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The Pathophysiology of Shock in Anaphylaxis
Immunol Allergy Clin N Am 27 (2007) 165–175
The Pathophysiology of Shock in Anaphylaxis Simon G.A. Brown, MBBS, PhD, FACEM Emergency Medicine Research Unit, The University of Western Australia and Fremantle Hospital, Alma Street, Fremantle, WA 6160, Australia
In one large study of deaths due to anaphylaxis, circulatory shock was a prominent clinical feature in 54% of cases (67 of 125 cases), the sole mode of death in half of these; in the other half, it was combined with upper and/or lower airway obstruction [1]. In the same study, shock was more often a feature in lethal iatrogenic and venom anaphylaxis (61 of 87 cases, 70%) than in lethal food anaphylaxis (5 of 37 cases, 14%). This article examines the current understanding of the pathophysiology of shock in anaphylaxis and discusses the implications of this knowledge for clinicians and researchers. Clinical manifestations A brief overview of the physiological determinants of blood pressure is provided in Box 1. Shock does not necessarily equate with hypotension, but is defined broadly as a condition where blood flow to vital organs is insufficient to meet the metabolic demands of the body. In some forms of shock, compensatory mechanisms maintain blood pressure and thus cerebral function at normal or near-normal levels for a time despite peripheral circulatory failure and progressively worsening metabolic acidosis. During severe anaphylaxis there is usually a rapid onset of hypotension, neurological compromise, and cardiac arrest (median time to cardiac arrest 5 to 15 minutes after reaction onset) [1]. In nonlethal cases, hypotension during anaphylaxis is associated with nausea, vomiting, dyspnea, dizziness (presyncope), diaphoresis, collapse, unconsciousness, and incontinence [2]. There are four broad types of shock: hypovolemic, cardiogenic, distributive, and obstructive [3]. It generally is considered that shock in human anaphylaxis may comprise variable components of hypovolemia because of E-mail address: [email protected] 0889-8561/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2007.03.003 immunology.theclinics.com
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Box 1. Determinants of blood pressure and cardiac output 1: Blood Pressure ðBPÞfCardiac output ðCOÞ Systemic Vascular Resistance ðSVRÞ SVR is determined by the tone of the precapillary arterioles (resistance vessels). 2: COfHeart Rate Stroke volume Preload Contractility 3: Stroke Volumef Afterload Preload = myocardial fiber length before contraction (= ventricular end diastolic volume), which depends upon venous return; which in turn depends upon blood volume and the tone of the veins (capacitance vessels) Afterload = tension in the ventricular wall during contraction, which depends upon SVR (to resistance vessels), the size of the ventricle according to Laplace’s law, and other obstructions to flow such as aortic valve obstruction Contractility = the inherent ability of the heart to contract, independent of preload and afterload
capillary fluid leak [4–6], distributive shock caused by vasodilation [4,7–9], and cardiogenic shock caused by reduced contractility [10,11] and perhaps inappropriate bradycardia [12]. Pulmonary vasospasm also may introduce an obstructive component, by reducing left ventricular filling [13–16]. These multiple effects, reducing the ability of the body to compensate, probably explain the rapid onset of severe hypotension and unconsciousness that is characteristic of anaphylaxis. A close examination of the literature, however, reveals numerous inconsistencies and unanswered questions. Few studies adequately investigate cardiovascular parameters to define the precise cause of hypotension. Hypotension can be caused by reduced cardiac output and/or reduced systemic vascular resistance. As outlined in Box 1, a fall in cardiac output can be caused by any combination of reduced venous return to the chest, increased pulmonary vascular resistance reducing venous return to the left heart, myocardial depression caused by a direct effect of mediators and myocardial ischemia. Myocardial ischaemia may be caused by reduced coronary blood flow (and/or severe hypoxemia), and increased systemic vascular resistance causing increased afterload on the myocardium.
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Animal models and the concept of anaphylactic shock organs In addition to interspecies variations, complicating factors in the interpretation of animal models include the methods of initial sensitization (eg, passive versus active, type of antigen) and subsequent exposure (ingested, intravenous, or subcutaneous), and whether the animal is awake or anaesthetized with blunted reflex responses. Nevertheless, some valuable insights into potential pathophysiological mechanisms in people can be obtained from animal studies. Early studies found organ system involvement to vary between animal models, with the major organ involved being termed the shock organ for that particular species [17]. In the guinea pig, intense bronchospasm leading to hypoxia was considered the principal cause of death [17,18], leading to secondary cardiac ECG abnormalities comparable to those caused by asphyxia [19]. In rabbits, severe vasoconstriction in the pulmonary arterial system appeared to cause hypoxia and circulatory collapse, and again cardiac ECG abnormalities were considered to be secondary to asphyxia [19]. In dogs, severe hepatic congestion was considered the major cause of lethal shock. Subsequently the manifestations of guinea pig anaphylaxis have been shown to include, in addition to intense bronchospasm, progressive impairment of atrioventricular conduction leading to complete block, increased ventricular automaticity (including ventricular fibrillation) and cardiac contractile failure in both intact whole-animal and isolated-heart models, indicating that these occur independent of hypoxia [20,21]. Reduced coronary blood flow caused by increased coronary vascular resistance also has been demonstrated [22]. In a canine ragweed model of anaphylactic shock, increased pulmonary vascular resistance and increased systemic vascular resistance have been demonstrated, along with reduced venous return and reduced cardiac output [14,23–25]; however in one recent study by the same group using the same model, systemic vascular resistance appeared to fall in some dogs [26]. Increased pulmonary vascular resistance also has been demonstrated in a monkey model [16], and in some monkeys, cardiovascular collapse can be attributed to decreased venous return and pulmonary hypertension, whereas in others, the decrease in cardiac output is more severe and seems to be associated with reduced myocardial contractility [15].
Human cardiovascular collapse Arguably the most important human study to date is a series of 205 episodes of anaphylactic shock occurring under anesthesia, where the treating anesthesiologist was asked to provide detailed clinical and laboratory information immediately after the event [5,6]. In this study, extravasation of up to 35% of circulating blood volume within 10 minutes was evident by increases in hematocrit. Additionally, in 46 patients who had central and/or pulmonary artery
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placed before or soon after the onset of anaphylaxis, there was a significant fall in filling pressures except in nine of 11 patients with cardiac disease, in whom pressures were elevated. Even so, these patients appeared to need volume expansion to achieve a stable blood pressure. In all six patients who had balloon pulmonary artery catheters, pulmonary arterial pressure rose initially and then fell over the subsequent 10 minutes [6]. In a single case report of a patient with iatrogenic anaphylaxis for whom systemic vascular resistance was determined using a pulmonary artery catheter and cardiac output measurements, 3 hours into a reaction, there was increased pulmonary vascular resistance, reduced pulmonary capillary wedge pressure, reduced cardiac output, and slightly elevated systemic vascular resistance [13]. What peripheral vascular changes occur during human anaphylaxis? The peripheral skin flushing and fall in diastolic blood pressure (widened pulse pressure) and tachycardia seen early in human anaphylaxis are suggestive of dilation of both resistance and capacitance vessels [12]. During this time, a transient peak in histamine, a potent vasodilator of both arterioles and veins, has been shown to occur [27]. Beyond these observation, the precise vascular events during anaphylaxis have not been characterized in people. It generally is presumed on the basis of the sudden reduction of central venous pressure at reaction onset seen in people, animal studies, and known mediator effects, that venodilation (increased venous capacitance) leading to reduced venous return is a significant feature of human anaphylaxis. Severe vasodilation resistant to epinephrine (adrenaline) and responding only to potent vasoconstrictors has been described in human case reports [7,8]. Such reports, however, only can assume that vasodilation has occurred on the basis of an apparent response to a selective vasopressor. Whether the primary sites of vasopressor action in these cases were the capacitance vessels, resistance vessels or both, is unknown. Is the human heart a target organ during anaphylaxis? Severe reversible cardiac dysfunction associated with nonspecific electrocardiogram changes and normal coronary arteries also has been described during human anaphylaxis [10,11,27]. Numerous case reports have indicated that intravenous glucagon [28], the phosphodiesterase inhibitor amrinone [29], and intra-aortic balloon pump support [11] may be useful for treating resistant anaphylactic shock where cardiac dysfunction is a problem because of beta blockade, pre-existing impairment of left ventricular function, or cardiac anaphylaxis. The author also has observed global ST segment changes in a patient without any cardiovascular instability, suggesting a direct mediator effect on the human heart [12]. Nevertheless, cardiac dysfunction during anaphylaxis in people has been considered to be exceptionally rare [30]. Even in closely monitored cases, an
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obvious difficulty in determining the contribution of cardiac dysfunction to anaphylactic shock in people lies with the problems in dissecting this component from other pathological events [31]. In lethal cases, owing to a rapid and unpredicted demise, few if any detailed clinical observations are possible. Therefore, although numerous animal studies and human observations support the concept of anaphylactic mediators having direct effects on the myocardium [32], the contribution of this cardiac anaphylaxis to morbidity and mortality remains to be defined. The presence of mast cells in human cardiac (mainly peri-vascular) tissue is well-recognized [33–35]. ECG changes suggestive of myocardial ischemia and enzyme changes indicating infarction also have been reported within 24 hours of anaphylaxis [27,36–38]. This raises the possibility of mediatorinduced plaque ulceration and/or coronary spasm, ischemia secondary to hypotension, and a direct mediator effect on the myocardium. Also, high catecholamine levels (either therapeutic or caused by endogenous release) can have an adverse effect in the myocardium, including significant reductions in cardiac output, ischemic chest pain, and ECG changes in the absence of coronary artery disease [39]. All of these can be argued as potential mechanisms. Although attempts have been made on the basis of a few case reports to give this allergic coronary syndrome an eponym [40–42], some cases simply may represent coincidence, and the underlying mechanisms are speculative. Relative bradycardia during anaphylaxis While performing a randomized controlled trial of venom immunotherapy, the author observed eight hypotensive anaphylactic sting reactions, two of which were associated with severe bradycardia and treated with intravenous atropine [43]. A careful review of these reactions revealed that hypotension was preceded by a fall in diastolic blood pressure (suggesting reduced systemic vascular resistance) with tachycardia. Following this, in every case, the onset of hypotension was accompanied by a relative bradycardia. That is, rather than the heart rate further increasing to compensate for falling blood pressure, it fell as the blood pressure fell. We postulated that this may have been caused by a neurocardiogenic reflex, triggered by cardiac mechanoreceptors, and enhanced by increased levels of serotonin, catecholamines, prostaglandins, and nitric oxide that are known to potentiate this reflex and also are elevated during anaphylaxis [12]. More recently, C5a and adenosine have been implicated as a potential mediators of bradycardia during cardiac anaphylaxis in pigs [44]. Bradycardia also may be a nonspecific feature of severe hypovolemic–distributive shock in awake animals. Paradoxical bradycardia has been reported as a common feature of traumatic hypotension in people [45], and physiological studies of awake mammals have identified two phases of response to hypovolemia, an initial phase of blood pressure maintenance by
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tachycardia and peripheral arteriolar constriction, followed by a second phase with more severe hypovolemia characterized by bradycardia, reduced peripheral arteriolar tone and a profound fall in blood pressure [46]. However, bradycardia has not been reported as a feature of anaphylaxis under anesthesia, where tachycardia is the norm except when there has been prior beta blockade or severe hypoxia [6]. This may be explained by the blunting of central reflexes that occurs under anesthesia and/or different allergen routes and dosage. One cannot be sure whether bradycardia during anaphylaxis is maladaptive, potentiated by various mediators, or an adaptive process that triggers collapse to a supine position and a slower heart rate to allow the heart to adequately fill between contractions when there is a severe reduction in preload. Biochemical mediators In the early 20th century, histamine was thought to be the principal mediator of anaphylaxis [30]. Since then, a huge range of inflammatory mediators has been implicated in anaphylaxis by human studies, in vitro cell stimulation studies, and animal models. These include: Preformed mediators, released immediately by mast cells and basophils: histamine, heparin, tryptase, chymase, tumor necrosis factor a (TNF-a); Mediators generated over minutes by mast cells, basophils, and possibly other cells: platelet-activating factor (PAF), nitric oxide (NO), TNF-a, cyclo–oxygenase products of arachidonic metabolism (PGD2), and lipoxygenase products of arachidonic metabolism (leukotrienes LTC4, LTD4, and LTE4); Mediators generated over hours by mast cells, basophils and possibly other cells: interleukin (IL)-4, IL-5, IL-13, and GM-CSF Mediators generated by contact system activation: bradykinin, plasmin, and complement pathway anaphylatoxins C3a and C5a Although tissue mast cells and circulating basophils play a pivotal role, other cells including platelets, eosinophils, monocytes/macrophages, endothelial cells, and antigen presenting cells also have been implicated. The large numbers of mediators provide for significant redundancy and positive feedback mechanisms by which other effector cells are recruited to release more mediators. This has led to the concept of a mast cell–leukocyte cytokine cascade that initiates, amplifies, and perpetuates the allergic response [29]. Many of these mediators variously may cause systemic venodilation, increased capillary permeability, reduced myocardial contractility, and constriction of some vessels (eg, precapillary arterioles, coronary arteries, and pulmonary vasculature). Analyzing their roles in people is difficult because of the opportunistic nature of anaphylaxis research, not only because of
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the near-impossibility of establishing causal relationships, but also because much of the action occurs locally in the tissue where the reaction is initiated, because the presence of some mediators in serum such as histamine is transient [30], and because of technical difficulties assessing the concentrations of some mediators. Variability between individuals in patterns of mediator release and target organ sensitivity also may complicate interpretation. Platelet-activating factor, nitric oxide, and tumor necrosis factor a In mice, PAF and platelets appear to play a central role in the hypotension of anaphylaxis, and there is good reason to suspect a similar role in people [47]. PAF is released by mast cells, basophils, and platelets upon IgE-mediated activation, and it may exert its effects largely through the activation of endothelial nitric oxide synthase (eNOS) and excessive NO synthesis, causing intense venodilation and perhaps myocardial depression [48,49]. PAF also promotes the synthesis of TNF-a, which in turn promotes later PAF synthesis, and thus delayed-phase reaction recurrence [50].
Clinical perspective A summary of key pathological mechanisms of human anaphylactic shock classified as proven, likely, and uncommon is presented in Box 2. The large number of mediators with redundant effects underlying these mechanisms indicates that physiological antagonism with fluid resuscitation, epinephrine and perhaps potent vasopressors will be more effective than individual receptor antagonists such as antihistamines. Canine studies indicate that epinephrine works predominantly by increasing cardiac output through a direct beta effect on the heart rather than by improving venous return, and that only the intravenous infusion works in established shock, with subcutaneous and intramuscular injections being ineffective, and intravenous boluses having only a transient effect [24,26]. It should be noted, however, that these studies were in dogs in which severe anaphylactic shock had been precipitated, In many human cases with reactions of milder severity, epinephrine is likely to provide some vasoconstriction. Prospectively evaluated protocols for the infusion of epinephrine in people are available [12,51]. Aggressive fluid resuscitation (volume expansion, eg, 20 mL/kg of normal saline over 3 to 5 minutes, infused under pressure through a wide-bore intravenous line and repeated if necessary) is a critical treatment adjunct. It often is forgotten that resuscitation can be initiated by laying a patient flat and elevating his or her legs. Conversely the upright position, by further enhancing blood pooling in the lower extremities, can be lethal [52]. Anecdotally, some cases not responding to fluid resuscitation and epinephrine respond to additional treatment with potent vasopressors such
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Box 2. Key pathophysiologic mechanisms of human anaphylactic shock Common/clearly demonstrated: supported by unambiguous observations of human anaphylaxis Fluid extravasation causing hemoconcentration, hypovolemia and reduced venous return to the heart manifested as low filling pressures and reduction in cardiac output Likely: unproven but supported by animal studies, studies of histamine infusion in volunteers, known mediator actions, and/or indirect physiological observations during human anaphylaxis Venodilation and blood pooling, contributing to reduced venous return Impaired myocardial contractility contributing, along with reduced venous return, to reduced in cardiac output Relative bradycardia (neurally mediated) in awake patients, contributing to reduced cardiac output Early transient increase in pulmonary vascular resistance, contributing to the reduction in cardiac output by obstructing venous return to the left heart Early arteriolar dilation manifested as a widened pulse pressure and contributing to hypotension (however an increase in systemic vascular resistance caused by increased arteriolar tone may predominate after this early phase) Uncommon/postulated: based on case reports, speculation, plausible mechanisms Severe global depression of myocardial contractility with non-specific ST segment ECG changes (unresponsive to adrenaline) possibly more likely in those with underlying cardiac disease or taking beta blockers Severe arteriolar dilation as well as venous dilation Coronary ischemia caused by coronary vasospasm and plaque ulceration
as metaraminol and vasopressin [7–9]. Presumably these work primarily by an effect on venous (capacitance vessel) tone. Atropine also may be required when severe bradycardia is a feature [12], and phosphodiesterase inhibitor inotropes (including glucagon) and mechanical circulatory support have been reported to be effective in patients who have severely depressed myocardial function [11,28,53,54].
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Summary Although human studies are difficult to perform, the balance of evidence from human observations and animal studies suggests that the main pathophysiological features of anaphylactic shock are a profound reduction in venous tone and fluid extravasation causing reduced venous return (mixed hypovolemic–distributive shock) and depressed myocardial function. Aggressive fluid resuscitation is required to ameliorate hypovolemic–distributive shock, and an intravenous infusion of epinephrine will increase vascular tone, myocardial contractility, and cardiac output in most cases. Where these measures fail, pathophysiological considerations and anecdotal evidence support the consideration of selective vasoconstrictors as the next step in treatment.
References [1] Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000;30(8):1144–50. [2] Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114(2):371–6. [3] Weil MH. Personal commentary on the diagnosis and treatment of circulatory shock states. Curr Opin Crit Care 2004;10(4):246–9. [4] Beaupre PN, Roizen MF, Cahalan MK, et al. Hemodynamic and two-dimensional transesophageal echocardiographic analysis of an anaphylactic reaction in a human. Anesthesiology 1984;60(5):482–4. [5] Fisher M. Blood volume replacement in acute anaphylactic cardiovascular collapse related to anaesthesia. Br J Anaesth 1977;49(10):1023–6. [6] Fisher MM. Clinical observations on the pathophysiology and treatment of anaphylactic cardiovascular collapse. Anaesth Intensive Care 1986;14(1):17–21. [7] Heytman M, Rainbird A. Use of alpha-agonists for management of anaphylaxis occurring under anaesthesia: case studies and review. Anaesthesia 2004;59(12):1210–5. [8] Schummer W, Schummer C, Wippermann J, et al. Anaphylactic shock: is vasopressin the drug of choice? Anesthesiology 2004;101(4):1025–7. [9] Kill C, Wranze E, Wulf H. Successful treatment of severe anaphylactic shock with vasopressin. Two case reports. Int Arch Allergy Immunol 2004;134(3):260–1. [10] Hanashiro PK, Weil MH. Anaphylactic shock in man. Report of two cases with detailed hemodynamic and metabolic studies. Arch Intern Med 1967;119(2):129–40. [11] Raper RF, Fisher MM. Profound reversible myocardial depression after anaphylaxis. Lancet 1988;1(8582):386–8. [12] Brown SGA, Blackman KE, Stenlake V, et al. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004; 21(2):149–54. [13] Silverman HJ, Van Hook C, Haponik EF. Hemodynamic changes in human anaphylaxis. Am J Med 1984;77(2):341–4. [14] Silverman HJ, Taylor WR, Smith PL, et al. Effects of antihistamines on the cardiopulmonary changes due to canine anaphylaxis. J Appl Physiol 1988;64(1):210–7. [15] Pavek K. Anaphylactic shock in the monkey: its hemodynamics and mediators. Acta Anaesthesiol Scand 1977;21(4):293–307. [16] Patterson R, Fink JN, Wennemark J, et al. The biologic consequences of the immediate-type hypersensitivity transferred from man to monkey. J Allergy 1966;37(5):295–310.
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[17] Melli G, Folli G, Mazzei D, et al. Shock organ and shock tissue in various animal species. Acta Allergol 1963;18:188–210. [18] Auer J, Lewis PA. Physiology of the immediate reaction of anaphylaxis in the guinea pig. J Exp Med 1910;12:151–75. [19] Criep LH. Electrocardiographic studies of the effects of anaphylaxis on the cardiac mechanism. Arch Intern Med 1931;48:1098–108. [20] Felix SB, Baumann G, Berdel WE. Systemic anaphylaxisdseparation of cardiac reactions from respiratory and peripheral vascular events. Res Exp Med (Berl) 1990;190(4):239–52. [21] Capurro N, Levi R. The heart as a target organ in systemic allergic reactions: comparison of cardiac anaphylaxis in vivo and in vitro. Circ Res 1975;36(4):520–8. [22] Regal JF, Heller LJ. Cardiac anaphylaxis in isolated guinea pig hearts perfused at constant flow or constant pressure. Proc Soc Exp Biol Med 1987;185(2):193–200. [23] Mink S, Becker A, Sharma S, et al. Role of autacoids in cardiovascular collapse in anaphylactic shock in anaesthetized dogs. Cardiovasc Res 1999;43(1):173–82. [24] Mink SN, Bands C, Becker A, et al. Effect of bolus epinephrine on systemic hemodynamics in canine anaphylactic shock. Cardiovasc Res 1998;40(3):546–56. [25] Mink SN, Becker A, Unruh H, et al. Effects of anaphylaxis mediators on partitioned pulmonary vascular resistance during ragweed shock in dogs. J Appl Physiol 1998;84(3):782–90. [26] Mink SN, Simons FE, Simons KJ, et al. Constant infusion of epinephrine, but not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs. Clin Exp Allergy 2004;34(11):1776–83. [27] Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest 1980;66(5):1072–80. [28] Zaloga GP, DeLacey W, Holmboe E, et al. Glucagon reversal of hypotension in a case of anaphylactoid shock. Ann Intern Med 1986;105(1):65–6. [29] Otero E, Onufer JR, Reiss CK, et al. Anaphylaxis-induced myocardial depression treated with amrinone. Lancet 1991;337(8742):682. [30] Fisher M. Treating anaphylaxis with sympathomimetic drugs. BMJ 1992;305(6862):1107–8. [31] Cooper DJ. Cardiac dysfunction during anaphylaxis in patients. Appl Cardiopulm Pathophysiol 1993;5:9–18. [32] Marone G, Bova M, Detoraki A, et al. The human heart as a shock organ in anaphylaxis. Novartis Found Symp 2004;257:133–49 [discussion: 149–60, 276–85]. [33] Patella V, de Crescenzo G, Ciccarelli A, et al. Human heart mast cells: a definitive case of mast cell heterogeneity. Int Arch Allergy Immunol 1995;106(4):386–93. [34] Patella V, Genovese A, Marone G. What are human heart mast cells for? Chem Immunol 1995;62:171–86. [35] Patella V, Marino I, Lamparter B, et al. Human heart mast cells. Isolation, purification, ultrastructure, and immunologic characterization. J Immunol 1995;154(6):2855–65. [36] Austin SM, Barooah B, Kim CS. Reversible acute cardiac injury during cefoxitin-induced anaphylaxis in a patient with normal coronary arteries. Am J Med 1984;77(4):729–32. [37] Levine HD. Acute myocardial infarction following wasp sting. Report of two cases and critical survey of the literature. Am Heart J 1976;91(3):365–74. [38] Quercia O, Rafanelli S, Emiliani F, et al. Anaphylactic reaction to cinoxacin: report of one case associated with inferior acute myocardial infarction. Allerg Immunol (Paris) 2003;35(2): 61–3. [39] Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352(6):539–48. [40] Soufras GD, Ginopoulos PV, Papadaki PJ, et al. Penicillin allergy in cancer patients manifesting as Kounis syndrome. Heart Vessels 2005;20(4):159–63. [41] Koutsojannis CM, Kounis NG. Lepirudin anaphylaxis and Kounis syndrome. Circulation 2004;109(22):e315, author reply e315. [42] Kounis NG, Grapsas ND, Goudevenos JA. Unstable angina, allergic angina, and allergic myocardial infarction. Circulation 1999;100(25):e156.
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[43] Brown SGA, Wiese MD, Blackman KE, et al. Ant venom immunotherapy: a double-blind, placebo-controlled, cross-over trial. Lancet 2003;361(9362):1001–6. [44] Szebeni J, Baranyi L, Savay S, et al. Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function. Am J Physiol Heart Circ Physiol 2006;290(3):H1050–8. [45] Demetriades D, Chan LS, Bhasin P, et al. Relative bradycardia in patients with traumatic hypotension. J Trauma 1998;45(3):534–9. [46] Schadt JC, Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol 1991;260(2 Pt 2):H305–18. [47] Kasperska-Zajac A, Rogala B. Platelet function in anaphylaxis. J Investig Allergol Clin Immunol 2006;16(1):1–4. [48] Cauwels A, Janssen B, Buys E, et al. Anaphylactic shock depends on PI3K and eNOSderived NO. J Clin Invest 2006;116(8):2244–51. [49] Lowenstein CJ, Michel T. What’s in a name? eNOS and anaphylactic shock. J Clin Invest 2006;116(8):2075–8. [50] Choi IW, Kim YS, Kim DK, et al. Platelet-activating factor-mediated NF-kappaB dependency of a late anaphylactic reaction. J Exp Med 2003;198(1):145–51. [51] Brown SGA. Anaphylaxis: clinical concepts and research priorities. Emerg Med Australas 2006;18(2):155–69. [52] Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003;112(2): 451–2. [53] Andjelkovic I, Zlokovic B. Protective effects of glucagon during the anaphylactic response in guinea pig isolated heart. Br J Pharmacol 1982;76(3):483–9. [54] Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta blockers. Emerg Med J 2005;22(4):272–3.
The Pathophysiology of Shock in Anaphylaxis Simon G.A. Brown, MBBS, PhD, FACEM Emergency Medicine Research Unit, The University of Western Australia and Fremantle Hospital, Alma Street, Fremantle, WA 6160, Australia
In one large study of deaths due to anaphylaxis, circulatory shock was a prominent clinical feature in 54% of cases (67 of 125 cases), the sole mode of death in half of these; in the other half, it was combined with upper and/or lower airway obstruction [1]. In the same study, shock was more often a feature in lethal iatrogenic and venom anaphylaxis (61 of 87 cases, 70%) than in lethal food anaphylaxis (5 of 37 cases, 14%). This article examines the current understanding of the pathophysiology of shock in anaphylaxis and discusses the implications of this knowledge for clinicians and researchers. Clinical manifestations A brief overview of the physiological determinants of blood pressure is provided in Box 1. Shock does not necessarily equate with hypotension, but is defined broadly as a condition where blood flow to vital organs is insufficient to meet the metabolic demands of the body. In some forms of shock, compensatory mechanisms maintain blood pressure and thus cerebral function at normal or near-normal levels for a time despite peripheral circulatory failure and progressively worsening metabolic acidosis. During severe anaphylaxis there is usually a rapid onset of hypotension, neurological compromise, and cardiac arrest (median time to cardiac arrest 5 to 15 minutes after reaction onset) [1]. In nonlethal cases, hypotension during anaphylaxis is associated with nausea, vomiting, dyspnea, dizziness (presyncope), diaphoresis, collapse, unconsciousness, and incontinence [2]. There are four broad types of shock: hypovolemic, cardiogenic, distributive, and obstructive [3]. It generally is considered that shock in human anaphylaxis may comprise variable components of hypovolemia because of E-mail address: [email protected] 0889-8561/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2007.03.003 immunology.theclinics.com
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Box 1. Determinants of blood pressure and cardiac output 1: Blood Pressure ðBPÞfCardiac output ðCOÞ Systemic Vascular Resistance ðSVRÞ SVR is determined by the tone of the precapillary arterioles (resistance vessels). 2: COfHeart Rate Stroke volume Preload Contractility 3: Stroke Volumef Afterload Preload = myocardial fiber length before contraction (= ventricular end diastolic volume), which depends upon venous return; which in turn depends upon blood volume and the tone of the veins (capacitance vessels) Afterload = tension in the ventricular wall during contraction, which depends upon SVR (to resistance vessels), the size of the ventricle according to Laplace’s law, and other obstructions to flow such as aortic valve obstruction Contractility = the inherent ability of the heart to contract, independent of preload and afterload
capillary fluid leak [4–6], distributive shock caused by vasodilation [4,7–9], and cardiogenic shock caused by reduced contractility [10,11] and perhaps inappropriate bradycardia [12]. Pulmonary vasospasm also may introduce an obstructive component, by reducing left ventricular filling [13–16]. These multiple effects, reducing the ability of the body to compensate, probably explain the rapid onset of severe hypotension and unconsciousness that is characteristic of anaphylaxis. A close examination of the literature, however, reveals numerous inconsistencies and unanswered questions. Few studies adequately investigate cardiovascular parameters to define the precise cause of hypotension. Hypotension can be caused by reduced cardiac output and/or reduced systemic vascular resistance. As outlined in Box 1, a fall in cardiac output can be caused by any combination of reduced venous return to the chest, increased pulmonary vascular resistance reducing venous return to the left heart, myocardial depression caused by a direct effect of mediators and myocardial ischemia. Myocardial ischaemia may be caused by reduced coronary blood flow (and/or severe hypoxemia), and increased systemic vascular resistance causing increased afterload on the myocardium.
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Animal models and the concept of anaphylactic shock organs In addition to interspecies variations, complicating factors in the interpretation of animal models include the methods of initial sensitization (eg, passive versus active, type of antigen) and subsequent exposure (ingested, intravenous, or subcutaneous), and whether the animal is awake or anaesthetized with blunted reflex responses. Nevertheless, some valuable insights into potential pathophysiological mechanisms in people can be obtained from animal studies. Early studies found organ system involvement to vary between animal models, with the major organ involved being termed the shock organ for that particular species [17]. In the guinea pig, intense bronchospasm leading to hypoxia was considered the principal cause of death [17,18], leading to secondary cardiac ECG abnormalities comparable to those caused by asphyxia [19]. In rabbits, severe vasoconstriction in the pulmonary arterial system appeared to cause hypoxia and circulatory collapse, and again cardiac ECG abnormalities were considered to be secondary to asphyxia [19]. In dogs, severe hepatic congestion was considered the major cause of lethal shock. Subsequently the manifestations of guinea pig anaphylaxis have been shown to include, in addition to intense bronchospasm, progressive impairment of atrioventricular conduction leading to complete block, increased ventricular automaticity (including ventricular fibrillation) and cardiac contractile failure in both intact whole-animal and isolated-heart models, indicating that these occur independent of hypoxia [20,21]. Reduced coronary blood flow caused by increased coronary vascular resistance also has been demonstrated [22]. In a canine ragweed model of anaphylactic shock, increased pulmonary vascular resistance and increased systemic vascular resistance have been demonstrated, along with reduced venous return and reduced cardiac output [14,23–25]; however in one recent study by the same group using the same model, systemic vascular resistance appeared to fall in some dogs [26]. Increased pulmonary vascular resistance also has been demonstrated in a monkey model [16], and in some monkeys, cardiovascular collapse can be attributed to decreased venous return and pulmonary hypertension, whereas in others, the decrease in cardiac output is more severe and seems to be associated with reduced myocardial contractility [15].
Human cardiovascular collapse Arguably the most important human study to date is a series of 205 episodes of anaphylactic shock occurring under anesthesia, where the treating anesthesiologist was asked to provide detailed clinical and laboratory information immediately after the event [5,6]. In this study, extravasation of up to 35% of circulating blood volume within 10 minutes was evident by increases in hematocrit. Additionally, in 46 patients who had central and/or pulmonary artery
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placed before or soon after the onset of anaphylaxis, there was a significant fall in filling pressures except in nine of 11 patients with cardiac disease, in whom pressures were elevated. Even so, these patients appeared to need volume expansion to achieve a stable blood pressure. In all six patients who had balloon pulmonary artery catheters, pulmonary arterial pressure rose initially and then fell over the subsequent 10 minutes [6]. In a single case report of a patient with iatrogenic anaphylaxis for whom systemic vascular resistance was determined using a pulmonary artery catheter and cardiac output measurements, 3 hours into a reaction, there was increased pulmonary vascular resistance, reduced pulmonary capillary wedge pressure, reduced cardiac output, and slightly elevated systemic vascular resistance [13]. What peripheral vascular changes occur during human anaphylaxis? The peripheral skin flushing and fall in diastolic blood pressure (widened pulse pressure) and tachycardia seen early in human anaphylaxis are suggestive of dilation of both resistance and capacitance vessels [12]. During this time, a transient peak in histamine, a potent vasodilator of both arterioles and veins, has been shown to occur [27]. Beyond these observation, the precise vascular events during anaphylaxis have not been characterized in people. It generally is presumed on the basis of the sudden reduction of central venous pressure at reaction onset seen in people, animal studies, and known mediator effects, that venodilation (increased venous capacitance) leading to reduced venous return is a significant feature of human anaphylaxis. Severe vasodilation resistant to epinephrine (adrenaline) and responding only to potent vasoconstrictors has been described in human case reports [7,8]. Such reports, however, only can assume that vasodilation has occurred on the basis of an apparent response to a selective vasopressor. Whether the primary sites of vasopressor action in these cases were the capacitance vessels, resistance vessels or both, is unknown. Is the human heart a target organ during anaphylaxis? Severe reversible cardiac dysfunction associated with nonspecific electrocardiogram changes and normal coronary arteries also has been described during human anaphylaxis [10,11,27]. Numerous case reports have indicated that intravenous glucagon [28], the phosphodiesterase inhibitor amrinone [29], and intra-aortic balloon pump support [11] may be useful for treating resistant anaphylactic shock where cardiac dysfunction is a problem because of beta blockade, pre-existing impairment of left ventricular function, or cardiac anaphylaxis. The author also has observed global ST segment changes in a patient without any cardiovascular instability, suggesting a direct mediator effect on the human heart [12]. Nevertheless, cardiac dysfunction during anaphylaxis in people has been considered to be exceptionally rare [30]. Even in closely monitored cases, an
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obvious difficulty in determining the contribution of cardiac dysfunction to anaphylactic shock in people lies with the problems in dissecting this component from other pathological events [31]. In lethal cases, owing to a rapid and unpredicted demise, few if any detailed clinical observations are possible. Therefore, although numerous animal studies and human observations support the concept of anaphylactic mediators having direct effects on the myocardium [32], the contribution of this cardiac anaphylaxis to morbidity and mortality remains to be defined. The presence of mast cells in human cardiac (mainly peri-vascular) tissue is well-recognized [33–35]. ECG changes suggestive of myocardial ischemia and enzyme changes indicating infarction also have been reported within 24 hours of anaphylaxis [27,36–38]. This raises the possibility of mediatorinduced plaque ulceration and/or coronary spasm, ischemia secondary to hypotension, and a direct mediator effect on the myocardium. Also, high catecholamine levels (either therapeutic or caused by endogenous release) can have an adverse effect in the myocardium, including significant reductions in cardiac output, ischemic chest pain, and ECG changes in the absence of coronary artery disease [39]. All of these can be argued as potential mechanisms. Although attempts have been made on the basis of a few case reports to give this allergic coronary syndrome an eponym [40–42], some cases simply may represent coincidence, and the underlying mechanisms are speculative. Relative bradycardia during anaphylaxis While performing a randomized controlled trial of venom immunotherapy, the author observed eight hypotensive anaphylactic sting reactions, two of which were associated with severe bradycardia and treated with intravenous atropine [43]. A careful review of these reactions revealed that hypotension was preceded by a fall in diastolic blood pressure (suggesting reduced systemic vascular resistance) with tachycardia. Following this, in every case, the onset of hypotension was accompanied by a relative bradycardia. That is, rather than the heart rate further increasing to compensate for falling blood pressure, it fell as the blood pressure fell. We postulated that this may have been caused by a neurocardiogenic reflex, triggered by cardiac mechanoreceptors, and enhanced by increased levels of serotonin, catecholamines, prostaglandins, and nitric oxide that are known to potentiate this reflex and also are elevated during anaphylaxis [12]. More recently, C5a and adenosine have been implicated as a potential mediators of bradycardia during cardiac anaphylaxis in pigs [44]. Bradycardia also may be a nonspecific feature of severe hypovolemic–distributive shock in awake animals. Paradoxical bradycardia has been reported as a common feature of traumatic hypotension in people [45], and physiological studies of awake mammals have identified two phases of response to hypovolemia, an initial phase of blood pressure maintenance by
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tachycardia and peripheral arteriolar constriction, followed by a second phase with more severe hypovolemia characterized by bradycardia, reduced peripheral arteriolar tone and a profound fall in blood pressure [46]. However, bradycardia has not been reported as a feature of anaphylaxis under anesthesia, where tachycardia is the norm except when there has been prior beta blockade or severe hypoxia [6]. This may be explained by the blunting of central reflexes that occurs under anesthesia and/or different allergen routes and dosage. One cannot be sure whether bradycardia during anaphylaxis is maladaptive, potentiated by various mediators, or an adaptive process that triggers collapse to a supine position and a slower heart rate to allow the heart to adequately fill between contractions when there is a severe reduction in preload. Biochemical mediators In the early 20th century, histamine was thought to be the principal mediator of anaphylaxis [30]. Since then, a huge range of inflammatory mediators has been implicated in anaphylaxis by human studies, in vitro cell stimulation studies, and animal models. These include: Preformed mediators, released immediately by mast cells and basophils: histamine, heparin, tryptase, chymase, tumor necrosis factor a (TNF-a); Mediators generated over minutes by mast cells, basophils, and possibly other cells: platelet-activating factor (PAF), nitric oxide (NO), TNF-a, cyclo–oxygenase products of arachidonic metabolism (PGD2), and lipoxygenase products of arachidonic metabolism (leukotrienes LTC4, LTD4, and LTE4); Mediators generated over hours by mast cells, basophils and possibly other cells: interleukin (IL)-4, IL-5, IL-13, and GM-CSF Mediators generated by contact system activation: bradykinin, plasmin, and complement pathway anaphylatoxins C3a and C5a Although tissue mast cells and circulating basophils play a pivotal role, other cells including platelets, eosinophils, monocytes/macrophages, endothelial cells, and antigen presenting cells also have been implicated. The large numbers of mediators provide for significant redundancy and positive feedback mechanisms by which other effector cells are recruited to release more mediators. This has led to the concept of a mast cell–leukocyte cytokine cascade that initiates, amplifies, and perpetuates the allergic response [29]. Many of these mediators variously may cause systemic venodilation, increased capillary permeability, reduced myocardial contractility, and constriction of some vessels (eg, precapillary arterioles, coronary arteries, and pulmonary vasculature). Analyzing their roles in people is difficult because of the opportunistic nature of anaphylaxis research, not only because of
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the near-impossibility of establishing causal relationships, but also because much of the action occurs locally in the tissue where the reaction is initiated, because the presence of some mediators in serum such as histamine is transient [30], and because of technical difficulties assessing the concentrations of some mediators. Variability between individuals in patterns of mediator release and target organ sensitivity also may complicate interpretation. Platelet-activating factor, nitric oxide, and tumor necrosis factor a In mice, PAF and platelets appear to play a central role in the hypotension of anaphylaxis, and there is good reason to suspect a similar role in people [47]. PAF is released by mast cells, basophils, and platelets upon IgE-mediated activation, and it may exert its effects largely through the activation of endothelial nitric oxide synthase (eNOS) and excessive NO synthesis, causing intense venodilation and perhaps myocardial depression [48,49]. PAF also promotes the synthesis of TNF-a, which in turn promotes later PAF synthesis, and thus delayed-phase reaction recurrence [50].
Clinical perspective A summary of key pathological mechanisms of human anaphylactic shock classified as proven, likely, and uncommon is presented in Box 2. The large number of mediators with redundant effects underlying these mechanisms indicates that physiological antagonism with fluid resuscitation, epinephrine and perhaps potent vasopressors will be more effective than individual receptor antagonists such as antihistamines. Canine studies indicate that epinephrine works predominantly by increasing cardiac output through a direct beta effect on the heart rather than by improving venous return, and that only the intravenous infusion works in established shock, with subcutaneous and intramuscular injections being ineffective, and intravenous boluses having only a transient effect [24,26]. It should be noted, however, that these studies were in dogs in which severe anaphylactic shock had been precipitated, In many human cases with reactions of milder severity, epinephrine is likely to provide some vasoconstriction. Prospectively evaluated protocols for the infusion of epinephrine in people are available [12,51]. Aggressive fluid resuscitation (volume expansion, eg, 20 mL/kg of normal saline over 3 to 5 minutes, infused under pressure through a wide-bore intravenous line and repeated if necessary) is a critical treatment adjunct. It often is forgotten that resuscitation can be initiated by laying a patient flat and elevating his or her legs. Conversely the upright position, by further enhancing blood pooling in the lower extremities, can be lethal [52]. Anecdotally, some cases not responding to fluid resuscitation and epinephrine respond to additional treatment with potent vasopressors such
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Box 2. Key pathophysiologic mechanisms of human anaphylactic shock Common/clearly demonstrated: supported by unambiguous observations of human anaphylaxis Fluid extravasation causing hemoconcentration, hypovolemia and reduced venous return to the heart manifested as low filling pressures and reduction in cardiac output Likely: unproven but supported by animal studies, studies of histamine infusion in volunteers, known mediator actions, and/or indirect physiological observations during human anaphylaxis Venodilation and blood pooling, contributing to reduced venous return Impaired myocardial contractility contributing, along with reduced venous return, to reduced in cardiac output Relative bradycardia (neurally mediated) in awake patients, contributing to reduced cardiac output Early transient increase in pulmonary vascular resistance, contributing to the reduction in cardiac output by obstructing venous return to the left heart Early arteriolar dilation manifested as a widened pulse pressure and contributing to hypotension (however an increase in systemic vascular resistance caused by increased arteriolar tone may predominate after this early phase) Uncommon/postulated: based on case reports, speculation, plausible mechanisms Severe global depression of myocardial contractility with non-specific ST segment ECG changes (unresponsive to adrenaline) possibly more likely in those with underlying cardiac disease or taking beta blockers Severe arteriolar dilation as well as venous dilation Coronary ischemia caused by coronary vasospasm and plaque ulceration
as metaraminol and vasopressin [7–9]. Presumably these work primarily by an effect on venous (capacitance vessel) tone. Atropine also may be required when severe bradycardia is a feature [12], and phosphodiesterase inhibitor inotropes (including glucagon) and mechanical circulatory support have been reported to be effective in patients who have severely depressed myocardial function [11,28,53,54].
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Summary Although human studies are difficult to perform, the balance of evidence from human observations and animal studies suggests that the main pathophysiological features of anaphylactic shock are a profound reduction in venous tone and fluid extravasation causing reduced venous return (mixed hypovolemic–distributive shock) and depressed myocardial function. Aggressive fluid resuscitation is required to ameliorate hypovolemic–distributive shock, and an intravenous infusion of epinephrine will increase vascular tone, myocardial contractility, and cardiac output in most cases. Where these measures fail, pathophysiological considerations and anecdotal evidence support the consideration of selective vasoconstrictors as the next step in treatment.
References [1] Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000;30(8):1144–50. [2] Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114(2):371–6. [3] Weil MH. Personal commentary on the diagnosis and treatment of circulatory shock states. Curr Opin Crit Care 2004;10(4):246–9. [4] Beaupre PN, Roizen MF, Cahalan MK, et al. Hemodynamic and two-dimensional transesophageal echocardiographic analysis of an anaphylactic reaction in a human. Anesthesiology 1984;60(5):482–4. [5] Fisher M. Blood volume replacement in acute anaphylactic cardiovascular collapse related to anaesthesia. Br J Anaesth 1977;49(10):1023–6. [6] Fisher MM. Clinical observations on the pathophysiology and treatment of anaphylactic cardiovascular collapse. Anaesth Intensive Care 1986;14(1):17–21. [7] Heytman M, Rainbird A. Use of alpha-agonists for management of anaphylaxis occurring under anaesthesia: case studies and review. Anaesthesia 2004;59(12):1210–5. [8] Schummer W, Schummer C, Wippermann J, et al. Anaphylactic shock: is vasopressin the drug of choice? Anesthesiology 2004;101(4):1025–7. [9] Kill C, Wranze E, Wulf H. Successful treatment of severe anaphylactic shock with vasopressin. Two case reports. Int Arch Allergy Immunol 2004;134(3):260–1. [10] Hanashiro PK, Weil MH. Anaphylactic shock in man. Report of two cases with detailed hemodynamic and metabolic studies. Arch Intern Med 1967;119(2):129–40. [11] Raper RF, Fisher MM. Profound reversible myocardial depression after anaphylaxis. Lancet 1988;1(8582):386–8. [12] Brown SGA, Blackman KE, Stenlake V, et al. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004; 21(2):149–54. [13] Silverman HJ, Van Hook C, Haponik EF. Hemodynamic changes in human anaphylaxis. Am J Med 1984;77(2):341–4. [14] Silverman HJ, Taylor WR, Smith PL, et al. Effects of antihistamines on the cardiopulmonary changes due to canine anaphylaxis. J Appl Physiol 1988;64(1):210–7. [15] Pavek K. Anaphylactic shock in the monkey: its hemodynamics and mediators. Acta Anaesthesiol Scand 1977;21(4):293–307. [16] Patterson R, Fink JN, Wennemark J, et al. The biologic consequences of the immediate-type hypersensitivity transferred from man to monkey. J Allergy 1966;37(5):295–310.
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[17] Melli G, Folli G, Mazzei D, et al. Shock organ and shock tissue in various animal species. Acta Allergol 1963;18:188–210. [18] Auer J, Lewis PA. Physiology of the immediate reaction of anaphylaxis in the guinea pig. J Exp Med 1910;12:151–75. [19] Criep LH. Electrocardiographic studies of the effects of anaphylaxis on the cardiac mechanism. Arch Intern Med 1931;48:1098–108. [20] Felix SB, Baumann G, Berdel WE. Systemic anaphylaxisdseparation of cardiac reactions from respiratory and peripheral vascular events. Res Exp Med (Berl) 1990;190(4):239–52. [21] Capurro N, Levi R. The heart as a target organ in systemic allergic reactions: comparison of cardiac anaphylaxis in vivo and in vitro. Circ Res 1975;36(4):520–8. [22] Regal JF, Heller LJ. Cardiac anaphylaxis in isolated guinea pig hearts perfused at constant flow or constant pressure. Proc Soc Exp Biol Med 1987;185(2):193–200. [23] Mink S, Becker A, Sharma S, et al. Role of autacoids in cardiovascular collapse in anaphylactic shock in anaesthetized dogs. Cardiovasc Res 1999;43(1):173–82. [24] Mink SN, Bands C, Becker A, et al. Effect of bolus epinephrine on systemic hemodynamics in canine anaphylactic shock. Cardiovasc Res 1998;40(3):546–56. [25] Mink SN, Becker A, Unruh H, et al. Effects of anaphylaxis mediators on partitioned pulmonary vascular resistance during ragweed shock in dogs. J Appl Physiol 1998;84(3):782–90. [26] Mink SN, Simons FE, Simons KJ, et al. Constant infusion of epinephrine, but not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs. Clin Exp Allergy 2004;34(11):1776–83. [27] Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest 1980;66(5):1072–80. [28] Zaloga GP, DeLacey W, Holmboe E, et al. Glucagon reversal of hypotension in a case of anaphylactoid shock. Ann Intern Med 1986;105(1):65–6. [29] Otero E, Onufer JR, Reiss CK, et al. Anaphylaxis-induced myocardial depression treated with amrinone. Lancet 1991;337(8742):682. [30] Fisher M. Treating anaphylaxis with sympathomimetic drugs. BMJ 1992;305(6862):1107–8. [31] Cooper DJ. Cardiac dysfunction during anaphylaxis in patients. Appl Cardiopulm Pathophysiol 1993;5:9–18. [32] Marone G, Bova M, Detoraki A, et al. The human heart as a shock organ in anaphylaxis. Novartis Found Symp 2004;257:133–49 [discussion: 149–60, 276–85]. [33] Patella V, de Crescenzo G, Ciccarelli A, et al. Human heart mast cells: a definitive case of mast cell heterogeneity. Int Arch Allergy Immunol 1995;106(4):386–93. [34] Patella V, Genovese A, Marone G. What are human heart mast cells for? Chem Immunol 1995;62:171–86. [35] Patella V, Marino I, Lamparter B, et al. Human heart mast cells. Isolation, purification, ultrastructure, and immunologic characterization. J Immunol 1995;154(6):2855–65. [36] Austin SM, Barooah B, Kim CS. Reversible acute cardiac injury during cefoxitin-induced anaphylaxis in a patient with normal coronary arteries. Am J Med 1984;77(4):729–32. [37] Levine HD. Acute myocardial infarction following wasp sting. Report of two cases and critical survey of the literature. Am Heart J 1976;91(3):365–74. [38] Quercia O, Rafanelli S, Emiliani F, et al. Anaphylactic reaction to cinoxacin: report of one case associated with inferior acute myocardial infarction. Allerg Immunol (Paris) 2003;35(2): 61–3. [39] Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352(6):539–48. [40] Soufras GD, Ginopoulos PV, Papadaki PJ, et al. Penicillin allergy in cancer patients manifesting as Kounis syndrome. Heart Vessels 2005;20(4):159–63. [41] Koutsojannis CM, Kounis NG. Lepirudin anaphylaxis and Kounis syndrome. Circulation 2004;109(22):e315, author reply e315. [42] Kounis NG, Grapsas ND, Goudevenos JA. Unstable angina, allergic angina, and allergic myocardial infarction. Circulation 1999;100(25):e156.
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[43] Brown SGA, Wiese MD, Blackman KE, et al. Ant venom immunotherapy: a double-blind, placebo-controlled, cross-over trial. Lancet 2003;361(9362):1001–6. [44] Szebeni J, Baranyi L, Savay S, et al. Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function. Am J Physiol Heart Circ Physiol 2006;290(3):H1050–8. [45] Demetriades D, Chan LS, Bhasin P, et al. Relative bradycardia in patients with traumatic hypotension. J Trauma 1998;45(3):534–9. [46] Schadt JC, Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol 1991;260(2 Pt 2):H305–18. [47] Kasperska-Zajac A, Rogala B. Platelet function in anaphylaxis. J Investig Allergol Clin Immunol 2006;16(1):1–4. [48] Cauwels A, Janssen B, Buys E, et al. Anaphylactic shock depends on PI3K and eNOSderived NO. J Clin Invest 2006;116(8):2244–51. [49] Lowenstein CJ, Michel T. What’s in a name? eNOS and anaphylactic shock. J Clin Invest 2006;116(8):2075–8. [50] Choi IW, Kim YS, Kim DK, et al. Platelet-activating factor-mediated NF-kappaB dependency of a late anaphylactic reaction. J Exp Med 2003;198(1):145–51. [51] Brown SGA. Anaphylaxis: clinical concepts and research priorities. Emerg Med Australas 2006;18(2):155–69. [52] Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003;112(2): 451–2. [53] Andjelkovic I, Zlokovic B. Protective effects of glucagon during the anaphylactic response in guinea pig isolated heart. Br J Pharmacol 1982;76(3):483–9. [54] Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta blockers. Emerg Med J 2005;22(4):272–3.