Introduction

Anaphylaxis is a severe, potentially life-threatening systemic hypersensitivity reaction. First-line therapy remains IM epinephrine 0.3-0.5 mg in the anterolateral mid-thigh, repeated every 5-15 minutes as needed.1

Refractory anaphylaxis is persistent symptoms or hemodynamic instability despite 2-3 appropriate IM epinephrine doses and adequate fluid resuscitation. Definitions vary, but the practical bedside signal is the same: repeated IM doses are no longer enough.

Key Points

  • Escalate to IV epinephrine infusion when shock persists after repeated IM epinephrine and fluids.
  • Aggressive crystalloid resuscitation is essential and commonly under-administered.
  • Avoid IV epinephrine bolus outside cardiac arrest because severe hypertension and arrhythmias are well described.
  • Use glucagon for beta-blocker-mediated refractory anaphylaxis; use norepinephrine or vasopressin when vasopressor support is still needed.

Pharmacology

AgentRoleAdult Dose
EpinephrinePrimary refractory strategy. Alpha-1 vasoconstriction, beta-1 inotropy/chronotropy, beta-2 bronchodilation and mast-cell stabilization.IM 0.3-0.5 mg q5-15 min initially. IV infusion 0.05-0.5 mcg/kg/min titrated to MAP and clinical response.
GlucagonAdjunct for patients on beta-blockers with inadequate epinephrine response; bypasses beta-receptor blockade through adenylyl cyclase activation.1-5 mg IV over 5 min, then 5-15 mcg/min infusion. Pretreat nausea/vomiting when feasible.
NorepinephrineMost commonly used second-line vasopressor when epinephrine infusion and fluids do not restore perfusion.0.05-1 mcg/kg/min, titrated to MAP. Central access preferred, but do not delay in extremis.
VasopressinAlternative/add-on for vasoplegic shock when catecholamine response remains inadequate.0.01-0.04 units/min.

Clinical Pearl

The key switch is not from IM epinephrine to IV epinephrine bolus. It is from repeated IM epinephrine to a carefully titrated IV epinephrine infusion with aggressive fluids.

Key Evidence

SourceEvidence TypePractical Takeaway
Brown 20045Prospective observational study in insect sting anaphylaxis.IV bolus epinephrine was associated with arrhythmias or hypertensive emergencies in 57% of bolus-treated cases.
Francuzik 20188European registry/case-report review.Severe anaphylaxis is often undertreated with epinephrine; delayed escalation remains a systems problem.
Tacquard 20249International perioperative anaphylaxis work.Refractory anaphylaxis may occur in up to 12% of perioperative cases; norepinephrine is commonly added second line.
Pouessel 20242International guideline synthesis.Guidelines align on IV epinephrine infusion and fluids; comparative data for second-line vasopressors are lacking.

Escalation Plan

Step 1

Confirm repeated IM epinephrine, airway/oxygen support, trigger removal, and rapid crystalloid resuscitation.

Step 2

Start IV epinephrine infusion 0.05-0.5 mcg/kg/min and titrate to perfusion, MAP, and respiratory response.

Step 3

Add glucagon for beta-blocker-mediated shock, norepinephrine or vasopressin for persistent vasoplegia, and rescue therapies only after standard escalation fails.

Pharmacist checkpoint

Prepare infusion concentrations early, clarify weight-based dosing, flag beta-blocker exposure, watch potassium/glucose/lactate, and keep sodium bicarbonate away from catecholamine Y-sites.

Clinical Conclusions

IV epinephrine infusion is the cornerstone. Refractory anaphylaxis should trigger infusion escalation rather than endless repeated IM dosing.

Avoid IV epinephrine bolus outside cardiac arrest. Observational data show high rates of serious cardiovascular adverse events with bolus dosing.

Glucagon is targeted, not routine. Reserve it for suspected beta-blocker-mediated refractory anaphylaxis and anticipate vomiting and hyperglycemia.

Second-line vasopressor choice is evidence-limited. Norepinephrine is commonly used; vasopressin, methylene blue, and ECMO/ECLS are selected for refractory vasoplegia or cardiovascular collapse.

Full Reference List

  1. Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: A 2023 practice parameter update. Ann Allergy Asthma Immunol. 2024;132(2):124-176.
  2. Pouessel G, Dribin TE, Tacquard C, et al. Management of Refractory Anaphylaxis: An Overview of Current Guidelines. Clin Exp Allergy. 2024;54(7):470-488.
  3. Dribin TE, Waserman S, Turner PJ. Who Needs Epinephrine? Anaphylaxis, Autoinjectors, and Parachutes. J Allergy Clin Immunol Pract. 2023;11(4):1036-1046.
  4. Mink SN, Simons FER, Simons KJ, Becker AB, Duke K. Constant infusion of epinephrine, but not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs. Crit Care Med. 2004;32(11):2340-2348.
  5. Brown SGA, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. J Allergy Clin Immunol. 2004;114(5):1044-1052.
  6. Brown SGA, Stone SF, Fatovich DM, et al. Anaphylaxis: clinical patterns, mediator release, and severity. J Allergy Clin Immunol. 2013;132(5):1141-1149.
  7. Thomas M, Crawford I. Best evidence topic report: glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Resuscitation. 2005;65(3):311-313.
  8. Francuzik W, Dolle S, Worm M. Risk factors and treatment of refractory anaphylaxis: a review of case reports. Allergy. 2018;73(5):1109-1112.
  9. Tacquard C, Iba T, Levy JH, et al. Refractory anaphylaxis: definition and management. Br J Anaesth. 2024;132(6):1217-1223.
  10. Cardona V, Ansotegui IJ, Ebisawa M, et al. World Allergy Organization Anaphylaxis Guidance 2020. World Allergy Organ J. 2020;13(10):100472.
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