From the laboratory to the bedside: searching for an understanding of anaphylaxis.

ALTHOUGH more than 100 yr have passed since anaphylaxis was first reported, clinicians continue to struggle with the definition and management of anaphylaxis. In a recent symposium organized by the National Institute of Allergy and Infectious Diseases (Bethesda, Maryland) and the Food Allergy and Anaphylaxis Network (Fairfax, Virginia), with representatives from the Center for Disease Control and Prevention (Atlanta, Georgia), the U.S. Food and Drug Administration (Rockville, Maryland), and five different medical specialties including anesthesiology, guidelines were elaborated to clarify the prevalence, diagnosis, and management of anaphylaxis. Another goal of this symposium was to discuss research objectives including molecular, immunologic, and physiologic mechanisms responsible for anaphylaxis. In this issue of ANESTHESIOLOGY, Dewachter et al. present an elegant Laboratory Investigation that helps to elucidate the pathophysiology of anaphylaxis during anesthesia and illustrates why timely diagnosis and management are essential to prevent rapid cell and organ dysfunction. The diagnosis of anaphylaxis during anesthesia is difficult. The incidence varies from 1:3,500 to 1:20,000, and many anesthesiologists are never exposed to an episode. Cutaneous manifestations are difficult to recognize because most of the body is covered with drapes, respiratory signs are often blunted by the bronchodilatory properties of inhalation anesthetics, and pharmacologically induced hypotension is common. As a result, the diagnosis is often delayed or missed unless severe bronchospasm or arterial hypotension occur. Although severe cardiovascular collapse occurs during anaphylaxis and is treated with epinephrine, its pathophysiology is not clear. Dewachter et al. address this issue by comparing severely decreased arterial blood pressure induced in Brown Norway anesthetized rats with nicardipine or with ovalbumin-induced anaphylactic shock. The time course and the magnitude of the hypotension were similar between the two groups. The skeletal muscle blood flow decreased in both groups after 20–40 min. Evidence of skeletal muscle vasoconstriction in the anaphylactic shock group was further supported by the higher plasma epinephrine and norepinephrine concentrations and the greater gradient between plasma and interstitial epinephrine, compared with pharmacology-induced hypotension. Anaphylactic shock was characterized by a more rapid decrease in tissue oxygen partial pressure values, a rapid and larger increase in interstitial lactate concentrations, and a decrease in interstitial pyruvate concentrations. The end result was a significant increase in the lactate-to-pyruvate ratio, a result not present in the nicardipine group. The authors conclude that the cellular oxygen consumption and metabolic failure present in anaphylaxis may lead to end organ dysfunction and a more difficult restoration of normal homeostasis. Although any agonist would increase blood pressure, the unique pharmacologic properties of epinephrine make it the first-line agent for treatment of anaphylactic shock. Epinephrine, the most potent activator of -adrenergic receptors, also stimulates 1 and 2 receptors. Incremental doses of epinephrine lead first to stimulation of 2 receptors followed by 1 and -adrenergic receptors. This is important in the setting of the findings of Dewachter et al., where cardiac function was preserved in the early stages of anaphylaxis. 2-Receptor effects lead to bronchodilation and the increased production of cyclic adenosine monophosphate. The importance of the latter property is often overlooked when another -agonist agent is chosen for the treatment of anaphylaxis. An allergic reaction, as opposed to a side effect, is not dose related; therefore, discontinuation of the triggering agent may not be at all helpful. In contrast, cyclic adenosine monophosphate is helpful because it decreases mediator release from tissue mast cells and peripheral blood basophils. The increases in heart rate and cardiac output that characterize higher doses of epinephrine are likely to compensate for the profound vasodilation, increased vascular permeability, and relative hypovolemia that occur later in anaphylaxis. Even if given promptly, epinephrine alone may not be sufficient for the treatment of severe anaphylactic shock. The cardiovascular effects of a continuous infusion of epinephrine are more pronounced than with an intravenous bolus injection. However, boluses can rapidly achieve high epinephrine concentrations and stop mast cell mediator release. Studies support the use of pure -adrenergic agents such as methoxamine and metaraminol for the treatment of anaphylaxis refractory to epinephrine. Interestingly, 1-adrenergic stimulation This Editorial View accompanies the following article: Dewachter P, Jouan-Hureaux V, Franck P, Menu P, de Telancé N, Zannad F, Laxenaire M-C, Longrois D, Mertes PM: Anaphylactic shock: A form of distributive shock without inhibition of oxygen consumption. ANESTHESIOLOGY 2005; 103:40–9.