Introduction

1. Anaphylaxis is a life-threatening, IgE-mediated allergic reaction most commonly triggered by medications, foods, and stinging insects.
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.
3. 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. Pharmacology
   Epinephrine
   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] o IM absorption > subcutaneous (SQ) absorption o 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 • Administration: o 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)
   o 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)
   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: Epinephrine premixed 8 mg/250 mL [specific to Grady Health]
   Adverse Effects Tachyarrhythmias, hypertension, myocardial ischemia, mesenteric ischemia, extravasation, lactic acidosis
   Glucocorticoids
   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
   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
   Literature
   Author, year Design Purpose Outcomes
   Route of Epinephrine Administration
   Simons et al. 1998 RCT (N=17) Evaluate epinephrine absorption between IM and SQ routes in children -IM injection of epinephrine led to a faster peak epinephrine concentration than the SQ route (8 min vs. 34 min)
   Simons et al. 2001 RCT (N=13) Evaluate the optimal route and site of epinephrine injection in adults
   [see figure below] -Mean epinephrine peak plasma concentration higher after epinephrine IM injection into the thigh than SQ injection or IM injection into the deltoid (9722 pg/mL, 2877 pg/mL, and 1821 pg/mL, respectively) -Peak epinephrine concentration with IM injection around ~10 minutes
   Brown et al. 2004 Prospective cohort study
   (N=19) Assess sting anaphylaxis management with carefully titrated IV epinephrine infusion (5-15 mcg/min titrated to response) and volume resuscitation -18/19 patients responded with symptomatic improvement and SBP >90 mmHg within 5 min -No adverse reactions attributable to epinephrine
   -Median total dose of epinephrine was 590 mcg (190-1310 mcg) and median total infusion duration was 115 min (52-292 min)
   Glucocorticoids & Antihistamines in Biphasic Anaphylaxis
   Grunau et al. 2015 Retrospective cohort study
   (N= 473) Determine the association of steroid administration with decreased relapses
   in ED allergy patients -4 biphasic reactions occurred in the steroid group and 1 in the non-steroid group
   -No difference in revisits during 7-day follow-up period between steroid and non-steroid group (5.8% vs. 6.7%)
   Ko et al. 2015 Retrospective cohort study
   (N= 415) Determine prevalence and clinical characteristics of biphasic reactions in patients treated with steroids -Biphasic reactions occurred in 9/415 (2.2%) patients -No difference in epinephrine use or H1 blocker use between those that did or did not develop a biphasic reaction

Conclusion

1. Epinephrine is the cornerstone of therapy in anaphylaxis, and delayed use of epinephrine has been associated with an increased rate of mortality.
2. Do not delay the administration of epinephrine for the administration of histamine receptor antagonists or glucocorticoids.
3. 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.
4. Histamine receptor antagonists and glucocorticoids do not prevent biphasic anaphylaxis, and patients should be counseled on this recurrent reaction.

References

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):599608.
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.