Diagnosis and Management of Anaphylaxis in Adults

Diagnosis and Management of Anaphylaxis in AdultsDiagnosis and Management of Anaphylaxis in Adults

Diagnosis and Management of Anaphylaxis in Adults – Introduction

Anaphylaxis is a potentially life-threatening condition that requires prompt recognition and management. Widely speaking, it is an uncommon disorder that requires acute measurements to prevent complications, including death. Many cases are encountered in the out-of-hospital setting; therefore, first responders’ training is relevant to the appropriate initial approach to an individual with anaphylaxis. Several cases are encountered in the Emergency Department and during in-hospital procedures.

This article aims to explain the processes by which anaphylaxis develops and give an overview of the diagnosis and management of this critical problem.

Definition and relevant concepts (1)

Anaphylaxis: an acute, potentially life-threatening immunological overreaction to an allergen.

Antigen: a molecule that produces an immune reaction.

Allergen is an environmental molecule that can produce an immunological reaction, specifically, a type one hypersensitivity reaction. Potential human allergens: foods, such as peanuts, some vegetables, or seafood; Hymenoptera stings; plants; drugs, especially beta-lactam antibiotics and aspirin.

Urticaria: a milder form of anaphylaxis, in which mucosal, submucosal, and skin findings predominate.

Angioedema is the affection of small vessels due to the release of vasodilatory molecules induced by a specific molecule or substance characterized by mucosal or submucosal edema.

Allergy is a condition in which there is a history of immune response to an allergen.

Epidemiology

Estimations of the incidence of anaphylaxis are approximately 1.5 to 7.9 per 100,000 persons/year. (2) Approximately 0.3% of the population will suffer from anaphylaxis during their lifetime.

Data available on these aspects are controversial and could be misleading since many anaphylaxis episodes occur outside the hospital and could be underreported. The dissimilarities in data also account for the different definitions of anaphylaxis throughout the years. (3)

Case-fatality rates are estimated to be around 0.5-1% of cases. (3)

Biphasic reactions, a situation characterized by a relapse of simptomatology, account for 4.6% of cases, with a median onset time of 11 hours (0.2-72 hours). (4)

Risk factors for the production of biphasic reactions include: (3)

  • Increased severity of the initial reaction.
  • Increased requirement of epinephrine during the initial reaction or failure to respond to intramuscular adrenaline.
  • Hypotension in presentation.
  • Wide pulse pressure in presentation.

Pathophysiology and clinical presentation (5, 6)

There are several mechanisms currently identified that account for the physiopathological processes involved in anaphylactic reactions:

Immune-mediated processes

These mechanisms are well studied among the others. A genetically susceptible individual exposes to an allergen, primarily an environmental one. Allergens contact the skin or mucous membranes, where different sets of dendritic cells reside. These recognize the molecule that gives itself the allergenic nature, processes the involved antigen, and presents it to naïve TH-2 cells.

Once activated, TH-2 cells secrete cytokines, including IL-4, IL-5, and IL-8, and naïve B cells differentiate into plasma cells, inducing the release of Ig-E into the serum. The latter attaches to the FcεRI receptor on mast cells, ready for a subsequent encounter with the antigenic molecule.

On reexposure, the allergen is now bound to the Ig-E-FcεRI complex, which induces dimerization of the receptors (a tyrosine-kinase receptor), inducing increased intracellular calcium concentration and producing the release of mast cell granules.

Substances released by mastoid cells and substances participating in anaphylactic reactions include:

  • Histamine: acts on H1 and H2 receptors producing skin and mucosal manifestations of anaphylaxis, including erythema, urticaria, vasodilation, and edema.
  • Tryptase physiology is not well defined but is a known biomarker of mast cell activity.
  • Prostaglandins act on endothelial cells, promoting vasodilation.
  • Leukotrienes induce inflammatory responses, including chemotaxis of eosinophils and neutrophils.
  • Platelet Activating Factor (PAF)
  • Interleukins induce the recruitment of inflammatory cells, including eosinophils and neutrophils.
  • Chymase.
  • Tumor necrosis factor.
  • Heparin.

The explained process produces several clinical manifestations, which account for the theory that mast cells are central and essential in developing this clinical picture.

Skin manifestations include erythema, pruritus, and urticaria-like lesions.

Subcutaneous and submucosal blood vessels undergo vasodilation, producing edema, diarrhea, conjunctivitis, and rhinorrhea. Laryngeal mucosal edema accounts for one of the life-threatening complications of angioedema: acute respiratory obstruction and consequent respiratory failure.

Activation of cardiac histamine receptors and peripheral vasodilation may induce cardiac arrhythmias, along with circulatory collapse and cardiac arrest.

Prostaglandins and leukotrienes induce smooth muscle contraction; in the bronchi, constriction leads to bronchospasm, further impeding normal ventilatory function.

A secondary reaction not mediated by the allergen may be present; this is a biphasic allergic reaction responsible for the late deterioration of patients suffering from anaphylaxis. The consequent reaction has been described to happen between 2-72 hours after the first reaction.

Non-immune-mediated processes

Research has recently demonstrated that not all patients with anaphylactic reactions have evidence of IgE-mediated mast cell activation. Therefore, studies have yielded other possible factors contributing to this life-threatening condition. IgG-related mast cell activation and a G protein receptor- (MRGPRX2) mediated mast cell activation have been described.

Non-mast cell-mediated processes

There are a few cases of patients in which none of the aforementioned processes are involved in producing anaphylaxis. For instance, anaphylactic reactions induced by exercise or exposure to heat have been described.

Diagnosis and management

Anaphylaxis is a medical emergency. Prompt recognition of signs and symptoms and a history of exposure to known allergens are usually conclusive.

Patients present with several to all the symptoms mentioned in the previous section. A complete history is necessarily delayed in these cases because the patient’s critical care is urgent.

Fig 1. Clinical criteria for diagnosing anaphylaxis (7)

Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:

  • 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both AND AT LEAST ONE OF THE FOLLOWING:
    • a. Respiratory compromise.
    • b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction.
  • 2. Two or more of the following that occurs rapidly after exposure to a likely allergen for that patient (minutes to several hours):
    • a. Involvement of the skin–mucosal tissue.
    • b. Respiratory compromise.
    • c. Reduced blood pressure or associated symptoms.
    • d. Persistent gastrointestinal symptoms.
  • 3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several hours):
    • b. Adults: systolic BP of <90 mmHg or >30% decrease from that person’s baseline.

The mainstay of treatment starts from the ABC approach.

  • Airway management is the first problem to address. Patients with anaphylaxis are usually affected by laryngeal edema due to angioedema. An experienced physician should perform a rapid-sequence intubation (intubation in a patient with laryngeal edema is considered a difficult airway) if indicated.
  • Breathing: deliver oxygen with a non-rebreather mask and attain a 94% oxygen saturation for non-intubated patients.
  • Circulation: after laryngeal edema, circulatory collapse due to widespread vasodilation is a possible cause of death. Attach a cardiac monitor. Hemodynamic stability can be achieved with the first-line pharmacological treatment: (1, 7, 8)
    • IV normal saline for volume expansion in cases of hypotension.
    • Adrenaline: (usually administered immediately after anaphylaxis is recognized) 0.5 mg of adrenaline is given as an intramuscular injection to the lateral thigh. It may be repeated if there is poor or no response in 3-5 minutes. Repeat 3-5 times.
    • Adrenaline infusion: 1 microgram·kg-1·min-1, titrate to clinical effect
      Bolus: 50–100 microgram·min-1

Remove the inciting allergen suspected to produce anaphylaxis if present. Raise the patient’s legs in dorsal decubitus to augment venous return.

Secondary pharmacological treatment:

Administering these series of drugs should not delay first-line treatment and should always proceed with the restoration of hemodynamic stability. (1,7)

  • Hydrocortisone 200mg IV. Especially for bronchospasm. It is believed that corticosteroids participate in the prevention of the second phase of anaphylaxis.
  • Difenhydramine 25-50 mg IV. H1 receptor inhibitor, useful for histamine-related symptoms.
  • Famotidine PO or IV 20 mg BID: plays a role in inhibiting H2 histamine receptors. It is believed to produce synergy with H1 receptor blockers.
  • Albuterol 90 mcg two inhalations: treatment for bronchospasm.
  • Glucagon 1-5 mg IV if suspected refractory case due to beta-blocker use.

A routine lab panel should be ordered to completely assess patients’ clinical status. Tryptase, if available, is helpful in the diagnosis of anaphylaxis. Measurements should be performed from 1-2 hours after onset, along with a baseline one at 24 hours after the episode. (1, 7, 9, 10)

Diferential Diagnosis (7, 10)

(This list is not extensive)

Anaphylaxis may mimic some other syndromes or overlap with them. Consider some of them as a spectrum of syndromes related to skin and mucosal, respiratory, cardiac, immunologic, and gastrointestinal conditions:

  • Hereditary angioedema: primarily edema of the face, and mucous membranes, including laryngeal edema. Family history in approximately half of the patients. Usually no skin findings.
  • Urticaria: Skin and mucous membranes symptoms predominate. It is not characterized by laryngeal edema. If the latter develops, then it is considered an anaphylactic reaction.
  • Septic shock: some etiologies of septic shock may present with skin findings and altered mental status. For instance: septic shock due to meningococcal meningitis.
  • Cardiogenic shock: signs and symptoms of heart failure along with hemodynamic instability.
  • Cardiac arrhythmias: especially if presenting with unstable arrhythmias.
  • Status asthmaticus: mainly respiratory symptoms and history of asthma. Circulatory collapse may be present.
  • Endocrinological disorders: hypoglycemia, carcinoid syndrome, and pheochromocytoma may present with several similar features.

Disposition (7, 9, 11, 12)

  • Patients requiring mechanical ventilation, or those with refractory hemodynamic instability, must be transferred to the Intensive Care Unit (ICU).
  • Any patient treated with adrenaline must be monitored for cardiac arrhythmias. If hemodynamic stability is present, inpatient monitoring for 6-12 hours due to the risk of second phase reaction is paramount.
  • Patients who presented with anaphylactic shock should be monitored for 12-24 hours.
  • Appropriate assessment of the risk of biphasic reaction according to the patient’s risk factors.
  • Consideration of auto-injectable epinephrine solutions and education about signs and symptoms of anaphylactic reactions, as well as instructions to return to the emergency department.
  • Education to patient’s relatives.
  • Referral to an allergy specialist for further investigation and assessment.
  • Avoidance of suspected allergens until further investigation by the allergy-specialty team.
  • Written instructions and plan of action.

Complications (1, 13, 14, 15)

  • Asphyxia.
  • Respiratory failure.
  • Cardiac arrest.
  • Myocardial infarction.
  • Cardiac arrhythmias.
  • A biphasic anaphylactic reaction.
  • Complications from intubation and ventilation.
  • Drug adverse reactions.

Prevention of contrast media-related anaphylaxis. (16)

  • Pre-treatment with corticosteroids previously to a procedure using contrast agents is controversial. Some guidelines recommend the use of corticosteroids 4-12 hours previous to the procedure if the patient has a known history of hypersensitivity reactions.
  • Local hospital policies should be followed in this regard.

Disclosures:

The author does not report any conflict of interest.

Disclaimer:

This information is for educational purposes and is not intended to treat disease or supplant professional medical judgment. Physicians should follow local policy regarding the diagnosis and management of medical conditions.

References:

  1. Gaudio FG, Johnson DE, DiLorenzo K, Anderson A, Musi M, Schimelpfenig T, Leemon D, Blair-Smith C, Lemery J. Wilderness Medical Society Clinical Practice Guidelines on Anaphylaxis. Wilderness & Environmental Medicine. 2022 Feb 2.
  2. Tanno LK, Bierrenbach AL, Simons F, Cardona V, Thong BY, Molinari N, Calderon MA, Worm M, Chang YS, Papadopoulos NG, Casale T. Critical view of anaphylaxis epidemiology: open questions and new perspectives. Allergy, Asthma & Clinical Immunology. 2018 Dec;14(1):1-1.
  3. Turner PJ, Campbell DE, Motosue MS, Campbell RL. Global trends in anaphylaxis epidemiology and clinical implications. The Journal of Allergy and Clinical Immunology: In Practice. 2020 Apr 1;8(4):1169-76.
  4. Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of onset and predictors of biphasic anaphylactic reactions: a systematic review and meta-analysis. The Journal of Allergy and Clinical Immunology: In Practice. 2015 May 1;3(3):408-16.
  5. Kumar, V., Abbas, A.K. and Aster, JC Robbins & Cotran Pathologic Basis of Disease. 9th Edition, Elsevier, Philadelphia. 2015; p. 201-205.
  6. Fowler J, Lieberman P. Pathophysiology of immunologic and nonimmunologic systemic reactions including anaphylaxis. Immunology and Allergy Clinics. 2022 Feb 1;42(1):27-43.
  7. Muraro A, Worm M, Alviani C, Cardona V, DunnGalvin A, Garvey LH, Riggioni C, de Silva D, Angier E, Arasi S, Bellou A. EAACI guidelines: Anaphylaxis (2021 update). Allergy. 2022 Feb;77(2):357-77.
  8. Sheikh A, Shehata YA, Brown SG, Simons FE. Adrenaline (epinephrine) for the treatment of anaphylaxis with and without shock. Cochrane Database of Systematic Reviews. 2008(4).
  9. Centre for Clinical Practice at NICE (UK). Anaphylaxis: Assessment to Confirm an Anaphylactic Episode and the Decision to Refer After Emergency Treatment for a Suspected Anaphylactic Episode. Manchester (UK): National Institute for Health and Clinical Excellence (UK); 2011 Dec. (NICE Clinical Guidelines, No. 134.) 3, Evidence review and recommendations. [Available from: https://www.ncbi.nlm.nih.gov/books/NBK327278/] [cited: September 29th, 2022]
  10. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Rivas MF, Fineman S, Geller M, Gonzalez-Estrada A, Greenberger PA, Borges MS, Senna G. World allergy organization anaphylaxis guidance 2020. World allergy organization journal. 2020 Oct 1;13(10):100472.
  11. Kim TH, Yoon SH, Hong H, Kang HR, Cho SH, Lee SY. Duration of observation for detecting a biphasic reaction in anaphylaxis: a meta-analysis. International Archives of Allergy and Immunology. 2019;179(1):31-6.
  12. Campbell RL, Kelso JM. Anaphylaxis: emergency treatment. Up to Date. [Available from: http://www. uptodate. com/contents/anaphylaxis-emergency-treatment] [cited: September 29th, 2022]
  13. Campbell RL, Bellolio MF, Knutson BD, Bellamkonda VR, Fedko MG, Nestler DM, Hess EP. Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. The Journal of Allergy and Clinical Immunology: In Practice. 2015 Jan 1;3(1):76-80.
  14. Tan PZ, Chew NW, Tay SH, Chang P. The allergic myocardial infarction dilemma: is it the anaphylaxis or the epinephrine?. Journal of Thrombosis and Thrombolysis. 2021 Oct;52(3):941-8.
  15. Krishnaswamy G. Critical care management of the patient with anaphylaxis: a Concise definitive review. Critical Care Medicine. 2021 Feb 12;49(5):838-57.
  16. Kang HR, Jeong J, Brockow K. Diagnosis and Prevention of Hypersensitivity Reactions to Iodinated Contrast Media. Allergy, Asthma & Immunology Research. 2022 Jul;14(4):348.

See Also

Acute Uncomplicated Pyelonephritis in Adults

Initial Management of Hip Fractures in Adults

Community Acquired Pneumonia in Adults

About the Author

Franco Cuevas, MD
Franco Cuevas is a physician who graduated from the National University of Córdoba, Argentina. He practices general medicine in the Emergency Department at Sanatorio de la Cañada, Córdoba. His focus is on writing medical content to improve physicians' access to relevant medical information for daily practice. He has participated in some research projects and has a special joy in teaching and writing about medical concepts.

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