allergy and anesthesia
TRANSCRIPT
Immune Function
and
Allergic Response
Karim Maasri
PGY1
April 30, 2010 Karim Maasri MD-AUBMC
Basic Immunologic Principles
Cellular HOST
DEFENSE
Antigen (1st exposure)
Humoral
Antibody-Mediated immune response
Free Antigens
Activation
B Cell
Giving rise
Plasma Cell
Secretion
Engulfed by
Macrophage
Becoming
Antigen Presenting Cell
Antibodies
Memory B Cells Memory T Cells
Stimulating
Helper T Cell
Memory helper T Cell
Antigen (2nd exposure)
Cytotoxic T cell
Display of Antigens by infected cells
Activation
Active Cytotoxic T cells
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The antigen
Molecule stimulating an immune response
Anesthesiologists
Use of few antigens
Polypeptides
Large macromolecules
Protamine
Dextrans
Other drugs
Immunogenic
Simple organic compounds with low molecular weight
Stable bond with circulating proteins /
tissue micromolecules
Hapten-macromolecular
complex Karim Maasri MD-AUBMC
Thymus – Derived (T – Cell) Lymphocytes
Thymus of Fetus Immature
lymphocytes T-Cells
Subpopulations of T cells
Killer cells Helper cells Suppressor cells
Cytotoxic cells
Destruction of myobacteria, fungi, viruses
Regulatory Cells
No specific stimulation
In HIV infection
Transplant rejection
Defense against tumor cells Karim Maasri MD-AUBMC
Bursa – Derived (B – Cell) Lymphocytes
Specific lymphocyte
line
Specific plasma
cells
Helper T-cell lymphocytes Suppressor T-cell lymphocytes
Important in producing cells responsible for Ab
synthesis
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Antibodies
Ag binding to Fab
Activation of Fc receptor
Conformational change
Heavy Chain
Light Chain
Disulfide Bridges
Constant region on heavy chain
Constant region on light chain
Variable region on heavy chain
Variable region on light chain
Antigen Binding Sites
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Monocytes and Macrohpages
Circulating monocytes
Confined to specific organs
(Lungs)
Macrophages
Ingesting Ag
Presenting Ag
Microbicidal
Tumorocidal
Inflammatory
Mediator Synthesis
Facilitating B-Lymphocyte and T-Lymphocyte response
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Polymorphonuclear Leukocytes (Neutrophils)
First cells appearing in acute inflammatory reaction
Containing
Hydrolases
Neutral Proteases
Lysosomes
Activation
Hydroxyl radicals
Superoxide
Hydrogen peroxide
Microbial killing
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Eosinophils
Function in host defense UNCLEAR
Presence at
Parasitic infections
Tumors
Allergic reactions
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Basophils
0.5% - 1% of circulating granulocytes in blood
Surface with IgE receptors
Similar function to those on mast cells
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Mast Cells
Important in immediate hypersensitivity responses
Tissue Fixed
Location in perivascular space
Skin
Lung
Intestine
Surface with IgE receptors Activation
Release of active mediators important to hypersenitivity
responses
Immune Stimuli
Nonimmune Stimuli
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Proteins – Cytokines / Interleukins
Synthesis by macrophages
Secondary messengers
Endothelial cells
White cells
Activation
IL-1
TNF
Important in infection and inflammatory responses
Neuropeptide release
Fever
Endothelial cell activation
Increased adhesion molecule expression
Neutrophil priming
Hypotension
Myocardial suppression
Catabolic state
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Proteins – Cytokines / Interleukins
IL1, IL8, TNF
Adherence of neutrophils to
pulmonary capillaries
Extravasation into alveolar space
Activation
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Proteins – Complement
Primary humoral response to Ag-Ab binding
Activation of complement system
20 different proteins Binding to
Cell membranes
Other complement proteins
Activated Ab
Important effector system of inflammation
Activation of complement system
Alternate Pathway Classic Pathway
IgG / IgM binding to Ag Endotoxins or drugs
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Proteins – Complement
Antigen
Antibody C1 Complex
C2a + C4b fragments
Classic Pathway
Alternate Pathway
C3 convertase
C3 hydrolysis
C3b + C3a fragments
C5 cleaved into C5a and C5b
C5b + C6 + C7 + C8 + C9 formation of membrane
attack complex
Swelling of cell And
busting
C3a + C4A + C5a
Important humoral and chemotactic
properties
+
Recognizing bacteria directly and indirectly
by attracting phagocytes
Increasing adhesions of phagocytes to Ag
Cell Lysis
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Proteins – Complement
Regulation of complement system by series of inhibitors
Angioneurotic edema
Hereditary (autosomal dominant)
Acquired (lymphoma, lymphosarcoma, CLL, macroglobulinemia)
C1 esterase deficiency
Recurrent increased vascular permeability of specific subcutaneous
and serosal tissues (angioedema)
Trauma Surgery No cause
Laryngeal obstruction Respiratory abnormalities
Cardiovascular abnormalities
Protamine administration Acute pulmonary vasoconstriction
Pathologic manifestation of complement activation
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Effects of Anesthesia on immune system
Anesthesia
Surgery
+ Depression of
nonspecific host resistance mechanisms
Direct and hormonal effects of anesthetic
drugs
Immunologic effects of
other drugs used
Coincident infections
Transfused blood
products
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Type I Reactions
Antigen
IgE - Ag
Fc receptor
IgE
Binding of IgE Ab to Fc receptors
Mast cell / Basophil cell
Antigen
+
Cross-linking of IgE
Degranulation
Intracellular activation
Release of mediators
Independent of Complement
Anaphylaxis Extrinsic Asthma Allergic rhinitis
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Type II Reactions
Individual own cell
Antigen
IgG or IgM
Complement activation and
cell lysis
Killer T Cell
Fc receptor
ABO – incompatible transfusion reactions Drug – induced anemia
Heparin – induced thrombocytopenia Karim Maasri MD-AUBMC
Type III Reactions
Antigen
IgG or IgM Soluble protein
Insoluble Protein – Ab complex
Recruitment of Inflammatory cells
Complement activation
Tissue Injury Classic Serum sickness after snake antisera Immune complex vascular injury
? Protamine mediated pulmonary vasoconstruction Karim Maasri MD-AUBMC
Type IV Reactions
Second contact with same antigen
Antigen
Sensitized T -cell
Lymphokines
Mononuclear cell infiltration
Macrophage activation
Lymphocyte regulation
Delayed tissue injury
Tissue rejection Graft-versus-host reactions
Contact dematitis Tuberculin immunity
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Intraoperative Allergic Reactions
Once in every 5,000 to 25,000 anesthetics Mortality rate of 3.4%
Allergic reactions due to an IV drug
Time (minutes)
5
90%
Circulatory collapse Most dangerous manifestation
May be the only manifestation Refractory hypotension
Vasodilation
Venous return
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Recognition of Anaphylaxis during Regional and General Anesthesia
Respiratory System
Dyspnea
Chest Discomfort
Coughing
Wheezing
Sneezing
Laryngeal Edema
Pulmonary Compliance
Acute Respiratory Failure
Fulminant Pulmonary Edema
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Recognition of Anaphylaxis during Regional and General Anesthesia
Cardiovascular System
Dizziness
Malaise
Disorientation
Diaphoresis
Loss of Consciousness
Hypotension
Tachycardia
SVR
Dysrhythmias
Retrosternal Oppression
Pulmonary HTN
Cardiac Arrest
Karim Maasri MD-AUBMC
Recognition of Anaphylaxis during Regional and General Anesthesia
Cutaneous System
Itching
Burning
Urticaria (Hives)
Flushing
Periorbital Edema
Perioral Edema Tingling
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Arachidonic Acid Metabolites
Arachidonic Acid
Metabolism
Activation
Prostaglandins Leukotrienes
Mast Cell
Lipoxygenase pathway Cylco-oxygenase pathway
C4, D4, E4
Classic slow reacting
Substance of anaphylaxis
Bronchoconstriction
Capillary permeability
Vasodilation
Coronary vasoconstriction
Myocardial depression
Bronchospasm
Capillary permeability
Vasodilation
Pulmonary HTN
PG D2
TX B2
Protamine reactions Karim Maasri MD-AUBMC
Kinins
Kinins
Kinins
Mast Cell
Basophil Cell
Small Peptides
Bronchoconstriction
Capillary permeability
Vasodilation
Stimulation of vascular endothelium
Release of vasoactive factors
Prostacyclin
EDRF (NO)
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Platelet – Activating Factor
Activation
Mast Cell
Platelet – Activating Factor Very potent
Unstored Lipid
Physiologic effect at 10-10 M
Aggregation of PAF
Platelets’ Activation
Release of inflammatory
products
Leukocytes’ Activation
?
Capillary permeability
Smooth muscle contraction
Intense Wheal and flare response Karim Maasri MD-AUBMC
Non-IgE Mediated Reactions – Complement Activation
Complement Activation
Immunologic pathway: Ab mediated (Classic) Non-immunologic pathway (Alternative)
Multimolecular self assembly proteins
Release of biologically active fragments of C3, C5
C3a, C5a
ANAPHYLATOXINS
Histamine release from
mast/basophil cells
Smooth muscle
contraction
Increase in capillary
permeability
Interleukin synthesis
Karim Maasri MD-AUBMC
Non-IgE Mediated Reactions – Complement Activation
C5a
Interaction with high affinity receptors on PMNs and platelets
Leukocyte Chemotaxis Aggregation Activation
Embolus
Liberation of inflammatory
products
Microvascular occlusion
IgG Directed against
antigenic determinants or granulocyte surfaces
LEUKOAGGLUTININS
Clinical Expression Transfusion reaction
Pulmonary vasoconstriction (protamine transfusion)
ARDS Septic Shock
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Non-IgE Mediated Reactions – Non Immunologic Release of Histamine
Molecules administered during the
perioperative period
Histamine release in a dose-dependent,
nonimmunologic fashion
Mechanism Not well understood
Human cutaneous mast cells
Only cell population responding to drugs and endogenous stimuli
Basophils not involved
What is know
Equimolar basis
Clinically recommended dose
Atracurium, d-Tubocurarine, metocurine
Same ability for degranulation
Newer aminosteroidal agents (Rocuronium, Rapacuronium)
Minimal effect on histamine release Karim Maasri MD-AUBMC
Treatment Plan
Anaphylactic Reaction
Vasodilation
Capillary permeability
Bronchospasm
Hypotension +
Hypoxia
Severe reactions Aggressive therapy
Lower respiratory obstruction
Pulmonary hypertension
Persistent hypotension
Laryngeal obstruction
Persistence of symptoms 5h-32h ICU 24h for observation Karim Maasri MD-AUBMC
Treatment Plan
Airway maintenance
100% Oxygen
Intravascular volume expanders
Epinephrine
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Treatment Plan
Airway maintenance + Oxygen Administration
Anaphylactic Reaction Ventilation / Perfusion abnormalities
Hypoxemia 100% O2
Ventilatory Support
Follow Up response with ABGs
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Treatment Plan
Discontinuation of all anesthetic drugs
Anaphylactic Reaction
Bronchospasm
Hypotension induction
Inhalational drugs
Not bronchodilators of choice
Interference with body’s compensatory mechanism to cardiovascular collapse
Hypotension
Stop all Inhalational
drugs
Halothane
Sensitization of myocardium to epinephrine Karim Maasri MD-AUBMC
Treatment Plan
Providing volume expansion
Anaphylactic Reaction
Intravascular space Interstitial space
Quick Process Acute Hypotension
40%
Lactated Ringer’s Colloid
Normal Saline
No advantage for any
2L – 4L 25 ml/kg – 50 ml/kg
Persistence of Hypotension
+
Karim Maasri MD-AUBMC
Treatment Plan
Providing volume expansion
TEE Accurate assessment of intravascular volume
Guidance of intervention
After anaphylaxis Fulminant noncardiogenic pulmonary edema
Careful hemodynamic monitoring while replenishing volume
Loss of intravascular volume
+
Karim Maasri MD-AUBMC
Treatment Plan Epinephrine
Drug of choice during resuscitation in anaphylactic shock
-adrenergic effect
Bronchodilation 2 receptor stimulation
Vasoconstriction Reversal of hypotension
Inhibition of mediator release from mast cells and basophils
5g – 10g IV
Volume
Epinephrine
+
Hypotensive patient
+
Cardiovascular collapse
S/C Epinephrine Laryngeal edema without hypotension
0.1mg – 1 mg IV Epinephrine
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Secondary Treatment
Antihistamines
Unclear indication
Diphenhydramine
No inhibition of anaphylactic reaction
? antidopaminergic effects
Competing with histamine over receptor
0.5mg/kg – 1mg/kg
Slow infusion to prevent potential hypotension
Karim Maasri MD-AUBMC
Secondary Treatment
Catecholamines
Resuscitation Persistent hypotension
Patient with anaphylactic
reaction
Give Catecholamine
Bronchospasm
Epinephrine
Norepinephrine
0.05g/kg/min - 0.1g/kg/min
Titrate according to response
Those with refractory hypotension to SVR Karim Maasri MD-AUBMC
Secondary Treatment
Bronchodilators
Bronchospasm as major feature
Ipratropium Patients receiving -adrenergic blockers
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Secondary Treatment
Corticosteroids
Anti-inflammatory effects
Anaphylactic Reaction
Infusion of corticosteroids
Benefits of corticosteroids
Attenuation of late phase reactions
Time (hours)
4 6 12 24
IgE mediated reactions
Complement mediated reactions
0.25g - 1g IV methylpredisone
1g - 2g IV methylpredisone
Catastrophic pulmonary vasoconstriction after protamine transfusion reactions Karim Maasri MD-AUBMC
Secondary Treatment
Bicarbonate
Persistent hypotension
Rapid Acidosis
Reduction in epinephrine effect on heart and systemic vasculature
Sodium Bicarbonate 0.5meq/kg – 1 meq/kg
Every 5 minutes according to response
Karim Maasri MD-AUBMC
Airway Evaluation
Profound laryngeal edema
WAIT
Evaluation of trachea
before extubation
Facial edema
Airway edema
Time for extubation
Deflation of ET tube cuff
Leak No Leak
Extubate Keep Intubated
Reassess
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Vasopressin
Important drug for refractory shock
Vasodilatory Shock
Cardiac Output
Hypotension
+
Activation of vasodilatory mechanisms
Inability of -adrenergic
mechanisms to compensate
Infusion: 0.01units/min
Karim Maasri MD-AUBMC
Perioperative management
Adverse Reactions
6% - 10%
Allergic Reactions Drugs: 1% - 3% risk of allergic reaction
Americans: 5% with allergy to 1 or 2 drugs
Adverse Reactions
Pharmacological action of drug
Predictable
Dose dependant
Serious Mild
Overdose
Unintentional route of administration
Opioid
Nausea
Vomiting
Local release of histamine
Allergy
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Perioperative management
Side effects
Most common adverse drug reactions
Undesirable pharmacologic actions occuring at usual prescribed dose
Morphine
Dilatation of venous capacitance bed
Heart Rate
Sympathetic Tone
Effect depending
on patient’s blood volume
In depleted patients
Rapid Hypotension Karim Maasri MD-AUBMC
Perioperative management
Drug interactions
Predictable
IV Fentanyl
Sedative – Hypnotic Drug
+ HYPOTENSION
Dose Dependant
IV Benzodiazepine
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Perioperative management
Unpredictable adverse drug reactions
Related to genetic
differences
Dose Dependant
Allergic reactions
Enzyme deficiency
Small percentage of patients
Clinical manifestations not resembling known
pharmacologic action
Exposure to drug Manifestations
TIME SPAN
Sulfa Drugs in G6PD deficient
patients
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Immunologic Mechanisms of Drug mechanism
Different reactions in different patients
Penicillin
Any Antigen
Different Immunologic
Responses
Different reactions 1 patient
Anaphylaxis Hemolytic Anemia
Serum Sickness
Contact Dermatitis
Type I Type II Type III Type IV
Localized Rash
Angio- neurotic edema
Karim Maasri MD-AUBMC
Evaluating a patient with allergic reactions
Direct challenge of patient with the drug
Hard
Temporal sequence of drug
administration
ANY DRUG Allergic Reaction
Only way to prove an allergic reaction
Relying on circumstantial
evidence
Identifying the
drug
DANGEROUS NOT REOMMENDED
Karim Maasri MD-AUBMC
Agents implicated in Allergic Reactions
Colloid Volume Expanders
Antibiotics
Muscle Relaxants
Protamine
NSAIDs
Blood Products
Induction Agents
Multiple Agents
Allergy to 1 muscle relaxant
Potential of allergy to other muscle relaxants
Cross-reactivity because similarity of the active site
Quaternary ammonium molecule
Vecuronium Pancuronium Karim Maasri MD-AUBMC
Latex
Important cause of perioperative anaphylaxis
Derived from the tree Hevea brasiliensis
Milky sap
Preservatives
Antioxidants
Accelerators +
Increased risk
Health care workers
Children with spina bifida
Children with urogenital abnormalities
Children with certain food allergies
Banana
Kiwi
Avocado
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Latex
Anesthesiologists
24% with irritation / contact dermatitis
12.5% with Latex – specific IgE positivity
Pretreatment with antihistamine
No data for prevention
No data for decreasing severity
Of those
Karim Maasri MD-AUBMC
Muscle Relaxants
62% - 81% of anaphylactic reactions
Unique molecular features Potential allergens
Divalent
Capable of cross-linking cell-surface IgE
Mediator release from mast cells / basophils
Muscle
Relaxant IgE
Mast Cell
Cross
linking
No need for haptenating to large carrier molecules
More in steroid derived agents
Karim Maasri MD-AUBMC