Introduction

Anaphylaxis is a life-threatening, IgE-mediated allergic reaction most commonly triggered by medications, foods, and stinging insects.1,2 Symptoms occur rapidly, within minutes up to as late as 1 hour, and can involve urticaria, angioedema, dyspnea, hypotension, nausea/vomiting, and abdominal pain among many other reactions.2,4

Some patients experience biphasic anaphylaxis, which is recurrent anaphylaxis that occurs an average of 10 hours (1 to 72 hours) after the resolution of the initial episode. Mechanisms of biphasic anaphylaxis are poorly understood.1,9

Key Points on Anaphylaxis

  • Anaphylaxis is IgE-mediated and most commonly triggered by medications, foods, and stinging insects1
  • Symptoms occur within minutes up to as late as 1 hour, with urticaria, angioedema, dyspnea, hypotension, and GI involvement2
  • Biphasic anaphylaxis recurs an average of 10 hours (range 1 to 72 hours) after the initial episode resolves1
  • Epinephrine is first-line; glucocorticoids and antihistamines are adjuncts and should never delay epinephrine

Pharmacology

Epinephrine First-line for uniphasic and biphasic anaphylaxis
Parameter Details
Role in Therapy
First-line therapy for uniphasic and biphasic anaphylaxis
Mechanism

Non-selective α- and β-adrenergic agonist

  • α1 receptor: vasoconstriction that alleviates hypotension, erythema, urticaria, angioedema, and upper airway mucosal edema
  • β2 receptor: bronchodilation and suppression of further mediator release from mast cells and basophils
  • β1 receptor: increases heart rate and contractility
Intramuscular Administration

Dose

  • 0.3 to 0.5 mg OR 0.01 mg/kg (max 0.5 mg in adolescents & adults; max 0.3 mg in children) IM every 5 to 15 minutes
  • Use 1 mg/mL epinephrine concentration

Route

  • Administer intramuscularly into the anterolateral aspect of the thigh [refer to literature section]
  • IM absorption > subcutaneous (SQ) absorption
  • Thigh absorption > deltoid administration
Intravenous Epinephrine

Indications

  • Inadequate response to multiple IM epinephrine injections
  • Hypotension unresponsive to fluids
  • Cardiac or respiratory arrest

Dose — Hemodynamically Stable

  • Initial: 1 mcg/min IV continuous infusion titrated by 0.5 mcg/min every 10 to 15 min to desired response

Fluid-Resuscitated

Inject 1 mg (1 mg/mL) epinephrine into 250 mL of NS or D5W and start infusion at 15 mL/hour (= 1 mcg/min) and titrate by 7.5 mL/hour (= 0.5 mcg/min)

Requires Fluid Resuscitation

Inject 1 mg (1 mg/mL) epinephrine into 1 L of NS or D5W and start infusion at 60 mL/hour (=1 mcg/min) and titrate by 30 mL/hour (= 0.5 mcg/min)

Dose — Anaphylactic Shock

  • Initial: 2 to 10 mcg/min titrated every 10 to 15 min to desired MAP (max 1 mcg/kg/min) with appropriate fluid resuscitation
  • Administration: Premixed epinephrine concentration is institution-specific (e.g., 8 mg/250 mL is one common preparation); verify your local protocol before use.
Adverse Effects
Tachyarrhythmias Hypertension Myocardial ischemia Mesenteric ischemia Extravasation Lactic acidosis

Clinical Pearl

Use the 1 mg/mL concentration for IM dosing. Injection into the anterolateral thigh produces faster and higher peak plasma concentrations than the deltoid or subcutaneous route (see Simons 1998 and Simons 2001 in the evidence table).

Glucocorticoids Limited role in acute treatment
Role in Therapy Limited role in acute treatment of anaphylaxis
Mechanism Bind to the glucocorticoid receptor on cell membranes and inhibit gene expression and production of new inflammatory markers
Dose Methylprednisolone (Solu-Medrol) 50 to 125 mg IV x 1 dose given after epinephrine
Onset Hours to prevent transcription and translation of inflammatory markers
Histamine Receptor Antagonists Adjuncts secondary to epinephrine
Role in Therapy Adjunct secondary to epinephrine to treat urticarial, pruritus, and flushing
Mechanism Inhibits the effect of released histamine at the H1/H2 receptors
Dose

H1 Receptor Antagonist

  • Diphenhydramine (Benadryl) 25 to 50 mg IV x 1 dose given after epinephrine

H2 Receptor Antagonist

  • Famotidine (Pepcid) 20 mg IV x 1 dose given after epinephrine
Onset Peak plasma concentrations are not reached until 60–120 minutes after administration

Do Not Delay Epinephrine

Histamine receptor antagonists and glucocorticoids are adjuncts only. Their onset of action is too slow for acute anaphylaxis (H1/H2 peak 60 to 120 minutes; steroids hours), and they do not prevent biphasic reactions. Administer them after epinephrine, never instead of or before it.

Overview of Key Evidence

Route of Epinephrine Administration

Author, Year Design Purpose Outcomes
Simons et al. 19985 RCT
N=17 		Evaluate epinephrine absorption between IM and SQ routes in children
IM faster peak

IM injection of epinephrine led to a faster peak epinephrine concentration than the SQ route (8 min vs. 34 min)
Simons et al. 20016 RCT
N=13 		Evaluate the optimal route and site of epinephrine injection in adults
Thigh IM > SQ > deltoid IM

Mean peak plasma concentration higher after IM thigh than SQ or IM deltoid (9722 pg/mL, 2877 pg/mL, and 1821 pg/mL, respectively). Peak with IM injection around ~10 minutes.
Brown et al. 20047 Prospective Cohort
N=19 		Assess sting anaphylaxis management with carefully titrated IV epinephrine infusion (5–15 mcg/min titrated to response) and volume resuscitation
18/19 responded

18/19 patients responded with symptomatic improvement and SBP >90 mmHg within 5 min. No adverse reactions attributable to epinephrine. Median total dose 590 mcg (190–1310 mcg); median infusion duration 115 min (52–292 min).

Glucocorticoids & Antihistamines in Biphasic Anaphylaxis

Author, Year Design Purpose Outcomes
Grunau et al. 20158 Retrospective Cohort
N=473 		Determine the association of steroid administration with decreased relapses in ED allergy patients
No reduction in relapses

4 biphasic reactions in the steroid group and 1 in the non-steroid group. No difference in 7-day revisits (5.8% vs. 6.7%).
Ko et al. 20159 Retrospective Cohort
N=415 		Determine prevalence and clinical characteristics of biphasic reactions in patients treated with steroids
2.2% biphasic

Biphasic reactions occurred in 9/415 (2.2%) patients. No difference in epinephrine use or H1 blocker use between those who did or did not develop a biphasic reaction.

Evidence Summary

PK data (Simons 1998, Simons 2001) support IM injection into the anterolateral thigh over SQ or deltoid IM. A small prospective series (Brown 2004) supports carefully titrated IV epinephrine infusion as feasible and effective in sting anaphylaxis with no attributable adverse events. Two retrospective cohorts (Grunau 2015, Ko 2015) found that glucocorticoids and antihistamines did not reduce biphasic reactions or relapses.

Clinical Conclusions

Bottom Line / Takeaway

Epinephrine is the cornerstone of therapy in anaphylaxis, and delayed use has been associated with an increased rate of mortality. Histamine receptor antagonists and glucocorticoids are adjuncts and do not prevent biphasic reactions; patients should be counseled on the possibility of recurrence within 1 to 72 hours.

Epinephrine is the cornerstone of therapy in anaphylaxis, and delayed use of epinephrine has been associated with an increased rate of mortality.

Do not delay the administration of epinephrine for the administration of histamine receptor antagonists or glucocorticoids.

Continuous epinephrine intravenous infusions may be started in patients that do not respond to multiple doses of IM epinephrine, have persistent hypotension, and cardiac and/or respiratory arrest.

Histamine receptor antagonists and glucocorticoids do not prevent biphasic anaphylaxis, and patients should be counseled on this recurrent reaction.

Full Reference List

  1. 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 Apr; 145:1082.
  2. Lieberman P et al. Anaphylaxis, a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115:341-384.
  3. Russell WS, Farrar JR, Nowak R, et al. Evaluating the management of anaphylaxis in US emergency departments: Guidelines vs. practice. World J Emerg Med. 2013;4(2):98-106.
  4. Campbell RL, Li JT, Nicklas RA, Sadosty AT; Members of the Joint Task Force; Practice Parameter Workgroup. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014 Dec;113(6):599-608.
  5. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. 1998 Jan;101(1 Pt 1):33-7.
  6. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001 Nov;108(5):871-3.
  7. Brown SG, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J. 2004 Mar;21(2):149-54.
  8. Grunau BE, Wiens MO, Rowe BH, McKay R, Li J, Yi TW, Stenstrom R, Schellenberg RR, Grafstein E, Scheuermeyer FX. Emergency Department Corticosteroid Use for Allergy or Anaphylaxis Is Not Associated With Decreased Relapses. Ann Emerg Med. 2015 Oct;66(4):381-9.
  9. Ko BS, Kim WY, Ryoo SM, Ahn S, Sohn CH, Seo DW, Lee YS, Lim KS, Kim TB. Biphasic reactions in patients with anaphylaxis treated with corticosteroids. Ann Allergy Asthma Immunol. 2015 Oct;115(4):312-6.
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