The Emergency Medical Treatment of Anaphylactic Reactions
Objective of document
Recognition of anaphylactic and anaphylactoid reactions
Considerations in relation to treatment
Recommendation for management
Anaphylaxis seems to be increasingly common, almost certainly associated with an appreciable increase in the prevalence of allergic disease over the last two or three decades. Although the drug treatment and management of anaphylaxis is described elsewhere,1 anaphylaxis continues to be poorly managed. There are two main problems. First, adrenaline (epinephrine) is greatly under-used: chlorphenamine (chlorpheniramine) and hydrocortisone injections are given more often. Second, there has been a vogue for inappropriate use of intravenous adrenaline, both by paramedics and in Accident & Emergency departments, when adrenaline should have been given intramuscularly.
Published recommendations for the management of anaphylaxis also vary. This document provides a broad consensus on the appropriate emergency management of acute anaphylactic reactions by first medical responders and community nurses who are unlikely to have specialised knowledge.
No definitive clinical trials exist to provide an unequivocal evidence base: moreover such evidence is unlikely to be forthcoming. A wealth of experience does, however, exist. This has been integrated through the wide membership of the Project Team which was convened under the aegis of the Resuscitation Council of the United Kingdom with representation from five Royal Colleges and three specialist associations: other members were co-opted because of their individual expertise.
Consensus was achieved after two meetings and multiple circulation of working papers. An earlier document from broadly the same group (but at that time representing the Joint Royal Colleges and Ambulance Liaison Committee) has dealt with the management of anaphylaxis by paramedics - who are often the first to attend out of hospital emergencies.2 This complementary document offers guidance to community nurses, general practitioners and Accident & Emergency staff who are usually the first to become involved. Anaphylactic reactions may occur after vaccinations, within hospital as a result of attempted hyposensitisation, after the administration of drugs including anaesthetic agents, or with contrast media. Some specialist groups have issued recommendations for the management of emergencies that occur under these specific circumstances.3 4 5 6 The present guidance is not intended to replace existing advice for defined groups in hospital nor to influence the essential individual advice and management provided in specialist clinics.
2. Recognition of anaphylactic and anaphylactoid reactions
2.1. There are no universally accepted definitions of anaphylactic and anaphylactoid reactions. Disparate mechanisms can lead to serious symptoms and signs due to sudden activation of mast cells and basophils. The term anaphylaxis is commonly used for hypersensitivity reactions typically mediated by immunoglobulin E (IgE). Anaphylactoid reactions are similar, but do not depend upon hypersensitivity. For simplicity the term anaphylaxis will be used here for both types of reactions unless there is an important distinction to be made. Their manifestations and management are similar so that the distinction becomes important only for follow-up management. Both may present clinically with angio-oedema, urticaria, dyspnoea, and hypotension. But some patients may die from acute irreversible asthma or laryngeal oedema with few more generalised manifestations. Other symptoms include rhinitis, conjunctivitis, abdominal pain, vomiting, diarrhoea, and a sense of impending doom. The skin colour usually changes: the patient may appear either flushed or pale. Cardiovascular collapse is a common manifestation 7 especially in response to intravenous drugs or stings, and is caused by vasodilatation and loss of plasma from the blood compartment. Any cardiac dysfunction is due principally to hypotension, or rarely to an underlying disease,8 9 or to adrenaline that has been administered intravenously.10
Anaphylactic reactions vary in severity and progress may be rapid, slow, or (unusually) biphasic.11 Rarely manifestations may be delayed by a few hours (adding to diagnostic difficulty), or persist for more than 24 hours.8 Reactions may follow exposure to a variety of agents - with insect stings, drugs or contrast media, and some foods being the most common. Peanut and tree nut allergy now accounts for a significant incidence of anaphylaxis.12 Muscle relaxants may cause anaphylaxis whilst anaesthetic agents are important causes of anaphylactoid reactions.3 13 Beta blockers may increase the severity of an anaphylactic reaction and antagonise the response to adrenaline.14 They may also increase the incidence of anaphylaxis, but the data are limited.14 15 The complex nature of anaphylaxis has been described in reviews.16 17 18
2.2. The lack of any consistent clinical manifestation and a wide range of possible presentations may cause diagnostic difficulty. Clinical experience has shown that many patients with genuine anaphylaxis do not always receive appropriate medication. Rarely, patients have been given injections of adrenaline inappropriately for vasovagal reactions or panic attacks. Diagnostic problems have arisen particularly in children. Guidelines for the management of shock from anaphylaxis must therefore take into account the inevitability of some diagnostic errors, with an emphasis on the need for safety of any recommended measures.
2.3. In each case, a full history and examination should be undertaken as soon as circumstances permit. The history of previous allergic reactions is important as well as that of the recent incident. Special attention should be paid to the condition of the skin, the pulse rate, the blood pressure, the upper airways, and auscultation of the chest. Peak flow should be measured where possible, and recorded.
2.4. Investigations prove anaphylactic sensitivity to an allergen by giving a challenge with the suspect agent. But an attempt should always be made retrospectively to assess the likelihood that a severe reaction was genuinely of an anaphylactic nature. Whilst this is a matter for a specialist clinic rather than part of emergency management, a possible anaphylactic emergency provides an opportunity for specific blood tests. Measurements of specific IgE antibody are useful but must be interpreted carefully. Measurement of mast cell tryptase can also assist with retrospective diagnosis.19 Both of these tests can be performed on 10 mL of clotted blood which hospitals can send to a reference laboratory. Ideally blood should be taken 45 to 60 minutes after the reaction, but in any case not later than six hours after the event. The use of blood tests is to be encouraged because future management can be helped by increased diagnostic certainty.
2.5. No reliable epidemiological data are available on the incidence of anaphylaxis partly because of the difficulty defining anaphylactic reactions, but one study found an incidence of 1:2300 attendees at an Accident & Emergency Department, (equivalent to 1 episode per 15,000 of the population per annum) and fourfold more (1 in 3,700 pa) in the second part of the study the following year.20 Another report, published since this monograph went to press, showed that 1 in 5800 emergency inpatient admission had a primary diagnosis of anaphylaxis.20a A detailed prospective survey of fatal and severe reactions in children 0-15 years, conducted primarily through British Paediatric Surveillance Unit, will be available in 2002.20b The overall mortality, however, is unknown. Some allergens may cause short lived sensitivity. Only a minority of patients may suffer second attacks in response to penicillin 21 and contrast agents, and approximately half do so after insect stings.22 Peanuts on the other hand, may leave patients with a persisting predisposition to anaphylaxis after a first attack, but eventual resolution occurs in some.
3. Considerations in relation to treatment
3.1. Adrenaline is generally regarded as the most important drug for any severe anaphylactic reaction,7 although there has been no standard recommendation for dose or route. As an alpha-receptor agonist, it reverses peripheral vasodilatation and reduces oedema. Its beta-receptor activity dilates the airways, increases the force of myocardial contraction, and suppresses histamine and leukotriene release. Adrenaline works best when given early after the onset of the reaction 23 but it is not without risk, particularly when given intravenously.10 But adverse effects are extremely rare with appropriate doses administered intramuscularly; the only reported case of myocardial infarction had numerous risk factors for coronary disease.24 Sometimes there has been uncertainty as to whether complications (for example myocardial ischaemia) have been due to the effects of the allergen itself or to adrenaline given as treatment for it.
3.2. Adrenaline is generally the only drug available for use by community nurses. After consultation with representatives of the Department of Health and the British National Formulary, the guidelines were modified for use in this setting.25 It is anticipated, however, that patients who have had this first line treatment will be transferred rapidly to hospital where any necessary further measures can be taken.
3.3. Adrenaline may rarely fail to reverse the clinical manifestation of anaphylaxis, especially in late reactions or in patients treated with beta blockers. Other measures then assume greater importance, particularly volume replacement.
3.4. Antihistamines (H1 blockers) should be used routinely in the management of all anaphylactic reactions by medical practitioners to help counter histamine mediated vasodilatation. They may be unhelpful for at least some anaphylactoid reactions that depend in part on other mediators but have the virtue of safety. Their use alone is, however, unlikely to be life-saving.
3.5. Corticosteroids are considered as slow acting drugs and may take up to 4-6 hours to have an effect even if given intravenously. They may, however, help in the emergency treatment of an acute attack, and they also have a role in preventing or shortening protracted reactions. They form an essential part of management in recurrent idiopathic anaphylaxis 26 27 and are also of special importance in asthma especially those who have been treated recently with corticosteroids. Although some authors are unenthusiastic about corticosteroids,27 and the contribution of individual drugs when several are given is difficult to prove, clinical experience shows that parenteral hydrocortisone is of value in anaphylaxis. The safest practice is to use corticosteroids for all victims likely to be suffering from a severe anaphylactic reaction.
4. Recommendation for management
4.1. The recommendations for treatment by medical practitioners are summarised in the algorithm shown in figure 1 (for adults) and figure 2 (for children). The modified algorithms for use by community nurses are shown in figure 3 (for adults) and figure 4 (for children).
4.2. All victims should recline in a position of comfort. Lying flat with or without leg elevation may be helpful for hypotension but unhelpful for breathing difficulties. If available, oxygen should be administered at high flow rates (10-15 L per minute). Cardiopulmonary resuscitation must be performed if the need arises.
4.3. Adrenaline should be administered intramuscularly to all patients with clinical signs of shock, airway swelling, or definite breathing difficulty,7 and will be rapidly absorbed. Manifestations such as inspiratory stridor, wheeze, cyanosis, pronounced tachycardia, and decreased capillary filling alerts the physician to the likelihood of a severe reaction. For adults, a dose of 0.5 mL adrenaline 1: 1000 solution (500 micrograms) should be administered intramuscularly, and repeated after about 5 minutes in the absence of clinical improvement or if deterioration occurs after the initial treatment especially if consciousness becomes - or remains - impaired as a result of hypotension. In some cases several doses may be needed, particularly if improvement is transient. See also further notes under figure 1 and figure 3.
of adrenaline recommended for children have been modified slightly 25
since the original publication to take account of difficulties that had been
reported relating to dilution of the smallest injections. We have also taken the
opportunity of modifying the age brackets to bring them more closely into line
with the recommendations from the Royal College of Paediatrics and Child Health.28
The consultations have also led to compatibility of dose recommendations between
the Project Team and the British National Formulary. The modified
recommendations are as follows:
As for adults, doses may be repeated after 5 minutes if necessary. See further notes under figure 2 and figure 4.
Devices are available for home use, currently known as the Epipen (or Anapen) and the Epipen Jr (or Anapen Junior) that can inject 300 micrograms or 150 micrograms respectively. The drug may therefore have been administered by parents before medical help is available. The doses can be regarded as equally suitable as the 250 micrograms and 125 micrograms more generally recommended. Other pre-loaded devices include Min-I-Jet Adrenaline (not for self-administration) which currently contains 1 mg (1000 micrograms) of adrenaline. This allows incremental dose selection, but it should not be used in children because of the risk of overdose.
4.4. Intravenous administration of adrenaline is hazardous and should be given in a dilution of at least 1:10 000 (never 1:1000). Intravenous injection of adrenaline must be reserved for patients with profound shock that is immediately life-threatening and for special indications, e.g. during anaesthesia. The injection should be given as slowly as seems reasonable while monitoring heart rate and the electrocardiogram.
An antihistamine (chlorphenamine) should be administered. Caution is needed to
avoid "drug induced" hypotension: administer either by slow intravenous
injection or by intramuscular injection. Its use may be helpful and is unlikely
to be harmful. The dose for children and adults is determined by age as follows:
As for adrenaline doses, the age brackets have been modified slightly since the previous publication.
Hydrocortisone (as sodium succinate) should be administered after severe attacks
to help avert late sequelae. This is of particular importance for asthmatics
(who are at increased risk of severe or fatal anaphylaxis) if they have been
treated with corticosteroids previously. The dose of hydrocortisone should be
given by slow intravenous or intramuscular injection - care being taken to avoid
inducing further hypotension. The dose for adults and children is determined by
age as follows:
As for adrenaline and chlorphenamine doses, the age brackets have been modified slightly since the previous publication.
4.7. If severe hypotension does not respond rapidly to drug treatment, fluid should be infused. A crystalloid may be safer than a colloid.29 A rapid infusion of 1-2 L may be needed. Children should receive 20 mL/kg rapidly, followed by another similar dose if there is no clinical response.
4.8. Patients with even moderately severe attacks should be warned of the possibility of an early recurrence of symptoms and in some circumstances should be kept under observation for up to 8 -24 hours. This caution is particularly applicable to:
· severe reactions with slow onset due to idiopathic anaphylaxis
· reactions in individuals with severe asthma or with a severe asthmatic component
· reactions with the possibility of continuing absorption of allergen
· patients with a previous history of biphasic reactions.
4.9. An inhaled beta2 agonist such as salbutamol is useful 30 as an adjunctive measure if bronchospasm is a major feature that does not respond rapidly to other treatment.
4.10. All sufferers from anaphylaxis should be advised of the benefits of wearing some device such as a bracelet that will inform bystanders at the time of any future attack. Precautions should be taken, where practicable, to avoid exposure to the suspected allergen.
4.11. Investigation and assessment at a specialist allergy clinic is recommended for all patients who have suffered a severe reaction
Patients who are taking tricyclic antidepressants or monoamine oxidase inhibitors should receive only 50% of the usual dose of adrenaline because of an interaction which is potentially dangerous. Some fluorohydrocarbons used as refrigerants as well as cocaine sensitise the heart to adrenaline and are contraindications to its use.31
5.2. The use of adrenaline by the intravenous route in the special circumstances given in paragraph 4.4 should usually be reserved for medically qualified personnel who have experience of it, who know that it must be administered with extreme care, and who are aware of the hazards associated with its use.
5.3. The subcutaneous route for adrenaline, sometimes recommended for children on anecdotal evidence only, has no role in anaphylaxis because its absorption is appreciably slower.32 Unnecessary delay in achieving adequate plasma concentrations is inappropriate when dealing with this emergency.
5.4. Warnings must be given, when appropriate, in relation to the two strengths of adrenaline that are available for injection. For anaphylaxis, adrenaline is used in a dilution of 1:1000 intramuscularly whereas a dilution of 1:10 000 is used intravenously principally for cardiac arrest (with the rare additional indications outlined in paragraphs 4.4 and 5.2).
5.5. All who treat anaphylaxis should be aware of the potential for confusion between anaphylaxis and a panic attack. Victims of previous anaphylaxis may be particularly prone to panic attacks if they think they have been re-exposed to the allergen that caused a previous problem. The sense of impending doom and breathlessness leading to hyperventilation are symptoms that resemble anaphylaxis in some ways. Whilst there is no hypotension, pallor, wheeze, or urticarial rash / swelling, there may sometimes be an erythematous rash associated with anxiety which adds to the diagnostic difficulty. A mild anaphylactic reaction that triggers panic causes particular diagnostic difficulty. Problems can also arise with vasovagal attacks after immunisation procedures, but the absence of rash, breathing difficulties, and swelling is a useful distinguishing feature as is the slow pulse of a vasovagal attack compared with the rapid pulse of a severe anaphylactic episode.