Anaphylaxis is a symptom complex accompanying the acute reaction to a chemical recognised as hostile. In the classical reaction the patient has been previously sensitised (immediate hypersensitivity or type 1 hypersensitivity), although the sensitising agent may be unknown. The term ‘anaphylactoid reaction’ is used to describe reactions clinically indistinguishable from anaphylaxis, in which the mechanism is non-immunological, or has not been determined. Recent consensus meetings have suggested the use of the term ‘anaphylactoid’ be discontinued and ‘anaphylaxis’ used to describe the symptom complex which may be either ‘non-immune’ or ‘immune’,1 but the ‘new’ terminology has not been generally accepted. The clinical signs of anaphylaxis may be produced by direct drug effects, physical factors or exercise, and a causative agent cannot always be determined. The mediators involved are the same as those in other acute inflammatory responses such as sepsis, but the rate of release is more rapid and of shorter duration.
Clinical anaphylaxis in hospital commonly follows injection of drugs, blood products, plasma substitutes, contrast media, or exposure to latex products or chlorhexidine. Outside hospital, ingestion of foods or food additives (especially peanut products) or insect stings may be more common causes than drugs.
Neugut et al2 estimated 1400–1500 deaths per year in the USA and between 3.3 and 40.9 million patients at risk. They estimated radiocontrast media and penicillin to be the greatest causes of death, with food and stings the next groups. In contrast a postmortem study of 56 deaths in the UK3 attributed 19 deaths to venoms, 16 to foods and 19 to drugs and radiocontrast media.
In anaphylaxis, sensitisation occurs following exposure to an allergenic substance, which either alone, or by combination with a protein or hapten, stimulates the synthesis of immunoglobulin E (IgE). Some IgE binds to the surface of mast cells and basophils. Later, re-exposure to antigen produces an antigen–cell surface IgE antibody interaction where two IgE molecules are bridged. This results in mast cell degranulation, and the release of histamine and other mediators, including interleukin, prostaglandins and platelet-activating factor. Histamine is responsible for the early signs and symptoms, but is rapidly cleared from plasma. The overall effects of the mediators are to produce vasodilatation, smooth-muscle contraction, increased glandular secretion and increased capillary permeability. The mediators act both locally and upon distant target organs.
Anaphylactoid reactions may be due to a direct histamine-releasing effect of drugs or other triggers on basophils and mast cells. The symptom complex may also be produced by other mechanisms. Some intravenous drugs and X-ray contrast media may activate the complement system. Plasma protein and human serum albumin reactions may be induced by either albumin aggregates or stabilising agent-modified albumin molecules. Other reactions, including those to dextrans and gelatin preparations, may be activated by non-IgE antibody already present in the plasma or osmotic factors (dextrose, mannitol).
The direct histamine-releasing effects of some drugs may produce reactions due to the effect of histamine alone, and such reactions are related to volume, rate and amount of infusion. Recent work suggests that the site of release of histamine may be important in its clinical effects. Drugs such as morphine and Haemaccel release histamine from skin alone,4 and are unlikely to produce symptoms such as bronchospasm, whereas drugs which produce release from lung mast cells (e.g. atracurium, vecuronium and propofol) may be more likely to produce bronchospasm.5 Direct histamine release is usually a transient phenomenon, but in some patients severe manifestations may occur, particularly with Haemaccel and vancomycin.
Anaphylactic reactions are usually seen in fit and well patients. It is likely that the adrenal response to stress ‘pretreats’ sick patients, and blocks the release and effects of anaphylactic mediators. The exception to this appears to be patients with asthma, in whom reactions to the additives in steroid and aminophylline preparations may occur, and this may be related to the reduced catecholamine response in asthma.6 Patients on beta blockers and with epidural blockade may be more likely to develop adverse responses due to histamine release, and this may also be related to reduced catecholamine responsiveness. Reactions occurring in these groups are more difficult to treat.
The latent period between exposure and development of symptoms is variable, but usually occurs within 5 minutes if the provoking agent is given parenterally. Reactions may be transient or protracted (lasting days), and may vary in severity from mild to fatal. Recurrent anaphylaxis is described. Cutaneous, cardiovascular, respiratory or gastrointestinal manifestations may occur singly or in combination.
Cutaneous features include piloerection, erythematous flush, generalised or localised urticaria, angioneurotic oedema, conjunctival injection, pallor and cyanosis. Awake patients may experience an aura, warning of an impending reaction. Cardiovascular system involvement occurs most commonly and may occur as a sole clinical manifestation.7 It is characterised by initial bradycardia then sinus tachycardia, hypotension and the development of shock.
In patients reacting due to venom desensitisation, bradycardia may be severe and require treatment.8 Respiratory manifestations include rhinitis, bronchospasm and laryngeal obstruction. Gastrointestinal symptoms of nausea, vomiting, abdominal cramps and diarrhoea may be present. Other features include apprehension, metallic taste, choking sensation, coughing, paraesthesiae, arthralgia, convulsions, clotting abnormalities and loss of consciousness. Pulmonary oedema is a rare sign. Rarely, some women develop a profuse, watery, vaginal discharge 3–5 days after anaphylaxis. It is self-limiting.
Anaphylaxis is rare in the intensive care unit (ICU), probably because of the protective effects of the adrenal response to stress. However, use of the mast cell tryptase assay (see below) may detect anaphylaxis as an unsuspected cause of shock in intensive care.
The traditional concept of the cardiovascular changes in clinical anaphylaxis is that of an initial vasodilatation, followed by capillary leak of plasma, which produces endogenous hypovolaemia, reduced venous return and lowered cardiac output.
Whether or not cardiac function is impaired has been controversial. Although most anaphylactic mediators adversely affect myocardial function in vitro, most case reports of anaphylaxis in which invasive cardiovascular monitoring has been used suggest minimal impairment of cardiac function. Patients with normal cardiac function before the reaction rarely show evidence of cardiac failure or arrhythmias other than supraventricular tachycardia, but the incidence of serious arrhythmias and cardiac failure increases in those with prior cardiac disease.7 Echocardiography in anaphylaxis usually shows an ‘empty’, normally contracting heart. Troponins are elevated after anaphylaxis, but these elevations do not normally predict coronary artery disease requiring intervention. A recent study of patients with anaphylaxis during venom desensitisation showed that bradycardia requiring treatment was a common finding.8 Two reactions in patients with no previous cardiac disease, where the major manifestation was prolonged global myocardial dysfunction, and the use of a balloon counterpulsator was life-saving, have been reported.9
There are no randomised controlled trials of treatment in anaphylaxis, and the unexpected onset, rapid course and usual rapid response to treatment preclude performing such trials. Treatment recommendations are based on historical practice, case reports, series of cases and animal models.
Oxygen is given by facemask. Endotracheal intubation may be required to facilitate ventilation, especially if angioedema or laryngeal oedema is present. Oedema of the upper airway is more common when anaphylaxis is due to foods than to drugs.3 Mechanical ventilation is indicated for severe bronchospasm, apnoea or cardiac arrest.
Epinephrine is universally recommended as the drug of choice for severe reactions. In the community epinephrine may be given intramuscularly in a dose of 0.3–1.0 mg early in anaphylaxis. Intramuscular epinephrine produces higher levels earlier in stable allergic patients than subcutaneous epinephrine.10 In severe shock or in patients in whom muscle blood flow is thought to be compromised by shock, intravenous injection of 3–5 ml of 1 : 10 000 epinephrine is given. A second dose is necessary in 35%11 and an infusion in 10%.
Epinephrine, by increasing intracellular levels of cyclic adenosine monophosphate (cAMP) in leukocytes and mast cells, inhibits further release of histamine. It has beneficial effects on myocardial contractility, peripheral vascular tone and bronchial smooth muscle, and stabilises mast cells. A common management error is not to institute external cardiac massage (ECM) as the arrhythmia is ‘benign’. If the patient is pulseless, ECM should be instituted irrespective of rhythm, although there are no data to support its efficacy.
There has been controversy regarding the best route of administration of epinephrine outside hospital. Both case reports and patients self-injecting show efficacy for intramuscular epinephrine when given early. Intravenous epinephrine may rarely cause arrhythmias and myocardial infarction, particularly in unmonitored patients. In our series it seems to be more hazardous when the diagnosis of anaphylaxis is incorrect. Recent recommendations endorse the use of intramuscular epinephrine.12
Other sympathomimetic drugs may reverse the symptoms, but appear (albeit in the absence of any randomised trials) to be less effective than epinephrine. Norepinephrine by infusion may be life saving in the absence of a response to fluid loading and epinephrine. Methoxamine and phenylephrine have been used to treat anaphylactic hypotension successfully as first-line treatment and in ‘rescue’ therapy when epinephrine appears ineffective. More recently, case reports have shown vasopressin and methylene blue to be effective in refractory cases of hypotension.
Plasma expanders are given rapidly to correct the hypovolaemia consequent to acute vasodilatation and leakage of fluid from the intravascular space.13 The author favours plasma protein solution or gelatin preparations rather than crystalloids, as they remain in the vascular compartment earlier and for longer. There are, however, no data showing improved outcomes from colloid over crystalloid, and there are many patients who have been successfully resuscitated with crystalloid alone. Greater volumes of crystalloid are necessary and on occasions very large volumes of fluid may be required; central venous pressure monitoring and measurement of haematocrit are helpful.
Epinephrine should be given. Nebulised salbutamol should be given for severe asthma. Aminophylline 5–6 mg / kg intravenously may be given over 30 minutes, if bronchospasm is unresponsive to epinephrine alone. Aminophylline increases intracellular cAMP by phosphodiesterase inhibition, and its effect on inhibiting histamine and interleukin release is theoretically additive to that of epinephrine. Adverse responses have not been observed in our series but a recent comprehensive review14 suggested safer agents with proven efficacy should be preferred. Volatile anaesthesia, ketamine and magnesium sulphate may produce improvement in some patients with severe asthma.
Steroids have no proven benefit, particularly early, and should be reserved for refractory bronchospasm. Conversely, steroids are often given and there is no evidence of harm.
Antihistamines are the treatment of choice in localised non-severe reactions. In severe reactions they are only indicated in protracted cases or in those with angioneurotic oedema, which may recur. The data on antihistamines are not conclusive, but in protracted anaphylaxis, improvement is often reported with H2-blockers.
A comprehensive review of the evidence for efficacy and recommendations from the evidence has recently been produced by the World Allergy Organisation.15
The most important advance in the diagnosis of anaphylaxis has been the introduction of an assay for mast cell tryptase. The mast cell enzyme is elevated 1 hour after a reaction begins, and the elevation may persist for up to 4 hours. It can also be helpful in the diagnosis of anaphylaxis from postmortem specimens.16 The assay is highly specific and sensitive for anaphylaxis, although elevated levels are found with direct histamine release, and at postmortem in some patients with myocardial infarction. A negative mast cell tryptase assay does not exclude anaphylaxis as the diagnosis. Mast cell tryptase has been used to diagnose anaphylaxis postmortem.
Following successful acute management, the drug or agent responsible should be determined by in vitro or in vivo testing if possible. Hyposensitisation should be considered for food, pollen and bee venom allergy. A medic alert bracelet should be worn and the patient should be given a letter stating the nature of the reaction to the particular causative agent.
If re-exposure to the allergen is likely at home, patients or their relatives should be instructed in the use of epinephrine, salbutamol inhalation and antihistamines. Clinical anaphylaxis may be modified by pretreatment with disodium cromoglycate, corticosteroids, antihistamines, salbutamol and isoprenaline.
In patients with recurrent anaphylaxis in whom no cause can be found corticosteroids on alternate days reduce the incidence and severity of attacks.
1. 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 Anaphylaxis Network symposium. J Allerg Clin Immunol. 2006; 117:391–397.
2. Neugut, AL, Ghatak, AT, Miller, RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. 2001; 161:15–21.
3. Pumphrey, RS, Roberts, IS. Postmortem findings after fatal anaphylactic reactions. J Clin Pathol. 2000; 53:273–276.
4. Tharp, MD, Kagey-Sobotka, A, Fox, CC, et al. Functional heterogeneity of human mast cells from different anatomic sites: in vitro responses to morphine sulphate. J Allergy Clin Immunol. 1987; 79:646–653.
5. Stellato, C, de Paulis, A, Cirillo, R, et al. Heterogeneity of human mast cells and basophils in response to muscle relaxants. Anesthesiology. 1991; 74:1078–1086.
6. Ind, PW, Causon, RC, Brown, MJ, et al. Circulating catecholamines in acute asthma. Br Med J. 1985; 290:267–269.
7. Fisher, MM. Clinical observations on the pathophysiology and treatment of anaphylactic cardiovascular collapse. Anaesth Intensive Care. 1986; 14:17–21.
8. Brown, SG, Blackman, KE, Stenlake, V, et al. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J. 2004; 21:149–154.
9. Raper, RF, Fisher, MM. Profound reversible myocardial depression following human anaphylaxis. Lancet. 1988; 8582:386–388.
10. Simons, FE, Roberts, JR, Gu, X, et al. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. 1988; 101:33–37.
11. Korenblat, P, Lundie, MJ, Dankner, RE, et al. A retrospective study of epinephrine administration for anaphylaxis: how many doses are needed. Allergy Asthma Proc. 1988; 20:83–86.
12. Project team of the Resuscitation Council UK. Emergency medical treatment of anaphylactic reactions. Resuscitation. 1999; 41:93–99.
13. Fisher, MM. Blood volume replacement in acute anaphylactic cardiovascular collapse related to anaesthesia. Br J Anaesth. 1977; 49:1023–1026.
14. Ernst, ME, Graber, MA. Methylxanthine use in anaphylaxis: what does the evidence tell us? Ann Pharmacother. 1999; 33:1001–1004.
15. Simons, FE, Ardusso, LR, Bilò, MB, et al. World Allergy Organisation Guidelines for the treatment of anaphylaxis. World Allergy Organ J. 2011; 4(2):13–37.
16. Fisher, MM, Baldo, BA. The diagnosis of fatal anaphylactic reactions during anaesthesia: employment of immunoassays for mast cell tryptase and drug-reaction IgE antibodies. Anaesth Intensive Care. 1993; 21:353–357.