Anaphylaxis during Anesthesia: Diagnosis and Treatment.

Dr. F. Soetens Department of Anesthesia Sint-Elisabeth Hospital, Turnhout.

Discovery: Anaphylaxis
1901: Portier and Richet
Toxin produced by the Sea Anemone
Vaccinate Dogs 1 Dose: no Reaction 2 Dose: quick and fatal Reaction

An- not and Phylaxis Protection

Nobel Prize 1912

Definition: Anaphylaxis
1. Hypersensitivity Reaction (IgE) to a Substance
Dose Independent Not Related to the Drugs Pharmacological Actions

2. Life-Threatening 3. Symptoms in 2 Organ Systems 4. Mast Cells (Connective Tissue) and Basophils (Blood)

Anaphylactoid Reaction
Clinically Indistinguishable from Anaphylactic Reaction Definite Diagnosis AFTER Investigation

Suspected Anaphylactic Reaction

Anaphylactic or Type I reaction

Anesthetics Low MW: Haptens + Protein Carrier: Ag 1 Exposure to Ag: IgE B-Lymphocyte IgE binds Mast Cells Basophils

Anaphylactic or Type I Reaction

2 Exposure to Multimeric Ag Bridging of 2 IgE Aggregation of IgE Receptors Degranulation
Confirmed by Skin or Biological Tests

Anaphylactoid Reaction
No IgE Antibody involved Skin or Biological Tests: normal MECH:
Complement Activation: Anaphylactoxins (C3a and C5a) Direct-Histamine Release from Mast Cells and Basophils
Mech? (Ca++-Influx, Hyperoncotic) Super Responders

Anesthesia = Unique Situation

Many Different Drugs:
Anesthetics + Antibiotics, Fluids, NSAIDs + (Disinfectants, Latex)
Intravenous Bypassing the Bodys primary Immune Filters Presenting High [Ag] directly to Effector Cells In rapid Succession In Bolus

Anaphylactic/Anaphylactoid Reactions Drug-Drug Interactions

Epidemiology
Incidence? 1:10.000 1:20.000 < USA, South Africa > France, New Zealand Problems with Incidence:
Numerator? Recognized? Completeness of Reporting? Definition? Investigation: Criteria of Positivity? Denominator? Amount of Drug sold? Number of Anesthetics?

Mortality: 3-5%

Epidemiology
789 Patients (1999-2000)
66% Anaphylactic Reactions 34% Anaphylactoid Reactions
NMBDs 58% Latex 17% Antibiotics 15% Hypnotics 3.4% Opioids 1.4% Others 5.2%

Mertes M., Laxenaire M. Anesthesiology 2003.

Epidemiology: NMBDs (1)

NMBDs: 1 in 6.500
On First Exposure: >50%!! (Fisher BJA 2001) Female Predominance: 2:1 8:1 Cross-Reactivity between NMBDs: 70%

Antigenic Determinant? Quaternary Ammonium Ion

Epidemiology: NMBDs (3)

Quaternary Ammonium Ions: Drugs, Cosmetics, Household Products
Cross Sensitivity: NMBDs and Cosmetics, Household Products

NMBDs: 2 Antigens (NH4+) per Molecule Bridging of 2 IgE, Mast Cell Degranulation Anesthetic Drugs have a Low MW: Haptens (+ Protein Carrier)
Explains: Highest Incidence of All Anesthetic Drugs
High Incidence: Succinylcholine (Flexible Molecule)

Epidemiology: NMBDs (4)

Anaphylactoid Reactions (Direct Mast Cell Degranulation)
Benzyl Isoquinolinium Compounds
d-TC, Atracuriun, Mivacurium (Except cis-Atracurium).

> Aminosteroid Compounds

Pancuronium, Vecuronium, Rocuronium, Pipecuronium.

> Succinylcholine. Mast Cell Atracurium Vecuronium Inh N-methyl transferase Morphine Propofol Skin + + + + + Lung + + Heart +

Marone G. Ann Fr Anesth Reanim 1993

Latex:

Epidemiology
IgE-mediated Symptoms later (after 30-60 Min) no Relation with any Drug Administration

Induction agents
Thiopental: 1:30.000 previous Exposure - IgE-mediated anaphylactoid Reactions Propofol: IgE-mediated direct Degranulation of Lung Mast Cell Etomidate, Ketamine: extremely rare

Opioids
IgE-mediated: rare Direct Histamine Release: frequent

Epidemiology
Local Anesthetics
Rare: Ester > Amide LA 205 Patients referred for Alleged Allergy to LA
Progressive Challenge 4 Immediate Allergy; 4 Delayed Allergic Reactions

Mostly Toxicity of LA and/or Epinephrine Vagal Reactions Reactions to Preservatives (Bisulphites)

Fisher M. Anaesth Intensive Care 1997

Pathophysiology: Mediators
Granule Content Release:
Histamine Proteasen: Tryptase, Chymase Preoteoglycan: Heparin ECF, NCF TNF

S E C

Membrane Derived Lipid Mediators: M

Leucotrienes: C4, E4, D4 (SRS-A) Prostaglandines: D2 Platelet Activating Factor

I N H

-- Inotropism + Chronotropism VC Cor., Pulm. Vasodilatation Permeability Bronchoconstriction Mucus Production Chemotaxis Act. Coagulation, Complement, Kinin-Kallekrein.

Cytokine Production:
IL 1, 3, 4, 5, 6, 8, TNF

Symptoms
Life-Threatening
>90% within 10 Min after Induction
Except Latex: 30-60 Min

Aggravating Factors: Asthma, -Blocking Drugs, Neuraxial Block

Efficiency of endogenous Catecholamine Response

Involved Organ Systems

The The The The Skin Lung Cardio-Vascular System Gastro-Intestinal System

Correct Diagnosis? Anesthesia Simulator

0/42 Anesthesiologists <10 Min
Jacobsen J. Acta Anaesth Scand 2001

Signs during Anesthesia

More Severe Anaphylactic vs. Anaphylactoid Cutaneous Respiratory Cardio-Vascular
Flushing, Urticaria, Angioedema, Periorbital Oedema Difficult to Ventilate (Laryngeal Oedema, Bronchospasm), PIP, Wheezing, Et CO2, SaO2 Tachycardia, Arrhythmias, Hypotension, Cardiac Arrest, Hct (+40%), Pulmonary Oedema

Gastro-Intestinal Abdominal Pain, N/V, Diarrhea

First Clinical Feature of an Anaphylactic Reaction During Anesthesia

No Pulse Difficulty to Ventilate the Lungs Flush Desaturation

26% 24% 18% 11%

Fisher M. Ballieres Clinical Anaesthesiology 1998

Incidence of Clinical Features of Anesthetic Anaphylaxis in 555 Patients (Fisher 1998)

% of Cases Sole Feature Worst Feature

Rash, Erythema, Urticaria Generalized Oedema Angioedema Bronchospasm

69% 7% 24% 37% 1% 6% 3% 18%

Asthmatics
Cardiovascular Collapse Pulmonary Oedema Gastro-Intestinal

16%
88% 2% 7% 11% 0.4% 78% (CA 10%) 0.5%

Treatment: Goals (1)

Interrupt Contact With Responsible Drug Modulate Effects of Released Mediators Prevent more Mediator Release and Production

Treatment: Initial Therapy (2)

Stop Administration of the Antigen and all Anesthetics Call for Help ETT - 100% O2 Volume Expansion - Leg Elevation (0.5 - 0.7L) EPINEPHRINE 1 : VC of Capacitance and Resistance Vessels 1: Contractility 2: Bronchodilatation cAMP: Mediator Release
No Pure -Agonists!!! No CaCl2

Treatment: Epinephrine (3)

Who? Respiratory Difficulty Cardio-Vascular Instability Dose? Dependent of Severity of Symptoms
IM: IV: 10 g/kg Lateral Thigh DILUTION TITRATION! (Arrhythmias, MI..)
5-10 g IV q 1-2 Min 100 g IV q 1 Min (+ Cardiac Massage)

Hypotension: CV Collapse:

Treatment: Initial Therapy (4)

Higher Dose During Anesthesia:
GA (Altered Sympathoadrenergic Response) Spinal/ Epidural Anesthesia (Partial Sympathectomy)

Resistant: -Blocking Drugs

Unopposed -Effects Glucagon IV

Sensitive: TCA, MAOI, Cocaine Mortality Delayed Epinephrine Inappropriate Use of Epinephrine Asthma, CV-Disease, Age

Treatment: Secondary Therapy (5)

Antihistamines: H1 Promethazine IM H2? CorVD, +Ino/Chronotropism, Bronchodilatation,
neg. Feedback on Histamine Release.

Steroids:

Inh. Phospholipase Arachidonic Acid Metabolites Works (?) After 12-24h 5 mg/kg Hydrocortisone IV

Inhaled Bronchodilators Inotropes in Infusion Extubation Airway Oedema?

Facial or Scleral Oedema Absence of Air Leak After ETT Deflation

Diagnosis: Goals
Anaphylactic or Anaphylactoid Reaction? Identify the Responsible Drug. If Responsible Drug = NMBDs.
Cross-Reactivity? Safe NMBD for future Anesthesia.

Medico-Legal. Epidemiology: identify low/high Risk Drugs.

Diagnosis
Intraoperative Testing
Immune mediated?

Postoperative Testing
Identify the responsible Drug.

Diagnosis: Intraoperative Testing

Blood Urine Histamine Mast Cell Tryptase N-Methyl Histamine

(N-methyl-) Histamine Mast cell Tryptase (MCT)

HISTAMINE Mast Cells + Basophils T1/2 = Short (Min) Sampling < 10 Min MASTCELL TRYPTASE (MCT) Mast Cells (99%) T1/2 = 90-120 Min Sampling: after initial Therapy 1 Hour 24 Hours Stable (Haemolysis, post-mortem) Anaphylactic > Anaphylactoid DD: Septic, Cardiogenic Shock N-METHYL HISTAMINE (low Sensitivity)

Not Stable

Histamine and MCT

Mast Cell Tryptase: Predictive Value

IgE AB? (IDT/RIA) Mast Cell Tryptase + Mast Cell Tryptase -

125/130 7/137

MCT + = IgE Antibodies DO Skin Testing MCT - = most of the Time no IgE Antibodies DO Skin Testing if Clinical Anaphylaxis
Fisher M. BJA 1998

Diagnosis: Postoperative Testing

Skin Testing
Cornerstone Principle: Injection of Allergen Bridging IgEs Mast Cell Activation Weal and Flare, Itching

Diagnosis: Skin Testing

at 4-6 Weeks: < reduced Stocks of IC Histamine
False negative Results!

Avoid Factors that interfere with Histamine R (stop: Antihistamines, ACE-I, NSAIDs, Neuroleptics, VC)
False negative Results!

Positive Control: Histamine, Codeine Negative Control: Saline (Dermatographism) Value + NMBDs, Hypnotics, Antibiotics - Colloids and Contrast Media Intradermal - Prick Testing

Diagnosis: Skin Testing

Intradermal Test
0.01 - 0.02 ml (0.05 ml) 1 - 2 mm (5 mm) Diluted Drugs (!) In the Dermis

Skin Prick Test

Undiluted Drugs
1:10: Atrac, Miv, Morphine.

In the Epidermis Through Drop of Drug

Intradermal or Prick Test?

Intradermal Skin Test
+ easier for infrequent User proven Reliability with Time

Skin Prick Test

+ Easier to Prepare Cheaper less Trauma (children)

93% Agreement between 2 Tests Both Tests: Improvement of Predictability

Fisher M. BJA 1997

Drug Dilutions used for Intradermal Skin Testing.

Diagnosis: Skin Testing

Positivity criteria:
Intradermal Skin Test: weal 8 mm + Flare, Itching Skin Prick Test: weal 3 mm + Flare, Itching After 10-15 Min, persisting >30 Min

Sensitivity: >95% Specificity: >95%

False + direct Histamine Release (Benzyl Isoquinolinium Compounds) Vasodilatation (Rocuronium)

Adverse Reactions: <0.3%

(Resuscitation Facilities!)

Diagnosis: Skin Testing

Which Drugs?
All Drugs used (Anesthetics, AB) + other Anesthetics: especially NMBDs
high Cross-Sensitivity between NMBDs!!
+ Skin Test to NMBD 66% + Skin Test to 1 NMBD 40% + Skin Test to >1 NMBD 0.5% + Skin Test to all NMBDs Vecuronium and Pancuronium Succinylcholine and Aminosteroid Compounds
Fisher M. BJA 1999 Rose M., BJA 2001

Anaphylaxis to a NMBD and Subsequent Anesthesia

Pre-Treatment: not useful dangerous (masks early Signs) Avoid NMBDs, if possible. Use a Skin-Test-negative NMBD: Safe?
# Received a Skin Test - NMBD Allergic Reaction? Leynadier F. 1989
Ann Fr Anaesth Reanim

16 26 179

None None 3

Soetens F. 2003 Acta Anaesth Belg Fisher M. 1999 BJA

Skin testing: Screening Test?

258 Patients: No Risk Factors 9.3% + Skin Prick to 1 NMBD poor predictive Value as a screening Test

Porri F. Clin Exp Allergy 1999

Diagnosis: Postoperative Testing

Specific IgE Basophil Activation Test Challenge
Only for LA after negative Skin Test

Specific IgE
Radio Immuno Assay Circulating [IgE] IgE on Mast Cell and Basophils Ag is bound to solid Support + Patients Serum, Serum washed away + radio-labelled anti-IgE: Radioactive Counting POSITIVE: Radioactive Counting 3x Baseline [spec IgE] during reaction = after 4-6 Weeks
Fast diagnosis

Skin Testing + IgE-Testing:

+5% Detection of Responsible Drug

BUT

Limited Availability (Succinylcholine, Latex) Specific but Not Sensitive

Diagnosis: Basophil Activation Test

Diagnosis: Basophil Activation Test

Advantages: Simple quick Result Specificity 100% IgE and non-IgE Reactions Sensitivity 66% after 4-6 Weeks

Disadvantages:

Investigation of Anaphylaxis
Time after the Reaction Immediately 1 Hour 24 Hour Clinical History Mast Cell Tryptase Skin Test Specific IgE
4-6 Weeks

X X X X X (X) (X)

Investigation
Letter to the Patient /the General Practitioner
(Anaphylactic and Anaphylactoid Reaction) Explanation of the Event Advice About Future Anesthesia Add Information of Future Anesthesia

Medical Alert Bracelet