Anaphylaxis during Anesthesia: Diagnosis and Treatment.

Dr. F. SoetensDepartment of AnesthesiaSint-Elisabeth Hospital, Turnhout.

Discovery: Anaphylaxis

1901: Portier and RichetToxin produced by the Sea Anemone

Vaccinate Dogs1° Dose: no Reaction2° Dose: quick and fatal Reaction

An- « not » and Phylaxis « Protection »

Nobel Prize 1912

Definition: Anaphylaxis 1. Hypersensitivity Reaction (IgE) to a Substance

Dose IndependentNot Related to the Drug’s Pharmacological Actions

2. Life-Threatening3. Symptoms in ≥ 2 Organ Systems4. Mast Cells (Connective Tissue) and Basophils (Blood)

Anaphylactoid ReactionClinically Indistinguishable from Anaphylactic ReactionDefinite 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: normalMECH:

Complement Activation: Anaphylactoxins (C3a and C5a)

Direct-Histamine Release from Mast Cells and BasophilsMech? (Ca++-Influx, Hyperoncotic…)Super Responders

Anesthesia = Unique Situation

Many Different Drugs:Anesthetics+ Antibiotics, Fluids, NSAIDs+ (Disinfectants, Latex)

Intravenous Bypassing the Body’s primary Immune FiltersPresenting High [Ag] directly to Effector Cells

In rapid SuccessionIn Bolus

Anaphylactic/Anaphylactoid ReactionsDrug-Drug Interactions

EpidemiologyIncidence? 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

Mertes M., Laxenaire M. Anesthesiology 2003.

NMBDs 58%

Latex 17%

Antibiotics 15%

Hypnotics 3.4%

Opioids 1.4%

Others 5.2%

Epidemiology: NMBDs (1)NMBDs: 1 in 6.500

On First Exposure: >50%!! (Fisher BJA 2001)

Female Predominance: 2:1 – 8:1Cross-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.

Marone G. Ann Fr Anesth Reanim 1993

+Morphine

++Propofol

++Vecuronium Inh N-methyl transferase

+++Atracurium

HeartLungSkinMast Cell

EpidemiologyLatex: IgE-mediated

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

Induction agentsThiopental: 1:30.000

previous Exposure - IgE-mediatedanaphylactoid Reactions

Propofol: IgE-mediateddirect Degranulation of Lung Mast Cell

Etomidate, Ketamine: extremely rareOpioids

IgE-mediated: rareDirect Histamine Release: frequent

EpidemiologyLocal Anesthetics

Rare: Ester > Amide LA205 Patients referred for Alleged Allergy to LA

Progressive Challenge4 Immediate Allergy; 4 Delayed Allergic Reactions

Mostly Toxicity of LA and/or EpinephrineVagal ReactionsReactions to Preservatives (Bisulphites)

Fisher M. Anaesth Intensive Care 1997

Pathophysiology: Mediators

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

MIN

Membrane Derived Lipid Mediators:Leucotrienes: C4, E4, D4 (SRS-A)Prostaglandines: D2

Platelet Activating Factor

-- Inotropism+ ChronotropismVC Cor., Pulm.Vasodilatation↑ PermeabilityBronchoconstriction↑ Mucus ProductionChemotaxis

Act. Coagulation,Complement, Kinin-Kallekrein.

SEC

Granule Content Release:HistamineProteasen: Tryptase, ChymasePreoteoglycan: HeparinECF, NCF

TNF

SymptomsLife-Threatening

>90% within 10 Min after InductionExcept Latex: 30-60 Min

Aggravating Factors: Asthma, β-Blocking Drugs, Neuraxial Block↓ Efficiency of endogenous Catecholamine Response

Involved Organ SystemsThe SkinThe LungThe Cardio-Vascular SystemThe Gastro-Intestinal System

Correct Diagnosis? Anesthesia Simulator0/42 Anesthesiologists <10 Min

Jacobsen J. Acta Anaesth Scand 2001

Signs during Anesthesia

More Severe Anaphylactic vs. Anaphylactoid

Abdominal Pain, N/V, DiarrheaGastro-Intestinal

Tachycardia, Arrhythmias,Hypotension, Cardiac Arrest, ↑ Hct (+40%), Pulmonary Oedema

Cardio-Vascular

Difficult to Ventilate (Laryngeal Oedema, Bronchospasm), ↑ PIP,Wheezing, ↑ Et CO2, ↓ SaO2

Respiratory

Flushing, Urticaria,Angioedema, Periorbital Oedema

Cutaneous

First Clinical Feature of an Anaphylactic Reaction During Anesthesia

No Pulse 26%Difficulty to Ventilate the Lungs 24%Flush 18%Desaturation 11%

Fisher M. Balliere’s Clinical Anaesthesiology 1998

Incidence of Clinical Features of AnestheticAnaphylaxis in 555 Patients (Fisher 1998)

18%6%37%Bronchospasm

7%Generalized Oedema

7%Gastro-Intestinal

0.5%0.4%2%Pulmonary Oedema

78% (CA 10%)11%88%Cardiovascular Collapse

16%Asthmatics

3%1%24%Angioedema

69%Rash, Erythema, Urticaria

Worst FeatureSole Feature% of Cases

Treatment: Goals (1)

Interrupt Contact With Responsible DrugModulate Effects of Released MediatorsPrevent more Mediator Release and Production

Treatment: Initial Therapy (2)Stop Administration of the Antigen and all AnestheticsCall for HelpETT - 100% O2

Volume Expansion - Leg Elevation (0.5 - 0.7L)EPINEPHRINE

α1: VC of Capacitance and Resistance Vesselsβ1: ↑ Contractilityβ2: Bronchodilatation

↑ cAMP: ↓ Mediator ReleaseNo Pure α-Agonists!!! No CaCl2

Treatment: Epinephrine (3)

Who? Respiratory DifficultyCardio-Vascular Instability

Dose? Dependent of Severity of SymptomsIM: 10 µg/kg Lateral ThighIV: DILUTION – TITRATION! (Arrhythmias, MI..)

Hypotension: 5-10 µg IV q 1-2 MinCV Collapse: 100 µg IV q 1 Min (+ Cardiac Massage)

Treatment: Initial Therapy (4)Higher Dose During Anesthesia:

GA (Altered Sympathoadrenergic Response)Spinal/ Epidural Anesthesia (Partial Sympathectomy)

Resistant: β-Blocking DrugsUnopposed α-EffectsGlucagon IV

Sensitive: TCA, MAOI, Cocaine↑ Mortality ≈ Delayed Epinephrine

Inappropriate Use of EpinephrineAsthma, CV-Disease, Age

Treatment: Secondary Therapy (5)

Antihistamines: H1 Promethazine IMH2? 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 BronchodilatorsInotropes in InfusionExtubation – Airway Oedema?

Facial or Scleral OedemaAbsence of Air Leak After ETT Deflation

Diagnosis: GoalsAnaphylactic 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 TestingImmune mediated?

Postoperative TestingIdentify the responsible Drug.

Diagnosis: Intraoperative Testing

Blood HistamineMast Cell Tryptase

Urine N-Methyl Histamine

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

Mast Cells (99%)Mast Cells + Basophils

Anaphylactic > AnaphylactoidDD: Septic, Cardiogenic Shock

N-METHYL HISTAMINE (low Sensitivity)

→ Stable (Haemolysis, post-mortem)→ Not Stable

T1/2 = 90-120 Min→ Sampling: after initial Therapy

1 Hour24 Hours

T1/2 = Short (Min)→ Sampling < 10 Min

MASTCELL TRYPTASE (MCT)HISTAMINE

Histamine and MCT

Mast Cell Tryptase: Predictive Value

MCT + = IgE AntibodiesDO Skin Testing

MCT - = most of the Time no IgE AntibodiesDO Skin Testing if Clinical Anaphylaxis

Fisher M. BJA 1998

7/137Mast Cell Tryptase -125/130Mast Cell Tryptase +

IgE AB? (IDT/RIA)

Diagnosis: Postoperative Testing

Skin TestingCornerstonePrinciple:Injection of Allergen → Bridging IgE’s → Mast Cell Activation→ Weal and Flare,

Itching

Diagnosis: Skin Testing

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

Avoid Factors that interfere with Histamine – R (stop: Antihistamines, ACE-I, NSAIDs, Neuroleptics, VC…)

False negative Results!

Positive Control: Histamine, CodeineNegative Control: Saline (Dermatographism)Value + NMBDs, Hypnotics, Antibiotics

- Colloids and Contrast Media Intradermal - Prick Testing

Diagnosis: Skin TestingIntradermal Test

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

Skin Prick TestUndiluted Drugs

1:10: Atrac, Miv, Morphine.

In the EpidermisThrough Drop of Drug

Intradermal or Prick Test?Intradermal Skin Test+ easier for infrequent User

proven Reliability with Time

93% Agreement between 2 TestsBoth Tests: Improvement of Predictability

Skin Prick Test+ Easier to Prepare

Cheaperless Trauma (children)

Fisher M. BJA 1997

Drug Dilutions used for Intradermal Skin Testing.

Diagnosis: Skin TestingPositivity criteria:

Intradermal Skin Test: weal φ 8 mm + Flare, ItchingSkin Prick Test: weal φ 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 TestingWhich 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 NMBD0.5% + Skin Test to all NMBDs

Vecuronium and PancuroniumSuccinylcholine and Aminosteroid Compounds

Fisher M. BJA 1999Rose M., BJA 2001

Anaphylaxis to a NMBD and Subsequent Anesthesia

Pre-Treatment: not usefuldangerous (masks early Signs)

Avoid NMBDs, if possible.Use a Skin-Test-negative NMBD: Safe?

None26 Soetens F. 2003Acta Anaesth Belg

3179Fisher M. 1999BJA

None16Leynadier F. 1989Ann Fr Anaesth Reanim

Allergic Reaction?# Received a Skin Test - NMBD

Skin testing: Screening Test?

258 Patients:

No Risk Factors9.3% + Skin Prick to ≥ 1 NMBD

poor predictive Value as a screening Test

Porri F. Clin Exp Allergy 1999

Diagnosis: Postoperative Testing

Specific IgEBasophil Activation TestChallenge

Only for LA after negative Skin Test

Specific IgERadio Immuno AssayCirculating [IgE] ≈ IgE on Mast Cell and Basophils

Ag is bound to solid Support+ Patient’s Serum, Serum washed away+ radio-labelled anti-IgE: Radioactive CountingPOSITIVE: Radioactive Counting 3x Baseline

[spec IgE] during reaction = after 4-6 WeeksFast 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: Simplequick ResultSpecificity 100%IgE and non-IgE Reactions

Disadvantages: Sensitivity 66%after 4-6 Weeks

Investigation of Anaphylaxis

XClinical History

(X)(X)Specific IgE

XSkin Test

XXXMast Cell Tryptase

4-6 Weeks24 Hour1 HourImmediatelyTime after the Reaction

Investigation

Letter to the Patient /the General Practitioner(Anaphylactic and Anaphylactoid Reaction)Explanation of the EventAdvice About Future AnesthesiaAdd Information of Future Anesthesia

Medical Alert Bracelet