Anaphylaxis: clinical features, management and avoidance

Transcription

1 Anaphylaxis: clinical features, management and avoidance James Bateman MRCP and Robin Ferner MSc, MD, FRCP VM Our series on serious ADRs focusses on rare but potentially fatal drug reactions and how to recognise and avoid them. This article describes the features, causes and management of anaphylaxis and how to avoid a recurrence. Figure 1. Intramuscular injection is the most effective way to give adrenaline, and those at considerable risk of anaphylaxis should carry an adrenaline pen Anaphylaxis is an important and potentially fatal immunologically-mediated reaction that presents as a medical emergency. Drugs, of course, are an important cause. Accurate clinical diagnosis and prompt treatment with the correct therapy saves lives. Death is usually a result of circulatory collapse and bronchospasm. All practitioners should understand the causes of anaphylaxis, know how to diagnose it and be able to administer effective treatment. In general all patients with suspected anaphylaxis should be referred to hospital for further clinical assessment and monitoring. Incidence Anaphylaxis is a severe allergic reaction of abrupt onset. It occurs when an antigen binds to immunoglobulin E (IgE) attached to mast cells, releasing inflammatory mediators. The true incidence of anaphylaxis is not known because events are rare, data are collected retrospectively and case definitions vary. In the UK, about four persons per per year are treated in hospital for anaphylaxis, and it is the reason for between 1 in 2300 to 1 in 5800 attendances to casualty departments. The risk of a fatal anaphylactic reaction to a prescribed penicillin is estimated as 2 per in the general population. 1 A recent study suggested that 1-15 per cent of the USA population were potentially at risk from an anaphylactic reaction, reflecting the great uncertainty in the estimates. 2 The rate of fatal and serious anaphylactic reactions to food allergens has probably increased over the past two decades. Pathophysiology Allergens cause anaphylaxis via their binding to specific IgE receptors attached to mast cells. The antigen-antibody complex then activates an immunological cascade, in which mast cells and basophils release mediators including histamine, cyclo-oxygenase products such as thromboxane A 2, leukotrienes and mast cell tryptase that in turn activate other vasoactive mediators such as bradykinin. The mediators increase smooth muscle tone in bronchi, 12 Prescriber 19 May

2 blood vessels and gut, and increase capillary permeability so that fluid leaks from the circulating blood volume, causing both hypotension and oedema and making airways obstruction worse. 3 Anaphylactoid reactions cause a clinically indistinguishable syndrome as a result of mast cell degranulation without the involvement of IgE. Triggers in such reactions act on the mast cells and mediator release is directly related to drug concentration. Consequently, such reactions are more readily terminated, tend to be more rare and are less serious. Angioedema is a more localised response but may be lifethreatening if it involves the upper airway. Some attacks may be triggered by medication. Clinical features The history often gives clues to the diagnosis of anaphylaxis, eg the recent intravenous administration of a drug or the introduction of a new treatment. Parenteral medications are more likely to result in severe anaphylactic reactions of rapid onset. A drug is unlikely to have caused anaphylaxis if the onset of symptoms is delayed for more than half an hour after intravenous administration of the putative allergen, although longer delays are possible after oral administration. A previous history of anaphylaxis to an allergen places the individual at high risk of further attacks if given the same allergen or a cross-reaction allergen of chemical structure, eg cephalosporins in a patient know to be allergic to penicillin. Patients with atopy are at higher risk, and patients with pre-existing asthma more likely to come to harm. System general pulmonary cardiovascular dermatological GI Clinical features collapse, shock, anxiety, restlessness, rhinitis, flushing, pallor respiratory distress, wheeze, stridor, airways oedema hypotension, collapse, loss of consciousness, tachycardia erythema, urticaria, oedema, pruritus abdominal cramp, vomiting, diarrhoea Table 1. Clinical features of anaphylaxis (key features in italics) Table 1 lists the signs and symptoms of anaphylaxis. Respiratory distress (due to bronchospasm and laryngeal or airways oedema) and hypotension (from loss of intravascular fluid) are two of the cardinal features of severe anaphylaxis. Urticaria or generalised erythema is also common. Anxiety disorder, asthma and vasovagal syncope can all be confused with anaphylaxis in the clinical context. Causes Adverse drug reactions comprise one-third of all cases of anaphylaxis. Reactions to foodstuffs, insect bites and hymenoptera stings are responsible for the other two-thirds. The most commonly used group of drugs to cause anaphylaxis are the penicillin derivatives. Other causes include other antibiotics, blood and immunological products, drugs used in anaesthesia and radiocontrast media. The common drugs causing anaphylaxis are shown in Table 2. Commonly used drugs that result in anaphylactoid reactions include NSAIDs, codeine phosphate and N-acetylcysteine. Management of anaphylaxis The cornerstone of management of anaphylaxis is the administration of adrenaline by intramuscular injection. The Resuscitation Council (UK) has issued guidelines for the management of anaphylaxis both in and outside of the hospital. 4 They are based on expert opinion and experience rather than randomised controlled clinical trials. Outside hospital, the presence of hypotension, cardiovascular collapse or respiratory distress should prompt basic life support measures and a call for an ambulance. Where relevant, further exposure to the allergen should be avoided. Adrenaline should be administered, either in or outside hospital, and oxygen should be given. Antihistamines, hydrocortisone, fluid replacement and nebulised salbutamol also play a role in management. Adrenaline Adrenaline has alpha- and betaagonist activity, increasing peripheral vascular tone, myocardial contractility and heart rate, and relaxing bronchial smooth muscle. There are several available preparations of adrenaline, of different concentrations and suitable for different routes of administration. This can lead to medication errors by emergency medical and paramedical staff. Intramuscular administration The safest effective way to give adrenaline is by intramuscular injection. The correct initial dose Prescriber 19 May

3 Antibiotics Contrast media Immunosuppressants Parenteral Miscellaneous penicillins iodine-based ciclosporin blood products NSAIDs* cephalosporins contrast media methotrexate immunoglobulin aspirin* tetracyclines vaccinations opiates* macrolides insulin local anaesthetics quinolones neuromuscular- hyposensitising blocking drugs (allergen) preparations heparin horse sera (eg snake antivenom) Table 2. Common groups of drugs causing anaphylaxis (*may be anaphylactoid) in an adult is 500µg, administered as a dose of 0.5ml im of a 1mg per ml (1:1000) preparation. Repeated doses of adrenaline can be given at two- to five-minute intervals until symptoms improve. The doses recommended by the Resuscitation Council (UK) in conjunction with the BNF are shown in Table 3. The available evidence suggests that the early administration of adrenaline increases survival in severe anaphylaxis. This means that adrenaline treatment should be given as soon as the clinical diagnosis is apparent, even though Age Adult Adult but taking TCA or MAOI Over 12 years Over 12 years but small or prepubertal From 6-12 years From 6 months- 6 years Less than 6 months adrenaline has potential adverse effects. Intravenous administration In life-threatening circumstances such as circulatory collapse, intravenous adrenaline administration may be warranted (in conjunction with intravenous access, suitable monitoring equipment and medical personnel experienced in its use). It should not normally be used, however, because intravenous adrenaline administration commonly causes serious ventricular arrhythmias, requires preexisting venous access and is prone to medication errors. 500µg im (0.5ml 1mg per ml solution) 250µg im (0.25ml 1mg per ml solution) up to 500µg im (0.5ml 1mg per ml solution) 250µg im (0.25ml 1mg per ml solution) 250µg im (0.25ml 1mg per ml solution) 120µg im (0.12ml 1mg per ml solution) 50µg im (0.05ml 1mg per ml solution; absolute accuracy not essential) Table 3. Intramuscular adrenaline doses in anaphylaxis Intramuscular adrenaline dose (strength always 1mg per ml) The intravenous dose is only one-tenth the intramuscular dose, and the concentration of solutions of adrenaline for intravenous administration is correspondingly 100µg per ml. Adrenaline is poorly and unreliably absorbed after subcutaneous administration, which is therefore inappropriate. Serious adverse reactions, including ventricular arrhythmia, are generally the result of administration of toxic doses, and especially of dosing errors if adrenaline has been given intravenously. This is a further reason for preferring the intramuscular route. 5 Other drugs can affect the actions of adrenaline. Patients taking beta-blockers, eg atenolol, may require larger doses of adrenaline because of competitive antagonism. Such patients may also be at increased risk of severe anaphylaxis in the first place. ACE inhibitors that inhibit the breakdown of bradykinin, an important mediator of anaphylaxis and angioedema, can also increase the risk of severe anaphylaxis. Adrenaline can precipitate arrhythmia in patients taking TCAs and provoke hypertensive crises in those taking MAOIs. The Resuscitation Council (UK) suggests that the dose of adrenaline should be halved in these patients. 14 Prescriber 19 May

4 Summary points anaphylaxis is a rare but potentially fatal immune-mediated reaction the diagnosis of anaphylaxis is made on the history and physical signs once anaphylaxis is identified, prompt treatment is vital intramuscular adrenaline is the emergency treatment of choice oxygen, chlorphenamine, and hydrocortisone are also valuable elevated activity of serum mast cell tryptase can support the diagnosis observe patients for at least 8 hours after severe anaphylaxis measures to prevent or treat recurrence should be put in place at the time of discharge Additional treatments Chlorphenamine, a histamine H 1 - antagonist, is the antihistamine of choice and can be given intravenously, acting within about 10 minutes of injection. It counteracts histamine-mediated vasodilatation, reduces the itching associated with urticaria and may reduce histamine-mediated bronchoconstriction. It is sedative, but this is not significant in this context. Hydrocortisone injection may hasten recovery by inhibiting leukotriene synthesis. It may take several hours to act, but can be of help in so-called biphasic anaphylactic reactions. Intravenous fluids should be considered in any patient with hypotension. In patients with predominant bronchoconstriction, nebulised salbutamol may also be helpful. Anaphylactoid reactions are common in some circumstances. For example, they occur during use of acetylcysteine (Parvolex) in paracetamol poisoning, and in codeine overdose. True anaphylactic reactions are almost unknown in these circumstances, where the use of chlorphenamine and salbutamol is normally all that is required. Subsequent management If there is doubt about the diagnosis, it can be supported by Prescriber 19 May

5 measurement of serum mast cell tryptase levels one and five hours following the event. Enzyme activity is high after mast cell degranulation, and so the test cannot distinguish anaphylaxis from an anaphylactoid reaction. Patients should be observed following resuscitation to ensure that all the clinical features resolve. In rare cases, features recur as late as eight hours after the initial event, so patients should be observed for at least that time. At discharge following a severe reaction, patients should be counselled about the suspected aetiology of the reaction and given information on avoidance. Staff should endorse the medical records and inform the GP of any suspected drug allergy. Preloaded auto-injector adrenaline syringes are appropriate for patients with severe anaphylactic reactions induced by environmental allergens such as food or insect stings, but not usually for patients with drug-induced anaphylaxis. Patients may wish to wear 16 Prescriber 19 May

6 identification, such as a Medic- Alert bracelet. Avoiding anaphylaxis A history of allergy to a drug is a relative contraindication to repeat administration. However, drug allergy reported by a patient may not represent a true IgE-mediated hypersensitivity reaction. For example, features such as diarrhoea and headache would not constitute an allergy, and the rash associated with ampicillin used in glandular fever does not herald anaphylaxis on re-exposure. Occasionally, records may show that patients state they are allergic to drugs that they have been reexposed to with no adverse effects. This sometimes happens with penicillins, and the likely explanation in this case is that impurities were present in early pharmaceutical preparations, which are no longer present due to more modern manufacturing processes. The most common drug allergy is to penicillin compounds. Prescriber 19 May

7 Penicillin therapy is often limited by unsubstantiated reporting of penicillin hypersensitivity. Skinprick testing has been used in an attempt to determine the response to penicillin. 6 Research estimates that only per cent of patients react to such testing. It is estimated that 98 per cent of patients with a negative skin prick test can safely take a penicillin derivative, although it does not exclude the risk of anaphylaxis. As such it should only be carried out in hospital by experienced staff, and with full resuscitation facilities available. People allergic to penicillins are at increased risk of reaction to cephalosporin antibiotics, which are of similar chemical structure. The practitioner may choose to avoid the cephalosporin group of drugs in patients thought to be allergic to penicillins. Alternatively, skin-prick testing can be carried out using penicillin in patients with a history of penicillin allergy. If the testing is negative, it is likely that the patient can receive the cephalosporin safely. Although the risk of an allergic response to cephalosporins in patients with true penicillin allergy is fairly low (approximately 2 per cent), it is probably best to avoid cephalosporins in any patient where there is a good history of moderate or severe reactions to penicillin. 7 Because anaphylaxis is a rare but dangerous and potentially recurrent condition, patients who have suffered a moderate or severe episode should ideally be referred for specialist evaluation and advice. Conclusion Anaphylaxis is rare and can often be avoided by taking a careful medical history including any previous drug allergies. Clinical symptoms and signs can evolve over a short period. Prompt recognition of the features of anaphylaxis will help in early identification. In the community setting adrenaline administration should be via the intramuscular route. All patients with suspected anaphylaxis should be urgently sent to hospital for assessment. Given the unpredictability of this potentially fatal adverse drug reaction, anyone who may prescribe or give drugs should know how to recognise and treat this life-threatening adverse effect. References 1. Peng MM, Jick H. A populationbased study of the incidence, cause, and severity of anaphylaxis in the United Kingdom. Arch Int Med 2004; 164: Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med 2001;161: Ewan PW. Anaphylaxis. BMJ 1998; 316: Resuscitation Council UK. Emergency medical treatment of anaphylactic reactions for first medical responders and for community nurses (Revised January 2002). org.uk. 5. McLean-Tooke AP, Bethune CA, Fay AC, et al. Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ 2003;327: Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA 2001;285: Kelkar PS, Li JT. Cephalosporin allergy. N Eng J Med 2001;345: Dr Bateman is specialist registrar in rheumatology, Mid Staffordshire NHS Trust, and Dr Ferner is consultant physician at City Hospital, Birmingham, and director of the West Midlands Centre for Adverse Drug Reaction Reporting 18 Prescriber 19 May