allergy and anesthesia

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

Karim Maasri MD-AUBMC

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


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


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


Polymorphonuclear Leukocytes (Neutrophils)

First cells appearing in acute inflammatory reaction

Containing

Hydrolases

Neutral Proteases

Lysosomes

Activation

Hydroxyl radicals

Superoxide

Hydrogen peroxide

Microbial killing


Eosinophils

Function in host defense UNCLEAR

Presence at

Parasitic infections

Tumors

Allergic reactions


Basophils

0.5% - 1% of circulating granulocytes in blood

Surface with IgE receptors

Similar function to those on mast cells


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


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


Proteins – Cytokines / Interleukins

IL1, IL8, TNF

Adherence of neutrophils to

pulmonary capillaries

Extravasation into alveolar space

Activation


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



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



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


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


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


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


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


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



Cardiovascular System

Dizziness

Malaise

Disorientation

Diaphoresis

Loss of Consciousness

Hypotension

Tachycardia

SVR

Dysrhythmias

Retrosternal Oppression

Pulmonary HTN

Cardiac Arrest



Cutaneous System

Itching

Burning

Urticaria (Hives)

Flushing

Periorbital Edema

Perioral Edema Tingling


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


Vasodilation

Pulmonary HTN

PG D2

TX B2

Protamine reactions Karim Maasri MD-AUBMC

Kinins

Kinins

Kinins

Mast Cell

Basophil Cell

Small Peptides

Bronchoconstriction


Vasodilation

Stimulation of vascular endothelium

Release of vasoactive factors

Prostacyclin

EDRF (NO)


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

?


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


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


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


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


Treatment Plan

Airway maintenance + Oxygen Administration

Anaphylactic Reaction Ventilation / Perfusion abnormalities

Hypoxemia 100% O2

Ventilatory Support

Follow Up response with ABGs


Treatment Plan

Discontinuation of all anesthetic drugs


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


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

+


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

+


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


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


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

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Secondary Treatment

Bronchodilators

Bronchospasm as major feature

Ipratropium Patients receiving -adrenergic blockers


Secondary Treatment

Corticosteroids

Anti-inflammatory effects


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


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


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


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



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


Drug interactions

Predictable

IV Fentanyl

Sedative – Hypnotic Drug

+ HYPOTENSION

Dose Dependant

IV Benzodiazepine



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


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


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


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


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


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


Thank You


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allergy and anesthesia

Technology

tnfkarim maasri mdaubmc

proteins complementantigen

antibodiesag binding

fc receptors

c3a fragments

hiv infection defense

ige receptorssimilar

ag endotoxins