Anaphylactic Shock: Mechanisms and Treatment 12, 89-100 A.F.T

Journal of REVIEW ARTICLE

Accident and J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from Emergency Medicine 1995 Anaphylactic shock: mechanisms and treatment 12, 89-100 A.F.T. BROWN

Department of Emergency Medicine, Royal Brisbane Hospital, Brisbane, Queensland, Australia

introduced the term 'allergy' although he assumed SUMMARY that the major allergic diseases, such as urticaria This paper reviews the mechanisms of and asthma, were due to the absence of anaphylactic shock in terms of the immunoglobulin antibodies.4 In 1921, Prausnitz and Kustner and non-immunoglobulin triggering events, and the demonstrated the ability to transfer a serum factor cellular events based on the rise in intracellular (termed reagin) in the serum of a sensitive patient cyclic AMP and calcium that release preformed to a non-sensitive recipient, although it was not granule-associated mediators and the rapidly until 1967 that Ishizaka and colleagues identified formed, newly synthesized mediators predo- this reagin as a new class of immunoglobulin minantly based on arachidonic acid metabolism. known as IgE. Finally, in 1975, Coombs and Gell These primary mediators recruit other cells with classified hypersensitivity reactions into three the release of secondary mediators that either immediate types and one delayed type, although potentiate or ultimately curtail the anaphylactic in practice these types need not necessarily occur reaction. The roles of these mediators in the various in isolation from each other.5 In immunological causes of cardiovascular collapse are examined. terms, anaphylaxis is an example of an immediate, The treatment of anaphylactic shock involves Type-1 hypersensitivity reaction. oxygen, adrenaline and fluids. The importance and safety of intravenous adrenaline are discussed. DEFINITION Combined Hi and H blocking antihistamines and

Currently, the term anaphylaxis is best used to http://emj.bmj.com/ steroids have a limited role. Glucagon and other describe the rapid, generalized and often adrenergic drugs are occasionally used, and unanticipated, immunologically mediated events several new experimental drugs are being that occur after exposure to certain developed. foreign substances in sensitized Key words: adrenaline, anaphylactic shock, previously persons. Anaphylactoid reactions describe a clinically anaphylaxis, histamine H1 receptor blockaders,

identical syndrome involving similar mediators but on September 24, 2021 by guest. Protected copyright. histamine H2 receptor blockaders not triggered by IgE antibody and not necessarily INTRODUCTION requiring previous exposure. Despite important aetiological distinctions, the term anaphylaxis is The first case of anaphylaxis was recorded on the commonly used to describe both of these clinical tomb of King Menes, an Egyptian Pharaoh who syndromes, even when the mechanisms are died suddenly in 2640 BC following a wasp sting.' unknown.3 The most common life-threatening The term anaphylaxis is derived from the Greek feature of acute anaphylaxis is cardiovascular and means literally 'against protection'.2 It was collapse or shock. Other life-threatening effects Correspondence: introduced in 1902 by Charles Richet and Paul include bronchospasm, angio-oedema and A.F.T. Brown, Portier following experiments with unexpected pulmonary oedema.6'7 This paper will focus on the Staff Specialist, fatal reactions on dogs sensitized to Portuguese mechanisms and both general and specific Department of man-of-war venom, observed the previous year treatment of anaphylactic shock. Emergency whilst on board Prince Albert of Monaco's yacht Medicine, Royal in the Brisbane Hospital, Mediterranean. Richet was subsequently awarded the Nobel Prize in Medicine and MECHANISMS OF Brisbane, ANAPHYLACTIC SHOCK Queensland 4029, Physiology in 1913.3 Australia At around the same time, in 1906, Von Pirquet Mechanisms of anaphylactic shock may be divided i 1994 Emergency Medicine A.F:T Brown into four main categories: the events that trigger the protein drugs acting as haptens such as antibiotics, anaphylactic reaction; the cellular events that then vitamins and steroids; vaccines; foods, including J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from lead to mediator release; the clinical pharmacology milk, fish and nuts; venoms, particularly of of these mediators; and finally the cardiovascular Hymenoptera; and many other substances as responses of patients to these mediators. diverse as ethylene oxide, hydatid cysts and latex.8 Latex allergy was first reported in 1979, and has MECHANISMS: TRIGGERING caused intra-operative anaphylactic reactions.12 In EVENTS addition, allergy to the latex catheter-tip used in barium enemas has also been recorded, most The events that trigger anaphylaxis are either commonly in children with spina bifida or anaphylactic and IgE immunologically mediated, congenital urological abnormalities.13 or anaphylactoid and non-immunoglobulin mediated, although in many reactions there is ANAPHYLACTOID REACTIONS evidence of the involvement of multiple pathways (see Table 1). Anaphylactoid reactions are non-immunoglobulin mediated and are caused by mediator release that ANAPHYLACTIC IgE is triggered independently of reaginic antibodies. ANTIBODY REACTIONS These reactions do not require prior exposure, and patients may not react on every occasion. Most cases of anaphylaxis are IgE, or rarely IgG4, Anaphylactoid reactions may be due to mediated.8 Following previous exposure to an complement activation, coagulation/fibrinolysis antigen, IgE reaginic antibodies are released into system activation, or the direct pharmacological the circulation by plasma cells derived from B- release of mediators.8 lymphocytes, under the influence of helper T-cells. These antibodies bind to glycoprotein receptors COMPLEMENT ACTIVATION on tissue mast cells or blood-borne basophils, thereby sensitizing them. Subsequent re-exposure Complement activation via the classical pathway to the antigen cross-links the Fab portions of two or alternate pathway leads to the formation of surface-bound IgE molecules, activating the cell anaphylatoxins C3a, C4a and C5a. These and triggering the release of chemical mediators.9'10 anaphylatoxins stimulate mast cells and basophils

In normal subjects there are up to 100 000 surface- to degranulate, releasing mediators that cause http://emj.bmj.com/ bound IgE molecules per mast cell, and in atopic local and systemic reactions. C3a and C5a also subjects up to half a million." directly induce increased vascular permeability, A vast range of substances induce IgE antibody smooth muscle contraction and neutrophil formation (see Table 2), including the following: chemotaxis.14,15 protein drugs such as insulin and ACTH; non-

COAGU LATION/FI BRINOLYSIS on September 24, 2021 by guest. Protected copyright. Table 1. Causes of anaphylaxis/anaphylactoid SYSTEM ACTIVATION reactions Activation of the coagulation/fibrinolysis system Anaphylactic: IgE mediated via Hageman Factor XII leads either to plasmin See Table 2 production and activation of complement, or to the production of kinins such as bradykinin that cause Anaphylactoid: Non-IgE mediated (1) Complement activation vasodilatation and increased vascular (a) Classical pathway permeability.8"11 (b) Alternate pathway (2) Coagulation/fibrinolysis system activation DIRECT PHARMACOLOGICAL (3) Direct pharmacological release of mediators (a) Direct histamine release RELEASE OF MEDIATORS (b) Modulators of arachidonic acid metabolism The pharmacological release of mediators is seen (c) Sulphiting agents with opioids or radiocontrast media that release (4) Physical histamine directly.1'617 Alternatively, aspirin and (a) Exercise induced other non-steroidal anti-inflammatory drugs 90 (5) Idiopathic modulate arachidonic acid metabolism by

1994 Emergency Medicine Anaphylactic Table 2. Common causes of IgE (1) Protein drugs (hormones) shock: antibody formation J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from Insulin, ACTH, vasopressin mechanisms and (2) Non-protein drugs (haptens) treatment (a) Antibiotics Penicillin, sulphonamides, cephalosporins (b) Vitamins Thiamine, folic acid (3) Vaccines (allergy probably to cultivating tissue) Pertussis, typhoid (4) Foods Eggs, fish, nuts, chocolate, fruits (5) Venoms Bee, wasp, fire ant, snake (6) Foreign protein agents Tetanus antitoxin, gamma globulin, venom antitoxin, semen (7) Enzymes Trypsin, chymotrypsin, penicillinase (8) Allergen extracts Pollen, mould, animal dander (9) Chemicals Ethylene oxide gas, formaldehyde (10) Parasites Hydatid cyst rupture (11) Latex Surgical gloves, catheter-tip

interfering with the cyclo-oxygenase pathway, plasma histamine, suggesting that other equally leading to enhanced formation of lipoxygenase important mediators are involved. Mast cells and products such as the leukotrienes. Mast cell circulating basophils are the key cells in the allergic degranulation is not involved.'4 response, and produce two main groups of mediators following triggering.22

RARE, PHYSICAL AND http://emj.bmj.com/ IDIOPATHIC CAUSES PRIMARY, PREFORMED, Rare causes of anaphylactoid reactions include GRANULE-ASSOCIATED sulphiting agents used as food preservatives, and MEDIATORS exercise-induced anaphylaxis, first described in 1980, in which anaphylaxis is triggered by exertion, First, antigen cross links two surface-bound IgE on September 24, 2021 by guest. Protected copyright. or exertion following food or specific single food molecules causing a transmembrane coupling items.18'19 Finally, idiopathic anaphylaxis is most protein to activate adenyl cyclase. This leads to a commonly seen in adults, the majority of whom short-lived rise in intracellular cyclic AMP, are asthmatic or atopic and who, after exhaustive activating protein kinases that catalyse the testing, are found to have no known cause of phosphorylation of certain cell proteins. A complex anaphylaxis.20'21 series of reactions, with microtubule formation allowing the movement of preformed granules towards the cell membrane, results in the release MECHANISMS: CELLULAR of mediators into EVENTS granule-associated the intercellular space.10'23 Primary, preformed, granule- Regardless of which of the above mechanisms associated mediators include the vasoactive triggers anaphylaxis, the cellular events leading to mediator histamine, chemotactic mediators such mediator release are similar. All the signs and as neutrophil chemotactic factor and eosinophil symptoms of anaphylaxis may be produced by chemotactic factor, enzymes such as tryptase, histamine. More severe reactions are usually chymase and beta-glucuronidase, and correlated with higher histamine levels. However, proteoglycans such as heparin and chondroitin 91 fatal reactions have occurred without elevation of sulphate24 (see Table 3).

1994 Emergency Medicine A.FT Brown Table 3. Preformed mast cell mediators the lipoxygenase pathway to form leukotrienes. These rapidly formed, newly synthesized primary J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from (1) Vasoactive mediator Histamine mediators include the following: prostaglandin D2; thromboxane A2; leukotrienes such as B4 (LTB4) and (2) Chemotactic mediators C, D and E4 (LTC4, LTD4 and LTE4) previously called (i) Neutrophil chemotactic factor slow-reacting substance of anaphylaxis; platelet - (ii) Eosinophil chemotactic factor activating factor (PAF); cytokines such as tumour necrosis factor and interleukins; adenosine and (3) Enzymes free oxygen radicals15'24 (see Table 4). (i) Neutral proteases At a cellular level, mediator release may be (a) Tryptase (b) Chymase modulated by the steady-state, resting intracellular (ii) Acid hydrolases cyclic AMP levels. The importance of this is that (a) Beta-glucuronidase substances that elevate cyclic AMP, such as (b) Beta-hexosaminidases adrenaline, inhibit mediator release, whereas (c) Arylsulphatase A substances that decrease cyclic AMP or increase reciprocal changes in cyclic GMP, such as (4) Proteoglycans cholinergic agents, augment mediator release.511 (i) Heparin (ii) Chondroitin sulphate MECHANISMS: CLINICAL RAPIDLY FORMED, NEWLY PHARMACOLOGY SYNTHESIZED MEDIATORS For simplicity, the actions of these primary mast Secondly, antigen causes receptor perturbation cell and basophil mediators may be divided into with the simultaneous opening of surface three categories5 (see Table 5). First, histamine, membrane calcium channels allowing an influx of PAF, tryptase and bradykinin are inflammatory calcium ions into the mast cell, leading to activation activators that induce vasodilatation and oedema. of phospholipase A2.10'11 This enzyme breaks down Secondly, histamine, prostaglandin D2, LTC4 and membrane phospholipids to release arachidonic LTD4 are spasmogens that cause bronchial smooth acid and lysophospholipid. Arachidonic acid is muscle contraction, increased mucus production then oxygenated by the cyclo-oxygenase pathway and mucosal oedema. Prostaglandin D2 is ten times http://emj.bmj.com/ to form prostaglandins and thromboxanes, or by more potent as a bronchoconstrictor than

Table 4. Rapidly formed, newly (1) Arachidonic acid metabolites synthesized mast cell mediators (i) Cyclo-oxygenase pathway (a) Prostaglandin D2

(b) Thromboxane A2 on September 24, 2021 by guest. Protected copyright.

(ii) Lipoxygenase pathway (a) Leukotriene LTB4 (b) Leukotrienes LTC4, LTD4 LTE4 (formerly called SRS-A: slow reacting substance of anaphylaxis)

(2) Platelet-activating factor (PAF)

(3) Cytokines (i) Interleukins (ii) Tumour necrosis factors (TNF) (iii) Granulocyte-macrophage colony-stimulating factor (GM-CSF)

(4) Adenosine

(5) Free oxygen radicals

1994 Emergency Medicine Anaphylactic Table 5. Actions of primary mast cell mediators Table 6. Causes of cardiovascular collapse in anaphylaxis

shock: J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from (1) Inflammatory activators and mechanisms (a) Histamine (1) Arrhythmias treatment (b) PAF (i) Direct mediator effects (c) Tryptase (ii) Hypoxia (d) Bradykinin (iii) Hypotension (iv) Acidosis (2) Spasmogens (v) Pre-existing cardiac disease (a) Histamine (vi) Exogenous drugs (b) Prostaglandin D2 (c) LTC4 (2) Hypovolaemia (d) LTD4 (i) Vasodilatation (ii) Increased vascular permeability (3) Chemotactic agents (iii) Decreased venous return (a) Neutrophil chemotactic factor (b) Eosinophil chemotactic factor (3) Decreased myocardial contractility (c) LTB4 (i) Hypoxia (ii) Myocardial ischaemia (iii) Acidosis histamine, and leukotriene D4 is up to 1 000 times (iv) Direct mediator effects more potent.25 Thirdly, neutrophil chemotactic (v) Exogenous drugs factor, eosinophil chemotactic factor and LTB4 are (4) Pulmonary hypertension chemotactic agents that attract a variety of new (i) Mediator-derived vasoconstriction cells to the area. (ii) Microvascular plugging Thus platelets, neutrophils, eosinophils, lymphocytes, monocytes, mast cells and basophils are recruited to the area. These newly recruited contractility and pulmonary hypertension are all cells in turn release secondary mediators of contributing factors29(see Table 6). Arrhythmias may anaphylaxis such as histamine-releasing factor, be due to direct mediator effects, hypoxia, major basic protein and lysosomal enzymes hypotension, pre-existing heart disease, acidosis causing more inflammation and tissue or exogenous drugs such as adrenaline.30 destruction.8'26 A further wave of mast cell Hypovolaemia results from a plasma volume loss

degranulation is induced, leading to a vicious cycle of up to 50% within 10 -15 min in severe reactions.31 http://emj.bmj.com/ of ongoing inflammation associated with increased This plasma volume loss is due to vasodilatation vascular permeability.24 with the peripheral pooling of blood in large capacity However, some of the secondary mediators splanchnic venous beds,32 increased vascular released, in particular by eosinophils, inhibit permeability with a shift of intravascular fluid to the anaphylaxis. For instance, histaminase breaks down extravascular space, and decreased venous return

histamine, arylsulphatase B inactivates the from raised intrathoracic pressures from broncho- on September 24, 2021 by guest. Protected copyright. leukotrienes, and phospholipase D destroys PAF.'1 spasm and positive pressure ventilation.' Decreased Furthermore, histamine itself, via H2 receptors, myocardial contractility is due to hypoxia, elevates intracellular cyclic AMP, thereby reducing myocardial ischaemia, acidosis, direct mediator mediator release.27'28 Thus the anaphylactic process effects and exogenous drugs such as beta-blockers may be self-limiting in less severe reactions. or calcium-channel blockers."333 Finally, pulmonary hypertension is due to mediator-derived vasoconstriction and to the plugging of microvascular MECHANISMS: CARDIOVASCULAR beds by aggregates of'platelets and neutrophils with RESPONSES secondary vasoactive mediator release.35'3 The final consideration in discussing mechanisms PRIMARY MYOCARDIAL of anaphylactic shock is the cardiovascular DEPRESSION response in humans to the primary and secondary mediators mentioned previously. Cardiovascular There is controversy over the existence in humans collapse is common in severe anaphylaxis.122 of primary myocardial depression in anaphylaxis.37 93 Arrhythmias, hypovolaemia, decreased myocardial Many authorities believe that significant primary

1994 Emergency Medicine A.FT Brown cardiac depression is seen only in patients with anecdotes, understanding of the pathophysiology

pre-existing cardiac disease.3032 Others report and, to a certain extent, animal studies.6 J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from cases of myocardial failure in patients without The severity of the reaction is related to the cardiac disease, although these are extremely speed of onset of symptoms. Parenteral rare.38 There are histamine receptors on the heart, administration of antigen is the route most often and in vitro histamine, prostaglandin D2, PAF and implicated in severe anaphylaxis, with the majority leukotrienes C4 and D4 cause coronary artery of reactions to intravenous drugs occurring within vasoconstriction and negative inotropic effects that 3 min.42 In addition, oral, topical and inhalational could all account for a degree of primary exposure to antigen have all been associated with myocardial depression.39 The situation is fatalities. Over 50% of people who die from complicated by the observation that histamine H2 anaphylaxis succumb within the first hour.43 In 75% receptors protect the heart by mediating coronary of cases the principal causes of death are asphyxia vasodilatation and increased myocardial from upper airway oedema and hypoxia from contractility. Therefore, the use of H2 receptor severe bronchospasm. In 25% of deaths there is blockers in anaphylactic shock should cause circulatory failure with hypotension.44 further clinical deterioration. Paradoxically, the opposite seems to be true, indicating that other INITIAL MANAGEMENT: pathways are operating.40'41 OXYGENATION The initial management of anaphylactic shock TREATMENT OF includes a rapid assessment of the extent and ANAPHYLACTIC SHOCK severity of the reaction, establishment of the The explosive nature, unpredictable onset and possibility of anaphylaxis, and cessation of further usually rapid response to treatment that absorption of the suspected agent. Maintenance characterize anaphylactic shock mean that few of an adequate airway, oxygenation, cardiac output controlled therapeutic trials have been undertaken and tissue perfusion with monitoring of vital signs, on humans.' Despite attempts to avoid or prevent ECG and pulse oximetry are essential. A careful reactions, the vast majority of serious anaphylactic watch is kept for the development of laryngeal reactions occur unexpectedly.3 Anaphylaxis is oedema or bronchospasm associated with the characteristically a disease of fit patients and is circulatory failure. Intubation and ventilation may rarely seen or described in critically ill or shocked be needed, and occasionally a surgical airway is subjects other than asthmatics.' Recommended required in the presence of gross laryngeal http://emj.bmj.com/ treatment is therefore based mainly on clinical swelling. The shocked patient should be placed in

Table 7. Treatment priorities in anaphylactic shock on September 24, 2021 by guest. Protected copyright. First line (1) Oxygen and airway maintenance (2) Adrenaline 1 in 100 000, 0.75-1.5 gg kg-' IV at 1 mL (10 ,ug) min-'. Follow by infusion at 1-4 ,ug min- (3) Colloid 10-20 ml kg-'IV.

Second line (1) Diphenhydramine 25mg IV and cimetidine 300mg IV slowly over 3-5 min, repeated at 6-h intervals. (2) Hydrocortisone 200mg IV at 6-h intervals (3) Glucagon 1 mg IV repeated at 5-min intervals, then infusion at 5-15 ,ug min-' (especially if on beta-blockers) (4) Vasopressors: noradrenaline (2-10 ,ug min-'), dopamine (5-20 gg kg-' min-') or metaraminol (30-200 ,ug mL-1) to maintain desired BPI

Anecdotal/experimental (1) Naloxone (2) MAST suit (3) Thryotropin-releasing hormone

94 IV, intravenous. All doses are quoted for a 70-kg adult.

1994 Emergency Medicine Anaphylactic the Trendelenburg position and rapid intravenous effects may have been responsible for the shock: access secured to support the circulation. The cardiovascular complications.54,55 J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from mechanisms and mainstay of treatment for anaphylactic shock is Fisher's leader in the British Medical Journal in treatment oxygen, adrenaline and fluids.' 3 22 (see Table 7). 1992 discussed the issues concerning the relevance and safety of intravenous adrenaline in anaphylaxis.6 He noted that no one route of ROLE OF ADRENALINE administration is likely to be right in all cases, and Adrenaline should be given to all patients with that the timing of administration of the drug may significant hypotension, airway swelling or be critical. He suggested that, as vasodilatation is bronchospasm.6 The actions of adrenaline reverse the main pathological change early in anaphylaxis, all features of anaphylaxis. Alpha-adrenergic this enables the subcutaneous or intramuscular stimulation increases peripheral vascular absorption of adrenaline to be rapid and effective. resistance and coronary artery perfusion raising Thus, when the disease is treated early and is the blood pressure, reverses peripheral progressing slowly, or venous access is difficult or vasodilatation and decreases angioedema and the patient is unmonitored, intramuscular urticaria.45 Beta-one-adrenergic stimulation has adrenaline has advantages in terms of safety and positive inotropic and chronotropic effects on is usually effective. Later, when intravascular cardiac muscle, and beta-two-adrenergic volume is depleted and shock occurs, or there is stimulation leads to bronchodilatation. Beta- severe dyspnoea or airway compromise, the adrenergic receptors also increase the production intravenous route is necessary to achieve optimal of intracellular cyclic AMP, which inhibits further absorption. In addition, Fisher considered that, in mast cell mediator release.4647 most cases, the recommended published intramuscular or subcutaneous doses were too high. ADRENALINE: DOSAGE AND He advised doses of 0.3-0.5mg of 1 in 1000 ROUTE adrenaline administered subcutaneously or Unfortunately, the correct dosage and route of intramuscularly, and he recommended that the administration of adrenaline have been a source standard intravenous dose should be up to 3 mL of confusion and conflict in the medical literature. of 1 in 10 000 adrenaline administered slowly. For instance, the British National Formulary Fisher concluded with the diplomatic assertion that

recommends 0.5-1.0 mg or 0.5-1 mL of 1 in 1000 'in severe anaphylaxis adrenaline by any route is http://emj.bmj.com/ adrenaline, administered intramuscularly, as the better than none'.6 standard initial adrenaline regime in anaphylaxis.48 The Association of Anaesthetists of Great Britain In the USA, 0.3-0.5 mg of 1 in 1000 adrenaline, and Ireland published a monograph in 1990 that administered subcutaneously, is recom- further supports the importance and safety of mended.3.14.26 In Sweden, 0.5-0.8 mg administered intravenous adrenaline in anaphylaxis.56 They subcutaneously, is recommended.49 The clinical recommended using adrenaline under ECG on September 24, 2021 by guest. Protected copyright. effectiveness of these dose variations is not well monitoring in an initial dose of 50-100pg, defined, nor is there convincing evidence for any particularly for hypotension or bronchospasm, difference in effect between the subcutaneous and followed by an infusion if prolonged therapy is intramuscular routes.6 The use of intravenous required. adrenaline in anaphylaxis is confounded by an even wider variation in proposed doses ranging from ADRENALINE: INTRAVENOUS DILUTION 1 pig min-1 to a 2-mg bolus.5051 Many authors conclude that the use of intravenous adrenaline is Finally, there is disagreement over the correct too dangerous and rarely if ever justified, as it dilution for the administration of intravenous causes cardiac arrhythmias, myocardial ischaemia adrenaline. Whilst the 1 in 10000 dilution is and severe hypertension.5253 However, cases cited favoured by some, a further tenfold dilution to 1 in from the literature to substantiate these claims fail 100 000 is suggested by many authors in order to to discuss the speed of delivery and concentration minimize adverse reactions.2944-4657 Thus Barach of the intravenous adrenaline administered, or to and Nowak recommend using 1 mL of 1 in 10 000 raise the possibility that other causes, such as adrenaline diluted to 10mL, giving a final 95 hypoxia, hypotension, acidosis and direct mediator concentration of 10pgmL ', administered under

This may be followed by an infusion from 1- Several authors have reported the successful J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from 4 ptg min-', according to Advanced Cardiac Life use of H2 receptor blockers in refractory Support (ACLS) guidelines, adding 1 mg (1 mL) of anaphylactic shock.4168 Although H2 receptor 1 in 1000 adrenaline to 250 ml of 5% dextrose in blockers should theoretically worsen cardiac water, giving a final concentration of 4 pg mL-1.58 function and increase mediator release by loss of histamine's own negative feedback inhibition, as discussed earlier, this has not been observed in ROLE OF FLUIDS clinical practice. However, until their role in shock Fluid therapy is recommended alongside is further established, H2 receptor blockers are not adrenaline in anaphylactic shock to replace the the drugs of first choice. plasma losses of up to 50% of the circulatory volume. A bolus of 10-20 mL kg-1 of colloid, given USE OF STEROIDS rapidly, most effectively restores the circulatory volume.2359 Some authorities prefer crystalloid for The role of steroids is also uncertain, as there is volume loading.445760 Others suggest the use of little evidence for any therapeutic benefit in fluids alone, questioning the central role of anaphylactic shock. Even if given intravenously, adrenaline.1'62 However, adrenaline and fluids they may take up to 4-6 h to be maximally should be given together, as there are compelling effective.814 Theoretical beneficial effects include arguments against using fluid alone, such as the an increase in tissue responsiveness to beta- additional efficacy of adrenaline in bronchospasm, adrenergic agonists, prevention of neutrophil and urticaria and angioedema, its ability to stabilize platelet aggregation, and inhibition of inflammatory mast cells and reduce further mediator release, and mediator synthesis.2969 Steroids are believed to the speed at which it may be administered, help prevent or shorten protracted reactions, particularly when intravenous access is delayed.' especially those associated with bronchospasm, although there is no clear guidance as to whether standard doses of 200 mg hydrocortisone, USE OF ANTIHISTAMINES administered intravenously at 6-h intervals, or high The roles of all other drugs used in the treatment doses of methyl prednisolone, up to 30 mg kg-', of anaphylactic shock are subsidiary to those of are best.' 3 However, oral steroid therapy is an

oxygen, adrenaline and fluids. In particular, essential part of the management of recurrent http://emj.bmj.com/ antihistamines and steroids should never be relied idiopathic anaphylaxis.21'70 upon alone as first-line therapy.' 22 There is conflicting and inconclusive data with regard to MISCELLANEOUS TREATMENT the use of antihistamines in anaphylaxis. On the basis of an extensive review of current data, The remaining treatment modalities that have been Lieberman concluded that for the prevention of tried in anaphylactic shock include vasopressors on September 24, 2021 by guest. Protected copyright. drug-induced anaphylactic and anaphylactoid such as noradrenaline, dopamine and metaraminol, reactions, combined Hi and H2 receptor blockade particularly when adrenaline and fluids have failed, is more effective than Hi blockade alone.63 although there is no conclusive data demonstrating Physiological rationale64 and a series of case any specific advantages in their use.'129 34 Glucagon reports indicate that combined H1 and H2 receptor is particularly recommended for patients on beta- blockade should also be more effective than H1 blockers, who appear to have more frequent and blockade alone in the treatment of anaphylaxis.65.66 severe anaphylaxis, resistant to standard However, controlled clinical trials are still awaited adrenergic therapy.71'72Glucagon raises intracellular to confirm this. Most importantly, antihistamines cyclic AMP by a calcium-dependent stimulation cannot have a central role in the management of which does not involve beta-adrenergic receptors, anaphylaxis, as the concentration of histamine in causing positive inotropic and chronotropic the vicinity of a mast cell after degranulation is so cardiac effects. The recommended dose is 1 mg great that, by the time anaphylaxis is diagnosed, it repeated every 5 min, followed by an infusion, is too late for a competitive blocker to be of value. although side-effects including nausea, vomiting, Furthermore, antihistamines do not actually dizziness, hypokalaemia and blood sugar 96 prevent mediator release, and mediators other than abnormalities necessitate care with its use.73

shock: and the MAST suit7677 have all been successful, USA)90 and aspirin or other non-steroidal anti- J Accid Emerg Med: first published as 10.1136/emj.12.2.89 on 1 June 1995. Downloaded from mechanisms and both experimentally and in occasional clinical inflammatory drugs are the two most common treatment cases. causes of anaphylactoid fatalities.91 The diagnosis of anaphylaxis is not difficult when ADMISSION AND MONITORING a patient presents with generalized urticaria, wheeze-and circulatory collapse following a bee Patients with significant anaphylactic reactions, sting. However, circulatory collapse may occur including all those presenting with shock requiring rapidly in anaphylaxis without preceding skin or adrenaline, should be admitted to a monitored respiratory manifestations. There is no immediately intensive-care area for at least 8-12 h following available laboratory test to confirm the diagnosis resolution of symptoms, as there is a risk of both of anaphylaxis. Serum tryptase levels are an protracted and biphasic responses to accurate marker of mast cell degranulation that anaphylaxis.1 811 Biphasic responses were may be measured up to 6 h after the event by observed in up to 20% of patients in Stark and radioimmunoassay, but they are restricted to Sullivan's original description in 1986 of 25 specialized immunology laboratories.92 Thus, the consecutive cases of anaphylaxis, most frequently purely clinical recognition and prompt treatment following oral antigen exposure or when symptoms of anaphylaxis represents one of the ultimate commenced over 30 min after exposure. They challenges to emergency physicians in their daily noted that hypotension, laryngeal oedema or practice. bronchospasm recurred from 1 to 8 h after an apparently symptom-free response to therapy.78 The incidence of biphasic anaphylaxis was much ACKNOWLEDGEMENT lower (approximately 1 %) in 276 cases of The author wishes to thank Hazel Sonter for her anaesthesia-related anaphylaxis reported by tireless efforts in the preparation of this document. Fisher.' This paper has been published by kind permission of the Editor of Emergency Medicine. THERAPY IN THE FUTURE In the future, new experimental drugs to treat REFERENCES anaphylaxis, targeted specifically at the various 1. Fisher M.M. (1987) Anaphylaxis. Disease A Month http://emj.bmj.com/ recognized mediators of anaphylaxis, will become 33, 441-479. available. These agents may include H3 receptor 2. Weiszer I. (1985) Allergic emergencies. In: Allergic modulators,79-81 platelet-activating factor Diseases: Diagnosis And Management (ed. Patterson antagonists,8283 leukotriene synthesis inhibitors, R.) pp. 418-439. Lippincott, Philadelphia. leukotriene antagonists, thromboxane synthetase 3. Bochner B.S. (1991) Anaphylaxis. New England inhibitors, neurokinin antagonists,84 free oxygen Journal of Medicine 324, 1785-1790. on September 24, 2021 by guest. Protected copyright. radical scavengers,85 nitric oxide synthesis 4. Samter M. (1987) Allergy and immunology 1947- blockers,86 and calcium-channel-blocking drugs.87 1987. Postgraduate Medicine 82, 147-150. Hippocrates stated that 'Between wisdom and 5. Roitt l.M. (1989) Hypersensitivity - Type I. In: medicine there is no gulf fixed; in fact medicine Immunology (ed. Roitt l.M.), pp. 19.1-19.20. possesses all the qualities that make for wisdom'.88 Blackwell Scientific Publications, Oxford. Ultimately, the success of these new experimental 6. Fisher M.M. (1992) Treating anaphylaxis with sympathomimetic drugs. British Medical Journal drugs will indicate how much we actually know 305, 1107-1108. about anaphylactic shock, and how much we still 7. Soreide E., Buxrud T. & Harboe S. (1988) Severe have left to learn. anaphylactic reactions outside hospital: etiology, symptoms and treatment. Acta Anesthesiologica CONCLUSIONS Scandinavica 32, 339-342. 8. Soto-Aguilar M.C. & de Shazo R.D. (1987) The three most common causes of anaphylactic Anaphylaxis. Why it happens and what to do about fatalities are parenteral penicillin administration it. Postgraduate Medicine 82, 154-170. (100-500 deaths per year in the USA), Hymenoptera 9. Roitt l.M. (1991) Hypersensitivity. In: Essential stings (40-100 deaths per year in the USA) and Immunology (ed. Roitt l.M.), pp. 253-275. Blackwell 97 food-related reactions.89 Radio-contrast media Scientific Publications, Oxford.

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