30 minutes
• False positives
• Spontaneous lysis
• Pregnancy gt 6 months
• Placental synthesis of diamine oxidase
• Heparin
• Increased diamine oxidase

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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 gt 6 hrs in severe cases

Mertes PM et al. J Investig Allergol Clin Immunol
201121(6)442-53.
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Assessing Tryptase in Anaphylaxis

• Commercial labs measure total tryptase
• One can have anaphylaxis with a normal total
  tryptase (lt 11.4 ng/mL)
• Best to compare baseline to acute tryptase (with
  anaphylaxis)
• an increase of gt135 of baseline indicates mast
  cell activation
• Example baseline 5 ng/mL with anaphylaxis 7
  ng/mL

Borer-Reinhold M et al. Clin Exp Allergy
2011411777-83.
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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 ( elevated)
IgE-mediated 78.2 60.5
Non-IgE-mediated 42.0 10.6
Dong SW et al. Minerva Anestesiol 201278868-78.
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Practical Steps to Consider

• Obtain anesthesia and surgery record including
  pre-op medications
• May need to contact anesthesiologist to interpret
• Identify any suspect medications
• Dont forget about antiseptics
• Consider lab work
• Baseline tryptase, latex-specific IgE

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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

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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

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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
20092942951.
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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 dAllergologie et
  dImmunologie Clinique)

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NMBA Skin Tests in Healthy Controls
Forearm
250
200
150
100
Percent Change Forearm
50
0
50
Atracurium
Mivacurium
Vecuronium
Rocuronium
Rapacuronium
Pancuronium
Cis-atracurium
Succinylcholine
Mertes PM et al. Anesthesiology 200710724552.
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Concentrations of Anesthetic Agents Normally
Nonreactive in Practice of Skin Tests
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Mertes PM et al. Immunol Allergy Clin N Am
20092942951.
63
Positive Rocuronium Skin Test
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Concentrations for Dyesand Antiseptics
Concentrations of Antiseptic and Dyes that Are Normally Nonreactive in Skin Tests Concentrations of Antiseptic and Dyes that Are Normally Nonreactive in Skin Tests Concentrations of Antiseptic and Dyes that Are Normally Nonreactive in Skin Tests Concentrations of Antiseptic and Dyes that Are Normally Nonreactive in Skin Tests Concentrations of Antiseptic and Dyes that Are Normally Nonreactive in Skin Tests
Available Agents Skin Prick Tests Skin Prick Tests Intradermal Tests Intradermal Tests
Available Agents Dilution mg/mL Dilution mg/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
Mertes PM et al. J Investig Allergol Clin Immunol
201121(6)442-53.
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Positive Isosulfan BlueSkin Test
Negative Control
Patient
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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 2012108947.
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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

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Challenge Tests

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

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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

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Moscicki RA et al. K Allergy Clin Immunol
199086325-32.
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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

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Soetens FM et al. Acta Anesthesiol Belg
20035459-63.
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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

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Fisher MM, Doig GS. Drug Safety 200426393-410.
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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

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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

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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

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