In Reply:
We thank Dr. Russell for his careful reading of our article.1As 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.1Common 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).2–6Recommendations 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.3,4French 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.2Scandinavian 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 EC50of epinephrine in a rat model of anaphylactic shock was 10 μg/kg.7Pulmonary 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,8with 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.9,10Finally, 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.”2–6Conversely, the need for careful epinephrine titration according to the hemodynamic response is strongly recommended.2–5
*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. pascale.dewachter@yahoo.fr