Anaphylaxis during Anesthesia: Diagnosis and Treatment. Dr. F. Soetens Department of Anesthesia Sint-Elisabeth Hospital, Turnhout.
Sep 21, 2014
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