Anaphylaxis

By : - Dr. Leul N.
• Anaphylaxis is a serious allergic reaction, with a rapid onset; it may cause death and
requires emergent diagnosis and treatment.

• Consensus clinical criteria provide consistency for diagnosis

• The terms anaphylactic and anaphylactoid were previously applied to immunoglobulin E

(IgE)-dependent and IgE-independent events, respectively.

• Because the final pathway in both events is identical, anaphylaxis is the term now used
to refer to both.

• Hypersensitivity is an inappropriate immune response to generally harmless antigens,

representing a continuum from minor to severe manifestations.

• Anaphylaxis represents the most dramatic and severe form of immediate

hypersensitivity.

• Foods, medications, insect stings, and allergen immunotherapy injections are the most
common provoking factors for anaphylaxis, but any agent capable of producing a sudden
degranulation of mast cells or basophils can induce anaphylaxis
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• Latex hypersensitivity is increasing in prevalence in the general population, with a
resultant risk for anaphylaxis.

• In addition, a significant number of anaphylaxis cases have no identified cause, termed

idiopathic anaphylaxis.

• The lifetime individual risk of anaphylaxis is estimated to be 1% to 3%,but the

prevalence of anaphylaxis may be increasing.

• Although allergic reactions are a common cause for ED visits, anaphylaxis is likely
underdiagnosed.

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 PATHOPHYSIOLOGY
• Anaphylaxis, for the most part, arises from the activation of mast cells and basophils
through a mechanism involving crosslinking of IgE and aggregation of the high-affinity
receptors for IgE.

• Upon activation, mast cells and/or basophils quickly release preformed mediators from
secretory granules that include histamine, tryptase, carboxypeptidase A, and
proteoglycans.

• Downstream activation of phospholipase A2, followed by cyclooxygenases and

lipoxygenases, produces arachidonic acid metabolites, including prostaglandins,
leukotrienes, and platelet-activating factor.

• The inflammatory cytokine, tumor necrosis factor-α, is released as a preformed

mediator and also as a late-phase mediator with other cytokines and chemokines.

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• These mediators are responsible for the pathophysiology of anaphylaxis.

• Histamine stimulates vasodilation and increases vascular permeability, heart rate,

cardiac contraction, and glandular secretion.

• Prostaglandin D2 is a bronchoconstrictor, pulmonary and coronary vasoconstrictor, and

peripheral vasodilator.

• Leukotrienes produce bronchoconstriction, increase vascular permeability, and promote

airway remodeling.

• Platelet-activating factor is also a potent bronchoconstrictor and increases vascular

permeability.

• Tumor necrosis factor-α activates neutrophils, recruits other effector cells, and
enhances chemokine synthesis.

• These overlapping and synergistic physiologic effects contribute to the overall

pathophysiology of anaphylaxis.

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 CLINICAL FEATURES
• The classic presentation of anaphylaxis begins with pruritus, cutaneous flushing, and
urticaria.

• These symptoms are followed by a sense of fullness in the throat, anxiety, a sensation
of chest tightness, shortness of breath, and lightheadedness.

• A complaint of a “lump in the throat” and hoarseness heralds life-threatening laryngeal

edema in a patient with symptoms of anaphylaxis.

• These major symptoms may be accompanied by abdominal pain or cramping, nausea,

vomiting, diarrhea, bronchospasm, rhinorrhea, conjunctivitis, and/or hypotension.

• As the cascade progresses, respiratory distress, decreased level of consciousness, and

circulatory collapse may ensue.

• In severe cases, loss of consciousness and cardiorespiratory arrest may result.

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• In most patients, signs and symptoms begin suddenly, often immediately and usually
within 60 minutes of exposure.

• In general, the faster the onset of symptoms, the more severe the reaction—one half
of anaphylactic fatalities occur within the first hour.

• After the initial signs and symptoms abate, patients are at a small risk for a recurrence
of symptoms caused by a second phase of mediator release, peaking 8 to 11 hours
after the initial exposure and manifesting symptoms and signs 3 to 4 hours after
the initial clinical manifestations have cleared.

• The late-phase allergic reaction is primarily mediated by the release of newly

generated cysteinyl leukotrienes, the former slow-reacting substance of anaphylaxis.

• The incidence of this biphasic phenomenon has been reported to vary widely up to 20%;
however, prospective studies specifically searching for clinically important biphasic
events report a much lower incidence (4% to 5%).

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 DIAGNOSIS
• The diagnosis of anaphylaxis is clinical.

• The diagnosis is easily made if there is a clear history of exposure, such as a bee sting,
shortly followed by the multisystem signs and symptoms described earlier.

• Unfortunately, the diagnosis is not always easy or clear, because symptom onset may be
delayed, symptoms may mimic other presentations (e.g., syncope, gastroenteritis,
anxiety), or anaphylaxis may be a component of other diseases (e.g., asthma).

• The differential diagnosis of anaphylactic reactions is extensive, including vasovagal

reactions, myocardial ischemia, dysrhythmias, severe acute asthma, seizure,
epiglottitis, hereditary angioedema, foreign body airway obstruction, carcinoid,
mastocytosis, vocal cord dysfunction, and non– IgE-mediated drug reactions.

• The most common anaphylaxis imitator is a vasovagal reaction, which is characterized by

hypotension, pallor, bradycardia, diaphoresis, and weakness, and sometimes by loss of
consciousness.

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 TREATMENT
• Triage for all acute allergic reactions should be at the highest level of urgency because
of the possibility of sudden deterioration.

• Current treatment recommendations are derived from the clinical experience of experts
as professed in consensus statements and guidelines.

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• FIRST-LINE THERAPY

• Airway and Oxygenation

• In severe anaphylaxis, securing the airway is the first priority.
• Examine the mouth, pharynx, and neck for signs and symptoms of angioedema:
uvula edema or hydrops, audible stridor, respiratory distress, or hypoxia.

• If angioedema is producing respiratory distress, intubate early, since any delay

may result in complete airway obstruction secondary to progression of
angioedema.

• Provide supplemental oxygen to maintain arterial oxygen saturation >90%.

• Decontamination

• If the causative agent can be identified, termination of exposure should be

attempted.

• Gastric lavage is not recommended for food-borne allergens and may be

associated with complications (i.e., aspiration) and delays in the administration
of more effective treatments (e.g., epinephrine).

• In insect stings, remove any remaining stinging remnants because the stinger
continues to inject venom even if it is detached from the insect

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• Epinephrine (adrenaline) is a mixed α1- and β-receptor agent.

• The α1-receptor activation reduces mucosal edema and treats hypotension, β1-
receptor stimulation increases heart rate and myocardial contractility, and β2-
receptor stimulation provides bronchodilation and limits further mediator release.

• Epinephrine is the treatment of choice for anaphylaxis.

• However, observational studies indicate that it is underused, often dosed

suboptimally, and underprescribed upon discharge for potential future self-
administration.

• Most of the reasons proposed to withhold epinephrine are flawed, and the
therapeutic benefits of epinephrine exceed the risk when given in appropriate
routes and doses, even in elderly patients.

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• In patients without signs of cardiovascular compromise or collapse, administer epinephrine
IM.
• Repeat every 5 to 10 minutes according to response or if relapse occurs.

• Injections into the thigh are more effective at achieving peak blood levels than injections into
the deltoid area.

• Intramuscular dosing is recommended because it provides higher, more consistent, and more
rapid peak blood epinephrine levels than SC administration.

• For convenience and accurate dosing, many EDs have adopted the use of epinephrine
autoinjectors, such as EpiPen® (0.3 milligrams of epinephrine for adults; Dey, L.P., Napa, CA)
and EpiPen Junior® (0.15 milligrams of epinephrine for children <30 kg; Dey, L.P.); however,
recent shortages in production have demonstrated the need for multiple sources of the drug.

• Some evidence suggests that expired epinephrine autoinjectors retain potency many months
to years after their expiration date.

• While retaining an expired EpiPen® may be a reasonable safety strategy for patients, it does
not negate the need for a new prescription.
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• Most patients with anaphylaxis need only a single dose of epinephrine IM.
• Blood pressure should be checked in patients taking β-blockers, because epinephrine use may result in
severe hypertension secondary to unopposed α-adrenergic stimulation.
• Age is not a barrier to epinephrine IM injections in patients with anaphylaxis.
• If the patient is refractory to treatment despite repeated doses of epinephrine IM or has signs of
cardiovascular compromise or collapse, then an epinephrine IV bolus and/or infusion should be
instituted

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• The initial epinephrine IV bolus is a dilute solution of 100 micrograms (0.1 milligram) IV,
given over 5 to 10 minutes.

• If the patient is refractory to the initial bolus, institute an epinephrine IV infusion,

starting at 1 microgram/min and titrating to effect.

• There is a higher risk of cardiovascular complications when epinephrine IV is used to

treat anaphylaxis.

• It should be stressed that the initial IV bolus dose is very dilute, is given over 5 to 10
minutes, and should be stopped immediately if dysrhythmias or chest pain occur.

• IV Crystalloids
• Hypotension is generally the result of distributive shock and responds well to fluid
resuscitation.

• A bolus of 1 to 2 L (10 to 20 mL/kg in children) of isotonic crystalloid solution

should be administered concurrently with epinephrine.

• There is no evidence that albumin or hypertonic saline should replace crystalloids.

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• SECOND-LINE THERAPY
• The second-line anaphylaxis treatments include corticosteroids, antihistamines,
inhaled bronchodilators, vasopressors, and glucagon.

• These drugs are used to treat anaphylaxis refractory to the firstline treatments
or associated with complications and also to prevent recurrences.

• Corticosteroids
• Patients with anaphylaxis often receive corticosteroids to prevent protracted
and biphasic reactions, although evidence for clinicalbenefit is scant and
primarily derived from acute asthma studies.

• Methylprednisolone, 80 to 125 milligrams IV (2 milligrams/kg in children; up to

125 milligrams), and hydrocortisone, 250 to 500 milligrams IV (5 to 10
milligrams/kg in children; up to 500 milligrams), are equally effective.

• The mineralocorticoid effects of corticosteroids are ranked in declining

order.

• Hydrocortisone and cortisone have the strongest effects, followed by

prednisone.

• Methylprednisolone and dexamethasone have the lowest mineralocorticoid

effect and produce less fluid retention than hydrocortisone and cortisone and
thus are preferred for the elderly and for those in whom fluid retention would
be problematic.
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• Antihistamines
• Most patients with anaphylaxis should receive an H1 antihistamine, such as
diphenhydramine, 25 to 50 milligrams IV by slow infusion or via IM
injection, although clinical benefit is unproven.

• In severe cases, especially with circulatory shock, guidelines recommend H2

antihistamines, such as ranitidine or cimetidine, although evidence for benefit
is lacking.

• Cimetidine should not be used for patients who are elderly (side effects),
have multiple comorbidities (interference with metabolism of many drugs),
have renal or hepatic impairment, or whose anaphylaxis is complicated by β-
blocker use (cimetidine prolongs metabolism of β-blockers and may prolong
anaphylactic state).

• After the initial IV dose of corticosteroids and antihistamines, the patient

may be switched to oral administration

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• Vasopressors
• In patients with anaphylaxis and shock resistant to initial treatment,
including repeated doses of IM epinephrine, oxygen, and IV crystalloids,
initiate IV epinephrine infusion.

• If dangerous dysrhythmias or tachycardia result from epinephrine, other

agents (e.g., dopamine, dobutamine, epinephrine, norepinephrine,
phenylephrine, or vasopressin) may be effective, and superiority from a
specific agent has not been demonstrated.

• Clinicians should use the agent they feel most comfortable with and titrate
according to the clinical response.

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• AGENTS FOR ALLERGIC BRONCHOSPASM
• A β2 bronchodilator, such as intermittent or continuous nebulized albuterol/
salbutamol, should be instituted if wheezing is present.
• Asthmatics are often more refractory to the treatment of allergic
bronchospasm.
• For severe bronchospasm refractory to inhaled albuterol/ salbutamol, inhaled
anticholinergics and IV magnesium sulfate can be added

• Bronchodilators should be given at a lower dose and at a slower rate in elderly

patients.

• IV aminophylline is not recommended.

• Leukotriene receptor antagonists are not effective for the treatment of

anaphylaxis
• GLUCAGON
• Concurrent use of β-blockers is a risk factor for severe prolonged anaphylaxis.

• For patients taking β-blockers with hypotension refractory to fluids and

epinephrine, glucagon IV should be used every 5 minutes until hypotension
resolves, followed by an infusion.

• The side effects of glucagon include nausea, vomiting, hypokalemia, dizziness,

and hyperglycemia.
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 DISPOSITION AND FOLLOW-UP
• With appropriate initial treatment, admission to hospital is rare, only required in about 1%
to 4% of acute allergic reactions treated in the ED.

• All unstable patients with anaphylaxis refractory to treatment or in whom airway

interventions were required should be admitted to the intensive care unit.

• While patients who receive epinephrine IM should be observed in the ED, the precise
duration of observation is unclear.

• Otherwise healthy patients who remain symptom free for one or 6 hours after
appropriate treatment can be discharged home with less than 5% or 3% incidence,
respectively of a biphasic reaction.

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• Discharge instructions should provide recommendations to prevent future episodes.

• For all allergic reactions, instruct the patient on how to avoid future exposure to the
causative agent (if the agent is known).

• Prescribe an epinephrine autoinjector to patients with serious allergic reactions or

anaphylaxis with clear instructions on the use of the autoinjector.

• Overall, less than one third of patients and parents of children with anaphylaxis can
demonstrate the effective use of an epinephrine autoinjector device, so education is a
key component of discharge instructions

• If delay in filling a prescription is anticipated, patients can be discharged from the ED

with an epinephrine autoinjector (EpiPen®).

• Reinforce this prescription with documentation in the ED discharge instructions. Because

allergic occurrences are unpredictable, prescriptions should include sufficient samples
for multiple locations (e.g., home, vehicle, work), and patients should be advised to carry
epinephrine with them at all times.

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• Refer patients with severe or frequent allergic reactions to an allergist for in-depth
preventive management and attempts at allergen identification.

• Offer patients information about this syndrome (e.g., from websites), advice on
advocacy groups, and education regarding food contamination for food allergies, and
encourage wearing of personal identification alerts about this condition (e.g.,
MedicAlert® bracelets).

• Because of the potential for severe and prolonged future reactions, patients with
anaphylaxis on β-blockers should be switched to an agent from a different therapeutic
class.

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 URTICARIA
• Urticaria, or hives, is a cutaneous reaction marked by acute onset of pruritic, erythemic
wheals of varying size that generally are described as “fleeting.”
• Erythema multiforme is a more pronounced variation of urticaria, characterized by
typical “target” skin lesions.

• Although these manifestations may accompany many allergic reactions, they also may be
nonallergic; many acute urticarial reactions are due to viruses, especially in children, and
present as hives persisting or recurring for more than 24 hours.

• Obtain a detailed history; if an etiologic agent can be identified (e.g., cold, exercise,
food), future reactions may be avoided

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• Treatment of urticarial reactions is generally supportive and symptomatic, with
attempts to identify and remove the offending agent.

• H1 antihistamines, with or without corticosteroids, are usually prescribed; however,

some evidence suggests the addition of corticosteroids to nonsedating antihistamines is
no better than antihistamines alone in preventing relapse or reducing itch.

• Epinephrine can be considered in severe or refractory cases.

• The addition of an H2 antihistamine, such as ranitidine, may also be useful in more

severe, chronic, or unresponsive cases.

• Cold compresses may be soothing to affected areas. Referral to an allergy specialist is

indicated in severe, recurrent, or refractory cases.

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 ANGIOEDEMA
• Angioedema is a similar reaction as urticaria, but with deeper involvement characterized
by edema formation in the dermis, generally involving the face and neck and distal
extremities.

• Angioedema of the tongue, lips, and face has the potential for airway obstruction.

• Although angioedemais caused by a variety of agents, an angiotensin-converting enzyme

inhibitor is a common trigger, with angioedema occurring in 0.1% to 0.7% of patients
taking angiotensin-converting enzyme inhibitors.

• The pathophysiology of angiotensin-converting enzym inhibitor–induced angioedema is

complex, involving both bradykinin and substance P.

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• Management of angiotensin-converting enzyme inhibitor–induced angioedema is supportive, with
special attention to the airway, which can become occluded rapidly and unpredictably.

• Drugs used to treat allergic reactions, such as epinephrine, antihistamines, and corticosteroids,
are not beneficial because angiotensin-converting enzyme inhibitor–induced angioedema is not
mediated by IgE.

• Icatibant, a bradykinin-2 antagonist, is an effective agent to reduce swelling and shorten time to
complete resolution.

• C1 esterase inhibitor (human) at a dose of 1000 U IV also appears effective based on a case
series compared to historical controls.

• Ecallantide, a kallikrein inhibitor, is not effective in angiotensinconverting enzyme

inhibitor–induced angioedema.

• Immediate withdrawal from the angiotensin-converting enzyme inhibitor is indicated, and another
antihypertensive should be prescribed, with the important exception that angiotensin II receptor–
blocking agents should not be used.

• Most cases resolve in a few hours to days, so patients with mild swelling and no evidence of airway
obstruction should be observed for 12 to 24 hours and discharged if swelling diminishes.

• Rebound or recurrent swelling will not occur unless the patient takes an angiotensin-converting
enzyme inhibitor again.

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• Hereditary angioedema
• Is a rare autosomal dominant disorder due to deficiency in C1 esterase inhibitor,
either low levels (type I) or a dysfunctional enzyme (type II).

• About 25% of cases are due to new mutations.

• The disorder is characterized by acute edematous reactions involving the upper

respiratory system, soft tissue of extremities or trunk, or gastrointestinal tract.

• Attacks can last from a few hours to 1 to 2 days.

• Minor trauma often precipitates an acute episode; however, triggers are often
elusive.

• Typical treatments for allergic reactions, such as epinephrine, corticosteroids, and

antihistamines, are ineffective.

• The best screening test is the C4 level.

• A C4 level <30% of normal suggests hereditary angioedema.

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• Acute attacks can be shortened by a C1 esterase inhibitor (either human plasma
derived or recombinant), the bradykinin-2 receptor antagonist icatibant, or the
kallikrein inhibitor ecallantide.

• Fresh frozen plasma may be used if C1 esterase inhibitor is not available, although
the dosing is not standardized, with 2 to 3 units described in most case reports.

• Prophylaxis of acute attacks is possible with attenuated androgens, such as stanozolol 2

milligrams PO TID or danazol 200 milligrams PO TID.

• Treatment of patients is complex and best done in coordination with the appropriate
specialist.

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 FOOD ALLERGY REACTIONS

• Hypersensitivity reactions to ingested foods are generally caused by IgE coated mast
cells lining the GI tract reacting to ingested food proteins and, rarely, to additives.
• More common in children

• Dairy products, eggs, nuts, and shellfish are the most commonly implicated foods

• A detailed dietary history within the 24 hours of allergic symptoms may provide the
best clues to food allergy, with particular attention to other allergic history and prior
reactions.

• Symptoms of food allergy include swelling and itching of the lips, mouth, and pharynx;
nausea; abdominal cramps; vomiting; and diarrhea.

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• Cutaneous manifestations, such as angioedema and urticaria, as well as anaphylaxis, can
occur.

• Treatment for mild reactions is supportive, with the administration of antihistamines

to lessen symptoms.

• More severe reactions and anaphylaxis are managed as described earlier.

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 ALLERGIC DRUG REACTIONS

• Adverse reactions to drugs are common; however, true hypersensitivity reactions probably account for
<10% of these occurrences, with the majority anaphylaxis from IgE-mediated drug reactions.

• Penicillin is the drug most commonly implicated in eliciting true allergic reactions and accounts for
approximately 90% of all reported allergic drug reactions and about 75% of fatal anaphylactic drug
reactions.

• Fatal reactions can occur without a prior allergic history; <25% of patients who die of penicillin-induced
anaphylaxis exhibited allergic reactions during previous treatment with the drug.

• Parenteral penicillin administration is more than twice as likely to produce fatal allergic reactions as is
oral administration.

• The cross-reactivity of penicillin allergy with cephalosporins is about 10%, so patients with a
previous life-threatening or anaphylactic reaction to penicillin should not be given cephalosporins.

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• The clinical manifestations of drug allergy vary widely.
• A generalized reaction similar to immune-complex or serum sickness reactions is very common
• Serum sickness usually begins in the first or second week after initiation of the drug and
can take many weeks to subside after drug withdrawal.
• Generalized malaise, arthralgias, arthritis, pruritus, urticarial eruptions, fever,
adenopathy, and hepatosplenomegaly are common signs and symptoms.

• Drug fever may occur without other associated clinical findings and may also occur without an
immunologic basis.

• Cytotoxic reactions include penicillin induced hemolytic anemia.

• Skin eruptions include erythema, pruritus, urticaria, angioedema, erythema multiforme, and
photosensitivity.
• Severe reactions, such as those seen in Stevens-Johnson syndrome and toxic epidermal
necrolysis, may also occur.
• Delayed hypersensitivity reactions may manifest as contact dermatitis from drugs applied
topically.
• Diagnosis is determined by a careful history.
• Treatment
• Supportive
• Oral or parenteral antihistamines and corticosteroids.
• Drug cessation is important, but reactions can continue.
• Referral to an allergy specialist is indicated for severe reactions

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