The Crashing Anaphylaxis Patient

Airway management ■ Epinephrine — which patients, by what route, and when to avoid ■
Second-line pharmacotherapy — antihistamines, corticosteroids ■ Patient disposition

Jonathan E. Davis and Robert L. Norris

Anaphylaxis is a severe, life-threatening, systemic reaction that has a rapid and often
unpredictable onset of potentially lethal symptoms. The disorder, which can affect patients in
every age group, must be swiftly and aggressively treated. 1 Anaphylaxis results from the sudden
release of active mediators from mast cells, which are located in tissues, and basophils in the
bloodstream. The clinical syndrome is variable and can involve multiple targets, including the skin
and respiratory, gastrointestinal (GI), cardiovascular, and central nervous systems (Table 21-1). 2
Respiratory and cardiovascular derangements carry the greatest potential for morbidity and
mortality.

The signs and symptoms of an acute allergic reaction are best viewed as a continuum (Figure 21-
1). It is useful to define a point along this spectrum that distinguishes anaphylaxis from milder
allergic phenomena because anaphylaxis necessitates aggressive treatment. A reasonable
working definition of the disorder involves allergic signs/symptoms with respiratory compromise
and/or hemodynamic instability (ranging from presyncope to cardiovascular collapse). Although
international experts have proposed clinical criteria for diagnosing anaphylaxis, the accuracy of
these guidelines in the emergency department is imperfect; clinical judgment remains
paramount (Table 21-2)

Pathophysiology

A classic IgE-mediated allergic response (Gell and Coombs type I, immediate hypersensitivity)
consists of three phases: 1. Sensitization: Allergen exposure leads to the production of IgE
antibodies. 2. Early reaction: Subsequent allergen exposure causes an IgEmediated release of
preformed substances from mast cells and basophils. 3. Late reaction: Immune cells produce
additional inflammatory mediators.

Etiology

Anaphylaxis has multiple etiologies, including foods, medications, stinging insects, latex, and
exercise (Table 21-3). Food is the most common cause of the disorder in children, whereas
medications are the most common culprit in adults. 4,6,7 Many infants outgrow their allergies to
eggs, milk, and soy products. On the other hand, food allergies in adults (eg, peanut, tree nuts,
fish, and shellfish) can remain problematic throughout life even if they first develop during
childhood.

Mortality

Certain factors are associated with severe or fatal anaphylaxis (Table 21-4). In particular, asthma
has been shown to be an independent risk factor for death from anaphylaxis. 8,9 Peanuts and
tree nuts have also been associated with severe symptoms, accounting for most fatal or near-
fatal food reactions in the United States. 10 Adolescents appear to be at increased risk for severe
or fatal reactions. Teenagers are more inclined to deny symptoms or engage in risky behaviors
despite a known allergy, and are less likely to recognize allergic triggers and carry or use their
epinephrine self-administration devices. 11 Concurrent medications such as beta-adrenergic
blockers and angiotensin-converting enzyme (ACE) inhibitors also may increase the risk of severe
sequelae or even death. 12

Emergency Department Treatment

As with any acute condition, initial attention must focus on the ABCs — airway, breathing, and
circulation. Definitive airway management is of paramount importance, as the window for
effective intervention can rapidly dwindle if decisions are not made swiftly and decisively.
Anticipate challenges with laryngoscopy, and simultaneously prepare initial and contingency
airway plans. Avoid sedatives that can depress blood pressure. Exercise extreme caution with
paralytics, as mask or supraglottic rescue ventilation can be significantly impaired in patients with
upper airway edema. An awake, sedated approach (eg, awake fiberoptic intubation) may be
preferable. 4 Optimizing success of the first look/first pass is essential regardless of the approach
employed. Most patients with anaphylaxis should be continuously monitored (cardiac and pulse
oximetry) and receive supplemental oxygen and intravenous crystalloid infusions via large-bore
lines. Optimally, patients should be placed in the supine position; pregnant women should be
placed on their left side. Remain vigilant for early clinical signs of shock. Compensated pediatric
shock can present with tachycardia alone; hypotension can be a late finding. The recommended
initial pediatric fluid infusion (crystalloid or colloid) is 10 to 20 mL/kg, titrated to response. 1 Fluid
administration (≥80–100 mL/kg) may become necessary in some cases. Common medications
used in the treatment of anaphylaxis are listed in Table 21-7.

**Be particularly vigilant in patients with a history of bronchospasm (eg, asthma, reactive airway
disease) in whom fatal anaphylactic reactions are more likely.
Epinephrine

Epinephrine should be considered a second “A” (adrenaline) in the “ABC” prioritization of

anaphylaxis management. Aggressive treatment with appropriate doses and routes of
epinephrine is universally recommended as first-line therapy. 21 Poor outcomes most often are
associated with failed or delayed administration. 8 Epinephrine has numerous identifiable
physiological benefits in the treatment of anaphylaxis (Table 21-8), although particular
indications and dosing regimens are a frequent source of confusion. 22 Practitioners should err
on the side of injecting epinephrine sooner except possibly in patients with clearly mild allergic
symptoms that do not appear to be progressing.

Generally, epinephrine is given intramuscularly in the anterolateral thigh. The intramuscular

route is preferred over subcutaneous administration regardless of the patient’s age. 22
Subcutaneous absorption is highly dependent on cutaneous blood flow, which can be
compromised in anaphylaxis and further aggravated by epinephrine’s potent local
vasoconstrictor activity, leading to slow and erratic absorption. 23,24 The typical dose for
intramuscular administration is 0.01 mg/kg, up to a maximum of 0.2 to 0.5 mg (maximum 0.3 mg
for children) of a 1:1,000 dilution, repeated every 5 minutes as needed. 25 Great caution should
be exercised when using IV epinephrine to manage anaphylaxis. Major adverse events can occur
when the drug is administered too rapidly or in excessive dosages. 26,27,28,29,30 Intravenous
epinephrine has been associated with the induction of fatal cardiac arrhythmias, myocardial
infarction, and intracranial hemorrhage; however, other factors related to the underlying
pathophysiological process (eg, hypoxia, acidosis, effects of inflammatory mediators) may be
responsible for the observed complications. 27,28,29,30,31 The IV route should be reserved for
cases of severe cardiovascular compromise (ie, a profound decrease in peripheral perfusion that
would significantly hamper intramuscular absorption) or when repeated intramuscular dosing
(eg, 2 or 3 doses) fails to alleviate symptoms. A firm intravenous dose cannot be recommended;
the appropriate quantity depends on the severity of the episode and should be titrated to
response. A frequently recommended adult intravenous dosing regimen uses a 1:100,000
epinephrine solution, slowly infusing 100 mcg (0.1 mg) over 5 to 10 minutes (Table 21-9).
17,25,32 During anaphylaxis, 5- to 10-mcg IV bolus doses have been suggested for treating
hypotension and 100- to 500-mcg IV boluses have been suggested for adults with severe
cardiovascular collapse. 33 A continuous IV epinephrine infusion is a reasonable option (1–10
mcg/min, titrated to response; pediatric patients, 0.1–2 mcg/kg/min). 34 It is paramount to
double check the dosage to avoid a medication error catastrophe

Whenever the intravenous route is required, a continuous low-dose infusion is likely the safest
and most effective approach for patients of any age, as the dose can be titrated to desired effect
while minimizing the potential for accidental administration of large or concentrated bolus doses.
2 There are, however, very few controlled studies to support these recommendations. 35
Although there is a paucity of controlled data to adequately address safety concerns, some
lessons can be gleaned from experience with the use of epinephrine for asthma. 26,27 These
data should not be overly generalized, but they suggest a more favorable safety profile for
epinephrine than is routinely acknowledged, particularly when the agent is administered via non-
IV routes. Younger patients have an even more attractive risk-benefit profile for the drug in
general, as they are likely to tolerate most complications better than adults. Of concern to many
practitioners is the administration of the medication to higher-risk patients, particularly those
who are elderly or have comorbid conditions such as hypertension, coronary artery disease, or
cerebrovascular disease. Such decisions must be evaluated on a case-by-case basis, with a rapid
weighing of benefits against potential risks. Critical to this equation is the fact that anaphylaxis is
a life-threatening emergency and, as such, is associated with morbidity and mortality in these
higher-risk cases. The potential risks associated with epinephrine need to be balanced against
the danger of withholding the most critical therapy in anaphylaxis management.

Antihistamines

Antihistamines should never be utilized in lieu of epinephrine in the management of anaphylaxis.

Although H1 antihistamines are commonly used in allergic emergencies, there is some debate
over their benefit in these scenarios. 36 Less-sedating H1 antagonists such as cetirizine (Zyrtec)
and loratadine (Claritin) may be used as a substitute for oral diphenhydramine in those with
milder allergic symptoms; however, these agents have no role in the crashing patient because
they are not available for intravenous use in the US. Although the precise role of H2 antagonists
in the treatment of allergic emergencies has yet to be completely elucidated, they are
recommended due to their potential benefits and low propensity for adverse events. 36,37,38
There is no specific evidence regarding the superiority of one particular H2 antihistamine, but
agents other than cimetidine might be preferable to avoid effects on the cytochrome P450
system.

Corticosteroids

Corticosteroids traditionally have been used as adjuncts in the management of anaphylaxis.

Although the effects of these agents have never been validated in controlled trials, their
administration is warranted in allergic emergencies (particularly severe cases) because of their
known benefits in the treatment of asthma and other allergic diseases. 40 The theoretical
objective of corticosteroid therapy is to temper the continued intracellular synthesis and release
of potent proinflammatory mediators. This may blunt — although not necessarily prevent —
biphasic or multiphasic anaphylaxis. In practice, the intravenous route often is preferred. There
is no evidence to support any specific dose, route of administration, or particular formulation.

Inhaled Bronchodilators

Nebulized inhaled bronchodilators (eg, albuterol sulfate) may be continuously or intermittently

used for the treatment of anaphylaxisinduced bronchospasm.

Glucagon

Alternative Vasopressors Glucagon can have a role in treating anaphylaxis refractory to standard
therapy, especially in the case of coexisting beta-adrenergic receptor blockade. 41 Epinephrine
stimulates intracellular cyclic AMP (cAMP) production through interactions with beta-adrenergic
receptors. Glucagon exerts its intracellular effects by mediating cAMP production independent
of the adrenergic system. 42 Despite limited evidence, glucagon might benefit patients who are
taking beta blockers when all other treatments have failed. 43 The initial pediatric bolus dose is
20 to 30 mcg/kg (maximum 1 mg). 17 The recommended adult dose is 1 to 5 mg IV over 5 minutes,
followed by a continuous infusion of 5 to 15 mcg/min titrated to clinical response. 17 Airway
protection should be considered prior to infusion, as glucagon can induce vomiting. Adjunctive
vasopressor agents should be considered in the event that epinephrine and volume expansion
fail to maintain adequate blood pressure or perfusion. In such cases, norepinephrine, dopamine,
or vasopressin should be considered.

Disposition

One of the greatest challenges in treating patients with allergic emergencies is determining their
appropriate disposition (Table 21-10). Patients with severe reactions (eg, hypotension or airway
involvement) or a slow response to standard therapies requires admission for continued
monitoring. On the other end of the spectrum, those with clearly mild reactions may be safely
discharged. Most patients fall somewhere in between, making such decisions more difficult.

It is critical to recognize the potential for recurrent (biphasic or multiphasic) anaphylaxis, which
is defined as the reappearance of allergic phenomena following the complete resolution of the
original reaction, without reexposure to the inciting allergen. Recurrence can involve only
nuisance-level symptoms or more ominous physiological derangements, including respiratory
compromise and hemodynamic instability. While the rate of recurrence has been reported to be
as high as 20%, the actual rate of clinically significant recurrence is likely much lower than this,
though manifestations can be severe and can recur as long as 72 hours after the inciting event.
44,45 Corticosteroid administration does not eliminate the possibility of recurrence. Clinically
important biphasic reactions during the index or subsequent emergency department visits are
very rare. 46 Protracted (prolonged or refractory) anaphylaxis has also been reported. 47 Patients
with this condition can present with refractory hypotension or bronchospasm, posing unique
challenges in terms of circulatory support and ventilator management, respectively.

Although there is no firmly established observation time following an episode of anaphylaxis,

clinicians should maintain a low threshold for prolonged observation, particularly when high-risk
features (eg, asthma, nut allergies) are present. A minimum of several hours following treatment
is reasonable for mild episodes, and at least 24 hours of observation is prudent for severe cases
or patients with highrisk or otherwise troubling features. Recent consensus statements
recommend 4 to 8 hours for most patients, with more prolonged times or admission for those
with severe or refractory symptoms or reactive airway disease.

Postreaction Treatment

There is little disagreement that epinephrine self-administration devices should be prescribed for
individuals with a history of anaphylaxis involving respiratory distress or shock and who cannot
reliably avoid the triggering allergen. 48 The immediate availability of self-injectable epinephrine
is important in the initial 72-hour period for the treatment of recurrent anaphylaxis induced by
any allergen. A more difficult decision involves patients who experienced only mild symptoms
after exposure. 49 An initial episode, no matter how innocuous, does not predict the severity of
future events, particularly in the case of food-induced allergy. 50 Approximately 50% of patients
with initially mild symptoms exhibit life-threatening anaphylaxis after a second exposure to the
same allergic trigger. 51 In a small percentage of patients, the symptoms are more severe than
during the initial event. 52 Patients, caretakers, and teachers should be instructed regarding the
proper use of epinephrine delivery devices; optimally, patients should leave the emergency
department with two devices in hand. Epinephrine commonly is formulated in premeasured 0.3-
mg or 0.15- mg dosage options (Table 21-11). 11 Great care must be exercised if the decision is
made to teach parents how to draw up a dose of the drug for children weighing less than 10 kg.
Evidence has demonstrated that caretakers have significant difficulty administering appropriate
doses.

Other recommended postreaction treatments include oral H1/H2 antihistamines and

corticosteroids. Oral medications can be continued for at least 72 hours, although there is no
specific evidence to support a firm recommendation.
KEY POINT

1.Risk factors for fatal anaphylaxis include a history of asthma or bronchospasm, a history of nut
allergy (peanut, tree nuts), delayed administration of epinephrine, use of betaadrenergic
blockers or ACE inhibitors, and adolescent age.

2. Patients who initially present with mild symptoms and appear to be stable can deteriorate
rapidly.

3. Cutaneous findings (eg, urticaria or flushing) might be entirely absent.

4. Involvement of the respiratory or cardiovascular system distinguishes anaphylaxis from other

allergic phenomena.

5. Up to 35% of the circulating blood volume can be lost within 10 minutes after the onset of
anaphylaxis, primarily from third spacing.

6. Epinephrine is the single most important and sole first-line pharmacological agent for the
treatment of anaphylaxis. It should be promptly administered to any patient with anaphylaxis.

7. Current guidelines recommend intramuscular epinephrine administration into the

anterolateral thigh. To save vital time in the management of a rapidly decompensating patient,
consider the use of an autoinjector unit (eg, EpiPen or AuviQ).

8. Administer IV epinephrine for severe cardiovascular compromise or when repeated

intramuscular doses have failed.

9. Anaphylaxis is a life-threatening emergency with inherent morbidity and mortality. Therefore,

the risks of epinephrine administration must be balanced against the risks of withholding the
most critical pharmacotherapy available.

10. Epinephrine Undisputed first-line agent and treatment of choice for anaphylaxis; despite this
status, the drug remains underutilized. Intramuscular administration in the anterolateral thigh is
preferred. Reserve intravenous administration for patients in extremis and unresponsive to
repeated intramuscular dosages and those in profound shock. There are no absolute
contraindications; exercise caution in patients taking beta-adrenergic blockers and in pregnant
patients.

11. Antihistamines Adjunctive therapy for anaphylaxis Should never be used as a substitute for
epinephrine Combined H1 + H2 blockade is preferable.

12. Corticosteroids Adjunctive therapy for anaphylaxis Should never be used as a substitute for
epinephrine Possible role in mitigating recurrent anaphylaxis
Conclusion

Anaphylactic reactions can be life-threatening and are almost always unanticipated. Any delay in
the recognition of initial signs and symptoms can result in a poor outcome. Even when the
symptoms are initially mild, the potential for progression to airway obstruction or vascular
collapse must be appreciated and treatment must be swiftly and aggressively initiated.
Epinephrine is the cornerstone of therapy; second-line pharmacotherapies include H1/H2
antihistamines and corticosteroids. Disposition from the emergency department is fraught with
potential dangers. Prolonged observation is prudent following significant reactions and for
patients with other high-risk features, particularly asthma or nut (eg, peanut, tree nut) allergies.
Ensuring that patients have continuous access to and familiarity with their epinephrine self-
administration device is critical to preventing morbidity and mortality.

References

Jonathan E. Davis and Robert L. Norris (2017). Emergency Department Resuscitation of The
Critically Ill (2th ed.). New York: Michael E. Winters