Critical - Anaphylaxis

Anaphylaxis Definition

• Anaphylaxis is a characteristic and often life-threatening clinical manifestation of an Immunoglobulin E (IgE)-mediated-immediate hypersensitivity reaction.

Pathophysiology

• Anaphylaxis is a type 1 hypersensitivity reaction
• B lymphocytes are stimulated by a definite allergen to produce IgE antibodies.
• IgE antibodies bind to receptors on the surface of tissue mast cells & basophils, which are then sensitized.
• A subsequent encounter with the same antigen instigates an IgE-mediated reaction.
• Free antigen binds to two adjacent IgE antibodies, causing crosslinking.
• This triggers mast cell and basophil cell degranulation.
• Degranulation leads to the release of histamine and other mediators like prostaglandin, platelet-activating factor, leukotrienes, heparin, and tryptase.
• The principal effects of these mediators include vasodilatation, capillary leak, and smooth muscle contraction.
• These effects can develop rapidly within minutes to less than 1 hour after exposure to the triggering allergen.

Anaphylactoid Reactions

• Anaphylactoid reactions are clinically indistinguishable from anaphylaxis but are not IgE-mediated.
• They result from direct mast cell degranulation or alterations in arachidonic acid metabolism.

Common Allergens Causing Anaphylaxis (IgE Mediated)

• Foods like nuts, eggs, fish, shellfish, and cow’s milk
• Vaccines and anti-toxins
• Anesthetics
• Insulin and other hormones
• Blood and blood products
• Latex
• Insect stings (e.g., bee, wasp, and ant)
• Snake bites

Common Allergens Causing Anaphylactoid Reactions

• NSAIDs (e.g., aspirin)
• Opiates
• Sulfides
• Radiocontrast media
• Neuromuscular blocking agents like succinylcholine
• Gamma globulin
• Antisera
• Exercise

Risk Factors Augmenting Anaphylactic Reactions

• Genetic susceptibility can increase the reaction

Augmentation Factors

• Physical exertion
• Infections
• Mental stress
• Beta-blockers
• ACE inhibitors
• Alcohol

Concomitant Factors

• Bronchial asthma
• Cardiovascular disease
• Thyroid disease
• Mastocytosis

Other Factors

• Certain allergens (Type & Amounts)
• Age
• Male sex
• Sensitization degree
• Level of sIgE
• Beta-blockers and ACEIs may increase the severity of anaphylaxis

Clinical Manifestations

• Skin: Pruritis, Flushing, Urticaria, Angioedema
• Eye: Pruritis, Conjunctival erythema, Lacrimation, Periorbital oedema
• Cardiovascular: Hypotension, Arrhythmia, Tachycardia & bradycardia when severe, Arrest
• Respiratory: Dyspnea, Stridor, Difficulty in swallowing, Wheezing, Hoarseness, Pulmonary oedema
• Gastrointestinal: Nausea, Vomiting, Diarrhea, Abdominal pain
• Neurological: Anxiety, Sense of doom, Presyncope and syncope, Seizure
• A second phase of symptoms & signs can occur hours after resolution of the initial symptoms and signs
• Shock with complications such as acute renal failure and impaired mentation can occur

Grading of Anaphylaxis and Anaphylactoid Reaction

• Grade 1 - Generalized mucocutaneous signs: Erythema, Urticaria, Angioedema
• Grade 2 - Multi-organ manifestations: Mucocutaneous signs, Bronchospasm, Hypotension
• Grade 3 - Severe life-threatening multi-organ manifestations: Arrhythmia, Cardiovascular collapse, Bronchospasm, Cutaneous signs
• Grade 4 - Cardiopulmonary arrest: Cardiac arrest

Diagnostic Criteria for Anaphylaxis (NIAID/FAAN)

• Criteria are sensitive and specific
• If any are fulfilled, anaphylaxis is likely
• Onset of symptoms must be acute (minutes to hours)

Known Allergen Exposure with Hypotension

• 1 month - 1 year: SBP < 70 mmHg or ≥ 30% decrease from person’s baseline
• 1-10 years: SBP < 70 mmHg plus (2 x age) or ≥ 30% decrease from person’s baseline
• 11-17 years: SBP < 90 mm Hg or ≥ 30% decrease from person’s baseline
• Adults: SBP < 90 mm Hg or ≥ 30% decrease from person’s baseline

Acute Illness with Skin and/or Mucosal Symptoms AND ≥ 1 of the following:

• Hypotension or associated symptoms of end-organ dysfunction
• Respiratory compromise (e.g., dyspnea, hypoxia, stridor, hoarseness, wheezing)

Suspected Allergen Exposure AND ≥ 2 of the following:

• Hypotension or associated symptoms of end-organ dysfunction
• Respiratory compromise (e.g., dyspnea, hypoxia, stridor, hoarseness, wheezing)
• Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
• Skin/mucosal involvement (e.g., hives, angioedema, pruritus, flushing)

Investigations

• Serum IgE level should be tested
• Serum Tryptase level should be tested
• Serum histamine and urinary methyl histamine should be tested
• Skin testing and patch test may be used
• Complete blood count (CBC) should be performed
• Neutrophils and eosinophils are prominent in the first 6-18 hours and may persist 2-3 days
• T helper 2 cells may accumulate around small blood vessels and persist 1-2 days
• Routine Liver and kidney function tests, rarely vitamin deficiency assessment need to be undertaken
• Investigations of concomitant allergic conditions as Peak expiratory flow rate or FEV1 need to be undertaken
• Investigations of patient with anaphylactic shock need to be undertaken

Management

• Resuscitation is key
• Removal of the inciting cause

Immediate Treatment is necessary and indicated

• Patients with significant cardiac - respiratory - gastrointestinal symptoms (mild to moderate, moderate and severe cases, grade 2, 3, 4)

Actions to avoid

• Laryngeal oedema
• Respiratory failure
• Death

Important Notes

• If patient is diagnosed before & carries Epinephrine Autoinjector (EpiPen), it should be administered as soon as anaphylaxis is highly likely.
• The patient should administer himself no more than 2 doses
• Call for help OR Hospitalization with attention focused on:

1. Airway - breathing - circulation - adequacy of mentation
2. Lips - tongue - oral pharynx are assessed for angioedema
3. The patient is asked to speak to assess the glottic swelling

Position Of Patient

• USUALLY: Placement of patient in supine position with Lower extremities elevated
• IF THERE IS PROMINENT UPPER AIRWAY OBSTRUCTION: Upright position
• IF PATIENT IS VOMITING: Semi recumbent with lower extremities elevated is preferred

Airway- Breathing

• AIRWAY: Intubation should be performed if stridor or respiratory distress due to upper airway compromise is present. Rarely, emergency cricothyroidotomy may be required if needed
• BREATHING: Supplemental oxygen at high flow rate providing at least 70% and up to 100% O2

Circulation

• 2 large IV catheters should be immediately inserted
• In normotensive adults, isotonic saline should be infused at a rate of 125mL/hour to maintain venous access.
• Fluid resuscitation is mandatory for patients with hypotension not responding promptly to epinephrine.
• Adults should receive 1-2 liters of normal saline within minutes.
• Volumes up to 7 liters may be required
• Monitor electronic of cardiopulmonary status: BP, heart rate, Respiratory rate - oxygen saturation by pulse oximetry

Drugs

• Epinephrine is the most effective drug to counteract the effects of anaphylaxis.

Epinephrine

• There is no absolute contraindication to epinephrine in anaphylaxis

Epinephrine IM injection

• Recommended dose is 0.01 mg/kg for patients of any age.
• Maximum dose is 0.5 mg per single dose.
• Site of injection is into the mid-outer thigh, i.e., Vastus lateralis muscle. -Dose should be drawn up using 1 mL syringe for 1mg/mL formulation of epinephrine. -IM epinephrine may be repeated at 5-15 minutes intervals if there is no response or inadequate response or even sooner if clinically indicated

IV bolus epinephrine

• Dose: 50-100 mcg over 10 minutes.
• Complications: Associated with significant dose error and cardiovascular complications and should be avoided as possible.

IV epinephrine infusion

• The preferred medication if patients have not responded to IM injections and refractory to IM epinephrine & volume resuscitation.
• Start infusion by 0.1 mcg/kg/minute
• Infusion could be increased every 2-3 minutes by 0.05 mcg/kg/minute until BP and perfusion improve.
• Rarely exceed 1 mcg/kg/minute.

Mechanism of Action

• A1 Adrenergic Agonist Effect: The drug causes vasoconstriction, mucosal oedema
• B1 Adrenergic Agonist Effect: Inotropic and chronotropic
• B2 Adrenergic Agonist Effect: This causes bronchodilation and releases inflammatory mediators from mast cells & basophils

Side Effects

• Mild Transient: Anxiety & Restlessness, Tremor, Headache, Dizziness, Palpitation, Pallor
• Rarely: Ventricular arrhythmia, Angina, Myocardial infarction, Pulmonary oedema, Hypertension, Intracranial hemorrhage

Antihistamines

• H1 BLOCKERS: DIPHENHYDRAMINE (Dose: 25-50 mg; Route: IV; Over: 5 minutes; NB: Can be repeated /4-6 hours), CETIRIZINE (Dose: 10 mg; Route: IV; Over: 5 minutes; NB: Can be repeated /4-6 hours)
• H2 BLOCKERS: RANITIDINE(Dose: 50 mg; Route: IV; Over: 5 minutes; NB: Can be repeated /4-6 hours), FAMOTIDINE (Dose: 20 mg; Route: IV; Over: 5 minutes; NB: Can be repeated /4-6 hours)

Inhaled Bronchodilators

• Albuterol or salbutamol by nebulizer for bronchospasm

Glucagon

• For patient taking home beta-blocker
• 1-2 mg IV or IM over 5 minutes, can be repeated or followed by infusion 5-15 mcg/minutes

Corticosteroids

• Given mainly to prevent 2nd phase reaction that could occur in some cases
• Methylprednisolone 1-2 mg/kg /day for up to 4 days oral or IV
• Suppress production of prostaglandins and leukotrienes
• Inhibits inflammatory cell recruitment and migration
• Causes vasoconstriction that reduces cell and fluid leakage from vasculature

Leukotriene Receptor Antagonist

• Montelukast in aspirin induced asthma

Omalizumab

• Monoclonal antibody to IgE

Cases of Refractory Anaphylaxis

• Other vasopressors like Dopamine or Vasopressin, Methylene blue (inhibitor of nitric oxide synthesis), Extracorporeal membrane oxygenator (ECMO) may be used

Prophylactic Treatment

• Patient education is key to a good outcome.

Patient Education

• Avoid exposure to allergen
• Carry pre-loaded EpiPen syringes
• Desensitization if exposure to allergen is unavoidable as insect stings

Desensitization

• This is used in IgE-mediated hypersensitivity

IDEA

• A course of SC injections of increasing doses of the allergen extract (Sublingual grass pollen extract tablets is used in hay fever)

Mechanism of Action

• IgG BLOCKING ANTIBODIES: During repeated exposure to desensitizing allergens, IgG class antibodies develop, These compete with IgE for allergen binding and prevent IgE-allergen complexes binding to mast cells receptors
• REGULATION: Repeated exposure to desensitizing allergens induces regulatory T cells that act to suppress immune response. This ends up in damping migration, infiltration and inflammation
• IMMUNE DEVIATION: A shift away from Th2 to Th1 producing CD4 cells results in the generation of cytokines as IFN-y that are inhibitory to IgE production