Editorial Views  |   July 2005
From the Laboratory to the Bedside: Searching for an Understanding of Anaphylaxis
Author Notes
  • Brigham and Women’s Hospital, Boston, Massachusetts.
Article Information
Editorial Views / Cardiovascular Anesthesia / Critical Care / Endocrine and Metabolic Systems / Infectious Disease / Pediatric Anesthesia / Pharmacology / Respiratory System
Editorial Views   |   July 2005
From the Laboratory to the Bedside: Searching for an Understanding of Anaphylaxis
Anesthesiology 7 2005, Vol.103, 1-2. doi:
Anesthesiology 7 2005, Vol.103, 1-2. doi:
ALTHOUGH more than 100 yr have passed since anaphylaxis was first reported,1 clinicians continue to struggle with the definition and management of anaphylaxis.2 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.2 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.  3 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.4 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.  3 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.3 
Although any α 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 α-adrenergic receptors, also stimulates β1and β2receptors. Incremental doses of epinephrine lead first to stimulation of β2receptors followed by β1and α-adrenergic receptors. This is important in the setting of the findings of Dewachter et al.  ,3 where cardiac function was preserved in the early stages of anaphylaxis. β2-Receptor effects lead to bronchodilation and the increased production of cyclic adenosine monophosphate.5 The importance of the latter property is often overlooked when another α-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.6 
Even if given promptly, epinephrine alone may not be sufficient for the treatment of severe anaphylactic shock.7 The cardiovascular effects of a continuous infusion of epinephrine are more pronounced than with an intravenous bolus injection.8 However, boluses can rapidly achieve high epinephrine concentrations and stop mast cell mediator release.9 Studies support the use of pure α-adrenergic agents such as methoxamine10 and metaraminol6 for the treatment of anaphylaxis refractory to epinephrine. Interestingly, α1-adrenergic stimulation causes a decrease in tissue concentrations of cyclic adenosine monophosphate,8 a condition that can enhance the release of mediators from tissue mast cells and peripheral blood basophils.
Other forms of distributive shock (e.g.  , septic shock) are characterized by the redistribution of blood flow to major organ systems but lack cellular oxygen consumption. Although sepsis is not associated with tissue hypoxia, cellular utilization of oxygen is impaired after septic shock.11 The role of inflammation in septic shock is well established, and treatment strategies that down-regulate proinflammatory cytokines have been used successfully.12 Furthermore, pentoxifylline, a phosphodiesterase inhibitor, has also been shown to down-regulate the inflammatory cytokines tumor necrosis factor α, interleukin (IL)-1β, and IL-6 in sepsis.13 The proinflammatory response after hemorrhage has also been attenuated by the potent vasodilatory peptide adrenomedullin and adrenomedullin binding protein 1, which down-regulate proinflammatory cytokines and up-regulate antiinflammatory cytokines (IL-10).14 
Murine models of anaphylaxis demonstrate that mast cell mediators interact with cytokines (IL-4 and IL-13) to increase the severity of anaphylaxis.15 Two pathways of murine anaphylaxis have been described: one is mediated by immunoglobulin (Ig) E, IgE-ϵ receptor, mast cells, and platelet activation factor and is triggered by small quantities of antigens; the other relies on IgG antibodies, low-affinity IgG-γ receptor III, macrophages, and platelet activation factor and is induced by large quantities of antigen.15 Interferon γ has been demonstrated to block the cytokine-mediated exacerbation that seems to be involved in both pathways of anaphylaxis in mice models. Furthermore, IgG antibody has been demonstrated in vitro  to block IgE-mediated anaphylaxis. However, adrenomedullin, despite having been demonstrated to be a potent pulmonary vasodilator and a cytokine down-regulator,16 did not reverse antigen-induced acute bronchoconstriction in guinea pigs.17 This indicates that the development of bronchospasm in anaphylaxis requires the presence of previous pulmonary inflammation in addition to mediator release.15 Asthmatic patients are more likely to experience pulmonary manifestations of anaphylaxis after antigen exposure. Furthermore, adrenomedullin binding protein 1 has been shown to enhance adrenomedullin-mediated cyclic adenosine monophosphate accumulation in cultured fibroblasts.14 Future interventions in the treatment of anaphylaxis may include the use of adrenomedullin binding protein 1 and anti-IgE and IL-4Rα antibodies. Further studies clarifying the role of inflammation and sympathetic nervous system activation may shed additional light on therapeutic options.
The complexity and severity of anaphylaxis is such that no single algorithm can adequately treat all cases. However, Dewachter et al.  3 take us a step further toward understanding the pathophysiology of anaphylaxis during anesthesia and the rationale for aggressive and prompt resuscitation.
The author thanks Eleanor R. Menzin, M.D. (Longwood Pediatrics, Children’s Hospital Boston, Boston, Massachusetts), and Mariana C. Castells, M.D. (Assistant Professor, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts), for a thorough review of this Editorial View.
Brigham and Women’s Hospital, Boston, Massachusetts.
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