Anaphylaxis: A Comprehensive Clinical Protocol for Emergency Management

Dr Neeraj Manikath , claude.ai

Abstract

Anaphylaxis represents one of the most critical medical emergencies encountered in clinical practice, demanding immediate recognition and intervention. Despite its well-established treatment paradigm, diagnostic delays and management errors continue to result in preventable morbidity and mortality. This review provides an evidence-based, practical approach to anaphylaxis management, emphasizing rapid recognition, appropriate use of epinephrine, and systematic post-event care. We present clinical pearls derived from contemporary evidence and expert consensus to enhance the diagnostic acumen and therapeutic decision-making of internists managing this life-threatening condition.

Introduction

Anaphylaxis is a severe, potentially fatal systemic hypersensitivity reaction characterized by rapid onset and multi-system involvement. The global incidence ranges from 50 to 200 episodes per 100,000 person-years, with mortality rates between 0.05% and 0.51% in population-based studies. Despite the availability of effective treatment, case fatality rates remain significant, largely attributable to delayed recognition, hesitation in epinephrine administration, and inadequate follow-up care.

The pathophysiology involves rapid mast cell and basophil degranulation, releasing mediators including histamine, tryptase, leukotrienes, and prostaglandins. These mediators precipitate vasodilation, increased vascular permeability, bronchoconstriction, and mucus hypersecretion, culminating in the clinical syndrome we recognize as anaphylaxis.

Clinical Recognition: The Diagnostic Challenge

Diagnostic Criteria

The World Allergy Organization and the National Institute of Allergy and Infectious Diseases have established clinical criteria for anaphylaxis diagnosis. Anaphylaxis is highly likely when any one of three criteria is fulfilled:

Criterion 1: Acute onset (minutes to several hours) with involvement of skin, mucosal tissue, or both, AND at least one of the following: respiratory compromise or reduced blood pressure with end-organ dysfunction.

Criterion 2: Two or more of the following occurring rapidly after exposure to a likely allergen: involvement of skin-mucosal tissue, respiratory compromise, reduced blood pressure or associated symptoms, or persistent gastrointestinal symptoms.

Criterion 3: Reduced blood pressure after exposure to a known allergen for that patient (infants/children: low systolic BP or greater than 30% decrease; adults: systolic BP less than 90 mmHg or greater than 30% decrease from baseline).

Clinical Pearl: The "Too Sick to Be Allergic" Phenomenon

A critical diagnostic pitfall occurs when patients present with profound cardiovascular collapse without prominent cutaneous manifestations. Up to 20% of anaphylaxis cases lack skin findings, particularly in cardiovascular-predominant anaphylaxis. Severe hypotension or cardiac arrest may represent the sole presenting feature, especially with intravenous drug administration or Hymenoptera stings. The absence of urticaria should never exclude anaphylaxis in the appropriate clinical context.

Oyster: Biphasic Reactions

Biphasic anaphylaxis occurs in 3% to 20% of cases, with symptom recurrence typically within 8 to 10 hours, though cases up to 72 hours post-initial reaction have been documented. Risk factors include severe initial presentations requiring multiple epinephrine doses, delayed initial epinephrine administration (greater than 30 minutes from symptom onset), and prior biphasic reactions. This phenomenon mandates appropriate observation periods and patient education regarding warning signs.

Immediate Management Protocol

Step 1: Recognition and Assessment (0-2 minutes)

Rapid systematic assessment follows the ABCDE approach:

Airway: Assess patency, listen for stridor, evaluate for angioedema
Breathing: Auscultate for wheezing, measure respiratory rate and oxygen saturation
Circulation: Assess pulse, blood pressure, capillary refill, mental status
Disability: Evaluate consciousness level using AVPU or GCS
Exposure: Examine skin for urticaria, angioedema, or flushing

Simultaneously, activate emergency response systems and call for assistance.

Step 2: Epinephrine Administration (2-3 minutes)

Intramuscular epinephrine represents the definitive first-line treatment and should be administered without delay. The anterolateral thigh (vastus lateralis muscle) provides the optimal injection site, achieving peak plasma concentrations within 8 minutes compared to 34 minutes with subcutaneous administration.

Dosing:

Adults: 0.3-0.5 mg (0.3-0.5 mL of 1:1000 solution)
Children: 0.01 mg/kg (maximum 0.3 mg for pre-pubertal children, 0.5 mg for adolescents)

Clinical Hack: Use the "thigh-high" rule—epinephrine auto-injectors should be administered to the mid-outer thigh, even through clothing if necessary. The needle length of standard auto-injectors (15.2 mm for EpiPen) penetrates adequately through most clothing materials.

Repeat doses may be administered every 5 to 15 minutes based on clinical response. Approximately 20% of patients require two or more doses. Refractory cases may necessitate continuous epinephrine infusion.

Clinical Pearl: Overcoming Epinephrine Hesitancy

Physician hesitancy in epinephrine administration contributes significantly to adverse outcomes. No absolute contraindications exist for epinephrine in anaphylaxis. While concerns about cardiovascular effects in elderly patients or those with coronary disease persist, the risk-benefit analysis overwhelmingly favors epinephrine use—the mortality risk from untreated anaphylaxis far exceeds any theoretical cardiovascular risk. Myocardial infarction from anaphylaxis-induced hypotension (Kounis syndrome) poses greater danger than epinephrine-related cardiac effects.

Step 3: Positioning and Oxygen (Simultaneous with Step 2)

Position the patient supine with legs elevated (modified Trendelenburg), unless contraindicated by respiratory distress or vomiting. Sudden postural changes in anaphylaxis have precipitated fatal outcomes, likely due to empty ventricle syndrome. Patients with respiratory distress may be positioned sitting upright.

Administer high-flow oxygen (10-15 L/min via non-rebreather mask) targeting oxygen saturation greater than 95%.

Step 4: Intravenous Access and Fluid Resuscitation (3-5 minutes)

Establish large-bore intravenous access. Aggressive fluid resuscitation addresses the distributive shock physiology of anaphylaxis. Up to 35% of circulating volume may extravasate into interstitial spaces within minutes.

Fluid Protocol:

Adults: Rapid bolus of 1-2 liters crystalloid (normal saline or Ringer's lactate) in first 5-10 minutes
Children: 20 mL/kg bolus, repeatable to maximum 60 mL/kg in first hour

Monitor for fluid overload, particularly in elderly patients or those with cardiac comorbidities.

Step 5: Adjunctive Medications (5-10 minutes)

These medications are adjuncts to—not replacements for—epinephrine:

H1 Antihistamines:

Diphenhydramine 25-50 mg IV/IM (1 mg/kg in children, maximum 50 mg)
Alleviates cutaneous symptoms but does not prevent progression

H2 Antihistamines:

Ranitidine 50 mg IV or famotidine 20 mg IV
Theoretical benefit from dual histamine receptor blockade

Corticosteroids:

Methylprednisolone 1-2 mg/kg IV or hydrocortisone 200 mg IV
May reduce biphasic reactions, though evidence remains controversial
Onset of action 4-6 hours; no benefit in acute phase

Bronchodilators:

Albuterol nebulization (2.5-5 mg) for persistent bronchospasm
Ipratropium bromide may be added for refractory cases

Oyster: The Beta-Blocker Conundrum

Patients receiving beta-adrenergic antagonists present unique challenges. Beta-blockade may render patients resistant to epinephrine and predispose to paradoxical responses. These patients may require:

Higher or more frequent epinephrine doses
Glucagon 1-5 mg IV over 5 minutes (acts independently of beta-receptors), followed by infusion of 5-15 mcg/minute
Consideration of alternative vasopressors (vasopressin, norepinephrine) in refractory cases

Special Scenarios and Refractory Anaphylaxis

Refractory Anaphylaxis

Defined as poor response to two appropriate epinephrine doses, refractory anaphylaxis occurs in 5% of cases. Management escalation includes:

Continuous epinephrine infusion: 0.1 mcg/kg/min, titrated to effect (typically 1-10 mcg/min in adults)
Alternative vasopressors: Norepinephrine, vasopressin, or methylene blue in documented refractory cases
Airway management: Early intubation for severe angioedema or respiratory failure. Recognize that intubation itself may be extremely difficult due to laryngeal edema—prepare for surgical airway.
Extracorporeal support: Case reports document successful use of ECMO in cardiac arrest from anaphylaxis unresponsive to conventional therapy

Clinical Hack: The Epinephrine Infusion Calculation

For continuous epinephrine infusion, use this simplified calculation:

Mix 1 mg epinephrine in 100 mL normal saline (10 mcg/mL concentration)
Infusion rate (mL/hr) = desired dose (mcg/min) × 6
Example: For 5 mcg/min, run infusion at 30 mL/hr

Perioperative Anaphylaxis

Neuromuscular blocking agents cause 60% of perioperative anaphylaxis cases, followed by latex and antibiotics. Tryptase levels should be measured at symptom onset, 1-2 hours post-reaction, and at baseline (greater than 24 hours later) to confirm mast cell activation. This triad enhances diagnostic certainty and guides subsequent allergy referral.

Post-Acute Management

Observation Period

Minimum observation duration remains controversial. Current recommendations suggest:

Standard cases: 4-8 hours post-symptom resolution
Severe reactions requiring multiple epinephrine doses: 8-24 hours
Patients with asthma, remote healthcare settings, or previous biphasic reactions: Extended observation or admission

Clinical Pearl: Discharge Criteria

Safe discharge requires all of the following:

Complete symptom resolution for minimum 4 hours
Normal vital signs for minimum 2 hours
Adequate response to initial treatment without requirement for continuous interventions
Access to emergency care within 30 minutes
Prescription for epinephrine auto-injector with demonstration of proper use
Clear written action plan provided

Epinephrine Auto-Injector Prescription

All patients experiencing anaphylaxis require epinephrine auto-injector prescription. Prescribe two devices (one backup) with clear instructions:

EpiPen/EpiPen Jr (0.3 mg/0.15 mg)
Auvi-Q (0.3 mg/0.15 mg)
Generic alternatives

Demonstrate proper technique: remove from carrier tube, place orange tip against mid-outer thigh, push down firmly until click heard, hold for 3 seconds, massage injection site for 10 seconds.

Allergy/Immunology Referral

Universal referral to allergy/immunology services is recommended for:

Allergen identification through skin or serum-specific IgE testing
Assessment for venom immunotherapy (Hymenoptera anaphylaxis)
Drug allergy evaluation and potential desensitization protocols
Development of comprehensive avoidance strategies
Consideration of omalizumab for idiopathic anaphylaxis

Long-term Management Pearls

Medic Alert Identification

Patients with identified triggers should wear medical identification jewelry indicating specific allergens and epinephrine auto-injector availability.

Anaphylaxis Action Plan

Provide written, personalized action plans including:

Trigger identification and avoidance strategies
Early warning symptom recognition
Step-by-step epinephrine administration instructions
Emergency contact information
Healthcare provider contact details

Oyster: Mastocytosis and Clonal Mast Cell Disorders

Elevated baseline tryptase (greater than 20 ng/mL) suggests underlying clonal mast cell disorders. These patients experience more severe anaphylaxis and require specialized evaluation. Consider bone marrow biopsy for definitive diagnosis in appropriate cases. These patients may benefit from prophylactic H1/H2 antihistamine therapy and consideration of omalizumab.

Common Errors in Anaphylaxis Management

Delaying epinephrine administration: The single greatest predictor of mortality. Fatal anaphylaxis cases consistently demonstrate delayed or absent epinephrine use.
Inappropriate patient positioning: Sudden upright positioning has precipitated cardiac arrest through empty ventricle syndrome.
Substituting antihistamines for epinephrine: Antihistamines are adjunctive only and cannot prevent cardiovascular collapse.
Discharging patients without epinephrine auto-injectors: Biphasic reactions necessitate patient preparedness for symptom recurrence.
Failure to refer to allergy services: Comprehensive evaluation identifies triggers and prevents recurrence.

Conclusion

Anaphylaxis management demands rapid recognition, immediate epinephrine administration, and systematic supportive care. While the treatment protocol appears straightforward, execution under time pressure requires practiced efficiency and overcoming therapeutic inertia. The internist's role extends beyond acute management to encompass comprehensive discharge planning, patient education, and coordination with allergy specialists for long-term preventive strategies.

The principles outlined in this protocol—early recognition, unhesitating epinephrine use, aggressive supportive care, and thorough follow-up—form the foundation for optimal patient outcomes in this medical emergency. Mastery of these principles, combined with the clinical pearls and awareness of potential pitfalls presented here, will enhance the clinician's capability to navigate this critical condition successfully.

Key Teaching Points:

Epinephrine is the only definitive treatment—administer immediately without hesitation
Absence of cutaneous findings does not exclude anaphylaxis
Patient positioning matters—avoid sudden upright positioning
All patients require discharge epinephrine auto-injectors
Universal allergy referral for trigger identification and prevention

References (Selected key references for a comprehensive review):

Simons FE, et al. World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis. WAO Journal. 2011;4(2):13-37.
Campbell RL, et al. Anaphylaxis: Emergency Treatment. UpToDate. 2024.
Lieberman P, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126(3):477-480.
Shaker MS, et al. Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123.
Turner PJ, et al. Fatal Anaphylaxis: Mortality Rate and Risk Factors. J Allergy Clin Immunol Pract. 2017;5(5):1169-1178.
Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med. 2016;54(10):1545-1559.
Muraro A, et al. EAACI guidelines: Anaphylaxis (2021 update). Allergy. 2022;77(2):357-377.

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