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doi: 10.1097/ALN.0b013e3181dea058

The Dose of Epinephrine to Treat Anaphylaxis

Dewachter, Pascale M.D., Ph.D.*; Mouton-Faivre, Claudie M.D.; Emala, Charles W. M.D.

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In Reply:

We thank Dr. Russell for his careful reading of our article.1 As highlighted by Russell, perioperative anaphylaxis remains a clinical diagnosis that is not always obvious. The Ring and Messmer four-step grading scale adapted for perioperative immediate reactions helps to stratify the severity and guides therapy for the ongoing clinical reaction.1 Common key points are highlighted in the various current clinical guidelines that recommend careful titration of epinephrine boluses according to the hemodynamic response during cardiovascular collapse (grade III reactions).2–6 Recommendations in the United States propose an initial dose of 100–300 μg intravenously, advise close monitoring because fatal overdoses of epinephrine have been reported, and suggest that an intravenous infusion of epinephrine (1–4 μg/min) may prevent the need to repeat epinephrine bolus administration.3,4 French guidelines recommend a 100–200 μg intravenous epinephrine bolus and state that intravenous infusion at a dose (0.05–0.1 μg · kg−1 · min−1) might be used in place of repeated bolus administration.2 Scandinavian recommendations state that a continuous infusion (0.05–0.1 μg · kg−1 · min−1) is advantageous in patients in need of repetitive doses of epinephrine (initial intravenous doses 100 μg), whereas British guidelines also state that an intravenous infusion should be considered in patients requiring repeated bolus dosing (initial intravenous boluses of 50 μg).5,6
Plotting the logarithm of the dose that fits a dose–response curve is a mathematical description of the receptor-occupancy theory that allows us to study the competition of a ligand (such as epinephrine) for receptor binding and allows the comparison of receptor agonists in terms of efficiency (Emax) and potency (EC50). The shape of the dose–response curve corresponds to drug binding to its receptor, and the slope of the curve identifies the range of doses useful for achieving a clinical effect. With such a design, we previously provided dose (epinephrine)–response (mean arterial pressure) relationships and showed that the EC50 of epinephrine in a rat model of anaphylactic shock was 10 μg/kg.7 Pulmonary edema and episodes of ventricular arrhythmia occurred at the highest doses of epinephrine in this rat model. However, most importantly, the magnitude of a pharmacologic drug response and the clinical use of a drug should be distinguished. Epinephrine has a relatively narrow therapeutic index,8 with pulmonary edema, ventricular dysrythmias, and poor outcomes, including myocardial and cerebral infarctions or deaths (and in recent years Tako-Tsubo cardiomyopathy), associated with its use after excessive dosing during anaphylaxis.9,10 Finally, none of the current clinical guidelines recommend that “the titration of epinephrine should be performed in a logarithmic fashion” or “by doubling the amount of epinephrine in each progressive dose.”2–6 Conversely, the need for careful epinephrine titration according to the hemodynamic response is strongly recommended.2–5
Pascale Dewachter, M.D., Ph.D.,*
Claudie Mouton-Faivre, M.D.
Charles W. Emala, M.D.
*Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Université Paris-Descartes, Institut National de la Santé et de la Recherche Médicale U970, Paris, France.
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1. Dewachter P, Mouton-Faivre C, Emala CW: Anaphylaxis and anesthesia: Controversies and new insights. Anesthesiology 2009; 111:1141–50

2. French Society of Anesthesiology and Intensive Care Medicine: Reducing the risk of anaphylaxis during anaesthesia. Abbreviated text. Ann Fr Anesth Reanim 2002; 21(suppl 1):7–23

3. American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care: Part 10.6: Anaphylaxis. Circulation 2005; 112:IV143–5

4. Practice Parameters of the Joint Task Force on Practice Parameters for Allergy and Immunology. The diagnosis and management of anaphylaxis: An updated practice parameter. J Allergy Clin Immunol 2005; 115:S483–523

5. Kroigaard M, Garvey LH, Gillberg L, Johansson SG, Mosbech H, Florvaag E, Harboe T, Eriksson LI, Dahlgren G, Seeman-Lodding H, Takala R, Wattwil M, Hirlekar G, Dahlén B, Guttormsen AB: Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anaesthesiol Scand 2007; 51:655–70

6. Harper NJ, Dixon T, Dugue P, Edgar DM, Fay A, Gooi HC, Herriot R, Hopkins P, Hunter JM, Mirakian R, Pumphrey RS, Seneviratne SL, Walls AF, Williams P, Wildsmith JA, Wood P, Nasser AS, Powell RK, Mirakhur R, Soar J: Suspected anaphylactic reactions associated with anaesthesia. Anaesthesia 2009; 64:199–211

7. Dewachter P, Jouan-Hureaux V, Lartaud I, Bello G, de Talancé N, Longrois D, Mertes PM: Comparison of arginine vasopressin, terlipressin or epinephrine to correct hypotension in a model of anaphylactic shock in anesthetized brown Norway rats. Anesthesiology 2006; 104:734–41

8. Kemp SF, Lockey RF, Simons FER, on behalf of the World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis: Epinephrine: The drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy 2008; 63:1061–70

9. Pumphrey RS: Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30:1144–50

10. Dewachter P, Mouton-Faivre C: Apical ballooning syndrome during anaphylaxis may be linked to inappropriate administration of epinephrine. Mayo Clin Proc 2010; 85:396–7

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