1. بسم الله الرحمن الرحیم 1

2. Anaphylaxis Rapid recognition and treatment DR jarahzadeh Intensivist

3. ANAPHYLAXIS In a few seconds it was extremely ill;
breathing became distressful and panting;
it could scarcely drag itself along, lay on its side, was seized with diarrhea, vomited blood and died in twenty five minutes.
Charles Richet 1902
First description of experimental anaphylaxis.

4. ANAPHYLAXIS Instead of inducing tolerance ( prophylaxis),
Richet’s experiments in dogs injected with
sea anemone toxin resulted in lethal
responses to doses previously tolerated.
He coined the word ‘ana’ (without) ‘phylaxis
(protection). He won the Nobel prize for this
work.
Victim was a dog previously injected with sea anemone toxin which it tolerated, then on re-exposure with the same dose three weeks later, developed fatal anaphylaxis.

5. Definition of Anaphylaxis
Definition in common use with various versions but may be supplanted –
An acute allergic reaction resulting in widespread allergic symptoms which involves two or more organ systems, and is potentially life-threatening, often resulting from an IgE-mediated mechanism.
Anaphylactoid – term falling into disuse but meant to describe anaphylaxis without IgE involvement ie a non-allergic mechanism.
Anaphylaxis now describes a clinical event, regardless of mechanism
IgE – Immunoglobulin E – defined later

6. Current Definition of Anaphylaxis
Short practical form – ‘Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death’
(Sampson et al. Second symposium on the definition and management of anaphylaxis…J Allergy Clin Immunol 2006;117:391-7)
More detailed diagnostic criteria are presented in slides at end of workshop

7. Anaphylaxis is highly likely when any ONE of the following 3 criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
A. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, reduced PEF in older children and adults, stridor, hypoxemia)
B. Reduced BP* or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse, syncope, incontinence)

8. 2. TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): A. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula) B. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF in older children and adults, hypoxemia) C. Reduced BP* or associated symptoms (eg, hypotonia, collapse, syncope, incontinence) D. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

9. 3. Reduced BP* after exposure to a known allergen for that patient (minutes to several hours): A. Infants and children: low systolic BP (age specific)* or greater than 30 percent decrease in systolic BP B. Adults: systolic BP of less than 90 mm Hg or greater than 30 percent decrease from that person's baseline

10. IgE Mediated Allergic Reactions
Allergen bridges 2 molecules of IgE causing mediator release
Early phase manifestations are due to release of preformed mediators , histamine & tryptase, and newly generated leukotrienes, which cause
vasodilation and increased vascular permeability,itch , sneeze and bronchospasm
Late phase manifestations are due to recruitment of eosinophils, neutrophils & TH2 cells and other inflammatory cells 4-12 hrs later due to cytokines released in the early phase eg platelet activating factor, TNFa, eosinophil chemotactic factor, IL 3-5 etc
As well , interleukin 4 formed by mast cells can stimulate further production of IgE and potentiate other allergic reactions

11. EARLY LATE PHASE
Immediate symptoms (mins to few hrs) due to mediator release
Begins 4-12 hrs after allergen exposure due to inflammatory cell influx
Allergic rhinitis – rhinorrhea, sneeze, itch
Asthma – bronchospasm, wheeze, dyspnea
Urticaria – short lived lesions < 24 hrs, responds well to antihistamines
Anaphylaxis – occurs
Allergic rhinitis – nasal congestion
Asthma – increased bronchial irritability and inflammation with increased tendency to asthma flareups and increased severity
Urticaria-lesions last >24 hrs, poor response to antihistamines
Anaphylaxis -No late phase .
Dyspnea –difficulty breathing; Bronchospasm – narrowing of bronchial airways due to smooth muscle spasm, resulting in dyspnea and wheeze;

12. EARLY LATE PHASE
Responds to symptom-relief therapy antihistamines for urticaria and rhinitis;
bronchodilators for bronchospasm
Limited response to symptom-relief therapy
Response to steroids – minimal for acute relief but symptoms subside with control of late phase reaction and its effects on target cells
Responds to steroids .

13. ACTIONS OF HISTAMINE Peripheral vasodilation
Increased vascular permeability
Altered cardiac conduction
Bronchial/intestinal smooth muscle contraction
Nerve stimulation-Cutaneous pruritus/pain
Increased glandular mucus secretions
Pruritus- itch

14. CLINICAL MANIFESTATIONS OF ALLERGY
Knowing the actions of histamine and other mediators , what would you predict to be the clinical effects on the body?
See the next series of slides which illustrate the effects of histamine

15. CLINICAL MANIFESTATIONS OF ALLERGY
Vasodilation – erythema, nasal congeston, hypotension, anaphylaxis
Increased vascular permeability – urticaria, hypotension, anaphylaxis
Smooth muscle spasm – asthma, intestinal cramps, diarrhea, anaphylaxis
Mucus secretion – allergic rhinitis, asthma
Nerve stimulation-itch, sneeze
See the next series of slides which illustrate the effects of histamine

16. URTICARIA Raised central white or red wheals
Surrounding erythema or flare, with itch or burning
Histamine mediated
Varies in shape & size – circular, gyrate, linear, isolated or coalescent
Well demarcated, blanch with pressure
Predisposition to warm areas, pressure sites
Lasts hours, max
The wheal is due to edema around the blood vessel due to vasodilation and extravasation of fluid into surrounding tissue. The flare is an axonal (nerve-mediated) reflex triggered by histamine causing reflex vasodilation of surrounding blood vessels causing redness or erythema

17. Urticaria, with central pale wheal, and surrounding erythema
Urticaria, with central pale wheal, and surrounding erythema. These are gyrate in appearance

18. ANGIOEDEMA Diffuse skin colored subcutaneous swelling
Pathology similar to urticaria except it occurs in deeper subcutaneous tissues
Not itchy or painful, unless in confined site
Can be histamine, bradykinin etc mediated
Can last hours or days
Not very responsive to antihistamines
Often found in 40% of urticaria cases

19. Angioedema

20. ANAPHYLAXIS: OVERVIEW
Anaphylaxis is a severe, potentially fatal systemic allergic reaction that occurs suddenly (minutes to hours) after contact with an allergy-causing substance
Death can occur in minutes, usually due to closure of airways
Allergic reaction affects many body systems : rash & swelling, breathing difficulties, vomiting & diarrhoea, heart failure & low blood pressure  ANAPHYLACTIC SHOCK

21. This Ottawa teen never liked nuts and would refuse them
This Ottawa teen never liked nuts and would refuse them. She never saw an allergist. Mom decided to hide peanut sauce in her meal to see if she was allergic to peanut or not. A taste of the sauce resulted in anaphylaxis and she was moribund by the time the ambulance arrived

22. Anaphylaxis: Rapid recognition and treatment

23. Minutes to cardiac arrest
Fatal anaphylaxis
Minutes to cardiac arrest
Median
Range
55 iatrogenic 5
1 – 80
37 food 30
6 – 360
32 venom 15
4 – 120
Pumphrey RSH, Clinical and experimental allergy, 2000

24. Anaphylaxis: Rapid recognition and treatment

25. recognition Underrecognized, undertreated
Most important diagnosis marker is trigger
Over 40 symptoms and signs described
cutaneuos
>80%
respiratory
up to 70%
gastrointestinal
up to 40%
cardiovascular
up to 35%

26. CLINICAL MANIFESTATIONS OF ANAPHYLAXIS
SKIN- urticaria, angioedema, pruritus, erythema
RESPIRATORY- rhinitis, conjunctivitis, cough, dyspnea, wheeze, stridor, voice change
GI – throat swelling or tightness, dysphagia, vomiting, diarrhea, cramps
CVS – hypotension, dizziness, syncope, cyanosis, secondary myocardial infarction
CNS –hypoxic seizures

27. Anaphylaxis: clinical features
Skin %
Upper respiratory %
Lower respiratory %
Cardiovascular %
(30%of adults, 5% of children)
Gastrointestinal %
Rhinitis %
BIPHASIC ANAPHYLAXIS %
Adults tend to have more cardiac symptoms – perhaps with age and some degree of coronary disease or arterial thickening, they are less resilient to cardiac insult than children

28. Anaphylaxis: Causes of Death
Upper and/or Lower Airway Obstruction (70%)
Cardiac Dysfunction (24%)

29. Diagnostic criteria
Criterion 1: acute onset (minutes – hours) involving skin and/or mucosa + at least one:
Respiratory compromise
Reduced blood pressure
Criterion 2: At least 2 of the following, minutes – hours after exposure TO A LIKELY ALLERGEN FOR THAT PATIENT:
Skin/mucosal involvement
Gastrointestinal symptoms
. Criterion 3: Reduced blood pressure minutes – hours after exposure TO A KNOWN ALLERGEN FOR THAT PATIENT
J Allergy Clin Immunol, 2006

30. BIPHASIC ANAPHYLAXIS
What is the importance?

31. BIPHASIC ANAPHYLAXIS
Early signs may be deceptively mild, resolves with or without treatment; the biphasic phase then occurs and may lead to fatal outcome
Delayed epinephrine treatment or inadequate dose are risk factors
Severe initial phase may predispose to biphasic
Important to monitor in ER for 4-6 hrs after an anaphylactic reaction
Steroids may not prevent it, but often used

33. Potentional pitfalls in recognition of anaphylaxis
Absent / missed skin symptoms
Non-specific signs of hypotension (confusion, collapse, incontinence...)
Certain conditions (surgery)
DD – asthma exacerbation
Lab tets to support Diagnosis (tryptase)

34. Causes of Anaphylaxis Food allergy Medication allergy
Insect (hymenoptera) sting allergy
Physical eg exercise, cold,
Latex allergy
Allergy to vaccines, hormones, seminal fluid
Allergic reactions to immunotherapy, skin tests
Idiopathic

35. Most common food causes of anaphylaxis in North America
Common (Anaphylaxis) Less Common
Peanut ) بادام زمینی ( Soy(لوبیا)
Tree Nuts ) (درخت دیوانه Wheat(گندم)
Fish
Shellfish: Crustaceans Shellfish: Mollusks
Cow’s Milk Sulfites
Egg
Sesame(کنجد)
Most common food causes of anaphylaxis in North America. Almost any food can cause anaphylaxis. This list was prepared for Health Canada in 1999 to introduce legislation to make labelling of these foods manfatory. This list of foods will soon finally be subject to mandatory labelling if present in a food product whatever the concentration – Currently in 2008 this is not the case even for foods such as nuts in Canada.

36. IMMUNOLOGICAL MECHANISMS OF ANAPHYLAXIS.
IgE-mediated
Foods, some drugs eg penicillin, insulin, insect venom, latex, biologicals eg allergy serum
Direct mast cell degranulation
Radiocontrast material, tubocurarine, dextran, opiates eg codeine
Complement activation
Incompatible drug transfusion ( type II hypersensitivity), tissue plasminogen activator
You need to know the different mechanisms and examples of each. Radiocontrast material is dye used for radiological examination of internal organs. Tubocurarine is a muscle relaxant used for general anaesthesia; dextran is a volume expander used during shock to increase circulating fluid volume.

37. IMMUNOLOGICAL MECHANISMS OF ANAPHYLAXIS.
COX-1 (cyclooxygenase1 ) inhibition
ASA; Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Unknown (yes, this is considered a mechanism)
Idiopathic anaphylaxis; Local anaesthetics; Physical (Exercise, Cold-induced anaphylaxis); Sulfites
ASA, NSAIDs inhibit the enzyme COX 1 and shunts arachidonic acid metabolism from the COX pathway to the lipo-oxygenase pathway, resulting in over-generation of inflammatory metabolites eg leukotrienes (remember their release from mast cells and their biological effects?) which then can cause anaphylaxis is some predisposed individuals

38. Anaphylaxis: Rapid recognition and treatment

39. GENERAL MANAGEMENT OF ANAPHYLAXIS
Airway
Breathing
Circulation
But use epinephrine promptly
You need to know the general principles of anaphylaxis management, but not drug doses at this stage

40. Fatal anaphylaxis: risk factors
Concomitant asthma
No epinephrine
Non effective epinephrine
Upright posture
Other cardiopulmonary disease

41. Fatal anaphylaxis: risk factors
Concomitant asthma
No epinephrine
Non effective epinephrine
Upright posture
Other cardiopulmonary disease

42. Initial AnaphylaxisTreatment
Epinephrine (adrenaline) is first line treatment
Epinephrine preferably given IM
Antihistamines & bronchodilators are not first line treatment but may be given after epinephrine.
Transportation to hospital should not be delayed to administer these once epinephrine has been given.
Higher blood levels of epinephrine are achieved when given intramuscularly( IM) in thigh rather than subcutaneously or IM in deltoid muscle (upper arm)

43. Management of anaphylaxis: Initial
Epinephrine 0.01mg/kg (max 0.5mg) IM X3, every 5-20min as needed. In severe cases epinephrine IV
H1 antagonists eg Diphenhydramine (Benadryl) mg
H2 antagonists eg cimetidine
IV fluids to maintain venous access and circulation
Oxygen
Corticosteroids
You need to know principles of anaphylaxis management but not the specific drug doses although the types of drugs used are important. H2 antagonists reduce some of the vasodilation in urticaria.

44. Management of anaphylaxis: Bronchospasm
Inhaled bronchodilators eg salbutamol. IV if unresponsive to inhaled
Oxygen
Intubation and ventilation if needed

45. Management of anaphylaxis: Laryngeal edema
Racemic epinephrine via nebulizer
Intubation or cricothyrotomy or tracheostomy

46. Management of anaphylaxis: Hypotension
Trendelenberg position
Volume expansion with crystalloid
Vasopressors eg dopamine, norepinephrine, metaraminol, vasopressin
Glucagon esp if on beta-blocker
Trendelenberg position- lying on back with legs elevated unless precluded by shortness of breath or vomiting. This shifts fluid to the heart in patients in shock. Raising patient in shock can lead to death.

47. Treatment of Anaphylaxis in Beta Blocked Patients
Give epinephrine initially.
If patient does not respond to epinephrine and other usual therapy:
Glucagon 1 mg IV over 2 minutes
Isoproterenol (a pure beta-agonist β1β2 agonist)
1 mg in 500 ml D5W starting at mcg/kg/min
Glucagon is thought to reverse refractory hypotension and bronchospasm by activating adenylcyclase independent of beta-receptors, thus bypassing the blocked beta adrenergic receptor

48. EFFECTS OF EPINEPHRINE
Increases BP, reverses peripheral vasodilation , ( alpha-adrenergic activity)
Reduces urticaria and angioedema by vasoconstriction (alpha)
Bronchodilation – relaxes bronchial smooth muscle (beta-2 adrenergic activity)
Increases cardiac contractility – force and volume, increasing heart rate & BP (beta-1)
Prevents further mast cell degranulation (beta)

49. SIDE EFFECTS OF EPINEPHRINE
Based on the effects of epinephrine, what would you predict as the possible side effects?
What conditions or factors would you consider as higher risk for side effects of epinephrine use?

50. SIDE EFFECTS OF EPINEPHRINE
Increased heart rate, shakiness, dizziness, headache, anxiety, fear
Hypertension and intracranial bleed
Myocardial ischemia, infarction, arrythmia

51. Epinephrine Auto-injectors
Epipen
Epipen Jr. (0.15 mg)
Epipen (0.30 mg)
One dose: auto-injection
Twinject
Twinject 0.15
Twinject 0.30
Two doses: first is an auto-injection, second dose is manual

52. Treatment Removal of the causing agent Epinephrine Oxygen
0.3 – 0.5 mg (0.01mg/kg) i.m. (vastus lateralis), repeat 5 – 15 minutes
i.v. – titrate the dose
Oxygen
Intubate, if stridor or arrest
Trendelenburg position
i. v. Fluids (cristalloids vs. colloids?)
Steroides, antihistamines, inhaled beta agonists, glucagon of secondary (and questionable) importance

53. Thank you for attention !
Questions?
Thank you for attention ! 53