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 — the World Allergy Organization requires ≥3 IM doses or initiation of an IV epinephrine infusion,10 while perioperative (ISPAR) criteria use sustained inadequate response after 10 minutes despite 2-3 doses9 — 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.

Earn CE — Companion Course

Refractory Anaphylaxis in Acute Care: When First-Line Epi Isn't Enough

ACPE UAN 0683-0000-26-030-H01-P

View the Course

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
Mink 20044Animal RCT (canine anaphylactic shock model, n=12).Constant IV epinephrine infusion (vs. saline) rapidly reversed hypotension and improved cardiac output; established the pharmacologic rationale for IV infusion over repeated bolus in refractory anaphylactic shock.
Brown 20045Prospective observational study (n=68) in insect sting anaphylaxis.IV bolus epinephrine was associated with arrhythmias or hypertensive emergencies in 57% of bolus-treated cases.
Thomas 20057Case series + literature review (n=16 refractory anaphylaxis cases).IV epinephrine infusion rates of 1–10 mcg/min were adequate for hemodynamic restoration in most cases; reinforced the infusion-over-bolus principle.
Brown 20136Pooled prospective cohort (n=209 ED-treated anaphylaxis).Cardiovascular collapse was most predictive of mortality; up to 16% required ≥2 epinephrine doses and 2.3% met refractory criteria — RA is uncommon but high-risk.
Francuzik 20188European Anaphylaxis Registry (NORA) analysis (n≈9,900).Severe anaphylaxis is often undertreated — only 27.4% of severe cases received pre-hospital epinephrine; delayed escalation remains a systems problem.
Dribin 20233Perspective / clinical review (J Allergy Clin Immunol Pract).No RCT will ever prove epinephrine's mortality benefit (ethically unfeasible); argues for liberal epinephrine use in suspected anaphylaxis given overwhelming pathophysiologic and observational support.
Golden 20241AAAAI/ACAAI Joint Task Force Practice Parameter Update (Ann Allergy Asthma Immunol).First-line IM epinephrine 0.3–0.5 mg q5–15 min; refractory → IV epinephrine infusion + aggressive fluids; glucagon 1–5 mg IV for beta-blocker-mediated RA; methylene blue and ECLS reserved as rescue therapy after standard escalation fails.
Pouessel 20242International guideline synthesis.Guidelines align on IV epinephrine infusion and fluids; comparative data for second-line vasopressors are lacking; methylene blue and ECLS are rescue therapies (case-series evidence only).
Tacquard 20249International perioperative anaphylaxis work.Refractory anaphylaxis may occur in up to 12% of perioperative cases; norepinephrine is the most common second-line vasopressor; methylene blue and ECMO are used in <5% of cases, generally as rescue when standard escalation fails.

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 — methylene blue (1–2 mg/kg IV) and ECMO/ECLS — 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.

Methylene blue and ECMO/ECLS are rescue therapies. Methylene blue 1–2 mg/kg IV over 5–10 min; reserved for refractory vasoplegia or cardiovascular collapse despite maximal medical therapy. Evidence is limited to case series.

Earn CE — Companion Course

Refractory Anaphylaxis in Acute Care: When First-Line Epi Isn't Enough

ACPE UAN 0683-0000-26-030-H01-P

View the Course

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.
Tags: Anaphylaxis Epinephrine Emergency Medicine Critical Care Pharmacy Friday Pearls