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Anaphylaxis Massive allergic reaction Always call 911 Causes of Anaphylactic Shock – Medications – Foods and food additives • Monosodium glutamate, peanuts – Plant pollens – Bee stings – Radiographic dyes Characteristics of Anaphylaxis – Usually comes on in minutes / Peaks in 1530 minutes – Sensation of warmth – Intense itching of soles of feet and palms of hands – Breathing difficulties – Tightness and swelling in throat – Coughing, sneezing, wheezing – Tightness in chest Characteristics of Anaphylaxis #2 – Increased pulse rate – Swollen face, tongue, mouth – Nausea and vomiting – Dizziness – Blue around lips and mouth Anaphylaxis: What To Do – Check ABC’s • Use ice pack on bee sting – Inject epinephrine (dilates bronchioles) • (hopefully victim will have some) • Inject in outside part of thigh, hold for 10 seconds • May need to repeat – Get help immediately - 911(float trip) – Benedryl – too slow for major emergency, but worth a try PATOGENESI DELLO SHOCK ANAFILATTICO S.N.C. Allergene IgE M.C. APP. RENALE CIRCOLO ISTAMINA LEUCOTRIENI CHININE APP. CARDIOVASCOLARE APP. INTESTINALE APP. POLMONARE A. TURSI Chemical Structure of Histamine and Representative H1-Receptor-Antagonist Drugs Simons, F. E. R. et al. N Engl J Med 1994;330:1663-1670 Dealing With Anaphylaxis Give EPIPEN. Remove grey cap from end. Press EPIPEN firmly into side of thigh until a click is heard, then hold in place and count to 10. Administer Benadryl (for breathing difficulties). Call 911 (emergency) to transport to hospital. Notify parents immediately after emergency call. Frequency of symptoms in Anaphylaxis Urticaria/angioedema Upper airway edema Dyspnea or wheeze Flush Dizziness, hypotension, syncope Gastrointestinal sx Rhinitis 88% 56% 47% 46% 33% 30% 16% Formulations and Dosages of Representative H1-Receptor Antagonists Simons, F. E. R. et al. N Engl J Med 1994;330:1663-1670 Anaphylaxis • Onset of symptoms of anaphylaxis: usually in 5 to 30 minutes; can be hours later • A more prolonged latent period has been thought to be associated with a more benign course. • Mortality: due to respiratory events (70%), cardiovascular events (24%) Prevention of anaphylaxis • Avoid the responsible allergen (e.g. food, drug, latex, etc.). • Keep an adrenaline kit (e.g. Epipen) and Benadryl on hand at all times. • Medic Alert bracelets should be worn. • Venom immunotherapy is highly effective in protecting insect-allergic individuals. Treatment of anaphylaxis • EPINEPHRINE (1:1000) SC or IM - 0.01 mg/kg (maximal dose 0.3-0.5 ml) - administer in a proximal extremity - may repeat every 10-15 min, p.r.n. • EPINEPHRINE intravenously (IV) - used for anaphylactic shock not responding to therapy - monitor for cardiac arrhythmias • EPINEPHRINE via endotracheal tube Treatment of anaphylaxis • • • • Place patient in Trendelenburg position. Establish and maintain airway. Give oxygen via nasal cannula as needed. Place a tourniquet above the reaction site (insect sting or injection site). • Epinephrine (1:1000) 0.1-0.3 ml at the site of antigen injection • Start IV with normal saline. Treatment of anaphylaxis • Benadryl (diphenhydramine) - H1 antagonist • Tagamet (cimetidine) - H2 antagonist • Corticosteroid therapy: hydrocortisone IV or prednisone po Treatment of anaphylaxis • Biphasic courses in some cases of anaphylaxis: - Recurrence of symptoms: 1-8 hrs later - In those with severe anaphylaxis, observe for 6 hours or longer. - In milder cases, treat with prednisone; Benadryl every 4 to 6 hours; advise to return immediately for recurrent symptoms Treatment of Anaphylaxis in Beta Blocked Patients • Give epinephrine initially. • If patient does not respond to epinephrine and other usual therapy: - Isoproterenol (a pure beta-agonist) 1 mg in 500 ml D5W starting at 0.1 mcg/kg/min - Glucagon 1 mg IV over 2 minutes Use of epinephrine in Food Allergy • Epinephrine should be used immediately after accidental ingestion of foods that have caused anaphylactic reactions in the past. • An individual who is allergic to peanut, nuts**, shellfish, and fish should immediately take epinephrine if they consume one of these foods. • A mild allergic reaction to other foods (e.g. minor hives,vomiting) may be treated with an antihistamine Immediate Hypersensitivity • Acute (type I) hypersensitivities begin in seconds after contact with allergen • Anaphylaxis – initial allergen contact is asymptomatic but sensitizes the person – Subsequent exposures to allergen cause: • Release of histamine and inflammatory chemicals • Systemic or local responses Immediate Hypersensitivity – The mechanism involves IL-4 secreted by T cells – IL-4 stimulates B cells to produce IgE – IgE binds to mast cells and basophils causing them to degranulate, resulting in a flood of histamine release and inducing the inflammatory response Acute Allergic Response Figure 21.20 Anaphylaxis • Reactions include runny nose, itching reddened skin, and watery eyes • If allergen is inhaled, asthmatic symptoms appear – constriction of bronchioles and restricted airflow • If allergen is ingested, cramping, vomiting, or diarrhea occur • Antihistamines counteract these effects Anaphylactic Shock • Response to allergen that directly enters the blood (e.g., insect bite, injection) • Basophils and mast cells are enlisted throughout the body • Systemic histamine releases may result in: – Constriction of bronchioles – Sudden vasodilation and fluid loss from the bloodstream – Hypotensive shock and death • Treatment – epinephrine is the drug of choice Definizione di anafilassi (AAAAI) • Sindrome multisistemica, dovuta al rilascio di mediatori da basofili e mast-cell • Inizio acuto • Gravità variabile da lieve e autolimitantesi a mortale Università di Torino - Divisione Universitaria di Allergologia e Immunologia Clinica - Ospedale Mauriziano Umberto I Sintomi e segni dell’anafilassi • sensazione di calore • flushing e prurito • orticaria e angioedema • sensazione di stare per svenire • tosse, dispnea, respiro sibilante • dolore addominale, nausea, vomito, diarrea • sensazione di vie aeree chiuse e dispnea • incapacità a deglutire, parlare • disorientamento • sudorazione • aritmia cardiaca, sincope, shock • incontinenza Frequenza delle manifestazioni cliniche nell’anafilassi • Segni e sintomi cutanei: • Segni e sintomi respiratori: 100 % 75 % • Segni e sintomi cardiovascolari: 30-50 % • Segni e sintomi gastrointestinali: 25 % Patogenesi dell’anafilassi Classificazione fisiopatologica dell’anafilassi • IgE mediata: cibi, farmaci, insetti • Rilascio diretto dei mediatori da basofili/mastcell (farmaci, esercizio, freddo, idiopatica) • Alterazione del metabolismo ac arachidonico (aspirina, FANS) • Immunoaggregati (gammaglobuline, IgG antiIgA, destrano, albumina) • Reazioni trasfusionali • Attivazione del complemento non IC mediata (mdc, protamina, membrana dialitica) Università di Torino - Divisione Universitaria di Allergologia e Immunologia Clinica - Ospedale Mauriziano Umberto I Diagnosi differenziale dell’anafilassi: sindrome vaso-vagale • • • • • Pallore vs flush, orticaria, angioedema, prurito Sudorazione Bradicardia vs tachicardia (eccezioni) Nausea e vomito +++ Circostanze (prelievo, stazione eretta prolungata in ambiente affollato e caldo, secondaria a dolore fisico etc) Università di Torino - Divisione Universitaria di Allergologia e Immunologia Clinica - Ospedale Mauriziano Umberto I Terapia immediata dell’anafilassi • Valutazione segni vitali • Adrenalina 0.3-0.5 ml i.m. ogni 10-20 min (nei bambini 0.1-0.3 ml , o 0.01 mcg/Kg) • Posizione supina, gambe sollevate • O2 Università di Torino - Divisione Universitaria di Allergologia e Immunologia Clinica - Ospedale Mauriziano Umberto I Terapia dell’anafilassi (in base alla valutazione clinica) • Liquidi e.v. : fisiologica 1 l nei primi 20 min • Antistaminici (anti-H1 + anti-H2) • Salbutamolo 2.5/5 mg in aerosol ogni 20-30 min (se broncospasmo ++) • Metilprednisolone 50 mg ogni 6 ore (4 dosi) • SE IPOTENSIONE GRAVE: adrenalina e.v. 10 ml della sol. 1:100.000 (10 mcg/ml) in 5-10 min oppure 1-2 ml ogni 5-20 min della sol. 1: 10.000 (100 mcg/ml) Università di Torino - Divisione Universitaria di Allergologia e Immunologia Clinica - Ospedale Mauriziano Umberto I Symptoms-Food Allergy* • • • • • • • • • • Nausea Diarrhea Abdominal cramps Pruritic rashes Angioedema Asthma/rhinitis Vomiting Hives Laryngeal edema Anaphylaxis * Exercise exacerbates symptoms Definition of Terms Anaphylactoid events vs. Anaphylaxis Anaphylaxis: an immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral blood basophils Anaphylactoid events: immediate systemic reactions that mimic anaphylaxis but are not caused by IgE-mediated immune responses Anaphylactic Shock • A type of distributive shock that results from widespread systemic allergic reaction to an antigen • This hypersensitive reaction is LIFE THREATENING Pathophysiology Anaphylactic Shock • Antigen exposure • body stimulated to produce IgE antibodies specific to antigen – drugs, bites, contrast, blood, foods, vaccines • Reexposure to antigen – IgE binds to mast cells and basophils • Anaphylactic response Anaphylactic Response • Vasodilatation • Increased vascular permeability • Bronchoconstriction • Increased mucus production • Increased inflammatory mediators recruitment to sites of antigen interaction Clinical Presentation Anaphylactic Shock • Almost immediate response to inciting antigen • Cutaneous manifestations – urticaria, erythema, pruritis, angioedema • Respiratory compromise – stridor, wheezing, bronchorrhea, resp. distress • Circulatory collapse – tachycardia, vasodilation, hypotension Management Anaphylactic Shock • Early Recognition, treat aggressively • AIRWAY SUPPORT • IV EPINEPHRINE (open airways) • Antihistamines, diphenhydramine 50 mg IV • Corticosteroids • IMMEDIATE WITHDRAWAL OF ANTIGEN IF POSSIBLE • PREVENTION Management Anaphylactic Shock • Judicious crystalloid administration • Vasopressors to maintain organ perfusion • Positive inotropes • Patient education • Table 4 The main important conditions to be distinguished in a patient presenting with a rash and/or itching Rash+/– itchItching alone Immune system mediatedImmune system mediated Anaphylaxis AnaphylaxisAnaphylactoid reactionAnaphylactoid reactionAllergic reaction— localSystemicUrticaria ("hives") and/or angioedema Idiopathic thrombocytopaenicSystemic upset (for example, uraemia, cholestasis, blood disorders)purpura (ITP)OtherInfectiveSenile itchBacterialSolid tumours Meningococcal septicaemiaHIV Cellulitis Impetigo Scarlet feverViral Varicella zoster Primary infection (chickenpox) Reactivation (herpes zoster or "shingles") Measles Rubella (German measles) Nonspecific viral rashOther conditions Henoch Schonlein purpura Psoriasis Eczema Heat Redness Swelling Pain Loss of Function Nature Reviews/Immunology Management of Allergic Reactions Generalized anaphylaxis involves all of the previously mentioned systems When hypotension occurs, it is termed Anaphylactic Shock Affected Area Manifestation Skin Flare Urticaria-Wheal & pruritis, angioedema, erythema Respiratory Dyspnea,wheezing,flushing, cyanosis,perspiration,tachycardia, Affected Area Manifestation Gastrointestinal Abdominal cramps, nausea, vomiting, diarrhea, incontinence Cardiovascular headedness, Pallor, lightpalpitations, tachycardia, Sequence of Reaction 1. Skin reaction 2. Smooth muscle spasm (GI, GU, and bronchial) 3. Respiratory distress 4. Cardiovascular collapse Type of Reaction Quick Onset==> Rapid Progression==> Intense Reaction Delayed Onset==> Slow Progression==> Less Severe Reaction Drugs Used in Allergic Reactions Epinephrine Has Alpha and Beta adrenergic effects Acts as a physiologic antagonist to the events that occur during an allergic reaction Epinephrine Actions Include Bronchodilation Increased heart rate Arterial constriction Cutaneous, mucosal, and splanchnic vasoconstriction Reverses rhinitis and urticaria Epinephrine Risks of repeated use: Excessive elevation of blood pressure CVA Cardiac rhythm abnormalities Antihistamine Benadryl (chlorpheniramine) most often used H-1 blocker Inhibits action of histamine released during reaction to allergen Corticosteroids Hydrocortisone used most often Stablilizes cell membranes against actions of histamines, bradykinins, and prostaglandins Supplements adrenal steroid output during stress Treatment of Immediate Skin Reactions Epinephrine 0.3 mg IM or SC (0.3ml of a 1:1000 Solution) Antihistamine Diphenhydramine (Benadryl) 50 mg IM Gell and Coomb’s reactions Type I- Immediate Hypersensitivity – Immediate – Allergen binds 2 molecules of IgE – Intracellular degranulation and immediate release of products – Ex. Allergic rhinitis, anaphylactic shock, asthma 27. Type I Hypersensi tivity Type I Hypers ensitivi ty Reactio n 28. 3 R’s for treating anaphylaxis recognize symptoms react quickly review what happened to try and prevent reoccurrance Anaphylaxis 3 Rs of An Allergic Emergency Plan • Recognize symptoms early • React quickly • Review what caused the reaction Anaphylaxis Management An emergency plan of action should include: • What symptoms to look for • What medications to use • Medication dosage instructions • Where will medications be kept • What others should do • Allergy emergency practice drills Key Steps in Anaphylaxis Management • Recognize students • Know what symptoms to look for • Administer epinephrine quickly • Transport to hospital after EpiPen® use, then call parents How to Use EpiPen® How to Hold • Form a fist around the center of the unit • Pull off gray activation cap How to Use • Hold black tip near outer thigh (always apply to thigh) Count to 10 • Swing and jab into outer thigh. Hold in place and count to 10 Type I Hypersensitivity: Sensitization BB7 7 B-cell MHCII-Peptide CD28 MHCII Peptide CD3 TH-2 TCR CD4 Memory B-Cell Plasmacyte IgE Production Type I Hypersensitivity: Sensitization Plasmacyte IgE Binding to Mast Cell Fc/IgE Receptor Sensitized Mast Cell IgE Production Sensitized Mast Cell Type I Hypersensitivity: Effector Calcium Influx Allergen Sensitized Mast Cell Eosinophil & Neutrophil Attraction Degranulation (enzymes, histamine) Histamine Cytokines Lipid Mediators Type I Hypersensitivity Type I Hypersensitivity Type I Hypersensitivity Preformed Mediators: stored in granules in mast cells 1) Histamine - most important mediator in humans, although a similar function is performed by serotonin in other species, e.g.,rodents most of the characteristics of anaphylaxis can be mimicked in humans by injection of histamine alone present in granules at very high concentrations as an electrostatic complex with heparin. After fusion of the granules histamine is released from the heparin complex by ion-exchange effects stimulates contraction in most smooth muscle, vasodilation and permeability in post-capillary venules, drop in blood pressure Type I Hypersensitivity Preformed Mediators: 2) Eosinophil chemotactic factor - attracts and prevents further migration of eosinophils and neutrophils 3) Neutrophil chemotactic factor - attracts and prevents further migration of neutrophils 4) Degradative enzymes including: Arylsulfatase - inactivates leukotrienes chymase degrades proteins N-acetylglucosaminidase - degrades heparin Type I Hypersensitivity 2. Causes and Results for humans can result from, bee or wasp sting, seafood, nuts. can also result from cross linking of drug to self protein (i.e., penicillin, insulin) • can result in asthma, hayfever, systemic or localized anaphylaxis Type I Hypersensitivity Lipid Mediators: formed and secreted after mast cells are activated 1) Leukotrienes B4, C4, D4: formerly known as SRS-A, slow reacting substance of anaphylaxis arachidonic acid metabolites structurally related to prostaglandins contracts bronchioles and increases capillary permeability 2) Platelet-activating Factor (PAF): synthesized from phospholipids in the cell membranes active at l0l0 M potent hypotensive agent most potent bronchorestricting agent in asthma and allergic rhinitis (hay fever) aggregates and lyses platelets releasing serotonin and other mediators promotes eosinophil infiltration PAF antagonists represent an active area of research, particularly for drugs to prevent abnormalities in reproduction 3) Prostaglandin D2 and other prostaglandins Type I Hypersensitivity Cytokines: stimulates production of lymphokines (IL-3, IL-4, IL-5, IL-6, GM-CS~), which stimulate production of leukocytes, more mast cells - stimulates production of bradykiniin, which causes vasodilation, hypotension Type I Hypersensitivity O O S CO2 H N O CH 3 CH 3 S CO2 H S NH O Self Protein SH Self Protein SH CH 3 CO 2H CO 2H SH CH 3 Type I Hypersensitivity Systemic Anaphylaxis: most severe and life-threatening type of allergic response characteristics: - generalized flush, palpitations, dizziness, apprehension, urticaria, angioedema and abdominal cramps - may proceed to dyspnea, seizures, cyanosis, shock, and/or death - begins 3 to 4 min after administration causes: -xenogenic sera, allergenic extracts, dextrans, therapeutic enzymes, polypeptide hormones, penicillins and cephalosporins. localized anaphylaxis affects only certain vasodilation smooth muscles most common is hayfever (allergic rhinitis) and asthma (localized brochial constriction) Skin grids are useful for detecting if a person will respond to an allergen; Risk of sensitizing the individual as well as leading to shock. Type I Hypersensitivity 3. Drugs that Affect TYPE I -Antihistamines -Cromolyn Sodium -Theophylline -Epinephrine -Cortisone Block Hl&H2 receptors Blocks Calcium influx Prolongs cAMP levels (inhibits phosphodiesterases). Degranulation is increased by lowering levels of cAMP Stimulates cAMP production through b-adrenergic receptor Blocks histimine production, stimulates mast cell cAMP production Type I Hypersensitivity Histamine Causes a Wide Array of Effects smooth muscle cells - Constriction small blood vessels - Vasodilation mucous glands - Mucous secretion blood platelets sensory nerve endings Histamine Receptors (H1 and H2 receptors Type I Hypersensitivity 4. Therapeutic Immediate-Hypersensitivity Antigens Therapy for allergies based on hyposensitivity Typical therapy depends on the injection of known quantities of an allergen in the hope of increasing the amount of IgG over IgE capable of reacting with the allergen IgG blocks the binding of the allergen with IgE Type I Hypersensitivity: Immunomodulation Type I Hypersensitivity Allergen extracts, Aqueous & Glycerinated Antigen Source FDA licenses over 600 distinct allergen extracts as safe and effective for immunotherapy. Composed of proteins and other components -Foods: Chicken egg albumin, casein, almond, scallops, etc. -Animals: cat, dog, horse, rat, chicken, duck, pigeon feathers, etc. -Grasses: Kentucky blue, red top, perennial rye, Bermuda, fescue, etc. -Insects: Cockroach, house-dust mite -Molds:Aspergillus, Rhizopus, etc. -Trees: White oak, cypress, cottonwood, maple, elm -Weeds: Ragweed, sagebrush, saltbush, wingsscalel, etc. Dosage and Route Progressive, escalating dose, modified to patient needs; SC Indications Treatment of patients with allergies upon natural exposure to allergens. Effective against rhinitis, allergic asthma from cat, dog, grass, dust mite. Adverse Reactions Most common cause of systemic anaphylaxis, managed by dosing with epinephrine and in some cases antihistimines. Efficacy 7~90% of patients demonstrate improvement in symptoms within 12 weeks and continuing for 1-2 years Type I Hypersensitivity Hymenoptera (Bee) Venom Protein Antigen Source Venoms of the following flying insects: Honey bee, Wasp, White-faced hornet, Yellow hornet, Yellow jacket-, Composed of purified venom. Dosage and Route Progressive, escalating dose, modified to patient needs; SC Indications Treatment of patients with history of systemic reaction to stings Adverse Reactions Anaphylaxis without warning within 20 mins. of injections, managed by dosing with epinephrine and in some cases antihistimines. Efficacy 97% of patients have reduced anaphylaxis from stings, without therapy 60% will develop anaphylaxis with next sting. Type I Hypersensitivity Benzylpenicilloyl Polylysine Antigen Source Hapten(Benzylpenicilloyl moiety-polypeptide (lysine) containing Dosage and Route Sterile skin test area on upper or outer arm, 5-10 mins. reaction time. Indications Used to assses risk of administering benzylpenicillins (i.e., penicillin G) Adverse Reactions Allergic reactions occur in <1% of recipients and is usually characterized by intense 1ocali inflammation. Efficacy The test is 89-96% sensitive and specific. Consequently, 4-11% of patients who test negative will react to treatment with penicillins. Urticaria Anaphylaxsis Histamine binds to H1 receptors triggers inflammatory responses these are exaggerated responses Histamine blood vessels vasodilation increased blood flow increased permeability tissue edema fluid leaking into interstitial space •Hypotension •Laryngeal edema •Angioedema •Conjunctivitis Extravascular Smooth Muscle bronchial and laryngeal smooth muscle constriction restricted airway Wheezing Bronchoconstriction NOTE: combined with laryngeal edema = high risk of losing airway GI Tract Inflammation of intestinal mucosa cramping malabsorption Mucosal Tissue conjunctivitis inflammation of eyelids nose rhinitis bronchial (asthma) bronchoconstriction hypersecretion of mucus Antihistamines Treatment for nonlifethreatening allergies H1 vs. H2 Receptors H1: Receptors located on Bronchial smooth muscle histamine causes constriction Arterioles dilation of capillaries in skin H1 vs. H2 Receptors Vascular epithelium increased permeability H1 vs. H2 Receptors H2 Gastric mucosa secretion of gastric acid and pepsin Mast cells tissues Basophils circulation blocks histamine release Drugs H1 Receptor Antagonists oldest class of antihistamines have a rapid onset Actions (H1 Receptor Antagonists) Bind to H1 receptors to block action of histamine **do block release cannot reverse effects of histamine already bound Indications (H1 antagonists) Allergic response (non-life-threatening) Motion sickness Sedation Cough H1 Receptor Antagonists Many possess anticholinergic effects Side effects: Increase heart rate Constipation Urinary retention Insomnia Nervousness First Generation Antihistamines bind with H1 receptors in the periphery and in CNS CNS effects sedation Peripheral effects decrease itching, mucus production, capillary permeability, saliva production Prototype First Generation H1 Antagonists Benadryl (diphenhydramine) Travist (clemastine) Zyrtec (cetirizine hydrocloride) Chlor-Trimetron (chlorpheniramine) Second Generation Bind selectively to peripheral H1 receptors do not cross the BBB Prototypes Zyrtec (cetirizine) Allegra (fexofenadine) Claritin (loratadine) H2 Receptor Antagonists AKA: H2 blockers Actions Target H2 receptors in the gastric mucosa Decrease secretion of gastric acid Examples Tagamet (cimetadine) Pepcid (famotidine) Zantac (ranitidine HCL) What would these drugs do during a Type I hypersensitivity reaction? MEDIATORS A VARIETY OF CHEMOTACTIC, VASOACTIVE AND SPASMOGENIC COMPOUNDS MEDIATE THE ANAPHYLACTIC REACTION. • IMMEDIATE (5-30 mins): histamines, leukotrienes Intense reaction characterised by oedema, mucus secretion, and smooth muscle spasm. • LATE (2-8 hours): leukotrienes, PAF, TNF-, cytokines Recruit other inflammatory cells and release additional waves of mediators that cause injury Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Pressure (BP) (continued) Summary of Effector Organ Responses to Autonomic Stimulation Part I Be sure to memorize all entries in this table Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9th Ed. p. 110-111 Summary of Effector Organ Responses to Autonomic Stimulation Part II This part of the table you do not need to memorize Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9th Ed. p. 110-111