Anaphylaxis

7 Interesting Facts of Anaphylaxis 

  1. Anaphylaxis is a life-threatening systemic or hypersensitivity reaction with sudden onset 
    • Signs and symptoms typically start minutes to hours after exposure to a trigger 
    • Rapid assessment and early treatment with intramuscular epinephrine is critical 
  2. Causes can include virtually any agent capable of directly or indirectly activating mast cells or basophils 
    • Common triggers include foods, medications, and insect stings or bites
  3. Multiorgan system disorder that includes combination of the following:
    • Cutaneous system (eg, urticaria, angioedema, pruritus)
    • Respiratory system (eg, dyspnea, cough, wheezing)
    • Cardiovascular system (eg, hypotension, angina, arrhythmias)
    • Gastrointestinal system (eg, crampy abdominal pain, vomiting)
    • Central nervous system (eg, confusion, dizziness, irritability, headache)
  4. Diagnosis of anaphylaxis is highly likely in patient presenting with skin symptoms (eg, itchy urticaria; flushing; swollen lips, tongue, or throat) and either respiratory difficulty (eg, dyspnea, wheezing, stridor) or reduced blood pressure after acute exposure 
  5. Primary treatment consists of early administration of intramuscular epinephrine into the lateral thigh; administer as soon as diagnosis is suspected 
    • Antihistamines and glucocorticoids are second line medications; do not use instead of or before epinephrine
  6. Disposition and observation periods are individualized
    • Provide longer periods of observation to those with history of risk factors for severe anaphylaxis
  7. Prevention plans for future anaphylactic events are vital
    • Prescribe autoinjector epinephrine to patients who have experienced or are at risk for anaphylaxis 
    • Provide personalized education on triggers, signs and symptoms, and initial treatment plans for anaphylaxis

Pitfalls

  • Delayed administration of epinephrine
    • Impossible to predict course and severity of reaction at onset of anaphylaxis; inject epinephrine promptly at onset of symptoms
  • Failure to prescribe autoinjectable epinephrine to a patient treated for anaphylaxis 
  • Failure to refer patient to allergy specialist for follow-up after anaphylactic episode 
  • Anaphylaxis is a life-threatening systemic or hypersensitivity reaction with sudden onset 
    • Caused by exposure to offending agent, typically a food, medication, or insect sting
    • Can involve multiple organ systems, including cutaneous, respiratory, gastrointestinal, cardiovascular, or central nervous
  • Rapid administration of intramuscular epinephrine can be lifesaving

Classification

  • Classification based on pathophysiology (clinically indistinguishable)
    • Immunologic
      • Classically, IgE-mediated release of mediators from mast cells and basophils
        • Common causative agents include foods, drugs, and insect stings
    • Nonimmunologic (often termed anaphylactoid reaction)
      • Agents or events (eg, opiates, exercise) that induce direct mediator release from mast cells and basophils in absence of immunoglobulins
    • Idiopathic
      • No identifiable cause is determined after diagnostic evaluation; diagnosis of exclusion

Clinical Presentation

History

  • Complete patient history (witness account is often helpful) with detailed information regarding exposures and events in the hours preceding symptom onset is necessary, including: 
    • Potential causes (eg, ingestants and/or medications taken within 6 hours of event, antecedent sting or bite, exercise) 
    • Time of occurrence and setting in which episode began
    • Treatments given
  • Symptom and sign patterns (ie, onset, range, severity, course) differ among patients and individual anaphylactic events in the same patient 
    • More rapid onset of signs and symptoms of anaphylaxis after exposure to offending stimulus correlates to higher likelihood that reaction will be severe and life-threatening 
      • Anaphylaxis often produces signs and symptoms within 5 to 30 minutes, but reactions sometimes do not develop for several hours 
    • Typically at least 2 organ systems are involved, but only 1 may be involved initially 
    • Symptoms may be protracted or biphasic
      • Protracted uniphasic anaphylaxis occurs when symptoms last for an unusually long time (sometimes days)
      • Biphasic anaphylaxis occurs when symptoms recur within 1 to 72 hours (usually within 6-12 hours) after the initial symptoms have resolved, despite no further exposure to the trigger 
        • Estimated incidence ranges from less than 1% to 20% of patients 
        • May be more common in medication-induced anaphylaxis 
  • Symptoms can include:
    • Cutaneous:
      • Flushing, pruritus, hives, and perioral and periorbital swelling
      • Initial symptoms in majority of adult patients 
    • Respiratory:
      • Dyspnea, cough, nasal itching, congestion and sneezing, throat itching or tightness, and chest tightness
        • Cough is a common symptom and frequently is a harbinger of wheezing
      • Children are more likely to present with respiratory symptoms before cutaneous manifestations
    • Cardiovascular:
      • Chest pain, palpitations, dizziness, generalized weakness, and syncope
    • Gastrointestinal: 
      • Nausea, vomiting, crampy abdominal pain, diarrhea, and dysphagia
    • Central nervous system (15% of patients): 
      • Headache, confusion, feeling of impending doom, dizziness, tunnel vision, and syncope
    • Other symptoms may include: 
      • Metallic taste in the mouth
      • Cramps and hemorrhage due to uterine contractions in females

Physical examination

  • The following signs may be associated with anaphylaxis:
    • Skin and mucosal signs (approximately 80%-90% of patients): 
      • Generalized urticaria and angioedema are most common manifestation
        • May be delayed or absent in rapidly progressive anaphylaxis 
      • Flushing, morbilliform rash, or pilar erection 
      • Periorbital erythema and edema, conjunctival erythema, and tearing 
      • Swelling of lips, tongue, and uvula 
    • Respiratory tract involvement (approximately 70% of patients): 
      • Rhinorrhea and sneezing 
      • Hoarseness, dysphonia, stridor, and dry staccato cough 
      • Tachypnea, deep cough, wheezing/bronchospasm, and decreased peak expiratory flow 
      • Respiratory arrest 
    • Cardiovascular system involvement (approximately 45% of patients): 
      • Tachycardia, bradycardia (less common), and other arrhythmias 
        • In infants, shock is more likely to manifest initially by tachycardia than by hypotension 
      • Hypotension and shock 
      • Cardiac arrest
    • Central nervous system involvement (approximately 15% of patients): 
      • Uneasiness or feeling of doom; in infants and children may manifest as sudden behavior change, such as irritability, cessation of play, or clinging to parent
      • Altered mental status or loss of consciousness
  • Depending on the trigger, only a subset of the above clinical signs may be present, for example: 
    • After an insect sting, hypotension might be the only manifestation of anaphylaxis 
    • After injection of a known allergen into patient during allergen immunotherapy, generalized urticaria (only 1 organ system affected) might be the only initial manifestation of anaphylaxis 

Causes

  • Virtually any agent capable of directly or indirectly activating mast cells or basophils can cause this syndrome, including: 
    • Foods 
      • Most common cause of anaphylaxis in the community setting
      • Any food can theoretically trigger anaphylaxis
        • Foods most commonly implicated include peanuts, tree nuts, fish, shellfish, milk, and eggs 
      • Risk factors for fatal food-induced anaphylaxis include:
        • Adolescent age range
        • History of reaction
        • Allergy to peanuts or tree nuts
        • History of asthma
        • Presentation with absence of cutaneous symptoms
        • Delayed administration of epinephrine
      • Exercise may trigger anaphylaxis in food-dependent events 
    • Medications:
      • Second most common overall cause of anaphylaxis in adults and of fatal anaphylaxis 
      • Most common classes include:
        • Antibiotics, especially β-lactams
          • Although many penicillin-allergic patients can tolerate aztreonam or carbapenems, rare cross-reactivity between penicillins and these drugs has been reported 
        • NSAIDs 
      • Other medication classes include:
        • Chemotherapeutic agents, including platinum salts (eg, cisplatin, carboplatin, oxaliplatin) and biologic agents (eg, rituximab, trastuzumab, cetuximab) 
          • May trigger hypersensitivity reactions ranging from mild skin reactions to life-threatening anaphylaxis
        • Radiocontrast material
          • 35% of patients with iodinated radiocontrast media–induced anaphylaxis developed it on first exposure 
            • Most anaphylactic reactions not mediated by IgE (anaphylactoid); clinically identical
          • Although gadolinium-based contrast agents are recommended in patients with a history of radiocontrast media–induced anaphylaxis, they can also trigger anaphylaxis 
        • Allergen immunotherapy
          • Fatal reactions to skin testing are rare
        • Vaccines
          • Rare, usually due to the inactive ingredients or excipients 
      • Medication contaminants (eg, oversulfated chondroitin sulfate in heparin, herbal formulations) 
    • Insect stings or bites
      • Clinically important insects include bees (eg, honeybees, bumblebees), vespids (eg, yellow jackets, hornets, wasps), and stinging ants 
      • Fire ants are an increasing cause of anaphylaxis, notably in the southern United States 
    • Perioperative anaphylaxis 
      • Associated with greater morbidity and mortality than other forms of anaphylaxis 
        • Possible explanations include more rapid exposure to triggers owing to frequent IV medication delivery, delay in recognition and treatment, and physiologic changes to patient due to surgery
          • Difficult to diagnose owing to inability of patient to communicate, number of medications administered simultaneously, and decreased occurrence of cutaneous manifestations
      • Causes to consider include medications (eg, opioids, neuromuscular agents, antibiotics), blood transfusions, dyes, and latex
    • Blood transfusions
      • Can result in anaphylactoid reactions, generally mediated by IgG specific for component within transudate, including RBC mismatch 
    • Natural rubber latex
      • Occurrence decreasing owing to increased vigilance and decreased use of latex products in health care settings, but remains important trigger in many countries 
        • Common medical sources of significant latex exposure include sterile examination gloves, drains, and urinary catheters
      • Nonmedical sources of latex include condoms, balloons, and household gloves
      • In some latex-sensitive patients, foods may be cross-reactive; common associations include avocado, banana, chestnut, and kiwi 
    • Exercise-induced
      • May require cofactors (eg, foods, NSAIDs) 
    • Seminal fluid
      • Rare but significant condition for those affected 
    • Rarely, airborne allergens such as aerosolized food particles, pollen, or animal dander can trigger anaphylaxis 
      • This likely involves some systemic absorption of the allergen through the airways and/or skin
  • Idiopathic anaphylaxis
    • Accounts for approximately one-third of cases in retrospective studies; however, it remains a diagnosis of exclusion 

Risk factors and/or associations

Age
  • Extremes of age can increase the severity of anaphylaxis
    • Young children, aged 0 to 4 years, have highest admission rates for food-induced anaphylaxis 
      • Rate is accelerating in the age groups 5 to 14 years and 15 to 29 years 
        • Teenagers are at increased risk of severe and/or fatal anaphylaxis owing to risk-taking behaviors (eg, failure to avoid triggers and/or carry self-injectable epinephrine)
    • Older age combined with comorbidities (eg, cardiovascular disease, chronic respiratory disease) are important risk factors for severe anaphylaxis with hospitalization, prolonged hospital stay, and fatality
      • Admission rates and fatality rates for anaphylaxis from drugs and insect stings were highest in the elderly 
Ethnicity/race
  • Food triggers differ according to local dietary habits, specific food exposures, and methods of food preparation; for example: 
    • In North America and in some countries in Europe and Asia, cow’s milk, hen’s eggs, peanuts, tree nuts, shellfish, and fish are common food triggers
    • In the Middle East, sesame is a common trigger
Other risk factors/associations
  • Cofactors
    • Potentially amplify anaphylaxis by:
      • Decreasing threshold of allergen exposure required to trigger anaphylaxis
      • Amplifying risk of anaphylaxis in patients with low or borderline allergen sensitization
    • Can include exercise, ethanol, NSAIDs, acute infections, stress, or perimenstrual status 
  • Concomitant diseases that increase risk of severe or fatal anaphylaxis include: 
    • Systemic mastocytosis (disorder characterized by abnormal mast cell infiltration of skin or other tissues and organs)
      • Increases risk for severe Hymenoptera sting–induced anaphylaxis 
    • Asthma
    • Cardiovascular disease 
    • Atopic diseases 
  • Concurrent medications
    • Some medications (eg, β-blockers, ACE inhibitors) can increase the risk or severity of anaphylaxis 
      • Monotherapy with β-blockers and, to a lesser extent, ACE inhibitors can increase risk of severe anaphylaxis; risk is further increased by concurrent use of a drug from each class 
  • Perimenstrual anaphylactic episodes in girls and women are attributed to various mechanisms, such as hypersensitivity to progesterone or prostaglandin 
    • Estrogen may enhance endothelial expression of nitric oxide synthase and nitric oxide production, increase vascular permeability, and intensify anaphylaxis severity 
  • History of atopy
    • Typically associated with heightened immune responses to allergens
      • May be risk factor for food-induced, seminal fluid–related, and idiopathic anaphylactic episodes 
  • Factors that can interfere with recognition of triggers and symptoms include:
    • Medications
      • Concurrent use of central nervous system–active medications (eg, sedatives, hypnotics, antidepressants) and first-generation sedating H₁ antihistamines 
    • Comorbid conditions
      • Patients with comorbid impaired vision or hearing, neurologic disease, and psychiatric illness might have diminished awareness of anaphylaxis triggers and symptoms 

Diagnostic Procedures

Primary diagnostic tools

  • Diagnose acute anaphylaxis episode based on clinical history and physical examination 
    • Involves pattern recognition: sudden onset of symptoms and signs (minutes to hours) after exposure to a known or potential trigger, often followed by rapid progression 
      • At beginning of anaphylactic event, it is difficult to predict the rate of progression or the ultimate severity
        • Fatality can occur within minutes (5 minutes for IV administration of allergen, such as antibiotics, and 30 minutes for food-induced anaphylaxis); do not rely on signs of shock to make the diagnosis 
        • Cannot predict severity of current or future episodes based on severity of any past episodes 
    • Anaphylaxis is likely when any 1 of the following 2 criteria are met:
      • Acute onset of an illness (minutes to several hours) with simultaneous involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at least 1 of the following:
        • Respiratory compromise (eg, dyspnea, wheeze/bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
          • Excluding lower respiratory symptoms triggered by common inhalant allergens or food allergens perceived to cause “inhalational” reactions in the absence of ingestion
          • Laryngeal symptoms include: stridor, vocal changes, odynophagia
        • Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, syncope, hypotonia, incontinence)
          • Adults: systolic blood pressure less than 90 mm Hg or greater than 30% decrease from patient’s baseline
          • Children over 10 years: systolic BP less than 90 mm Hg
          • Infants and children under 10 years: systolic BP less than 70 mm Hg + (2 x age in years)
        • Severe gastrointestinal symptoms (eg, severe crampy abdominal pain, repetitive vomiting), especially after exposure to non-food allergens
      • 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
    • Anaphylaxis is possible even when not all criteria are fulfilled; use clinical judgment 
      • After an insect sting, hypotension might be the only manifestation
        • Absence of cutaneous manifestations does not preclude diagnosis of anaphylaxis 
      • During allergen immunotherapy, after injection of known allergen, generalized urticaria (only 1 organ system affected) might be the only initial manifestation
    • Laboratory tests
      • No laboratory tests or biomarkers are available to confirm diagnosis of anaphylaxis at initial presentation 
      • Tests performed on blood samples obtained during anaphylactic episode include serum tryptase and plasma histamine levels; may be useful in subsequent confirmation of diagnosis after initial treatment
        • Obtain serum tryptase optimally within 15 minutes to 3 hours of symptom onset to confirm occurrence of anaphylaxis 
        • Obtain plasma histamine levels within 1 hour of episode onset 

Laboratory

  • Serum tryptase
    • Marker of mast cell degranulation
      • Levels typically increase about 30 minutes after start of reaction, peak at around 1 to 2 hours, and remain elevated for approximately 6 to 8 hours 
    • Useful in confirming diagnosis of anaphylaxis in certain patients during subsequent follow-up 
      • Reference range is 1 to 11.4 nanograms/mL 
      • Increased serum tryptase levels often support the clinical diagnosis of anaphylaxis when it is caused by insect stings or injected medications as well as in patients who are hypotensive 
        • Levels are often within reference range in patients with anaphylaxis triggered by food and in those who are normotensive 
        • Serial tryptase measurement during anaphylactic episode and of baseline level after recovery (at least 24 hours after resolution) are more useful than single measurement made once
      • Tryptase level within reference range does not rule out the diagnosis; levels can be within reference range in patients with clinically documented anaphylaxis 
  • Plasma histamine levels
    • May be more sensitive than serum tryptase levels, but by the time most patients are seen, levels have returned to reference range 
      • Levels typically peak within 5 to 10 minutes of onset of anaphylaxis symptoms, then decline to baseline within 60 minutes 
    • If levels are elevated, results may support a diagnosis of anaphylaxis; however, levels within reference range do not rule out anaphylaxis
    • Reference range is 10 nmol/mL or lower 

Differential Diagnosis

Most common

  • Asthma:
    • Chronic disorder characterized by inflammation of the bronchi, leading to dyspnea and other respiratory symptoms
    • Wheezing, cough, and dyspnea can occur with both asthma and anaphylaxis 
    • Differentiate by history and physical examination; exposure to an allergen, presence of pruritus, urticaria, angioedema, abdominal pain, and hypotension are common during anaphylaxis but unlikely in acute asthma 
    • Lung function testing can confirm a diagnosis of asthma 
  • Anxiety/panic attack:
    • Abrupt onset of overwhelming feelings of fear, panic, and anxiety that reach a peak within minutes and are associated with a wide range of constitutional symptoms 
    • A sense of impending doom, dyspnea, flushing, tachycardia, and gastrointestinal symptoms can occur in both anxiety/panic attacks and in anaphylaxis 
    • Differentiate by history and physical examination; urticaria, angioedema, wheezing, and hypotension are common during anaphylaxis but unlikely during a panic attack 
  • Acute coronary syndrome: 
    • Spectrum of clinical conditions caused by reduced blood flow in the coronary arteries, including myocardial infarction and unstable angina
    • Angina pectoris and arrhythmias may occur in both acute coronary syndrome and anaphylaxis 
      • Both conditions may lead to myocardial infarction
    • Acute coronary syndrome, unlike anaphylaxis, does not typically present with urticaria or pruritus
    • Diagnosis of acute coronary syndrome is supported by a physical examination documenting the absence of urticaria and of patient reports of pruritus; diagnostic electrocardiogram is supportive
  • Syncope
    • Temporary loss of consciousness and postural tone, mostly associated with orthostatic hypotension or vasovagal reactions
      • Characterized by hypotension, bradycardia, pallor, weakness, nausea, vomiting, and diaphoresis
    • Hypotension can occur in both syncope and anaphylaxis 
    • Differentiate by history and physical examination
      • Syncope diagnosis is supported when it is relieved by recumbency and physical examination reveals pallor, diaphoresis, and orthostatic hypotension; urticaria, flushing, respiratory, and gastrointestinal symptoms are typically absent 
      • Bradycardia is more common in syncope; tachycardia is typical in anaphylaxis (but can transition into bradycardia in end-stage anaphylaxis as cardiovascular collapse occurs)

Treatment Goals

  • Treat acute anaphylactic reaction to minimize morbidity and mortality 
  • Prevent future anaphylactic events 

Admission criteria

Base decision to admit on the following: 

  • Symptom severity
  • Response to treatment
  • Pattern of previous anaphylactic reactions (eg, protracted or biphasic reactions)
  • Medical comorbidities
  • Patient age, reliability, and access to medical care
Criteria for ICU admission
  • Refractory anaphylaxis

Recommendations for specialist referral

  • Refer to allergist or immunologist after acute episode for definitive evaluation, including the following: 
    • Confirm diagnosis of anaphylaxis and the trigger
    • Clarify diagnosis with additional investigations to reveal trigger, if unknown
    • Identify comorbidities (eg, systemic mastocytosis)
    • Initiate comprehensive preventive care including:
      • Individualized education regarding allergen avoidance, anaphylaxis recognition, and epinephrine autoinjector use
        • Provide personalized anaphylaxis emergency action plans and medical identification jewelry regarding condition
      • Conduct medication desensitization if a vital medication was the trigger 
      • Administer allergen immunotherapy (eg, venom immunotherapy) to prevent recurrence of insect sting anaphylaxis 
  • If possible, refer patients with refractory anaphylaxis not responding to initial treatments (intramuscular epinephrine injections, oxygen, IV fluids, and second line medications) to specialist team (eg, including critical care, emergency medicine, and anesthesia) 

Treatment Options

American Academy of Allergy, Asthma & Immunology and the World Allergy Organization provide guidelines for the management of anaphylaxis 

Treatment of acute anaphylactic event

  • Out-of-hospital care
    • Administer epinephrine intramuscularly in mid-outer thigh as soon as anaphylaxis is recognized
      • Lifesaving when administered promptly; there is no absolute contraindication to the administration of epinephrine in the setting of anaphylaxis
      • Epinephrine autoinjectors preferred in community settings; removal of clothing is unnecessary 
      • More than 1 injection may be required
    • Remove inciting allergen, if possible (eg, stop an infusion) 
    • Assess airway, breathing, circulation, and mentation while summoning emergency assistance
      • Start cardiopulmonary resuscitation if indicated 
    • Place patient in supine position (pregnant patients on left side) to prevent circulatory collapse 
      • Patients with respiratory distress or vomiting may require more upright positioning (eg, semi-Fowler position)
  • Treatment in medical venue, including emergency medical services
    • Immediate intervention (started concomitantly)
      • Assess airway, breathing, and circulation
        • Maintain airway using least invasive, most effective method (eg, bag-valve mask) 
          • Prepare for airway management, including intubation, for any sign of airway edema (eg, hoarseness, stridor) or associated respiratory compromise 
            • Upper airway obstruction (eg, severe laryngeal edema) is absolute contraindication for endotracheal intubation; use surgical airway (eg, cricothyrotomy) in this setting 
        • Administer oxygen to all patients with respiratory or cardiovascular involvement or no response to initial treatment with epinephrine 
          • Consider for any patient with anaphylaxis, regardless of respiratory status 
        • Obtain IV access with large-bore catheters to maintain hemodynamic stability
          • If IV access is not readily available, obtain intraosseous access (epinephrine can be administered by this route) 
      • Provide patients who have known or suspected anaphylaxis with continuous hemodynamic monitoring (eg, blood pressure, pulse oximetry, electrocardiographic monitoring) 
      • Maintain supine position to prevent circulatory collapse (pregnant patients on left side) 
        • Fatality can occur within seconds if patient sits or stands suddenly (empty vena cava/ventricle syndrome) 
        • Patients in respiratory distress may require more upright positioning
      • Administer intramuscular epinephrine (anterolateral thigh) promptly if symptoms are ongoing; first line therapy 
        • Intramuscular epinephrine achieves peak concentrations quickly and is safer than IV bolus injection 
    • Adjunctive therapies (based on initial response)
      • Administer fluid resuscitation with normal saline in patients with circulatory collapse (eg, hypotension) and for patients who do not respond to intramuscular epinephrine 
        • May require large volumes of normal saline, especially in early stages; significant plasma leak can be associated with anaphylaxis
          • Adults: may require 1 to 2 L of 0.9% normal saline infused rapidly (eg, 5-10 mL/kg within first 5 minutes) 
          • Children: may require successive boluses of 20 mL/kg (up to 30 mL/kg in first hour) 
        • Adjust fluid rates as blood pressure stabilizes; observe for fluid overload
      • Repeat intramuscular epinephrine if initial dose is inadequate
        • May repeat dosage (typically once or twice) at 5- to 15-minute intervals 
      • Consider inhaled β-agonists (eg, albuterol) for bronchospasm not responding to intramuscular epinephrine 
        • Do not substitute for epinephrine; does not prevent or relieve laryngeal edema and upper airway obstruction, hypotension, or shock 
    • Optional therapies (second line medications)
      • H₁ antihistamines (eg, diphenhydramine, cetirizine) and H₂ antihistamines (eg, cimetidine) 
        • H₂ antihistamines, if used, are administered concurrently with H₁ antihistamines 
        • No direct evidence of effectiveness of antihistamines in anaphylaxis; not lifesaving 
      • Glucocorticoids
        • No role in acute management of anaphylaxis
          • Not lifesaving; consider only after administration of epinephrine
        • Theoretically prevent biphasic or protracted anaphylaxis; little or no effect on initial signs and symptoms 
          • No definitive evidence that use decreases risk of biphasic or prolonged reactions 
    • Refractory anaphylaxis
      • Defined as anaphylaxis that is unresponsive to treatment with at least 2 doses of minimum 300 mcg adrenaline; rare and often fatal 
      • Consider glucagon (especially for those on β-blockers) if symptoms not responding to epinephrine and fluid resuscitation 
        • Maintain airway protection; emesis and aspiration are possible adverse effects
      • Consider IV epinephrine infusion in a monitored setting if patient is not responding to injections 
        • Typically after 3 to 4 intramuscular injections 
      • Consider other vasopressors (eg, vasopressin, dopamine, norepinephrine) 
        • Have been used with success in anaphylaxis with refractory hypotension; controlled studies evaluating efficacy of these drugs in treatment of anaphylaxis are lacking 
      • Consider extracorporeal membrane oxygenation in patients with anaphylaxis who are unresponsive to traditional resuscitative efforts 
        • May bridge recovery in patients with life-threatening anaphylaxis, cardiovascular collapse, and cardiac arrest 
    • Consider methylene blue 
        • Use in anaphylaxis based on case reports and extrapolated from use in septic shock
          • Limitations include adverse events and interference with pulse oximetry
        • Some success has been shown in patients with distributive shock and profound vasodilation 
  • Determine duration of observation/patient disposition
    • Individualize based on severity and duration of anaphylactic event, response to therapy, patterns of previous reactions (eg, protracted, biphasic), medical comorbidities, access to medical care, and reliability 
    • Observe all patients in a setting capable of treating anaphylaxis at least until symptoms have fully resolved 
    • Observe patients aged 16 years or older for 6 to 12 hours from the onset of symptoms, depending on their response to treatment 
      • Admit children younger than 16 years to hospital
    • Patients with mild anaphylactic symptoms occurring in medical setting (eg, office-based allergy injection) or reactions that are controlled quickly and easily may be observed for a shorter period 
    • Biphasic reactions occur in up to 20% of patients, usually within 10 hours after resolution of symptoms 
      • Risk factors for biphasic anaphylaxis include:
        • Severe anaphylaxis
        • Need for more than 1 dose of epinephrine
        • Wide pulse pressure
        • Unknown anaphylaxis trigger
        • Cutaneous signs and symptoms
        • Medication-triggered anaphylaxis in children
      • Other predictors of biphasic response include severity at presentation, hypotension, laryngeal edema, chronic β-blocker use, and delayed or inadequate dose of epinephrine 
      • No current evidence that systemic glucocorticoids or antihistamines will prevent biphasic reactions but may be considered as secondary treatment 
      • Observe patients at risk of biphasic reaction for an extended period or admit to hospital
    • Other indications for an extended period of observation or hospital admission include: 
      • Risk factors for severe anaphylaxis (eg, asthma, cardiovascular disease, previous biphasic reactions)
      • Protracted anaphylactic event
      • Allergen exposure via ingestion
      • Pharyngeal edema or hypotension
  • Upon release from treatment 
    • Prescribe 2 doses of autoinjectable epinephrine to all patients after anaphylactic episode and to those at risk for severe anaphylaxis 
      • Provide clear instructions to patient and family on how and when to administer; demonstrate proper administration
      • 2 autoinjectors should be carried at all times (up to 30% of patients require greater than 1 dose) 
    • Consider prescriptions for oral antihistamines and glucocorticoids; not routinely needed 
      • Patients with complete resolution of symptoms after treatment with epinephrine do not need to be prescribed antihistamines or glucocorticoids afterward 
    • Refer all patients after an episode of anaphylaxis to allergy/immunology specialist to identify cause of episode, if not known, and for further evaluation 
      • Tests to establish cause of event include skin and in vitro tests for serum-specific IgE, serum IgE to galactose-α-1,3-galactose, baseline serum tryptase, 24-hour urine histamine metabolites, prostaglandin D₂, oral challenges, and occasionally bone marrow determination 
        • Skin tests or in vitro tests can determine presence of specific IgE antibodies to foods, medications (eg, penicillin, insulin), and stinging insects as cause of anaphylaxis 
          • Skin testing with venom is recommended for patients experiencing anaphylactic reaction to insect sting
            • Patients experiencing only large local reactions and children with only mild cutaneous systemic reactions to insect stings do not generally require testing 
        • Challenge procedures with suspected agents may be considered when tests for specific IgE antibodies are inconclusive 
      • The Joint Task Force on Practice Parameters (comprised of members from American Academy of Allergy, Asthma and Immunology; and the American College of Allergy, Asthma and Immunology) has published the following practice parameters:
        • Food allergy: a practice parameter update (2014) 
        • Drug allergy: an updated practice parameter (2010) 
        • Stinging insect hypersensitivity: a practice parameter update (2016) 

Drug therapy

  • Epinephrine
    • Administer epinephrine intramuscularly (anterolateral thigh) to all patients as soon as anaphylaxis is suspected 
      • Prevents or decreases upper airway mucosal edema, hypotension, and shock (vasoconstrictor effects); has bronchodilator and cardiac inotropic and chronotropic effects 
    • Intramuscular is preferred route of administration
      • Epinephrine absorption is rapid and complete if administered intramuscularly in the anterolateral aspect of the thigh; subcutaneous epinephrine is not routinely recommended owing to delayed absorption
    • Autoinjectable epinephrine (eg, EpiPen, EpiPen Jr, Adrenaclick auto-injectors)
      • Premeasured fixed doses are currently available in the following doses in the United States: 0.1 mg, 0.15 mg, and 0.3 mg 
        • Children weighing less than 15 kg
          • Epinephrine Solution for injection; Infants and Children weighing 7.5 to 14 kg: 0.1 mg/dose IM into the anterolateral aspect of the thigh. Patients should seek medical attention immediately after first injection. May repeat for severe persistent anaphylaxis; do not administer more than 2 sequential doses unless under direct medical supervision.
            • A 0.1 mg epinephrine autoinjector is now available for infant/child weighing 7.5 to 14 kg; previously, only the 0.15 mg epinephrine autoinjector was available and was frequently used in this age group
              • Given safety profile of epinephrine in children and the fact that underdosing may not provide adequate treatment, it was felt that a dose slightly above the ideal dose was preferable to giving a dose below the recommended dose
        • Infants and Children weighing 15 to 24 kg
          • Epinephrine Solution for injection; Infants and Children weighing 15 to 24 kg: 0.15 mg/dose IM into the anterolateral aspect of the thigh. Patients should seek medical attention immediately after first injection. May repeat every 5 to 20 minutes as needed; do not administer more than 2 sequential doses unless under direct medical supervision.
        • Patients of any age weighing 25 kg or more
          • Epinephrine Solution for injection; Children and Adolescents weighing 26 kg or more and Adults: 0.3 mg/dose IM into the anterolateral aspect of the thigh. Patients should seek medical attention immediately after first injection. May repeat every 5 to 20 minutes as needed; do not administer more than 2 sequential doses unless under direct medical supervision.
    • Intramuscular dosing
      • Epinephrine Hydrochloride Solution for injection; Infants and Children weighing 30 kg or less: 0.01 mg/kg/dose (0.01 mL/kg/dose of a 1 mg/mL solution) IM. Max: 0.3 mg/dose. May repeat every 5 to 15 minutes as needed for up to 3 injections; more frequent administration may be appropriate in certain circumstances.
      • Epinephrine Hydrochloride Solution for injection; Children and Adolescents weighing more than 30 kg: 0.01 mg/kg/dose (0.01 mL/kg/dose of a 1 mg/mL solution) IM. Max: 0.5 mg/dose. May repeat every 5 to 15 minutes as needed for up to 3 injections; more frequent administration may be appropriate in certain circumstances.
      • Epinephrine Hydrochloride Solution for injection; Adults: 0.3 to 0.5 mg IM; may be repeated if necessary, every 5 to 10 minutes.
    • Intermittent IV dosage
      • Epinephrine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.01 mg/kg/dose (0.1 mL/kg/dose of a 0.1 mg/mL solution) IV; may repeat every 3 to 5 minutes. Max: 1 mg/dose (10 mL/dose of a 0.1 mg/mL solution).
      • Epinephrine Hydrochloride Solution for injection; Adults: 0.1 to 0.25 mg (of a 0.1 mg/mL solution) IV may be required for severe reactions; may repeat every 5 to 15 minutes.
    • IV/intraosseous continuous infusion
      • Not first line treatment; consider if patient is not responding to doses of intramuscular epinephrine after 3 to 4 injections 
      • No established dosage or regimen for use in anaphylaxis; suggested dosages include:
        • Epinephrine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.1 to 1 mcg/kg/minute continuous IV infusion.
        • Epinephrine Hydrochloride Solution for injection; Adults: 1 to 4 mcg/minute continuous IV infusion.
  • β₂-adrenergic agonist:
    • Useful for bronchospasm in patients not responding to intramuscular epinephrine
      • Relieves reversible bronchospasm by relaxing smooth muscle of bronchi
        • Does not prevent or treat upper airway obstruction or laryngeal edema 
    • Usage and dosing in anaphylaxis are extrapolated from asthma treatment 
      • Albuterol
        • Albuterol Sulfate Nebulizer solution; Children weighing 15 kg or more: 2.5 mg via nebulizer every 15 minutes as needed. Usual Max: 4 doses/day.
        • Albuterol Sulfate Nebulizer solution; Adults and Adolescents: 2.5 to 5 mg via nebulizer every 15 minutes as needed. Usual Max: 4 doses/day.
  • Glucagon
    • Consider glucagon (especially for those on β-blockers) if symptoms do not respond to epinephrine and fluid resuscitation
      • Activates adenyl cyclase directly, bypassing β-adrenergic receptor, and can reverse refractory bronchospasm and hypotension. 
    • Suggested dosages:
      • Glucagon Hydrochloride Solution for injection; Infants and Children: 20 to 30 mcg/kg IV bolus over 5 minutes (Max: 1 mg/dose); followed by a continuous infusion of 5 to 15 mcg/minute IV, titrate to clinical effect. 
      • Glucagon Hydrochloride Solution for injection; Adults: Initially, 1 to 5 mg IV bolus over 5 minutes; followed by a continuous infusion of 5 to 15 mcg/minute IV, titrate to clinical effect.
  • Glucocorticoids 
    • No role in acute management of anaphylaxis
      • Oral administration can be considered in less acute situations, for patients who are able to tolerate oral medications.
    • Dosages extrapolated from use in asthma
      • Methylprednisolone
        • IV
          • Methylprednisolone Sodium Succinate Solution for injection; Infants, Children, and Adolescents: 1 to 2 mg/kg (Max: 125 mg) IV or IM load. Follow with 0.5 mg/kg/dose every 6 hours or 1 mg/kg/dose every 12 hours for 1 to 2 days. For anaphylaxis, given as adjunctive therapy after the administration of epinephrine. 
          • Methylprednisolone Sodium Succinate Solution for injection; Adults: 1 to 2 mg/kg/dose (Max: 125 mg/dose) IV for anaphylaxis. Follow with 0.5 mg/kg/dose every 6 hours or 1 mg/kg/dose every 12 hours for 1 to 2 days. For anaphylaxis, given as adjunctive therapy after the administration of epinephrine. For drug-induced angioedema failing to respond to epinephrine or H1-blockers, short courses of 40 to 125 mg/day IV can be given for the late phase of an acute reaction. FDA-approved general dosage: 10 to 40 mg IV infused over several minutes.
        • Oral
          • Methylprednisolone Oral tablet; Infants, Children, and Adolescents: 0.11 to 2 mg/kg/day PO in 1 to 4 divided doses is the general initial dose range. Similar dosing has been used IM or IV if needed.
          • Methylprednisolone Oral tablet; Adults: 4 to 48 mg/day PO, given in 4 divided doses; adjust dose to condition treated and patient response.
  • Antihistamines
    • Not indicated in acute treatment of anaphylaxis
    • Can relieve cutaneous symptoms (eg, itching, urticaria) not relieved by epinephrine 
      • Does not prevent or treat upper airway obstruction or hypotension
    • Usage and dosing in anaphylaxis are extrapolated from urticaria treatment 
      • H₁ antihistamines
        • Diphenhydramine
          • IV
            • Diphenhydramine Hydrochloride Solution for injection; Infants and Children: 1 to 2 mg/kg/dose (Max: 50 mg/dose) IV or IM every 4 to 8 hours as needed, up to 5 mg/kg/day (Max: 200 mg/day).
            • Diphenhydramine Hydrochloride Solution for injection; Adolescents: 25 to 50 mg/dose IV or IM every 4 to 6 hours as needed (Max: 400 mg/day).
            • Diphenhydramine Hydrochloride Solution for injection; Adults: 10 to 50 mg IV or IM every 4 to 6 hours, as needed. Single doses of 100 mg may be given if required. Max: 400 mg/day.
          • Oral
            • Diphenhydramine Hydrochloride Oral syrup; Infants, Children, and Adolescents: 1 to 1.5 mg/kg/dose (Max: 25 to 50 mg/dose) PO 3 to 4 times daily, up to 5 mg/kg/day (Max: 300 mg/day).
            • Diphenhydramine Hydrochloride Oral capsule; Adults: 25 to 50 mg PO 3 to 4 times per day, given every 4 to 6 hours, as needed. Max: 300 mg/day.
      • H₂ antihistamines
        • Cimetidine:
          • Cimetidine Hydrochloride Solution for injection; Adults: 300 mg IV with an H1-blocker.
        • Note: The FDA has requested manufacturers withdraw all prescription and OTC ranitidine drugs from the market owing to concerns regarding the contaminant N-Nitrosodimethylamine 
          • The FDA has advised that consumers taking OTC ranitidine stop taking any tablets or liquid they currently have, dispose of them properly, and not buy more; those who wish to continue treating their condition, they should consider using other approved OTC products 
          • Advise patients taking prescription ranitidine to speak with their health care professional about other treatment options before stopping the medicine, as there are multiple drugs approved for the same or similar uses as ranitidine 

Nondrug and supportive care

  • Educate patient and family about prevention, recognition, and treatment of anaphylaxis 
    • Avoidance measures are individualized; consider patient age, activity, occupation, hobbies, living situation, access to medical care, and level of personal anxiety 
    • Patient may reencounter inciting allergen (or have biphasic reaction after initial treatment)
      • Advise patients to seek emergency medical attention in conjunction with using autoinjectable epinephrine; these devices are not substitutes for medical attention 
    • Consider providing initial anaphylaxis action plan, including how and when to administer epinephrine (permanent plan typically completed by allergy specialist) 
      • Basic plan should be in simple, clear language and minimally include: 
        • Signs and symptoms of anaphylaxis
        • Patient’s known triggers
        • First and only medication to administer is epinephrine; administer regardless of severity of symptoms
        • A demonstration of the correct use of the epinephrine injector and when to use it
        • Call 911; notify family if appropriate
        • Information about the risk of a biphasic reaction
        • Information about the need for referral to a specialist allergy service and the referral process
        • Information about patient support groups
      • Anaphylaxis action plans are available online at various websites, including: 
        • American Academy of Pediatrics
        • American Academy of Allergy, Asthma, and Immunology 
        • Food Allergy Research and Education 

Special populations

  • Although overall treatment regimen remains unchanged, certain populations require additional considerations
    • Pregnant patients:
      • Anaphylaxis is uncommon in pregnancy, but potentially catastrophic because it can place mothers and infants at high risk for hypoxic-ischemic encephalopathy or death 
        • Supplemental oxygen and management of hypotension are critically important 
      • Potential symptoms and signs of anaphylaxis during pregnancy include itching in the vulvar/vaginal areas, low back pain, uterine cramps, fetal distress, and preterm labor 
      • Position pregnant patients supine on left side during treatment (prevent uterine compression of inferior vena cava) 
      • Fetal heart monitoring (continuous electronic monitoring, if possible) is recommended for patients with anaphylaxis who are at more than 24 weeks’ gestation 
      • Performing skin tests and challenge tests and initiating allergen immunotherapy are typically avoided owing to the associated small but definite risk of anaphylaxis 
      • Consider emergency cesarean delivery for anaphylaxis refractory to medical management or for persistent fetal distress 
    • Elderly patients:
      • Management of anaphylaxis can be complicated by coexisting cardiovascular disease and limited cardiac reserve and by concurrent use of medications (eg, β-adrenergic blockers) 
    • Patients taking β-adrenergic antagonists (orally or topically):
      • May experience more severe anaphylactic reactions characterized by paradoxical bradycardia, profound hypotension, and severe bronchospasm; these agents might impede effectiveness of treatment with epinephrine
      • Glucagon, with non–catecholamine-dependent inotropic and chronotropic cardiac effects, may be necessary in patients who have hypotension and bradycardia and who do not respond optimally to epinephrine 
  • Monitor all patients’ blood pressure, cardiac rate and function, respiratory status, and oxygenation 
  • Duration of monitoring should be individualized 
    • Patients with severe or protracted anaphylaxis might require monitoring and interventions for days 

Complications

  • Common complications include shock, respiratory failure, upper airway obstruction, cardiac arrest, and hypoxic-ischemic encephalopathy 
  • Overdose of epinephrine
    • Typically reported after IV epinephrine dosing but can occur by any route 
      • Owing to dosing error (eg, using incorrect solution concentration) and/or overly rapid IV infusion and bolus administration
      • Physician error, in confusing dose and route of initial treatment of anaphylaxis with the correct dose and routes of infusion for cardiac arrest and shock
    • Manifestations include ventricular arrhythmias, hypertensive crisis, and pulmonary edema 
  • Empty vena cava/empty ventricle syndrome
    • Can occur within seconds when patients with anaphylaxis suddenly assume or are placed in an upright position
    • Characterized by obstructed blood flow to the patient’s heart
    • High risk for sudden death; unlikely to respond to epinephrine regardless of route of administration, as it does not reach the heart and cannot be circulated throughout the body 

Prognosis

  • Overall prognosis is good; most patients respond favorably to aggressive medical management 
    • Majority of deaths caused by anaphylaxis are due to lack of or delay in epinephrine administration 
    • Risk of death is increased in those with preexisting conditions (eg, asthma)
  • Fatal anaphylaxis is rare, occurring in 0.25% to 0.33% of anaphylaxis hospitalizations or emergency department visits 

Screening and Prevention

Prevention

  • Educate patients about:
    • Recognition and avoidance of triggers, including hidden allergens and cross-reactivity between various allergens and drugs 
    • Use of medications that could worsen or complicate future anaphylactic events (eg, β-adrenergic blockers) 
    • Emergency management in event of exposure to trigger 
  • Prescribe autoinjectable epinephrine to be carried at all times by patients at risk of recurrence 
  • Encourage follow-up investigations, preferably by allergist or immunologist
    • Specific preventive therapies considered by specialist (eg, allergist-immunologist) can include:
      • Drug allergies
        • Short-term drug desensitization
          • Consider in patients who require causative drug that has no equally efficacious alternative 
            • Performed by physicians skilled in procedure in appropriate monitored setting
          • Procedures vary with individual drugs; can typically be accomplished within 4 to 12 hours 
        • Pharmacologic prophylaxis (eg, glucocorticoids, antihistamines)
          • May be recommended to prevent reactions to radiocontrast material
      • Insect stings
        • Allergen (ie, venom) immunotherapy
          • Recommend venom immunotherapy for patients with systemic sensitivity to flying Hymenoptera insects (80%-98% effective) 
      • Food allergies
        • Avoidance of food allergens remains the mainstay for long-term treatment of food-induced anaphylaxis 
          • Immunotherapeutic approaches (eg, oral immunotherapy) for treating food allergies remain investigational; inadequate evidence for therapeutic benefit over risks of therapy
  • Patients with a history of anaphylaxis should have: 
    • Personalized anaphylaxis emergency action plan
    • Medical identification, such as a bracelet or wallet card
    • Notification of allergy placed in the medical record

References

Cardona V et al: World allergy organization anaphylaxis guidance 2020. World Allergy Organ J. 13(10):100472, 2020

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