CONTENTS

diagnosis

• Clinical findings
• Diagnosis & diagnostic criteria
• Subtypes of anaphylaxis
• Causes
• Differential diagnosis
• Investigation

treatment

• Basic components of anaphylaxis resuscitation:
  • [1] Source control
  • [2] Epinephrine
  • [3] Fluid resuscitation
  • [4] Antihistamines
  • [5] Steroid
  • [6] Additional beta-2 agonists
  • [7] Methylene blue
• Specific management situations:
  • Anaphylaxis in the beta-blocked patient
  • Airway management (intubation & extubation)
• Disposition

related topics

• Pathophysiology of anaphylaxis

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clinical findings

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clinical findings

• Cardiovascular:
  • Hypotension.
  • Tachycardia.
  • Syncope, presyncope.
• Pulmonary/Airway:
  • Upper airway obstruction (stridor, tongue/uvula swelling, voice change).
  • Bronchospasm (wheeze originating in the lower airways on auscultation).
  • Dyspnea, cough.
• Skin/mucosa (involved in ~90% of patients):
  • Flushing.
  • Itch.
  • Urticaria.
  • Angioedema (~80% sensitive) – may involve lips, eyelids, airway, hands, feet, and genitalia.
  • Conjunctivitis, conjunctival swelling, and tearing.
  • Nasal discharge & congestion, sneezing.
• GI (involved in ~45% of patients): (34052784)
  • Crampy abdominal discomfort.
  • Nausea, vomiting.
  • Diarrhea.

timing of anaphylaxis onset

• Anaphylaxis due to intravenous medication or a bee sting usually begins within <30 minutes.
  • Initiation of reaction immediately following exposure is a poor prognostic sign.
• Anaphylaxis due to food or oral medication usually begins within a few hours.
• Among patients who die, the time between exposure & death is: (10931122)
  • ~5 minutes for iatrogenic anaphylaxis (e.g., IV medication induced).
  • ~15 minutes for insect venom anaphylaxis.
  • ~30 minutes for food anaphylaxis.

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diagnosis & diagnostic criteria

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approach to the diagnosis: main pieces to consider

• [1] Exposure history and chronicity:
  • Exposure to a known causative agent increases the index of suspicion.
  • Some patients can have idiopathic anaphylaxis, so the absence of a trigger doesn't exclude anaphylaxis.
• [2] Number of organ systems involved:
  • Having two organ systems involved strongly supports the diagnosis.
  • The diagnosis of anaphylaxis can be made on the basis of only one organ, within a highly suggestive clinical context.
• [3] Competing diagnoses (when in doubt, it's generally wise to treat empirically for anaphylaxis while continuing to investigate other diagnostic possibilities).

diagnostic criteria (World Allergy Organization 2020)

• Anaphylaxis is highly likely when either one of the following two criteria is fulfilled:
• [1] Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at least one of the following:
  • a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
  • b. Reduced BP or associated symptoms of end-organ dysfunction (eg, collapse, syncope, incontinence)
  • c. Severe gastrointestinal symptoms (eg, severe crampy abdominal pain, repetitive vomiting), especially after exposure to non-food allergens
• [2] Acute onset of hypotension or bronchospasm or laryngeal involvement after exposure to a known or highly probable allergen for that patient (minutes to several hours), even in the absence of typical skin involvement.
  • Excluding lower respiratory symptoms triggered by common inhalant allergens or food allergens perceived to cause “inhalational” reaction in the absence of ingestion.

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subtypes of anaphylaxis

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uniphasic anaphylaxis

• Most common.
• Symptoms resolve within about an hour. (33653974)
• This usually doesn't require ICU admission (symptoms resolve before the patient can be transferred to ICU).

biphasic anaphylaxis

• Basics:
  • Biphasic anaphylaxis is a repeated episode of anaphylaxis following >1 hour of clinical resolution, without any additional exposures.
  • This may be roughly conceptualized as a delayed rebound of symptoms.
• Rate: Studies vary, but overall, the rate is ~5% of patients. (34782089)
• Biphasic reactions are usually mild, and there have been no reported deaths due to biphasic reactions. (34782088) Although the absolute rate of biphasic reactions may be ~5%, the rate of clinically significant biphasic reactions is probably much lower (e.g., <2%). (34782089)
• Risk factors:
  • The initial episode of anaphylaxis was severe (e.g., required high doses of epinephrine).
  • Delayed initial administration of epinephrine.
  • History of biphasic reactions.
  • Unknown anaphylaxis trigger.
  • Diarrhea.
  • Wheezing. (38108678; 34782089)
• Management:
  • Same as the management of anaphylaxis in general.
  • Steroids could theoretically have a greater role in preventing ongoing inflammation.

persistent anaphylaxis

• This refers to ongoing anaphylaxis for >4 hours.
• This occurs in ~4% of cases. (34782089)

refractory anaphylaxis

• Definition: Ongoing anaphylaxis, despite appropriate epinephrine dosing and adjunctive therapies.
• Epidemiology:
  • Rare (<0.5% of severe anaphylaxis cases).
  • Associated with drug etiology.

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causes

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• Foods, especially:
  • Peanuts, tree nuts.
  • Seafood, egg, shellfish.
  • Egg.
  • Red meat (alpha-gal syndrome).
• Insects (e.g., bees).
• Medications, especially:
  • Antibiotics (especially penicillin & first-generation cephalosporins).
  • NSAIDs, aspirin.*
  • Monoclonal antibodies (e.g., anti-TNF antibodies).
  • Radiocontrast dye.*
  • Paralytics.
  • Protamine.
  • Local anesthetics (e.g, lidocaine, benzocaine, mepivacaine).
  • Topical medications (e.g., chlorhexidine).
• Blood products in an IgA-deficient person.
• Less common:
  • Exercise, cold or heat exposure.
  • Latex.
  • Semen. (39654057)

* The reaction to NSAIDs, aspirin, or radiocontrast dye is technically an anaphylactoid reaction, not anaphylaxis. The two disorders are treated in the same fashion, however.

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differential diagnosis

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• Anaphylactoid reaction (e.g., vancomycin infusion reaction).
• Asthma:
  • Severe asthma is a risk factor for anaphylaxis.
  • Wheeze and dyspnea in an “asthmatic” are likely to be presumed due to asthma.
• Systemic mastocytosis, which may be suggested by:
  • Repeated episodes of anaphylaxis.
  • Male gender.
  • Anaphylaxis is unprovoked or caused by hymenoptera venom allergy.
  • Severe anaphylaxis with hypotension, presyncope/syncope, and GI symptoms (but absence of urticaria, angioedema, or wheezing).
  • Elevated baseline tryptase level.
  • (Additional manifestations of systemic mastocytosis may include cutaneous lesions (urticaria pigmentosa), fevers, weight loss, night sweats, bone pain, gastrointestinal symptoms, and hepatosplenomegaly.) (38108678)
• Angioedema due to bradykinin accumulation. 📖
• Upper airway obstruction of any etiology:
  • Foreign body aspiration.
  • Vocal cord dysfunction.
  • Epiglottitis.
  • Abscess compressing the airway.
• Acute pulmonary deterioration:
  • Pulmonary embolism.
  • Pneumothorax.
• Sepsis, toxic shock syndrome.
• Poisoning, e.g.:
  • Scombroidosis (“histamine fish”).
• Psychiatric:
  • Panic attack.
  • Somatoform anaphylaxis (functional).
• Flushing syndromes:
  • Neuroendocrine tumors (e.g., carcinoid, pheochromocytoma).
  • Vasoactive intestinal peptide-secreting tumor.

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investigation

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evaluation of competing diagnoses

• Depending on the presentation, it may be necessary to evaluate for other diagnostic possibilities.
• Clinical example: A patient presents with vasodilatory shock and urticaria. Anaphylaxis is suspected, but there is also a concern for septic shock. The patient is treated empirically for both conditions (with IV epinephrine infusion, steroids, antihistamine, and antibiotics). Infectious workup is pursued with chest radiograph, procalcitonin, and blood cultures. The infectious evaluation is negative, so antibiotics are stopped, leaving the patient with a clinical diagnosis of anaphylaxis.

serum tryptase during an episode

• Should be obtained as early as possible during an episode (ideally <2 hours after presentation).
• Systemic mast cell activation (e.g., anaphylaxis, systemic mastocytosis) is supported if one of the following is present:
  • [1] Tryptase above the laboratory-defined normal level (>11.4 ng/mL).
  • [2] Elevation compared to the patient's baseline value:
    • Traditional criteria: serum tryptase is at least 20% plus 2 ng/mL above the patient's bST level. (38108678)
    • The NIH calculator for comparing to the baseline level is available here.

baseline serum tryptase (bST)

• Refers to the tryptase level while the patient is feeling well (in between episodes).
• Indications to check bST:
  • Recurrent anaphylaxis.
  • Idiopathic anaphylaxis.
  • Severe anaphylaxis (especially in patients presenting with hypotension).
  • Hymenoptera venom anaphylaxis (especially if severe, or in the absence of urticaria).
  • Suspected mastocytosis.
• A normal median tryptase level is ~4.5-5 ng/mL. (38108678)
• bST >8 ng/mL suggests:
  • Clonal mast cell disease (especially if tryptase is >11.4 ng/mL).
    • Systemic mastocytosis.
    • Mast cell activation syndrome.
    • Myeloid neoplasm.
  • Hereditary alpha-tryptasemia (genetic disorder due to increased copy number of alpha-tryptase genes, which can predispose patients to mast cell activation; may cause mild tryptase elevations).
  • Anaphylaxis.
  • Complement (and mast cell) activation-related pseudoallergy.
  • Helminth infection.
  • Renal failure.
  • Hypereosinophilic syndrome. (38108678)

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(1|7) source control

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• Stop any potentially causative infusions of medication or blood.
• Consider placing a tourniquet proximal to the site of sting or antigen infiltration (e.g., local anesthetic) until the patient can be stabilized.
  • In the case of a bee sting, attempt to gently remove any stinger embedded in the skin. (34782088)
• Rocuronium or vecuronium anaphylaxis: Sugammadex 💉 will bind the paralytic agent and arrest the anaphylactic process.

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(2|7) epinephrine

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Epinephrine is the most powerful disease-modifying therapy for anaphylaxis. Beta-2 receptor stimulation causes mast cell stabilization and bronchodilation. Alpha-1 stimulation treats vasoplegia and may reduce mucosal edema. (34782088)

indications for epinephrine

• Epinephrine is indicated for anyone with definite or probable anaphylaxis.
• This includes the following indications:
  • A = Airway involvement
  • B = Breathing difficulty
  • C = Circulation (hypotension)
  • Involvement of any two organ systems (e.g., nausea/vomiting plus urticaria).

i.m. (intramuscular) epinephrine

• This is the traditional approach, which is useful in most situations.
• Start with 0.5 mg IM into the mid anterolateral thigh. (33895231) If symptoms are refractory to treatment, then one or two additional 0.5-mg doses may be given every five minutes. (33895231) If three doses fail to work, then consider initiation of an epinephrine infusion (as below). (33895231)
• If symptoms recur, then consider a repeat dose or initiation of an IV epinephrine infusion (as below).

intravenous epinephrine infusion

• Advantages of IV epinephrine:
  • Faster onset (if the patient has an IV placed and if IV epinephrine is available, this is the fastest way to get the medication into circulation).
  • Smoother tapering – the infusion can be gradually weaned off in a controlled fashion.
  • Ability to immediately reduce the dose if problems are encountered (e.g., hypertension).
  • Patients who are already shocked may not perfuse their muscle tissue well, so they may have poor absorption of IM epinephrine.
• The dose is discussed below. However, these are rough numbers, and the dose should be titrated to effect. (more here).
• 🙏 Please aggressively wean OFF the epinephrine after anaphylaxis resolution:
  • The major problem with epinephrine infusions is that once the patient is stabilized, practitioners are afraid to wean off the epinephrine. This leads to prolonged, unnecessary exposure to epinephrine and unnecessary ICU admissions.
  • A couple of hours after the anaphylaxis has resolved, start trying to wean off the epinephrine. Follow the patient carefully and resume the epinephrine if needed. IV epinephrine works almost immediately, so if the patient deteriorates during epinephrine weaning, you can just resume epinephrine immediately.

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(3|7) fluid resuscitation

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• Large volumes of crystalloid may be required for hemodynamic stability (e.g., several liters of Lactated Ringer's).
  • About a third of the plasma volume may extravasate out of the vasculature in minutes. (34782088)
• Aggressive fluid resuscitation is particularly important for:
  • Patients requiring high doses of epinephrine to maintain hemodynamic stability.
  • Patients about to be intubated.
• POCUS may help guide resuscitation.

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(4|7) antihistamines

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typical regimen

• Diphenhydramine 💉 50 mg IV q6hr.
• Famotidine 💉 20 mg IV q12 hr.

(how important are antihistamines?)

• Histamine is a key mediator of anaphylaxis. Exogenous administration of histamine has been demonstrated to cause angioedema-like tissue swelling. Histamine causes tissue edema by increasing endothelial cell permeability via stimulation of the H1 +/- H2 receptors.
• Antihistamines may reduce skin and mucus membrane manifestations. Most of the effects of antihistamines are primarily cosmetic (e.g., treatment of erythema, pruritus, flushing, and rhinorrhea). However, antihistamines should, in theory, also reduce airway edema.

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(5|7) steroid

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the following steroid regimens may be reasonable

• 10 mg IV dexamethasone x1 dose (then stop).
• 60 mg IV methylprednisolone x1 dose (then stop).

(are steroids beneficial at all?)

• The benefit of steroids in anaphylaxis is unclear and controversial.
• Some guidelines recommend against the routine use of steroids. (33895231) 
• The primary rationale for steroids is to reduce late-phase inflammatory responses (e.g., recurrent or biphasic reactions). However, data doesn't seem to support this.
• Situations where steroids may be more beneficial include:
  • [1] Anaphylaxis refractory to two IM doses of epinephrine (most patients admitted to the ICU would probably meet this definition).
  • [2] Anaphylaxis in the context of asthma (it may be difficult to clearly differentiate between the two entities).
• If a steroid is utilized, there is usually no need for ongoing steroid therapy. A single dose will generally be sufficient.

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(6|7) additional beta-2 agonists

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indication for additional beta-2 agonists?

• Epinephrine is the front-line therapy for respiratory symptoms. Inhaled beta-2 agonists shouldn't be used alone as an alternative to epinephrine. (33895231)
  • For patients with anaphylaxis refractory to low-dose epinephrine, escalating doses of epinephrine should probably be used (rather than relying on a beta-2 agonist).
• Beta-2 agonists may be appropriate for isolated wheezing that occurs despite adequate treatment of systemic anaphylaxis with epinephrine (e.g., other manifestations of anaphylaxis have resolved).

optimal beta-2 agonist?

• This is an evidence-free area.
• Terbutaline 💉 might be ideal here, in order to provide systemic beta-2 agonist activity (which will treat the underlying anaphylaxis by promoting mast-cell stabilization). However, terbutaline may increase the risk of side effects associated with beta-2 agonist stimulation (e.g., tachycardia).
• Nebulized albuterol may be considered as well (especially if the systemic anaphylaxis seems to be otherwise well-treated).
• Nebulized epinephrine is another option (especially consider in angioedema).

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(7|7) methylene blue

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• Methylene blue may be used for anaphylaxis refractory to therapies listed above (including generous doses of epinephrine).
  • Also consider the possibility of ongoing fluid extravasation with persistent hypovolemia.
• Methylene blue acts as a guanylate cyclase inhibitor, which counteracts nitric oxide-mediated vasodilation (which is a key contributor to refractory shock in anaphylaxis; figure below).
• The use of methylene blue is supported only by case reports and small case series. (22633725, 14586280, 17505688, 17941276, reviewed in 33653974)
• (Further discussion of methylene blue is here.)

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anaphylaxis in the beta-blocked patient

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• Anaphylaxis may be more severe in patients who are on beta-blockers.
• Epinephrine arrests anaphylaxis by causing mast cell stabilization via beta-2 receptor stimulation. For patients on nonselective beta-blockers (e.g., propranolol, nadolol, carvedilol, labetalol), epinephrine may be less effective at causing mast cell stabilization.
• The usual therapies for anaphylaxis will generally work fine for patients on beta-blockers (especially patients on beta-1 selective beta-blockers). So don't get too fancy – start with the basics.
• If conventional therapies are failing, additional therapies listed below may be considered (although there is no clear data regarding this):
  • [#1] Higher doses of epinephrine than usual (to overcome the beta-blockade). Theoretically, this could be limited by unopposed alpha-adrenergic stimulation, causing hypertension, so the BP needs to be monitored carefully to avoid hypertension.
  • [#2] Methylene blue 💉.
  • [#3] The addition of an isoproterenol infusion 💉 provides additional beta-agonist stimulation. As a nonselective (beta-1 & beta-2) agonist, isoproterenol is a rational therapy to overcome beta-blockade. It could theoretically help stimulate beta-2 receptors on mast cells.
  • [#4] Use an additional beta-2 agonist (e.g., terbutaline 💉 or high-dose continuous albuterol nebulization).
  • (Glucagon is often suggested, but this carries a high risk of emesis, which may be problematic for patients without a secured airway. The theoretical and evidentiary support for glucagon is weak, consisting of scattered case reports and mechanistic parallels with beta-blocker poisoning. Please note that the rationale for using glucagon is to bypass beta-1 receptors in the heart, leading to an increase in inotropy and chronotropy. Consequently, there is little reason to use glucagon for patients with adequate hemodynamics.)

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airway management

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• This is generally the same as for airway management in angioedema.
• Further discussion is here.

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disposition

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duration of observation in the hospital

• Recurrent (biphasic) reactions can occur, but they are rare and tend to be less severe.
• There is little evidence supporting any specific duration of time to observe the patient prior to discharge.
• The UK Anaphylaxis Working Group recommends the following:(33895231)

discharge instructions & medications

• [1] Efforts should be made to avoid the causative agent.
• [2] EpiPen is the key medication for discharge:
  • Patients should be prescribed two EpiPens and taught how to self-administer them. (34782089)
• [3] Discharge instructions:
  • Patients should be instructed to return to the hospital if a recurrent reaction occurs.
  • This set of discharge instructions looks helpful.
• Things to avoid:
  • There is no need to discharge patients with antihistamines. (34782088) If anything, anthistamines might theoretically mask symptoms of recurrent anaphylaxis, leading to delays in appropriate therapy.
  • There is no need to discharge patients with steroids (steroids are discussed above). (34782088) 
  • 💡 Discharging patients on a bunch of different medications only causes side effects and confusion. Just focus on the EpiPen.

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pathophysiology of anaphylaxis

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• Anaphylaxis may be triggered by various stimuli, as shown below.
• The diagram below illustrates potential mechanisms of action for the therapies of anaphylaxis (e.g., epinephrine, antihistamines, steroids, and methylene blue). (33653974)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

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