Treatment of Anaphylaxis

Dr.Ramnarayanreddy

Aims & Objectives

• To describe the presentation and cellular basis for anaphylaxis

• Highlight important differentials that can mimic it
• Discuss in detail its drug management
• Introduce other hypersensitivity-based drug reactions
 Treatment of Anaphylaxis

• No accepted definition

• ‘A life threatening activation of mast cells and basophils’

• Not necessarily type I hypersensitivity/IgE mediated

• Death from asphyxiation or cardiovascular collapse

• Incidence uncertain (probably heavily underreported)

• ? 1:2,300 A&E admissions (=1:15,000 general population/year)

Anaphylactic vs. Anaphylactoid reactions

Anaphylactoid reactions mimic the features of

an anaphylactic reaction but mast cell/basophil
activation is not IgE-dependent.

Certain drugs (and venoms) are able to directly

activate mast cells including:

• Succinylcholine
• Morphine
• Tubocurarine
• Vancomycin (‘Red-man Syndrome’)
• N-acetyl-cysteine

Treatment is the same as for Anaphylaxis.

 Clinical Features of Anaphylaxis

- Is there a predisposition? Latex and food allergies usually occur

Urticarial Rash
against a background of atopy and other allergic disorders e.g.
asthma and eczema.

- Onset is rapid (5-10 minutes of exposure) peaking in 30 minutes.

Duration can be long especially if allergen persists (e.g. swallowed)
or the response is biphasic (classical ‘late-phase’ allergic response
in the airways)

- May be heralded by impending sense of doom. Subsequent

features reflect to some extent route of allergen exposure:

• Systemic (IV drugs) - cardiovascular (hypotension/syncope)

• Ingested (food allergens) - respiratory (laryngeal
oedema/bronchoconstriction)
• Percutaneous (insect stings) - respiratory or cardiovascular
problems equally likely

All may be accompanied by cutaneous features

e.g. urticarial rash.
Features Suggesting Severe Anaphylactic Reaction

• Wheeze
• Stridor
• Cyanosis
• Skin Pallor*
• Prominent Tachycardia**

* 80% of fatal food-related anaphylactic reactions have no skin signs

** Compared to bradycardia in vasovagal attack
Anaphylactic Reactions: Differential Diagnosis

•Anxiety (Panic Disorder)

•Asthma
•Epiglottitis Wheeze/Stridor/SOB
•Foreign body Inhalation
•AMI
•PE Syncope/Collapse
•Vasovagal Attack*

* but bradycardic NOT tachycardic

 A real allergic response?
Non-allergens and hidden allergens

‘Allergy’ to fish could be due any one of the following:

– Histamine intoxication (Scombroidism)

– Dinoflagellate poisoning (algal blooms)
– Cod worm (Anisarkis) allergy
– Latex allergy (latex gloves used in food preparation)
Histamine & the Mast cell

Intradermal histamine produces the classical Triple

response: central red spot (vasodilatation) ; flare; wheal
(oedema overlying initial red spot).

Intravenous histamine causes: (1) marked

vasodilatation (largely from endothelial derived NO); (2)
increased capillary leak. These H1-mediated effects
contract effective blood volume.

Importance of mast cell-derived histamine in anaphylaxis

depends on species & tissue.

In humans, protection offered by H1 blockade is

variable:

• oedema/itch - good
• hypotension - modest
• bronchoconstriction - negligible
2005 Guidelines of the UK
Resuscitation Council
 Effects of Adrenaline (Epinephrine)

Comparison of its cardiovascular

effects (at 10g/min IVI) with
noradrenaline (-dominant) and
isoprenaline (2-dominant).

Other important (if not crucial) 2 effects:

• Mast-cell stabilisation (against IgE activation)

• Bronchodilatation
 The Use of Adrenaline in Anaphylaxis

The problems with its use:

• Variable Absorption - give IM AVOID SC

• Arrhythmogenic in high dose - NEVER give 1:1000 ADRENALINE IV

If using ADRENALINE as an IVI, it must be diluted and do not delay administration

of ADRENALINE to set up IVI and gain IV access.

Therefore:

1. Give ADRENALINE IM promptly (can repeat at 5-10 min intervals)

2. Gain IV access
3. If patient remains shocked resort to IVI thus ….
Dilute 0.5ml of 1:1000 ADRENALINE in 50ml of N/saline (1:100,000)
4. Infuse at 0.1-2ml/min (1-20ug/min) until haemodynamically stable
 Drugs that Interact with Adrenaline

• The effects of adrenaline are markedly potentiated in patients taking

concurrent tricyclic antidepressants, MAOIs or cocaine.

• The -effects of adrenaline may also be antagonised (and the

manifestations of anaphylaxis more severe) if the patient is taking
concurrent -blockers (especially non-selective agents).

• Phenothiazines (especially chlorpromazine) are potent -blockers

hence adrenaline may cause unexpected hypotension (unrestrained 2-
mediated vasodilatation).
 Histamine (H1) receptor antagonists

FIRST-GENERATION e.g Chlorpheniramine* and Diphenhydramine

• sedating (although paradoxical excitation in overdose)

• anticholinergic effects

SECOND- GENERATION e.g. Terfenadine and Cetirizine

• Non-sedating (poor CNS penetration)

• No anticholinergic effects
• Risk of VT (Torsade de Pointes) with Terfenadine and Astemizole**

*Only chlorpheniramine has a preparation for systemic use

– but not licensed for IV administration!

** This is a PK problem due to their clearance through CYP 3A4/5. Drugs (e.g. erythromycin,
ketoconazole, or grapefruit juice) block conversion of parent drug to the active H 1 antagonist - the parent
drugs block delayed rectifier (K-current) in the heart prolonging QTc I.e. behave like class III agents.
 Other drugs used in Anaphylaxis

Nebulised or IV 2 agonist (e.g. salbutamol) - useful where bronchospasm

is the major sign and fails to respond promptly to IM adrenaline.

IV Glucocorticoid (e.g. hydrocortisone 200-500mg) - probably of limited

efficacy (onset of action delayed 3-6 hrs) except where the response is
biphasic or asthmatic features predominate.

IV Glucagon (1mg in 1L, infused at 5-15ml/min) - anecdotal reports of efficacy in refractory

hypotension. Releases catecholamines and +ve inotrope (raising cAMP independent of cardiac
-adrenoceptors).

H2 Antagonists - isolated reports of increased efficacy of combined blockade NB histamine

relaxes VSM directly by H2 effect - this is slower in onset but much more sustained than H 1
effect on endothelial cells. Efficacy in systemic mastocytosis clearer.
 Further Ix and Management

Collect (preferably within 1hr and NOT >6hr) 10ml of clotted blood for:

• Mast Cell Tryptase assay (if diagnostic doubt exists)

• Assay of Allergen-Specific IgE levels (RAST).

Refer to Allergist for:

• Identification of allergen (RAST, skin-prick testing etc)

• Desensitisation (especially Bee/Wasp venoms)
• Assessment of need for Px of Epipen (Adrenaline autoinjector)
 Drug-Induced Allergic Reactions

Type I - IgE dependent. Needs previous exposure to allergize.

Type II - Cytolytic IgG/M antibodies causing C activation. Usually fade with drug withdrawal.
Form basis of :

• Methyl-DOPA induced haemolysis

• Quinidine/Quinine-induced thrombocytopenia
• Sulphonamide-induced granulocytopenia
• Drug-induced lupus (hydralazine & procainamide)

Type III - Serum sickness (Arthus reaction). Deposition of C fixing IgG-Ag complexes in
vessel wall produces urticaria, arthritis, lymphadenopathy and fever. Offenders include:

• Antibiotics (sulphonamides* and penicillin)

• Anticonvulsants (phenytoin and carbamazepine)
• Iodides.

*Also cause Steven-Johnson syndrome as a rare & severe form of type III immune vasculitis.
Allergic reactions: Angioedema

Usually localised (to head & neck) but may be more

generalised (especially GI) +/- urticaria.

Presents as swelling of the face, neck and

oropharynx.

Represents mast cell degranulation in skin deep to

dermis vs. superficial dermis in urticaria.

• Inherited - C1 esterase inhibitor deficiency due to

mutation of the C1-INH gene (autosomal dominant).

• Acquired - usually autoantibodies to C1-INH in the

context of autoimmune disease or lymphoproliferative
disorders. Rarer reports of hypercatabolism of C1-
INH in infection.

• Drug-induced - commonest culprit ACE inhibitors

(and OMAPATRILAT).
 ACE inhibitors & Angioedema

• Mechanism probably related to massive elevation of BK but unclear why it

can appear days to years after 1st dosing.

• Incidence probably <0.1% - Afro-Caribbean and renal/cardiac transplant

patients may be at increased risk.

• Treatment is usually with standard therapy for an anaphylactic reaction +/-

inhaled Epi but not mast cell dependent! If airway threatened, intubation or
tracheostomy needed.

• Under recognised especially in milder forms. ACE inhibitors should be

stopped and an AT1 receptor antagonist substituted if necessary (e.g.
Losartan) BUT isolated reports have appeared of angioedema with these
agents!

• New combined ACE/NEP inhibitors suffer same problem.

 Allergic Reactions to Penicillins
• Allergization often occult (food containing pen. or the pen. mould itself)
• Anti-pen antibodies are detectable in almost everyone
• Patients reports of previous ‘allergy’ are frequently inaccurate
• A class problem manifesting as -

Rash (MP > urticarial)

Frequency
Fever
Bronchospasm
Vasculitis
Serum sickness/Stevens-Johnson
Anaphylaxis*

• Rashes most frequent with ampicillin (10%); essentially 100% in EBV infection.
• Rashes more likely if allopurinol co-administered
• Cross-sensitisation with cephalosporins now thought to be <1% and reactions usually mild
• If pen drug-of-choice consider either ‘controlled’ challenge or desensitisation

* VERY uncommon <1/10,000 prescriptions; 2/3 have previously received it and of these
only 1/3 report previous reaction.
 Further Information

• Treatment algorithms in pdf format (Clin Pharm Website)

• Allergy section of E-medicine (www.emedicine.com/emerg)
• Resuscitation council - (http://www.resus.org.uk/pages/reaction.htm)