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Management of anaphylaxis in
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Worth, Soar & Sheikh

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Recognition & differential diagnoses

The incidence of anaphylaxis is widely c...
Management of anaphylaxis in the emergency setting

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IgE. Historically, these type 1 immediate
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Worth, Soar & Sheikh

Box 2. National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Net...
Management of anaphylaxis in the emergency setting

Review

anaphylaxis suffers cardiac arrest, standard
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Worth, Soar & Sheikh

Anaphylactic reaction?

Airway, Breathing, Circulation, Disability, Exposure

Diagnosis – lo...
Management of anaphylaxis in the emergency setting

Atropine may be given to treat bradycardia
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In...
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Worth, Soar & Sheikh

Antihistamines and oral steroid therapy may also be prescribed
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Management of anaphylaxis in the emergency setting

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  1. 1. Review For reprint orders, please contact reprints@expert-reviews.com Management of anaphylaxis in the emergency setting Expert Rev. Clin. Immunol. 6(1), 89–100 (2010) Allison Worth, Jasmeet Soar and Aziz Sheikh† Author for correspondence Allergy & Respiratory Research Group, Centre for Population Health Sciences: General Practice Section, University of Edinburgh, 20 West Richmond Street, Edinburgh EH8 9DX, UK Tel.: +44 131 651 4151 Fax: +44 131 650 9119 aziz.sheikh@ed.ac.uk † Anaphylaxis is a life-threatening emergency that appears to be increasing in frequency. It affects males and females of all ages and ethnic groups. The most common triggers include foods, drugs and venom from stinging insects, although any of a number of other triggers may also be implicated. Death, when it occurs, tends to be due to respiratory and/or cardiovascular compromise, but most of these fatalities can be prevented by appropriate avoidance measures and emergency management. The management of anaphylaxis is hampered by scientific and clinical uncertainty. KEYWORDS : adrenaline • allergy • anaphylaxis • antihistamines • corticosteroids • emergency management • epinephrine • long-term management Anaphylaxis is a potentially lethal allergic emergency. Time is of the essence as, when fatal, death usually occurs very rapidly after exposure to the trigger. The management of anaphylaxis is often hindered by scientific and clinical uncertainty. There is, for example, no universally agreed definition of anaphylaxis, and its true incidence is therefore unknown. Emergency management has furthermore been described as based mainly on extrapolation and anecdote rather than robust scientific evidence [1,2] . There is considerable variation in international guidelines on emergency management [3–7,101] , and these discrepancies reflect this scientific uncertainty [8,9] . A recent comparison of international guidelines [9] found consensus on the use of epinephrine (adrenaline), but little agreement on the role of other approaches, with differences on the use of corticosteroids, antihistamines, oxygen, bronchodilators and patient positioning. The authors called for the strength of evidence underpinning guideline recommendations to be made much more explicit. Clinical decision making is also reported to be flawed, with misdiagnosis and a lack of knowledge about the correct course of action and correct administration of rescue medication commonplace [10–12] . This review aims to present the best available evidence to support the effective, systematic management of anaphylaxis in the emergency setting. Definition Descriptions of anaphylaxis date back to the Ancient Egyptian period, but it was not until just over a century ago that Richet and www.expert-reviews.com 10.1586/ECI.09.73 Portier first coined the term ‘anaphylaxis’ to describe the fatal reactions they induced when trying to immunize dogs to the venom of sea anemone. The term anaphylaxis was used to indicate that, rather than offer protection, they had inadvertently induced an inappropriately exaggerated response. There are a number of available working definitions of anaphylaxis [13] and important international differences in criteria for diagnosis. For example, the European Academy of Allergy & Clinical Immunology (EAACI) definition, modified by the Resuscitation Council (London, UK) [6,101] emphasizes the nature of the reaction and suggests that the most important clinical features are respiratory and/or cardiovascular involvement. The working definition is: “Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction. This is characterised by rapidly developing life-threatening airway and/or breathing and/or circulation problems usually associated with skin and mucosal changes” [101] . By contrast, the second National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network (NIAID/ FA AN) symposium on the definition and management of anaphylaxis [3] , on which US guidelines are based, suggested the following broad definition: “Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death’’. We discuss international differences in clinical criteria for recognizing anaphylaxis later. © 2010 Expert Reviews Ltd ISSN 1744-666X 89
  2. 2. Review Worth, Soar & Sheikh Epidemiology Recognition & differential diagnoses The incidence of anaphylaxis is widely considered to be underestimated, as many patients experiencing anaphylaxis will not present for medical attention. Even when they do present, they may be misdiagnosed as suffering from a range of other conditions, such as asthma. Anaphylaxis is not even always recognized at postmortem examination [1,101] . A review of international epidemiological studies suggested that incidence lies between 30 and 950 cases per 100,000 persons per year, with a lifetime prevalence of 0.05–2% [14] . Case–fatality ratios have been reported to be less than 1% in a number of case series, although figures of up to 5% have been published [15–19] . There are approximately 20 anaphylaxis deaths reported each year in the UK and 1500 in North America, although as noted previously these are widely believed to be underestimated [20–22,101] . People with poorly controlled asthma have been shown in a number of case series to have a higher risk of death, particularly if epinephrine use is delayed [20] . Young people are also at increased risk of severe and fatal episodes [23–25] , as are those with peanut allergy [26] . Epidemiological work from the UK, studying cases of anaphylaxis resulting in hospitalization, has revealed quite marked independent variations in anaphylaxis rate by age, gender, geography and socioeconomic profile, with the usual socioeconomic gradient of higher admission rates in deprived populations being reversed [27] . There are only limited epidemiological data on trends over time in anaphylaxis and, where available, these suggest there may be important increases in disease frequency taking place. A striking increase in the rate of hospital admissions for anaphylaxis in England has been noted, from 0.5 to 3.6 admissions per 100,000 patients between 1990 and 2004, an increase of 700% [28] . Increases have also recently been noted in a US study, although the magnitude of the increase is less marked than that reported in England [29,30] . Recognition of anaphylaxis can be problematic in an emergency setting and this can hinder effective treatment. Paradoxically, it is both under- and over-recognized, with many patients who are genuinely experiencing anaphylactic reactions not treated appropriately with epinephrine, whereas in other cases epinephrine may be given inappropriately for mild allergic reactions and panic attacks, for example [11,29] . Anaphylaxis can be difficult to recognize if it is the first episode or if a trigger is not apparent [24,29] . Diagnosis is particularly difficult in young children, who are likely to be experiencing a first episode and who may furthermore be unable to articulate subjective symptoms [35] . Skin manifestations can be transient and can be overlooked in children, among whom respiratory features dominate [1,17] . Anaphylaxis can begin with apparently minor symptoms and progress rapidly to a life-threatening reaction, death can occur within minutes of onset, reactions may also be biphasic (recurrent) or protracted [36] , and its course is therefore difficult to predict [10] . Clinical presentation varies, with no single set of criteria able to identify all anaphylactic episodes; some diagnostic errors are therefore inevitable [101] . Certain combinations of signs do, however, make the diagnosis of anaphylaxis more likely [3,37,101] . Again, however, international experts disagree over the clinical criteria for recognizing anaphylaxis. The Resuscitation Council suggests criteria based on the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach, commonly used to treat medical emergencies in general for the recognition of anaphylaxis (BOX 1) . The NIAID/FAAN symposium proposed three clinical criteria for diagnosing anaphylaxis, which they suggest recognize the varied presentations of anaphylaxis rather than emphasizing respiratory and/or circulation problems (BOX 2) . They suggest that 80% of cases of anaphylaxis should be identified by criterion 1, which emphasizes skin symptoms, with criteria 2 and 3 picking up those without obvious skin symptoms and with more unusual presentations. Less severe systemic allergic reactions with generalized urticaria, angioedema and rhinitis lack the characteristic life-threatening airway, breathing and/or circulatory problems, and should therefore not be classed as anaphylaxis. Differential diagnoses include severe asthma, septic shock, vasovagal reactions, panic attack, hypotension, numerous causes of skin rashes, hereditary angioedema, ‘restaurant syndromes’ such as scombroid fish poisoning, syndromes associated with flushing and systemic mastocytosis [1, 4,5,24,38,101] . TABLE 1 considers important differential diagnoses and reviews features that may help to distinguish these conditions from anaphylaxis. Care must be taken, however, not to diagnose dyspnea and bradycardia as anxiety [1] . Triggers Anaphylaxis is most commonly triggered by food, drugs and venom, with latex, immunotherapy, contrast media and exerciseinduced anaphylaxis also being well-known triggers [2,3,31] . Physical causes, such as heat, cold and UV light, are also recognized. Foodinduced anaphylaxis is most frequent in children – milk, eggs, peanuts and other legumes, tree nuts, fruit, fish and shellfish are particularly important triggers. In adults, peanuts, tree nuts, fish and shellfish are common causes [26] . Medicines are the most common triggers in older people; specifically, muscle relaxants used during anesthesia, antibiotics, nonsteroidal anti-inflammatory drugs and aspirin [32] . The venom of stinging insects such as wasps and bees is also an important seasonal trigger. In many cases, particularly in adults, however, no trigger can be identified: anaphylaxis was judged to be idiopathic in 59% of 601 cases reviewed retrospectively in one very large US-based case series [33] . The role of cofactors such as inter-current illness, stress, alcohol and exercise is also important in that the presence of these factors may reduce the threshold of exposure needed to trigger a reaction – this phenomenon has been labeled as ‘summation anaphylaxis’ [34] . 90 Pathophysiology Although IgG- and IgM-dependent immunological reactions have been described, in most cases anaphylaxis involves the release of a range of inflammatory mediators from mast cells and/or basophils following allergen interaction with cell-bound Expert Rev. Clin. Immunol. 6(1), (2010)
  3. 3. Management of anaphylaxis in the emergency setting Review IgE. Historically, these type 1 immediate Box 1. UK guidelines on the recognition of anaphylaxis. hypersensitivity or ‘anaphylactic reactions’, as they were known, were distinguished “A diagnosis of anaphylaxis is likely if a patient who is exposed to a trigger (allergen) from the less common, but nonetheless develops a sudden illness (usually within minutes of exposure) with rapidly progressing important, ‘anaphylactoid reactions’, skin changes and life-threatening airway and/or breathing and/or circulation problems. The reaction is usually unexpected” [101] . which involve non-IgE-mediated or even nonimmune release of mediators. This Features suggestive of anaphylaxis: Anaphylaxis is likely when all of the following three criteria are met: mechanistic distinction is largely now 1. Sudden onset and rapid progression of symptoms AND seen as redundant in clinical practice, as 2. Life-threatening airway and/or breathing and/or circulation problems AND the clinical picture and emergency treat- 3. Skin and/or mucosal changes (flushing, urticaria or angioedema) ment of anaphylaxis are similar regardless The following supports the diagnosis: of trigger factor or pathophysiological • Exposure to a known allergen for the patient mechanisms [39] . Remember: The release of histamine and other • Skin or mucosal changes alone are not a sign of an anaphylactic reaction inflammatory mediators are responsible for • Skin and mucosal changes can be subtle or absent in up to 20% of reactions (some the vasodilation, capillary leak and bronchopatients can only have a decrease in blood pressure, that is, a circulation problem) spasm that can lead to shock, edema and • There can also be gastrointestinal symptoms (e.g., vomiting, abdominal pain wheeze in patients with anaphylaxis. or incontinence) Although diagnosis is clinical, serum Reproduced from Resuscitation Council (UK) [101]. mast cell tryptase measurements can be useful in cases of diagnostic uncertainty at follow-up. Tryptase which clinicians in any setting might find particularly useful as is the major protein component of mast cell secretory granules it applies the ABCDE approach commonly used for other medical and can lead to markedly increased blood tryptase concentra- emergencies to recognizing and treating anaphylaxis [101] . This tions in anaphylaxis and mast cell degranulation [40,101] . Mast ABCDE approach involves the assessment of: cell tryptase levels can, therefore, be useful in confirming the • Airway: airway swelling, hoarseness and stridor diagnosis of anaphylaxis once the initial treatment phase is complete. The optimal timing of measurement is between 1 • Breathing: shortness of breath, wheeze, tiredness, confusion due to hypoxia, cyanosis and respiratory arrest and 2 h after the onset of the reaction; mast cell tryptase has a short half-life and thus serial measurements over a 24-h period • Circulation: signs of shock, tachycardia, hypotension, faintness, from the onset of the reaction are recommended if possible. collapse, loss of/decreased consciousness, ECG changes and Serum tryptase is, however, generally not raised in food-induced cardiac arrest anaphylaxis; the role of other biomarkers including mast cell carboxypeptidase and platelet-activating factor acetylhydol- • Disability: confusion, agitation and loss of consciousness ase for the diagnosis of anaphylaxis are the subject of ongoing • Exposure: skin and/or mucosal changes – erythema, urticaria investigation [24] . and angioedema Clinical features Virtually any organ system can be affected. As noted previously, the UK guidelines indicate that involvement of the cardiovascular and/or respiratory systems are essential for diagnosis, but not all experts agree, and the NIAID/FAAN guidelines emphasize skin changes more than respiratory and cardiovascular symptoms. Cutaneous symptoms are particularly common, affecting the vast majority of affected individuals. BOX 3 details the main clinical features that tend to occur in anaphylaxis. It is important to note that, although shock has been considered an essential feature of anaphylaxis, this is no longer the case as it is now recognized that many people develop important symptoms but do not manifest symptoms of shock. Emergency management Compared with the previous situation in which there were different algorithms depending on first responder, the most recent Resuscitation Council guideline on the emergency treatment of anaphylactic reactions simplifies this to an ABCDE approach, www.expert-reviews.com The anaphylaxis algorithm sets out the keys steps in treatment (FIGURE 1) . Assessment Anaphylaxis is a dynamic process, requiring prompt intervention and then periodic reassessment [1,7,31,38] . Life-threatening features typically manifest early, but may become apparent up to an hour after the onset of symptoms. Anaphylaxis should be considered wherever upper airway obstruction, bronchospasm or hypotension is present, and the diagnosis is supported by skin/ mucosal features as outlined before [1,101] . The priority is the assessment of physiological compromise to determine the severity of the reaction and rapid treatment of life-threatening symptoms [1,10] . Once these are managed, assessment should include the removal of possible triggers, obtaining a detailed history and, in particular, information on possibly relevant exposures, and a detailed examination. Careful recording of this information is often helpful in later confirming if the diagnosis is correct and guiding future management [1] . 91
  4. 4. Review Worth, Soar & Sheikh Box 2. National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network clinical criteria for diagnosing anaphylaxis. Anaphylaxis is highly likely when any one of the following three criteria are fulfilled: 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue or both (e.g., generalized hives, pruritus or flushing, swollen lips/tongue/uvula), and at least one of the following: a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF or hypoxemia) b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope or incontinence 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush or swollen lips/tongue/uvula) b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF or hypoxemia) c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope or incontinence) d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain or vomiting) 3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP * b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that person’s baseline * Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 1 year of age, less than (70 mmHg + [2 × age]) from 1 to 10 years of age, and less than 90 mmHg from 11 to 17 years of age. BP: Blood pressure; PEF: Peak expiratory flow. Reproduced from [3]. Previous history of anaphylaxis is a risk factor for recurrence [41] . Patients with a history of atopy and asthma are also at increased risk of severe anaphylaxis [25,33] . Core principles of emergency anaphylaxis management Emergency treatment of anaphylaxis begins with an ABCDE assessment and the instituting of basic and advanced life-support measures if necessary. Epinephrine injected intramuscularly is the key treatment for anaphylaxis and subsequent interventions depend on the patient’s response to it [7,10,25] . Rapid treatment is very important to ensuring the best possible outcome [7,10] . Epinephrine Universal agreement exists on the central role of epinephrine in the emergency treatment of anaphylaxis and recent guidelines appear to be moving towards consensus on dose, route of administration and timing of administration [42] . The scientific basis Table 1. Differential diagnosis of anaphylaxis. Condition Distinguishing feature Acute urticaria Generalized rash in the absence of respiratory symptoms and/or hypotension Angiodema and No flushing, pruritis, urticaria, bronchospasm hereditary or hypotension angiodema History of C1-esterase inhibitor deficiency Globus hystericus No clinical evidence of upper respiratory obstruction No flushing, pruritis, urticaria, angiodema, bronchospasm, hypotension Vasovagal episode Bradycardia not tachycardia. No urticaria, pruritis, angioedema or upper respiratory obstruction Pallor instead of flushing Nausea without abdominal pain Adapted from [38]. 92 for these considerations on dosage, route and timing of administration is weak in humans, with limited supporting evidence coming from work in canine models [43,44] . Although there are no randomized, controlled trials assessing the effectiveness of epinephrine in humans, its use is supported by consistent case reports and case series of its value in restoring adequate cardiac output and easing respiratory distress [45] . Epinephrine has both -adrenergic effects, which result in vasoconstriction, and -adrenergic effects, which result in inotropic and chronotropic effects on the heart, and bronchodilation; it also stems the release of inflammatory mediators, therefore helping to abort the reaction [45,101] . Epinephrine is indicated for all patients with the life-threatening features of anaphylaxis. It is best delivered by intramuscular injection. If the patient fails to improve, further doses can be given at repeated 5-min intervals. The antero-lateral aspect of the thigh is the optimal site for injection, both in order to maximize the speed of absorption while also minimizing the risk of adverse effects. The recommended doses are based on what is considered to be safe and practical to draw-up and inject in an emergency situation [101] . The most directive guideline is from the Resuscitation Council [101] , which recommends precise dosing regimens (BOX 4) . Other guidelines suggest a range, such as 0.2–0.5 ml for adults [3] . Weight rather than age is an alternative advised method for determining epinephrine dose in children; 0.01 mg/kg intramuscularly every 5–10 min as necessary [4] . Intravenous epinephrine administration is not recommended in the UK guidelines, except when used by experts in specialist settings (e.g., intensivists, anesthetists and emergency physicians), and even then only with cardiac monitoring due to the smaller margin for error and the increased risk of inducing fatal cardiac arrhythmias, myocardial ischemia and severe hypertension [101] . The doses of epinephrine given intravenously are much smaller than the recommended intramuscular doses and require careful titration to avoid these harmful side effects. If a patient with Expert Rev. Clin. Immunol. 6(1), (2010)
  5. 5. Management of anaphylaxis in the emergency setting Review anaphylaxis suffers cardiac arrest, standard Box 3. Clinical features of anaphylaxis. guidelines for cardiopulmonary resuscitation should be followed, including intravenous General epinephrine administration using the much • Anxiety, malaise, weakness, feeling of impending doom larger doses of intravenous epinephrine • Paresthesia (hands, lips/mouth and tongue), dry mouth, abnormal taste in the mouth (1 mg in adults) that are recommended for Cutaneous, subcutaneous and mucosal tissues cardiac arrest treatment. • Nasal congestion, rhinorrhoea, conjunctival erythema, tearing It is a matter of concern that, given • Itch – often localized to the palms or soles, groin, armpit, face/eyes or nose the importance of rapid administration • Flushing (erythema, typically most noticeable on the face, neck and upper trunk), of epinephrine to prevent mortality and urticaria (typical skin wheals and erythema), periorbital edema morbidity, it is under-used by clinicians, • Angioedema of the tongue, lips, ears, neck and other areas of the body including in emergency settings [12,46–48] . Gastrointestinal/abdominal In retrospective reviews of the treatment • Nausea, vomiting, abdominal pain including uterine contraction pain or diarrhea of patients with insect sting allergy and Respiratory food allergy, only 12% of patients with • Upper airway edema causing difficulty speaking and/or swallowing, hoarse voice, stridor systemic reactions to insect sting and 16% • Chest or throat tightness/pain, dyspnea, tachypnea, bronchospasm, cough of patients with anaphylactic reactions to • Hypoxemia/central cyanosis food were treated with epinephrine [12,46] . • Respiratory arrest Gaeta et al. found that second-line treatments were more commonly used to treat Cardiovascular anaphylaxis in US emergency departments • Tachycardia than epinephrine – that is, antihistamines • Hypotension with either tachycardia or a relative bradycardia were used for 63% of patients and steroids • Diaphoresis and circulatory failure (capillary refill >2 s) with pallor and/or peripheral cyanosis for 61%, but epinephrine for only 50% of patients [48] . Confusion about the correct • T inversion and/or ST depression in multiple leads (with or without chest pain), arrhythmias route of administration is also common; • Cardiogenic shock and pulmonary edema* one UK study presenting case studies to senior house officers (residents) starting • Cardiac arrest work in emergency departments found Neurological that 42% would choose to use intravenous • Throbbing headache epinephrine, and of those using the recom- • Dizziness/presyncope, visual loss, loss of consciousness, incontinence‡ mended intramuscular route, only 20% • Confusion§ suggested using the correct dose. Only *Cardiogenic shock and pulmonary edema appear to be uncommon, and are probably more likely to occur disease. 5% suggested administering epinephrine in those with underlying cardiacnot always, associated with hypotension and poor cerebral perfusion. ‡ These features are usually, but § in accordance with the Resuscitation Confusion appears to have a strong association with hypoxemia rather than hypotension. Council guidelines [11] . Factors contribut- Adapted from [1]. ing to the reluctance to administer epinephrine in the emergency setting include clinicians’ perceptions infusion of 500–1000 ml in an adult and 20 ml per kg in a child of its potential for adverse effects, and lack of experience and should be given, the response monitored and further doses given knowledge about treating anaphylaxis [22] . These studies sup- as necessary [101] . Crystalloids (e.g., 0.9% sodium chloride or port the contention that guidelines on anaphylaxis management Hartmann’s solution) are recommended if a colloid is thought are often not followed in practice [3,10,12,22] . to be the original cause of the anaphylaxis [3,101] . Patient positioning Oxygen Patients should be placed in a position comfortable to them, depending on their symptoms. Lying flat with elevated legs is advised for patients with hypotension, as this may increase stroke volume and cardiac output in patients with vasodilatory shock [3,101] . Patients with breathing problems or vomiting may prefer to sit up, but if the patient feels faint they should not sit or stand up, as this can cause cardiac arrest and death [3,49,101] . High-flow oxygen should also be given as soon as possible, particularly where respiratory distress and/or hypoxia are apparent [3,101] . Pulse oximetry should be used to guide oxygen therapy [50] . Fluids Intravenous fluids should be given as soon as possible, and this is particularly important in patients with signs of shock. A rapid www.expert-reviews.com Antihistamines H1-antihistamines such as chlorphenamine can be used as a second-line treatment for anaphylaxis, as the relatively slow onset of action means they have little impact on the initial reaction [3,4,101] . They are, however, useful for the symptomatic treatment of urticaria, angioedema and pruritus [4,39] . The 93
  6. 6. Review Worth, Soar & Sheikh Anaphylactic reaction? Airway, Breathing, Circulation, Disability, Exposure Diagnosis – look for: • Acute onset of illness • Life-threatening airway and/or breathing and/or circulation problems1 • Usually skin changes Call for help Lie patient flat Raise patient’s legs Adrenaline2 When skills and equipment are available: • Establish airway Monitor: • High-flow oxygen • Pulse oximetry • IV fluid challenge3 • ECG • Chlorphenamine4 • Blood pressure • Hydrocortisone5 1. Life-threatening problems: Airway: swelling, hoarseness, stridor Breathing: rapid breathing, wheeze, fatigue, cyanosis, SpO2 < 92%, confusion Circulation: pale, clammy, low blood pressure, faintness, drowsy/coma Some guidelines do not recommend H2 antagonists such as cimetidine and ranitidine [1,101] ; a US guideline recommends them cautiously in combination with H1 antagonists [4] ; and an Australian review recommends oral selective nonsedating antihistamine use only for the symptomatic relief of skin symptoms [1] . Glucocorticoids Corticosteroids have no role in the acute management of anaphylaxis, as they may have no effect for 4–6 h [3] . They are a possible second-line treatment, which may help reduce the risk of biphasic reactions or shorten protracted reactions, and they may be of use in patients with concurrent asthma [4,101] . There is little evidence on which to base the use of steroids in anaphylaxis, with recommendations based on their use in asthma [1,3] . Steroids are usually given by slow intravenous or intramuscular injection; care is needed to avoid inducing further hypotension [101] . An ongoing Cochrane review of the use of glucocorticoids is examining the evidence base for their use in anaphylaxis [51] . Other drugs Bronchodilators can safely be administered in those individuals experiencing asthma-like symptoms. Bronchodilators are best given through the inhaled route, although intravenous administration may Stop IV colloid if this occasionally be necessary [101] . might be the cause of anaphylaxis Some animal work and several case reports suggest that adding low-dose vasopressin to the emergency treatment regimen of anaphylaxis may, through revers4. Chlorphenamine: 5 Hydrocortisone: ing the histamine-induced vasodilatation, (IM or slow IV) (IM or slow IV) help reverse cardiovascular collapse in Adult or child over 12 years of age 10 mg 200 mg anaphylactic shock and thereby improve Child 6–12 years of age 5 mg 100 mg Child 6 months–6 years of age 2.5 mg 50 mg outcomes [52–57] . Child under 6 months of age 250 µg/kg 25 mg Glucagon given as an intravenous infusion may have a role in those with refractory anaphylaxis, particularly in patients Figure 1. Anaphylaxis algorithm. taking -blockers, which can attenuIM: Intramuscular; IV: Intravenous; SpO2: Oxygen saturation measured by ate the effects of epinephrine [5] . This pulse oximetry. is because glucagon has inotropic and recommended route of administration is by slow intravenous or chronotropic effects on the heart that do not rely on the stimintramuscular injection, the dose depending on age [101] . There is, ulation of - and -adrenergic receptors, and its use can thus however, little robust evidence for their use [39] . Based on animal potentiate the effects of epinephrine. However, the evidence models, it has been suggested that they may, if administered base in support of glucagon is weak, as with all other treatparenterally, be harmful in anaphylaxis, the main risk being the ments, consisting of only a few case reports in humans and induction of cardiac arrhythmias [1,9] . some animal work [58] . 2. Adrenaline (give IM unless experienced with IV adrenaline): IM doses of 1:1000 adrenaline (repeat after 5 min if no better) • Adult 500 µg IM (0.5 ml) • Children over 12 years of age 500 µg IM (0.5 ml) • Children 6–12 years of age 300 µg IM (0.3 ml) • Children under 6 years of age 150 µg IM (0.15 ml) Adrenaline IV to be given only by experienced specialists Titrate: adults: 50 µg; children: 1 µg/kg 94 3. IV fluid challenge: Adult: 500–1000 ml Child: crystalloid 20 ml/kg Expert Rev. Clin. Immunol. 6(1), (2010)
  7. 7. Management of anaphylaxis in the emergency setting Atropine may be given to treat bradycardia if this develops [1,4] . Investigations Review Box 4. Recommended doses of adrenaline in anaphylaxis. Adrenaline im. dose – adults: • 0.5 mg im. (= 500 µg = 0.5 ml of 1:1000) adrenaline Guidelines suggest that investigations Adrenaline im. dose – children (the equivalent volume of 1:1000 adrenaline is appropriate for any medical emergency, shown in brackets): such as 12-lead ECG, chest x-ray, urea • >12 years: 500 µg im. (0.5 ml) – that is, same as adult dose and electrolytes, and arterial blood gases, • 300 µg (0.3 ml) if child is small or prepubertal should be carried out [101] . Diagnosis of • >6–12 years: 300 µg im. (0.3 ml) anaphylaxis is largely based on clinical • >6 months–6 years: 150 µg im. (0.15 ml) assessment and a good history. Mast cell • <6 months: 150 µg im. (0.15 ml) tryptase levels can help to confirm the im.: Intramuscularly. diagnosis once initial treatment is complete Reproduced from Resuscitation Council (UK) [101]. The provision of epinephrine auto-injectors is a matter of [101] . Timing of blood samples is crucial, as tryptase concentrations in the blood may not increase significantly until 30 min or some debate, particularly in relation to children, as there is more after the onset of symptoms, and peak 1–2 h after onset [40] . concern that auto-injectors may have a detrimental psychoThe half-life of tryptase is short ( 2 h), and concentrations may logical effect on children and their carers [62,63] . Furthermore, be back to normal within 6–8 h. Serial measurement is therefore there are risks associated with the incorrect administration of recommended if possible, with an initial sample taken as soon as epinephrine, mainly inadvertent injuries to the thumb and finthe resuscitation process allows; a second sample 1–2 h after the ger, emphasising the need for training in correct use of the onset of symptoms and a third sample at 24 h or later to provide auto-injector device [64] . The Resuscitation Council recommends that prescription of self-injectable epinephrine is given baseline levels [23,59,101] . to patients at high risk of further episodes, along with educaMonitoring & discharge tion on its use [101] . Auto-injectors are not usually required for Following treatment of initial problems, patients with suspected patients with drug-induced anaphylaxis, as avoidance is likely anaphylaxis should be observed for at least 6 h in case further to be relatively straightforward, but are necessary for patients life-threatening symptoms occur [101] . Observation times should with idiopathic or venom- and food-induced reactions [101] . be individually determined, based on the severity of the reac- Sampson et al. report that consensus indicates auto-injector tion and a patient’s ability to access care rapidly after discharge prescription for patients who have experienced respiratory or should a biphasic reaction occur [4] . Biphasic reactions may occur cardiovascular symptoms from exposure to a known allergen in up to 20% of patients, in most cases within 6–8 h of the pri- in the community, but also point out that this would exclude mary reaction, but occasionally up to 72 h later [60] . Although a significant proportion of high-risk individuals [3] . Although unpredictable, with little understanding about their true inci- guidelines generally advocate the prescription of epinephrine dence, they appear to be most likely in idiopathic anaphylaxis, auto-injectors, many patients leave emergency settings without in patients with severe asthma, where absorption of the allergen them [48,65] . There is also debate on the number of auto-injectors may be continuing, and in those with a history of biphasic reac- to be given, with some arguing that two or more auto-injectors tions [60,101] . In these circumstances, patients should be observed should suffice, so that if the first preparation is not appropriately for a longer period (e.g., 24 h) or until their symptoms settle [4] . administered, or if there is a failure to respond, the second can Caution may also be appropriate when considering discharge of then be given [66] . A repeat dose of epinephrine in the treatment patients at night or where access to emergency care is difficult of food-induced anaphylaxis has been estimated as necessary [101] . All patients who have experienced severe anaphylaxis should in up to 20% of cases [67,68] . Others argue that the vast majorbe reviewed by a senior clinician prior to discharge and given clear ity of individuals will respond to the first injection [69] . More instructions to return to hospital if their symptoms recur [101] . importantly, however, is the need for patients and carers to be Recording details of the anaphylactic episode is important, appropriately trained in the use of these auto-injectors, which but often done inadequately [31,48] . In the interests of patient in itself is something of an uphill struggle, as many clinicians safety, flagging a patient’s case notes or electronic record with are themselves not competent in the use of auto-injectors [64,70] . a clear warning, particularly when a patient has experienced There are currently only two preparations of epinephrine autodrug-induced anaphylaxis, should help to reduce accidental re- injector available, namely the 0.15-mg preparation intended for exposure [61] . Better communication between the emergency children under 30 kg and the 0.3 mg preparation for those weighdepartment, primary and specialist care is needed [7] . Inadequate ing 30 kg and over. This limited range of preparations poses coding and recording of anaphylactic events contributes to the the potential risk of excessive administration in the very young lack of knowledge about its prevalence, although this is in part although, on balance, the convenience of using an auto-injector due to inconsistent definitions [7,48] . The creation of national and pen (as opposed to a parent being asked to draw up a more optiEuropean databases is important to generate better quality data mal dose from a vial in an emergency) is thought to outweigh and improve the management of anaphylaxis [7] . the risks [71,72] . www.expert-reviews.com 95
  8. 8. Review Worth, Soar & Sheikh Antihistamines and oral steroid therapy may also be prescribed for up to 3 days to treat urticaria and possibly reduce the chance of further reactions [101] . Post-treatment follow-up Although this review focuses on emergency management, we would argue that those treating anaphylaxis in emergency settings have a responsibility to consider long-term management of anaphylaxis, as this can potentially improve patient outcomes [3,31,38] . Anaphylaxis should be conceptualized as a long-term condition, with supported patient self-management instigated at the point of initial diagnosis, which may well be in the emergency setting. Most cases of anaphylaxis can be managed in the emergency department as long as follow-up is arranged, including referral to an allergy clinic and clear discharge information on emergency care and long-term management [17] . Before leaving the emergency department, patients who have experienced anaphylaxis need to know how to recognize the early symptoms of anaphylaxis and how to use emergency medication [101] . They should, if possible, also receive information on the allergen responsible, advice on allergen avoidance and advice about ongoing management, as well as referral for a more detailed follow-up evaluation [20,22,25,101] . Individual anaphylaxis management plans are widely advocated as beneficial in reducing episodes of anaphylaxis, although there are no randomized, controlled trials [73,74] . Management plans should include a brief, clear emergency action plan and information about triggers, their avoidance and prevention of emergencies [7,31,38,73–78] . The use of a medical alert system, such as a MedicAlert ® bracelet, should also be recommended to ensure first responders in any future emergency have information about the patient’s condition. The clinicians’ ability to educate patients and their families in the recognition of anaphylaxis and management of emergencies is, however, often inadequate [3,23] . Furthermore, failure to refer to allergy clinics is common. In one Scottish study, 40% of children with life-threatening reactions attending a pediatric emergency department received no follow-up, a finding echoed in other international studies [12,17,65,79] . Patients’ lack of knowledge contributes to deaths from anaphylaxis [20] and the opportunity to improve patient care is being lost in the emergency department [3,22] . A study of fatal reactions indicates that the most important aspects of advice in preventing deaths are allergen avoidance, optimal management of asthma and patient alertness to risk [20] . Referral to an allergy specialist for further investigation and an individual management plan is optimum but often not arranged [65] ; in one Australian study, only 28% of patients were referred to an allergist from the emergency department and 19% had no follow-up arranged [17] . Lieberman et al. designed the acronym ‘SAFE’ to improve ongoing supportive care arranged by emergency department personnel for patients who have experienced anaphylaxis [22] . SAFE comprises the essential advice and arrangements to be discussed with the patient prior to discharge from the emergency setting: 96 • Seek support: advise on actions to be taken if further reactions occur • Allergen identification: emphasize the need for allergen avoidance and testing, and avoidance strategies • Follow-up for speciality care: advise or arrange follow-up in primary care and/or with an allergy specialist • Epinephrine: prescribe self-injectable epinephrine and instruction for its use in emergencies The patient’s primary care physician should be informed of the event, treatment given and any follow-up arranged. Patient support organizations such as the Anaphylaxis Campaign in the UK and the Food Allergy and Anaphylaxis Network in the USA can provide information and education to support self-management. The specialist assessments that should follow any emergency admission for anaphylaxis will also offer the opportunity to investigate for potential triggers using either in vitro or in vivo testing, or a combination of the two. An allergy specialist will also optimize management of any comorbidity (e.g., asthma) and review the use of medication, which may increase the risk of poor outcomes in future reactions (e.g., discontinuing -blockers). An allergy specialist may also consider the opportunity for more curative treatment in the form of desensitization therapy, particularly in those with venom- and aspirin-induced anaphylaxis. Although still early days, oral desensitization therapy also appears promising in relation to certain foods such as peanuts, milk and eggs [80–82] . Expert commentary Anaphylaxis is an inherently slow-moving field. This is due in part to the rarity of the condition under study, the fact that episodes tend to be very short-lived, and that conducting research in the context of a potentially lethal medical emergency is, invariably, extremely difficult. That said, progress is being made, both in relation to trying to agree on a working definition for anaphylaxis [3] , developing a better understanding of its epidemiology internationally [13,14] , and identifying the means to risk stratify and identify those who are at most risk of poor outcomes [24] . The role of better biomarkers for those at risk is currently also being pursued internationally. For example, recent work has identified the potentially important role of the inflammatory mediator platelet-activating factor, and in particular the risks associated with low levels of platelet-activating factor acetylhydrolase activity in those with fatal outcomes [83] . Recent work has also started to make explicit the lack of a sound evidence-base for the treatments currently employed to manage anaphylaxis. It is hoped that such work will, in due course, help stimulate the development of more explicit guidelines for anaphylaxis management and, more fundamentally, the much needed intervention studies. These will most probably begin by establishing the efficacy and effectiveness of second-line agents such as antihistamines and corticosteroids. Experimental studies on aspects of longer term management, such as the use of anaphylaxis management plans, Expert Rev. Clin. Immunol. 6(1), (2010)
  9. 9. Management of anaphylaxis in the emergency setting different alerting mechanisms and oral desensitization, are also planned and these will, in addition, help to clarify the evidence with respect to these approaches. While all of the aforementioned would certainly help in improving aspects of clinical care, the one issue that would most probably help in improving outcomes – and in particular reduce fatalities – is the prompt use of epinephrine where indicated. Currently, however, there seems to be considerable professional, patient and carer reluctance to its administration, with the effect that lives may needlessly be lost. Five-year view The biggest change that we anticipate over the next 5 years is the more widespread use of oral and perhaps cutaneous desensitization therapies in those with food-induced anaphylaxis. By this Review time, a clearer idea of the longer term impact of these potentially exciting disease-modifying treatment approaches will, we believe, also have emerged. We hope that there will also be, within this period, more consistent use of epinephrine, at least by professionals, when clearly indicated. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Key issues • Anaphylaxis is a life-threatening emergency that appears to be increasing in frequency. • Management of anaphylaxis is often hindered by scientific and clinical uncertainty, with no universally agreed definition of anaphylaxis or knowledge of its true incidence. • Emergency management is based mainly on expert clinical opinion rather than robust scientific evidence. • Recognition of anaphylaxis can be difficult in an emergency setting, and this can hinder effective treatment. • Clinical presentation varies, with no single set of criteria able to identify all anaphylactic episodes, but certain combinations of signs make the diagnosis of anaphylaxis more likely. • Emergency treatment of anaphylaxis begins with an intramuscular epinephrine injection and subsequent interventions depend on the patient’s response. • Rapid treatment is crucial for recovery and survival. • Prompt use of epinephrine where indicated would most probably help in improving outcomes and, in particular, fatalities. Currently, however, there seems to be considerable professional, patient and carer reluctance to the administration of epinephrine. • Anaphylaxis should be viewed as a long-term condition, with supported patient self-management instigated in the emergency setting. • Patients with suspected anaphylaxis should attend an emergency department for assessment and treatment. • Emergency departments should have arrangements to ensure the further investigation and follow-up of patients with suspected anaphylaxis. • Over the next 5 years, the more widespread use of oral and perhaps cutaneous desensitization therapies in those with food-induced anaphylaxis is likely. Anaphylaxis Network symposium. J. Allergy Clin. Immunol. 117, 391–397 (2006). References Papers of special note have been highlighted as: •• of considerable interest 1 Brown SGA. Anaphylaxis: clinical concepts and research priorities. Emerg. Med. Australas. 18, 155–169 (2006). •• Comprehensive review of the literature on the emergency management of anaphylaxis. 2 Simons FER, Sheikh A. Evidence-based management of anaphylaxis. Allergy 62, 827–829 (2007). 3 Sampson HA, Munoz-Furlong A, Campbell RL et al. Second symposium on the definition and management of anaphylaxis: summary report – Second National Institute of Allergy and Infectious Disease/Food Allergy and •• www.expert-reviews.com The views of an international group of experts working towards a universally accepted definition of anaphylaxis, improving recognition and outlining research needed to improve management. 4 Joint Task Force on Practice Parameters. The diagnosis and management of anaphylaxis: an updated practice parameter. J. Allergy Clin. Immunol. 115, S483–S523 (2005). 5 American Heart Association. Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 10.6: Anaphylaxis. 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  12. 12. Review Worth, Soar & Sheikh Website 101 Working Group of the Resuscitation Council (UK). Emergency treatment of anaphylactic reactions. Resuscitation Council (UK), London, UK (2008) www.resus.org.uk/pages/reaction.pdf •• Most recent guideline on emergency management of anaphylaxis, aiming to clarify and simplify guidance on recognition and treatment for ease of translation into clinical settings. 100 Affiliations • Allison Worth, BSc (Hons), PhD Research Manager/Senior Research Fellow, Allergy & Respiratory Research Group, Centre for Population Health Sciences: General Practice Section, University of Edinburgh, 20 West Richmond Street, Edinburgh EH8 9DX, UK Tel.: +44 131 650 9463 Fax: +44 131 650 9119 allison.worth@ed.ac.uk • • Aziz Sheikh, MD, FRCP, FRCGP Professor of Primary Care Research and Development, Allergy & Respiratory Research Group, Centre for Population Health Sciences: General Practice Section, University of Edinburgh, 20 West Richmond Street, Edinburgh EH8 9DX, UK Tel.: +44 131 651 4151 Fax: +44 131 650 9119 aziz.sheikh@ed.ac.uk Jasmeet Soar, FRCA Chair, Resuscitation Council UK, Consultant in Anaesthetics & Intensive Care Medicine, Southmead Hospital, North Bristol NHS Trust, Bristol BS10 5NB, UK Tel.: +44 117 323 5114 Fax: +44 117 323 5075 jasmeet.soar@nbt.nhs.uk Expert Rev. Clin. Immunol. 6(1), (2010)
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