GLORIA Module 3

Allergic Emergencies

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 GLORIA™ is supported by unrestricted educational grants from

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Global Resources in Allergy (GLORIA™)
Global Resources In Allergy (GLORIA™) is the
flagship program of the World Allergy
Organization (WAO). Its curriculum educates
medical professionals worldwide through
regional and national presentations. GLORIA
modules are created from established guidelines
and recommendations to address different
aspects of allergy-related patient care.

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 World Allergy Organization (WAO)

The World Allergy Organization

is an international coalition of 77
regional and national allergy and
clinical immunology societies.

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 WAO’s Mission

WAO’s mission is to be a global resource

and advocate in the field of allergy,
advancing excellence in clinical care,
education, research and training through
a world-wide alliance of allergy and
clinical immunology societies

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 GLORIA Module 3
Allergic Emergencies

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 Allergic Emergencies
WAO Expert Panel

Authors:
Richard F Lockey, USA
Connie H Katelaris, Australia
Michael Kaliner, USA

Contributors:
F.Estelle R. Simons, Canada
Daniel Vervloet, France

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 Allergic Emergencies

Section 1: Anaphylaxis

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 Anaphylaxis Lecture Objectives
After this lecture, participants will:

Have knowledge of the different
mechanisms which cause anaphylaxis and
the agents which are most likely to cause it;

Be able to recognize the signs and
symptoms of anaphylaxis;

Understand how to treat anaphylaxis.

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 Definition of Anaphylaxis

Anaphylaxis – a syndrome with varied mechanisms,
clinical presentations, and severity.

An acute life-threatening reaction.

Usually mediated by an immunologic
mechanism, allergic anaphylaxis, but not always.


Includes non-allergic anaphylaxis (formerly
referred to as an anaphylactoid reaction).

Results from the release of mast-basophil
mediators.
WAO Nomenclature Review Committee JACI 2004

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 Gell and Coombs’ Hypersensitivity
(immunopathologic reactions)

Type I Immediate

Type II Cytotoxic

Type III Immune Complex

Type IV Delayed Hypersensitivity


Types I, II and III can result in
immunologically-induced or allergic anaphylaxis

Kemp and Lockey JACI 2002

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 Biochemical Mediators
and Chemotactic Substances

Degranulation of mast cells and basophils.

Preformed granule-associated substances, e.g.,
histamine, tryptase, chymase, heparin, histamine-
releasing factor, other cytokines.

Newly generated lipid-derived mediators, e.g.,
prostaglandin D2, leukotriene B4, PAF, LTC4, LTD4, and
LTE4.

Eosinophils may play pro-inflammatory role (release of
cytotoxic granule-associated proteins) or anti-
inflammatory role (e.g., metabolism of vasoactive
mediators).

Kemp and Lockey JACI 2002

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 Shock Organs in Anaphylaxis

Guinea pig – bronchial smooth muscle constriction.

Rabbit – fatal pulmonary artery vasoconstriction
with right ventricular failure.

Dog – venous system of liver contracts producing
hepatic congestion.

Human – shock organs are the cardiovascular
system, respiratory tract, skin, and gastrointestinal
tract. Laryngeal oedema, respiratory failure, and
circulatory collapse are common.

Asthma is an important risk factor for death from
anaphylaxis.
Kemp and Lockey JACI
2002
Bock, Munoz-Furlong, Sampson JACI 2001

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 Incidence

Analysis of published studies of most common causes

3.3 to 4 million Americans at risk.

1,433 to 1,503 at risk for fatal reaction.
Neugut, Ghatak, Miller Arch Int Med 2001

Incidence Based on Epinephrine Rx for

Out-of-Hospital Use

From Canada and Wales.

0.95% of population in Manitoba, Canada.

0.2 per 1000 in Wales.

Incidence increased in Wales between 1994 & 1999.

Simons, Peterson, Black JACI 2002

Rangaraj, Tuthill, Burr, Alfaham JACI 2002

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 Incidence of Anaphylaxis to Specific Agents 1
Antibiotics

Most common cause of drug induced anaphylaxis.
Latex

Increased incidence last decade.

Population at risk includes multiple mucosal
exposure to latex (catheterization & surgery) and
healthcare workers.
Radiocontrast agents

Introduction of lower osmolarity agents
reduced reaction rate

Lieberman In: Allergy: Principles and Practice. Mosby, 2003

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Incidence of Anaphylaxis to Specific Agents 2

Hymenoptera stings

Incidence ranges from 0.4% to 5%

Estimated fatalities 100 per year in U.S.A.

Food

Estimated 2% of US population has food
allergies with up to 100 deaths per year

Shellfish most common in adults; peanuts
in children

Lieberman In Allergy: Principles and Practice Mosby, 2003

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Incidence of Anaphylaxis to Specific Agents 3

Perioperative anaphylaxis

Incidence ranges from 1 in 4500 to 1 in 2500
cases of general anaesthesia

Mortality rate can be as high as 3.4%

Most common agents responsible are
muscle relaxants, which account for 50%
to 75% of reactions.

Lieberman In Allergy: Principles and Practice Mosby, 2003

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Incidence of Anaphylaxis to Specific Agents 4

Non Steroidal Anti-Inflammatory Drugs

(NSAIDs)

Incidence varies depending on whether
asthmatic subjects are included


NSAIDs probably second most common
offending drug next to antibiotics.

Lieberman In Allergy: Principles and Practice Mosby, 2003

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 Incidence of Anaphylaxis to Specific
Agents 5

Antisera

Heterologous antisera to treat snake bites (4.6%
to 10%)

Immunosuppression, incidence for anti-
lymphocyte globulin as high as 2%
Idiopathic

Estimated to be between 20,592 and 47,024 cases
in USA – deaths rare

Lieberman in Allergy: Principles and Practice Mosby 2003

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 Allergen Immunotherapy

•
Incidence of systemic reaction from 0.8% to
46.7% depending on the dose of allergen and
schedule used.


Deaths occur at a rate of 1 per 2,000,000
injections.

Stewart and Lockey JACI 1992

Kemp et al In: Allergens and Allergen Immunotherapy

Marcel Dekker, 2004

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 Signs and Symptoms of Anaphylaxis


Diffuse erythema 
Cardiac arrhythmias

Diffuse pruritus 
Nausea

Diffuse urticaria 
Vomiting

Angioedema 
Lightheadedness

Bronchospasm 
Headache

Laryngeal edema 
Feeling of impending doom

Hyperperistalsis 
Unconsciousness

Hypotension 
Flushing

Kemp and Lockey JACI 2002

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 Differential Diagnostic
Considerations in Anaphylaxis

Vasovagal reactions

Idiopathic flushing

Mastocytosis

Carcinoid syndrome

Anxiety-induced hyperventilation

Globus hystericus

Serum sickness

C-1 esterase inhibitor deficiency

Shock-associated with myocardial infarction, blood
loss, septicemia

Scombroid poisoning

Montanaro and Bardana JACI 2002

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Comments About Signs and Symptoms
of Anaphylaxis

Urticaria or angioedema and flush most common
( > 90%).

Cutaneous manifestations may be delayed or absent

Next most common manifestations are respiratory
(40% to 60%).

Next are dizziness, unconsciousness (30% to 35%).

Gastrointestinal symptoms (20% to 30%).

More rapid onset, more likely serious.

Signs and symptoms within 5 to 30 minutes, but
may not develop for hours.

Lieberman In Allergy: Principles and Practice Mosby, 2003

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 Agents that Cause Anaphylaxis 1
Anaphylactic (IgE-Dependent)

Foods (peanut, tree nuts, 
Muscle relaxants
and crustaceans) 
Colorants

Milk, egg and fish also (insect-derived, such as
important, especially in carmine)
children 
Enzymes

Medications (antibiotics) 
Polysaccharides

Venoms 
Aspirin and other non-

Latex steroidal anti-

Allergen vaccines inflammatory drugs

Hormones (probably)

Animal or human proteins

Exercise (possibly, in
food and medication-

Diagnostic allergens dependent events)

Kemp Immunol Allergy Clin N Am 2001

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 Agents that Cause Anaphylaxis 2
(Allergic but not IgE Mediated)

Immune aggregates (Type II)


Intravenous immunoglobulin

Dextran (possibly)

Cytotoxic (Type III)


Transfusion reactions to cellular elements
(IgG, IgM)

Kemp Immunol Allergy Clin N Am 2001

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 Agents that Cause Anaphylaxis 3
(Non-allergic or IgE-independent)
Multimediator complement
activation/activation of contact system:

Radiocontrast media


Ethylene oxide gas on dialysis tubing

Protamine (possibly)

ACE-inhibitor administered during renal dialysis with
sulfonated polyacrylonitrile, cuprophane, or
polymethylmethacrylate dialysis membranes

Kemp Immunol Allergy Clin N Am 2001

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 Agents that Cause Anaphylaxis 4
(Non-allergic or IgE Independent)
Nonspecific degranulation of mast cells
and basophils

Opiates

Idiopathic

Physical factors:

Exercise

Temperature (cold, heat)

Kemp Immunol Allergy Clin N Am 2001

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 -Adrenergic Blockade

By mouth or topically.

Paradoxical bradycardia, profound hypotension,
and severe bronchospasm.

Can exacerbate disease and may impede treatment.

Selective β-blockers do not produce clinically
significant adverse respiratory effects in mild-
moderate asthma (including COPD). Not studied in
anaphylaxis.

Toogood CMAJ 1987

Kivity and Yarchovsky JACI 1990
Salpeter, Ormiston, Salpeter Annals Int Med 2002

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 Recurrent and Persistent Anaphylaxis


Recurrent or biphasic anaphylaxis occurs 8 to 12
hours in up to 20%.

Subjects with biphasic do not differ clinically but
more epinephrine may be necessary for initial
symptoms.

Persistent anaphylaxis may last from 5 to 32 hours.

Lee and Greenes Pediatrics, 2000

Kemp and deShazo In: Allergens and
Allergen
Immunotherapy to Treat Allergic Diseases. Marcel Dekker, 2004
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 Physician-Supervised Management of
Anaphylaxis 1

I. Immediate Intervention
a) Assessment of airway, breathing, circulation, and
mentation.
b) Administer EPI, 1:1000 dilution, 0.3 - 0.5 ml
(0.01 mg/kg in children, max 0.3 mg dosage) IM, to
control SX and BP. Repeat, as necessary.

Kemp and Lockey JACI

2002
Simons et al JACI 1998
Simons, Gu, Simons JACI 2001
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 Physician-Supervised Management of
Anaphylaxis 2
I. Immediate Intervention continued

c) IM into the anterolateral thigh (vastus lateralis)

produces higher & more rapid peak plasma level
versus SQ & IM in arm. Therefore, with moderate,
severe, or progressive ANA, EPI IM into anterolateral
thigh. Alternatively, an EPI autoinjector given
through clothing in same manner. Repeat, as
necessary.

Kemp and Lockey JACI

2002
Simons et al JACI 1998
Simons, Gu, Simons JACI 2001
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 Physician-Supervised Management of
Anaphylaxis 3
I. Immediate Intervention - continued

d) Aqueous EPI 1:1000, 0.1- 0.3ml in 10ml NS (1:100,000

to 1:33,000 dilution), IV over several minutes prn.

e) For potentially moribund subjects, tubercular

syringe, EPI 1:1000, 0.1 ml, insert into vein (IV),
aspirate 0.9 ml of blood (1:10,000 dilution). Give as
necessary for response.

Kemp and Lockey JACI 2002

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 Physician-Supervised Management of
Anaphylaxis 4
II. General measures
a) Place in recumbent position and elevate lower
extremities.
b) Maintain airway (endotracheal tube or
cricothyrotomy).
c) O2, 6 - 8 liters/minute.
d) NS, IV. If severe hypotension, give volume
expanders (colloid solution).
e) Venous tourniquet above reaction site.
Question if decreases absorption of allergen.
Kemp and Lockey JACI 2002

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 Physician-Supervised Management of
Anaphylaxis 4
III. Specific Measures that Depend on
Clinical Scenario
a) Aqueous EPI 1:1,000, ½ dose (0.1- 0.2 mg) at
reaction site.
b) Diphenhydramine, 50 mg or more in divided
doses orally or IV, maximum daily dose 200 mg
(5 mg/kg) for children and 400 mg for adults.
c) Ranitidine, 50 mg in adults and 12.5 - 50 mg
(1 mg/kg) in children, dilute in 5% G/W, total 20 ml,
inject IV, over 5 minutes. (Cimetidine 4 mg/kg OK
for adults, not established for pediatrics).
Kemp and Lockey JACI 2002

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Physician-Supervised Management of
Anaphylaxis 5

III. Specific Measures that Depend on

Clinical Scenario
d) Bronchospasm, nebulized albuterol 2.5 - 5
mg in 3 ml NS or levalbuterol 0.63 - 1.25 mg
as needed.
e) Aminophylline, 5mg/kg over 30 min IV may be
helpful. Adjust dose based on age,
medications, disease, current use.
f) Refractory hypotension, give dopamine,
400 mg in 500 ml G/W IV 2 - 20 μg/kg/min
more or less.
Kemp and Lockey JACI 2002

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Physician-Supervised Management of
Anaphylaxis 6

III. Specific Measures that Depend on

Clinical Scenario
g) Glucagon, 1- 5 mg (20 - 30 μg/kg [max
1 mg] in children), administered IV
over 5 minutes followed with IV infusion
5-15 μg/min.

h) Methylprednisolone, 1- 2 mg/kg per

24 hr; prevents prolonged reactions
and relapses.
Kemp and Lockey JACI 2002

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 Vasodepressor (Vaso-Vagal)
Definition

Non-allergic reaction characterized by slow pulse
nausea, pallor, sweating, clammy skin, and/or
hypotension.

Kemp and Lockey JACI 2002

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 Vasodepressor (Vaso-Vagal)

Management

a) Place patient in supine position with elevated lower

extremities.

b) For severe vasodepressor reaction ONLY (i.e.,

bradycardia, nausea, pallor, sweating, cool clammy
skin, hypotension), atropine 0.3 - 0.5 mg (0.02
mg/kg) SQ every 10 minutes (max 2 mg/adult and 1
mg/child).
c) If hypotension persists, give IV fluids.

Kemp and Lockey JACI

2002
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 Measures to Reduce the Incidence of Drug-
Induced Anaphylaxis and Anaphylactic
Deaths 1
General Measures

Obtain thorough history for drug allergy.

Avoid drugs with immunological or biochemical
cross-reactivity with any agents to which the patient is
sensitive.

Administer drugs orally rather than parenterally when
possible.

Check all drugs for proper labeling

Keep patients in clinic for 20 to 30 minutes after
injections.

Slide 41 Lieberman In: Allergy: Principles and Practice Mosby, 2003

12/30/23
 Measures to Reduce the Incidence of
Anaphylaxis and Anaphylactic Deaths 2

Measures for Patients at Risk


Avoid causative factor/s.


Have patient wear and carry warning identification.

Teach self-injection of epinephrine and caution patient
to keep epinephrine kit with them.

Discontinue -adrenergic blocking agents, ACE
inhibitors (controversial), monoamine oxidase
inhibitors, and tricyclic antidepressants, where
possible.
Lieberman In: Allergy: Principles and Practice. Mosby, 2003
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 Measures to Reduce the Incidence of
Anaphylaxis and Anaphylactic Deaths 3

Measures for Patients at Risk


Use preventive techniques when patient is required to
undergo a procedure or take an agent which places
them at risk. Such techniques include:
Pretreatment
Provocative challenge
Desensitization

Lieberman In: Allergy: Principles and Practice. Mosby, 2003

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 Summary
Prognosis
Factor Poor Good
Dose of antigen (allergen) Large Small
Onset of symptoms Early Late
Initiation of treatment Late
Early
Route of exposure Parenteral
Oral*
β-adrenergic blocker use Yes No
Presence of underlying disease Yes No

* True for drugs, not foods

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 Allergic Emergencies

Section 2: Upper Airway Oedema

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 Upper Airway Oedema
Lecture Objectives


To understand the causes of angioedema;


To review the spectrum and management of
hereditary angioedema;


To review Angiotensin Converting Enzyme (ACE)
inhibitor related angioedema.

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 Outline of Lecture

Clinical description


Classification


Examples of life-threatening oedema:


Hereditary angioedema

Acquired oedema

Angiotensin enzyme inhibitor-induced oedema


Clinical description

Pathophysiology

Management

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 Angioedema

First described by Quincke in
1882

Well-demarcated non-pitting
oedema

Caused by same pathological
factors that cause urticaria

Reaction occurs deeper in
dermis and subcutaneous
tissues

Face, tongue, lips, eyelids most
commonly affected

May cause life-threatening
respiratory distress if larynx
involved

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 Classification of Angioedema 1
Hereditary

Type 1: C1 esterase inhibitor deficiency

Type 2: functional abnormality of C1 esterase
inhibitor
Acquired

Idiopathic

IgE-mediated

Non-IgE-mediated

Systemic disease

Physical causes

Other

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 Classification of Angioedema 2
IgE-mediated

Drugs

Foods

Stings

Infections (eg viral, helminthic)

Non-IgE-mediated

Cyclooxygenase inhibition (ASA and other
NSAIDS)

Angiotensin converting enzyme inhibition

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 Classification of Angioedema 3

Systemic diseases


Systemic lupus erythematosis


Hypereosinophilia


Lymphoma:
abnormal antibodies activate complement
system

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 Classification of Angioedema 4

Physical causes

Cold

Cholinergic

Solar

Vibratory
Other

Some contact reactions

Autoantibodies to C1-esterase inhibitor

Unopposed complement activation

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 Incidence

Chronic idiopathic urticaria/angioedema occurs in
0.1% population

65% remit within 3 years
85% remit within 5 years
95% remit within 10 years

Angioedema occurs most commonly with
urticaria (40% cases)

May occur in isolation (10% cases)

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 Hereditary Angioedema (HAE)


1888 - family described by William Osler


1963 - Donaldson and Evans described the
biochemical defect responsible - absence of C1
inhibitor

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 Hereditary Angioedema (HAE)

Subtypes
Type 1*

Autosomal dominant

 Markedly suppressed C1 esterase

inhibitor protein levels

* Accounts for 85% cases

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 Hereditary Angioedema (HAE)
Subtypes

Type 2*

Autosomal dominant, with a point mutation
leading to synthesis of a dysfunctional protein

Functional assay required for diagnosis as
level may be normal

* Accounts for 15% cases

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 Hereditary Angioedema (HAE)

Epidemiology

1:10,000 - 1:150,000 with no racial or gender
predilection

Clinical manifestations

Usually manifests in 2nd decade

May be seen in young children

Oedema may develop in one or several organs

Presentation depends upon site of swelling

Attacks last 2- 5 days before spontaneous resolution

Nzeako Arch Intern Med, 2001

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 Clinical Manifestations 1


Angioedema may
develop in
subcutaneous tissues
of extremities,
genitalia, face, trunk.

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 Clinical Manifestations 2


Oedema of wall of intestine may present as an
acute abdominal emergency.


Submucosal oedema of larynx or pharynx may
cause asphyxiation – this may occur on first
presentation.

Bork Mayo Clin Proc 2000

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 Clinical Manifestations 3

Laryngeal oedema
Commonest cause of mortality in HAE

Time from onset of swelling to death 1- 14 hours
(mean 7 hours)

May be presenting feature

Death may occur in those with no previous
laryngeal oedema episodes

Increased risk within certain families

Early symptoms - lump in throat, tightness in throat

Hoarseness, dysphagia, progressive dyspnoea

Bork Mayo Clin Proc 2000

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 Hereditary Angioedema (HAE)

Diagnosis

Clinical presentation

For screening - quantitative and functional
assays of C1 inhibitor
 C4 and C2 levels reduced in acute attack
 C4 persistently low in most patients

Nzeako Arch Intern Med 2001

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 Hereditary Angioedema (HAE)
Pathophysiology 1
C1 inhibitor

Single chain glycoprotein; molecular weight
104,000; serine protease family

Important regulatory protein of complement
cascade
 Inactivates C1 esterase complex

Regulates coagulation, fibrinolytic, kinin,
complement systems

Nielson Immunopharmacology 1996

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 Hereditary Angioedema (HAE)
Pathophysiology 2
 Lack of C1 inhibitor leads to abnormal activation
of complement pathway, reduced C2 and C4 levels

Hageman factor induces formation of kallikrein
from prekallikrein

Bradykinin is released from high molecular
weight kininogen

All these mediators increase capillary
permeability and are responsible for attacks of
angioedema

Kaplan JACI 2002

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 Genetics

Autosomal dominant; all patients heterozygous


25% no prior family history - spontaneous
mutations


More than 100 different mutations reported


Varied clinical pattern may be explained by variable
effect of mutations on C1 inhibitor synthesis

Agostini Medicine (Baltimore) 1992

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 Hereditary Angioedema (HAE)
Management

Principles


Action plan for acute episodes


Strategy for long term prophylaxis


Short term prophylaxis for high risk procedures


Regular follow up for education and monitoring
side effects of therapy

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Management 1

Acute attacks


Treatment of choice is C1 inhibitor concentrate,
500 - 1,000U intravenous infusion

Safe and effective - no long term side effects reported

Excellent and prompt response in most patients

Not available in USA, but in clinical trials

Bork Arch Intern Med 2001

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Management 2

Acute attacks when C1 inhibitor concentrate not

available


Intubation and respiratory support may be necessary
when laryngeal oedema present


Fresh frozen plasma (FFP) has been used successfully
for acute attacks. Exacerbation of symptoms by
supplying more kallikrein substrate is a theoretical
consideration but is rarely seen

Bork Arch Intern Med 2001

Slide 67 12/30/23
 Management 3

Long term – adults


Attenuated androgens (stanozolol, danazol,
oxandrin) can prevent attacks

Increase levels of C1 inhibitor, C4 and C2

Titrate to lowest effective dose to control attacks
- for danazol may be able to reduce to 200 mg/d
every second day

Regular monitoring necessary

Nzeako Arch Intern Med

Slide 68 12/30/23
2001
 Management 4

Long term – children


Antifibrinolytic agents have been used as first
line prophylaxis


Low dose danazol

Nzeako Arch Intern Med

2001
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 Management 5
Short term prophylaxis

Necessary for high risk interventions,
eg, dental procedures, tonsillectomy

C1 inhibitor concentrate, where available, given
before procedure

Increasing dose of attenuated androgen for a few
days beforehand

Fresh frozen plasma

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 Management 6
Other


Avoid oral contraceptive pill, ACE inhibitor medication

Premedicate before procedures requiring
radiocontrast media or streptokinase as they may
decrease C1 inhibitor levels

Reassurance; address issues such as ongoing stress

Treat infections promptly

Genetic counseling and screening

Slide 71 12/30/23
Acquired Angioedema (AAE) 1
Type 1

Associated with rheumatologic diseases, B cell
lymphoproliferative disorders


Activation of complement by complexes of anti-idiotypic
antibodies and surface immunoglobulins consumes C 1
inhibitor so levels decline
Type 2

Development of autoantibodies against C 1 inhibitor

Autoantibodies bind at active site on molecule leading to
inactivation

Markovic Ann Int Med 2000

Slide 72 12/30/23
 Acquired Angioedema (AAE) 2

Decreased C1q levels distinguish AAE from HAE where
C1q is usually normal


Treatment of underlying condition may result in
resolution


For acute attacks, C1 inhibitor concentrate, where
available should be used


Attenuated androgen may be useful in Type 1


Immunosuppressive therapy for Type 2

Laurent Clin Rev Allergy Immunol 1999

Slide 73 12/30/23
 Angiotensin Converting Enzyme (ACE)
Inhibitors and Angioedema 1


Angioedema develops in 0.1% to 0.5% of those
receiving the drug

Onset from 1st week of use to 2 - 3 years of use

Symptoms resolve within 24 - 48 hours of cessation of
drug

Most commonly seen with captopril and enalopril but
described with all in class

Genetic factors may be important

Subjects with a history of angioedema from other
causes are more susceptible to ACE-induced
angioedema
Slater JAMA 1988
Slide 74 12/30/23
 Angiotensin Converting Enzyme (ACE)
Inhibitors and Angioedema 2

Face and lips most commonly involved
but laryngeal oedema reported


Risk factors include obesity, prior endotracheal
intubation and face and neck surgery


ACE inhibitors will trigger attacks in those with
HAE so avoid in these patients

Jain Chest 1992

Slide 75 12/30/23
 Angiotensin Converting Enzyme (ACE)
Inhibitors and Angioedema 3

Pathophysiology


ACE inhibitors may cause bradykinin
accumulation resulting in vasodilatation, capillary
leakage and angioedema


Patients may have a congenital or acquired
impairment of kininase 1 which degrades
bradykinin leading to bradykinin accumulation
once ACE is blocked

Slide 76 12/30/23
 Angiotensin Converting Enzyme (ACE)
Inhibitors and Angioedema 4
Management


Stop drug and use other classes of
antihypertensive agents

ALL ACE inhibitors are to be avoided

Management of angioedema depends on site of
involvement - securing the airway by intubation
may be necessary

ACE receptor antagonists are generally
considered to be safe

Slide 77 12/30/23
 Angioedema - Conclusions


Most often occurs in association with urticaria

When angioedema occurs alone, consider HAE,
AAE

HAE is a rare disease but must be identified as it
can be life-threatening

Refer to appropriate specialist for ongoing
management

ACE-inhibitor induced angioedema is an
important cause in older people

Slide 78 12/30/23
 Allergic Emergencies

Section 3:
Severe Asthma Exacerbations

Slide 79 12/30/23
 Lecture Objectives

At the end of this lecture participants will be able to:


Understand the risk factors for asthma
exacerbations;


Identify the signs and symptoms of acute
asthma;


Outline appropriate treatment strategies.

Slide 80 12/30/23
Features of a Severe Asthma Exacerbation
One or more present:


Use of accessory muscles of respiration

Pulsus paradoxicus >25 mm Hg

Pulse > 110 BPM

Inability to speak sentences

Respiratory rate >25 - 30 breaths/min

PEFR or FEV1 < 50% predicted

SaO2 <91- 92%

McFadden Am J Respir Crit Care Med 2003

Slide 81 12/30/23
 Risk Factors for Fatal or Near-Fatal
Asthma Attacks

Previous episode of near-fatal asthma

Multiple prior ER visits or hospitalizations

Poor compliance with medical treatments

Adolescents or inner city asthmatics

(USA) African-Americans>Hispanics>Caucasians

Allergy to Alternaria

Recent use of oral CCS

Inadequate therapy:

Excessive use of β-agonists

No inhaled CCS

Concomitant β-blockers

Ramirez and Lockey In: Asthma, American College of Physicians, 2002

Slide 82 12/30/23
Physical Findings in Severe Asthma
Exacerbations

Tachypnea

Tachycardia

Wheeze

Hyperinflation

Accessory muscle use

Pulsus paradoxicus

Diaphoresis

Cyanosis

Sweating

Obtundation

Brenner, Tyndall and Crain In: Emergency Asthma. Marcel Dekker 1999

Slide 83 12/30/23
 Causes of Asthma Exacerbations


Lower or upper respiratory infections

Cessation or reduction of medication

Concomitant medication, e.g. β-blocker

Allergen or pollutant exposure

Slide 84 12/30/23
 Differential Diagnosis

COPD 
Non-cardiogenic

Bronchitis pulmonary edema

Bronchiectasis 
Pneumonia

Endobronchial 
Pulmonary emboli
diseases 
Chemical pneumonitis

Foreign bodies 
Hyperventilation

Extra- or intra-thoracic syndrome
tracheal obstruction 
Pulmonary embolus

Cardiogenic 
Carcinoid syndrome
pulmonary edema

Brenner, Tyndall, Crain In: Emergency Asthma. Marcel Dekker, 1999

Slide 85 12/30/23
 Peak Flow Meters
Use peak flow meters to monitor asthma and
prevent exacerbations:

Inexpensive

Easy to use

Accurate

Provide “real life” measurements at worst and
best times of the day

Provide objective measurement of pulmonary
function

Detect early changes of asthma worsening

Slide 86 12/30/23
 Patient “Self Management”
If personal best peak flow measurements:

Fall 10+%, double dose of inhaled CCS

Fall 20+%, use short-acting bronchodilator Q4
-6 hour, plus 2 x inhaled CCS

Call office, try to determine if infection is
present

Fall 40 - 50%, add oral CCS

Fall greater than 50%, urgent visit to either

Outpatient office

Emergency room

Kaliner In: Current Review of Asthma. Curent Medicine, 2003

Slide 87 12/30/23
 Stages of Asthma Exacerbations
Stage 1:

Symptoms

Somewhat short of breath

Can lie down and sleep through the night

Cannot perform full physical activities without shortness of
breath
Signs

Some wheezes on examination

Respiratory rate, 15 (normal <12)

Pulse 100

Peak flows and spirometry reduced by 10%

Slide 88 12/30/23
 Stages of Asthma Exacerbations
Stage 2:
Symptoms

Less able to do physical activity due to shortness of
breath

Dyspnea on walking stairs

May wake up at night short of breath

Uncomfortable on lying down

Some use of accessory muscles of respiration

Signs

Wheezing

Respiratory rate 18

Pulse 111

Peak flows and spirometry reduced by 20+%

Slide 89 12/30/23
 Stages of Asthma Exacerbations
Stage 3:
Symptoms

Unable to perform physical activity without
shortness of breath

Cannot lie down without dyspnea

Speaks in short sentences

Using accessory muscles
Signs

Wheezing

Respiratory rate 19 - 20

Pulse 120

Peak flows and spirometry reduced by 30+%

Slide 90 12/30/23
 Stages of Asthma Exacerbations
Stage 4:
Symptoms

Sitting bent forward

Unable to ambulate without shortness of breath

Single word sentences

Mentally-oriented and alert

Use of accessory muscles
Signs

Wheezing less pronounced than anticipated

Respiratory rate 20 - 25

Pulse 125+

Peak flows and spirometry reduced by 40+%

SaO2 91- 92%

Slide 91 12/30/23
 Stages of Asthma Exacerbations
Stage 5:

Symptoms

Reduced consciousness

Dyspnea

Silent chest – no wheezing
Signs

Fast, superficial respiration

Respiratory rate >25

Unable to perform peak flows or spirometry

Pulse 130 - 150+

SAO2 <90

Slide 92 12/30/23
 Severity of Asthma as Graded by %
Predicted FEV1

FEV% predicted Severity


70 - 100 Mild

60 - 69 Moderate

50 - 59 Moderately severe

35 - 49 Severe

< 35 Very severe
(life-threatening)

Slide 93 12/30/23
 Treatment of Asthma Exacerbations 1

Preferred treatment choices


β2-agonists

Inhaled by MDI or nebulizer

Injected

Anticholinergics

Inhaled by MDI or nebulizer

Corticosteroids

Parenteral, oral or inhaled

Slide 94 12/30/23
 Treatment of Asthma Exacerbations 2

Secondary treatment choices


Aminophylline or theophylline (oral,
parenteral)

Leukotriene receptor antagonists (oral)

Oxygen

Magnesium sulfate

Slide 95 12/30/23
 Treatment of Asthma Exacerbations 3
Beta Agonists
Inhaled is preferred route


MDI plus spacer, 4 - 8 puffs Q 20 min x 3

Nebulizer, 2.5 - 5 mg albuterol Q 20 min x 3

Epinephrine SQ, 0.3 - 0.5ml (0.01 ml/kg children)

Levalbuterol, 0.63 - 1.25 mg Q 4 - 8 hours (if
available)

Slide 96 12/30/23
 Treatment of Asthma Exacerbations 4
Anticholinergics

Ipratropium


Preferred use: combined with beta agonist

MDI plus spacer, 2 - 4 puffs Q 20 min x 3

Nebulizer, 500 μg Q 20 min x 3

Slide 97 12/30/23
 Treatment of Asthma Exacerbations 5
Corticosteroids

No immediate effect

Earliest effects 6 hours after high dose

Oral is as effective as parenteral

Prednisone (equivalent), 45 - 60 mg

Higher doses have increased side effects and no
appreciable increased therapeutic benefit

Methylprednisolone, 1 – 2 mg/kg/24 hours

No substantial data for usefulness in acute
setting

Slide 98 12/30/23
 Treatment of Asthma Exacerbations 6
Aminophylline and Theophylline

Controversial:

Added no benefit to inhaled beta agonists

Increased complications

Loading dose for aminophylline: 5 – 6 mg/kg over
20 - 30 min

Maintenance dose: 0.4 mg/kg/hr (adjust for heart
and liver disease)

Try to achieve 5 - 15 μg/ml, monitor plasma levels
to adjust dose

Doses for theophylline similar but slightly less

Slide 99 12/30/23
 Treatment of Asthma Exacerbations 7
Leukotriene Modifiers


Few studies

Suggest usefulness in reducing hospitalizations

Montelukast, 10 mg orally

Zafirlukast, 20 mg orally

Slide 100 12/30/23

 Treatment of Asthma Exacerbations 8
Magnesium Sulfate

Controversial:

Inconsistent data

Used in very severe asthma in emergency
settings:

FEV1 < 25% predicted

Other signs of severe disease

1.2 - 2 gm IV over 10 - 20 min in 50 ml saline

Minor side effects

Slide 101 12/30/23

Preventing Exacerbations 1
Oral Corticosteroids


Oral corticosteroids are the most powerful
medications available to reduce airway
inflammation


Use until attack completely abated:

PEFR and FEV1 at baseline levels

Symptoms gone


Taper to QOD and determine if patient can remain
well if corticosteroids are withdrawn completely

Slide 102 12/30/23

Preventing Exacerbations 2
Inhaled Corticosteroids

Place patient on high dose inhaled corticosteroids

Fluticasone, 880 - 1760 μg

Budesonide, 800 - 1600 μg


Once oral corticosteroids are withdrawn, reduce the
inhaled dose incrementally, while maintaining PEFR at
personal best level


Consider combination of long acting β2-agonist and
inhaled corticosteroid in order to achieve the lowest
dose of corticosteroid possible

Slide 103 12/30/23

 Preventing Exacerbations 3
Underlying Causes and Patient Education

Evaluate patient for:


Allergy

Infection

Compliance

Inappropriate concomitant medications

Social factors

Tobacco, drugs, irritants, fumes

Psychiatric disorders

Patient education

Slide 104 12/30/23

 World Allergy Organization (WAO)

For more information on the World Allergy Organization

(WAO), please visit www.worldallery.org or contact the:

WAO Secretariat
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: [email protected]

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Slide 106 12/30/23