9 Anaphylactic and anaphylactoid reactions

9 Anaphylactic and anaphylactoid reactions TIM

WHITTINGTON

MB, ChB, FRCA

Research Fellow

M A L C O L M M. F I S H E R MD, FANZCA, FFICANZCA, FRCA Clinical Professor, University of Sydney Intensive Therapy Unit, Royal North Shore Hospital, St Leonards, New South Wales, Australia

Anaphylaxis is a rare event during anaesthesia but may lead to death, even when expertly treated. Reactions may be immune related (anaphylactic) or as a result of direct stimulation (anaphylactoid). The clinical features result from massive release of histamine and the release of other mediators. There is a wide spectrum of severity of reaction but the mainstay of treatment is adrenaline, intravenous colloid and 100% oxygen. Investigation is important, enabling identification of the agent and other agents potentially causing lifethreatening reactions. Mast cell tryptase is measured in the first 6 hours, to identify the reaction as anaphylactic, and skin testing 4-6 weeks later is best at identifying the trigger agent. Giving the patient full documentation of the reaction and investigations along with an explanation of the seriousness of the situation is imperative. Key words: anaphylaxis; tryptase; histamine; skin testing; neuromuscular blocking drugs; latex.

The systemic inflammatory response is controlled by the release and formation of mediators that interact with defence and endothelial cells in a complex fashion. This interaction is usually beneficial, but in some circumstances, especially septic shock, adult respiratory distress, auto-immune disorders, and anaphylaxis, an exaggerated or prolonged effect produces a response detrimental to the host. In anaesthesia release of endogenous mediators can produce a spectrum of effects. The most common example is the non-immunological release of histamine in response to drugs, and surgical or anaesthetic stimuli, producing effects which are usually minor, transient effects confined to the skin and blood vessels (Lorenz et al, 1982). At the other end of the spectrum is the allergic release of massive quantities of histamine, which is invariably detrimental, and when released in response to an antigen-antibody reaction leads to the activation of other longer-acting mediators, producing a sustained effect. In anaesthesia the frequent use of intravenous drugs, the administration of multiple drugs in Baillikre ~ Clinical Anaesthesiology-Vol. 12, No. 2, June 1998 ISBN 0-7020-2403-1 0950-3501/98/020301 + 23 $12.00/00

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rapid succession, and the administration of bolus doses of drugs increases the risk of adverse responses. ANAESTHESIA AND THE IMMUNE SYSTEM Anaesthesia generally has a depressant effect on the immune system but in human studies this is difficult to separate from the effects of surgery and blood transfusion. Anaesthetic drugs in vitro decrease resistance to bacterial and viral infection, but in the absence of studies of prolonged anaesthesia without surgery the relevance of the effect is still uncertain. There is little evidence of a relevant impairment of the immune response due to anaesthesia, the major effect being due to the trauma of surgery. MEDIATORS OF ALLERGY Histamine Histamine is released in response to a variety of stimuli such as antigen-antibody reactions, drugs and noxious stimuli. There is a marked variability in release in individuals. There is a correlation between the quantity of histamine released due to drugs or given by infusion and the cardiovascular, cutaneous, and subjective symptoms but not to bronchospasm (Kaliner et al, 1981; Lorenz et al, 1982). This may be related to the histamine-induced release of endogenous catecholamines protecting the subject from bronchospasm. Intravenous histamine infusions produce bronchospasm only in patients taking ~-adrenoceptor antagonists (PloySong-Sang et al, 1978). Histamine can produce all of the clinical features of anaphylaxis. Histamine release has been shown to produce adverse effects in anaesthetized patients, and studies have shown that these adverse effects can be blocked by pre-treatment with H 1and H2 receptor antagonists (Moss et al, 1981; Philbin et al, 1981; Hosking et al, 1988). However, plasma levels of greater than 15 nmol (at which profound hypotension occurs) are rarely produced by direct histamine release and levels of 10 to 100 times this are common in anaphylaxis (Laroche et al, 1991, 1992b). The degree of histamine release by a particular drug is related to its ability to produce minor but not severe reactions. Potent releasers such as morphine and d-tubocurarine are not as commonly associated with severe events as are weak histamine releasers such as suxamethonium and alcuronium. The 'super responders' (Lorenz et al, 1991), however, show severe non-immunological reactions to potent histamine-releasing drugs. Studies of histamine release from human mast cells may be of relevance to anaesthesia. Mast cell populations from different parts of the body, skin, lung, heart, intestinal and basophils, show a different response to a particular drug. Morphine, for example, causes histamine release from skin mast cells only. Propofol, atracurium and vecuronium release histamine from the lung mast cells, which may explain a number of referrals with non-immunological bronchospasm when these drugs are given together. In contrast, ketamine,

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a releaser of histamine from pulmonary mast cells, is effective in treating bronchospasm (Stellato et al, 1991 a,b; Genovese et al, 1996). Other mediators Chemotactic factors are also released during anaphylaxis. Their exact role is unclear but they may be involved in the attraction of eosinophils which produce histamine breakdown enzymes, so limiting the inflammatory response. Likewise, enzymes such as tryptase, chymase and peroxidases are also released from mast cells at degranulation along with heparin; all of these have an uncertain role. Synthesized mediators from lipid and protein molecules are formed on mast cell activation. These include arachadonic acid metabolites (prostaglandins, thromboxanes, prostacyclines and leukotrienes), platelet aggregating factor and kinins, and serotonin. These have varying effects on smooth muscle, vascular permeability and cardiac muscle. All of these factors add to the clinical effects of anaphylaxis (Bach, 1982; Barnes et al, 1988; Levi, 1988).

ANAPHYLAXIS Mechanisms of mediator release are shown in Table 1. Anaphylactic reactions are allergic reactions due to antigens bridging IgE or IgG antibodies attached to mast cells and basophils and producing a massive release of inflammatory mediator. Anaphylactoid reactions are non-immune reactions leading to a response that may be clinically indistinguishable from an anaphylactic reaction. The classification is sometimes difficult, as the immunological mechanism is not always identified, and so the reaction is wrongly placed in the anaphylactoid group. Immunological reactions have been classified into various types, according to Coombs and Gell (Coombs and Gell, 1975). Type I or allergic release may be immediate and mediated via IgE or IgG antibodies. Type II or cytotoxic release is delayed and produced by aggregates or protein complexes. It is mediated by IgG or IgM. In anaesthesia, blood transfusion and possibly protamine are common causes of these reactions. Table 1. Mechanisms of mediator release producing clinical anaphylaxis. Mechanism

Example

Direct histamine release IgE-mediated anaphylaxis lgG-mediated anaphylaxis Aggregate anaphylaxis Complement activation Cytokine-induced Osmotic reactions Physical Direct vascular effects IgE anti-IgA antibodies Kallikrein system

Modified fluid gelatin, morphine Penicillin, latex, neuromuscular blocking drugs Protamine, dextrans Antivenoms Cremophor®, Protamine Aspirin Mannitol, contrast media, dextrose Exercise, vibration Antibiotics Plasma proteins Aprotinin

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Type III or complement-mediated release results in the formation .of soluble antigen-antibody complexes or immune complexes. In the presence of antibody excess the reaction leads to precipitation and local effects, particularly the classical Arthus reaction. In antigen excess systemic reactions occur due to the deposition of complexes in the kidneys, joints and skin, characteristically producing serum sickness. Type IV or delayed release involves T cells combining with the antigen, and is characteristically delayed for 24 to 48 hours. The above classification is a simplification as reactions may involve more than one mechanism.

Host factors in mediator release

Responsiveness A number of important host factors influence the clinical effects of mediator release. These factors relate to the individual's histamine releasability, assessed by cutaneous challenge to codeine phosphate, and histamine responsiveness, assessed by a challenge with injected or inhaled histamine. The considerable variability of histamine release to individual drugs and stimuli is reflected in both plasma levels of histamine and in histamine release from individual mast cells. At one end of the spectrum are patients with mastocytosis and the 'super responders' described by Lorenz and colleges (Lorenz et al, 1991) who have massive release of histamine. Patients with allergy, atopy and asthma may have increased histamine releasability, and responsiveness. At the other end of the spectrum are patients who are at the extremes of age, and shocked patients in whom anaphylaxis is rare. Neonatal mast cells, however, do release histamine in response to morphine (Tharp et al, 1987). Anaphylaxis is rare in shocked patients. In shock the natural catecholamine response is activated, opposing the actions and inhibiting the release of anaphylactic mediators. Immunosuppressed patients have a dampened response. Patients taking l]-adrenoceptor antagonists manifest anaphylaxis with bradycardia rather than tachycardia, and the anaphylactic reaction is more difficult to treat as increased doses of I]-adrenoceptor agonists are required. Recent work has suggested that the clinical manifestations of anaphylaxis may be associated with impairment of the renin/angiotensin system. Hermann and Ring (1995) showed that patients who had anaphylaxis to hymenoptera venom had significantly lower levels of renin, angiotensin I and II, and angiotensinogen than did healthy controls. The levels correlated inversely with the severity of symptoms and were returned to normal by immunotherapy. A failure of a protective mechanism is an attractive hypothesis to explain the lack of correlation between antibody levels, histamine responsiveness, and histamine releasability and the severity of reactions (Hermann et al, 1993).

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Atopy and allergy All studies have shown an increased incidence of allergy, atopy, or asthma in patients who have anaphylactic reactions under anaesthesia. When compared to non-reacting controls, typically a three to five times higher incidence is shown (Laforest et al, 1980), although a French study where reactors were matched for age, gender and social class and atopy was measured by antigen testing suggested that this increase may be spurious (Charpin et al, 1988). This increase in incidence in allergy and asthma is not an indication that these are significant risk factors. The majority of patients in all series who develop anaphylaxis do not have such a history, and the majority of patients with such a history have uneventful anaesthetics. History of asthma, atopy and allergy as a predictor of anaphylactic reactions has a very low specificity and sensitivity and an unacceptably high false-alarm rate (Fisher et al, 1987). However, in Nancy, France, where the incidence of allergy to neuromuscular blocking drugs (NMBDs) is high, Moneret Vautrin (personal communication) found allergy to suxamethonium in 1:300 surgical patients and 1:60 patients at the allergy clinic. In a prospective study, the Nancy Group showed that patients with atopy, previous exposure to NMBDS and systemic reactions to other drugs may have up to a 3.7% chance of a positive prick test to NMBDs (Albrech et al, 1995).

Gender The male-to-female ratio of patients undergoing anaphylaxis to neuromuscular blocking drugs (NMBDs) is 1:4, although this difference is less marked with colloids and thiopentone. This may not be a true preponderance and may relate to a higher female exposure to NMBDs.

Previous exposure In anaphylaxis to thiopentone, multiple uneventful exposures is not unusual, with up to 47 previous exposures in our series and usually more than five (Clark and Cockburn, 1971). A history of previous exposure is found in less than 50% of patients who are allergic to NMBDs, despite the demonstration of IgE antibodies which, traditional wisdom suggests, require previous exposure to form the antibody (Fisher and Munro, 1983). It is likely that the antibody which binds NMBDs is formed in response to exposure to some other antigen outside the field of anaesthetic drugs. This is especially so of suxamethonium, which is such a simple structure that it is unlikely that it could lead to antibody formation. It also possible that, even with previous exposure, the antibody is not formed to the NMBDs themselves but to the outside antigen. Over 20 years of research still has not determined how people become sensitized to NMBDs. Clinical expression of mediator release The clinical effects of mediator release have variable expression, depending on the mediator released, the quantity and the timing. As a general

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principal the effects are on smooth muscle producing bronchoconstricfion in the airway and vasodilatation in the peripheral blood vessels, increased capillary leakage and increased secretions of exocrine glands. In general, the symptoms and signs relate to the blood levels to a degree, but local release may produce dramatic signs with low systemic levels. Very high blood levels of histamine or mast cell tryptase generally correlate with the severity of the reaction and suggest an immunological cause (Laroche et al, 1991, 1992a). Minor skin changes are the most common sign of histamine release (Lorenz et al, 1982) but do not suggest a risk of anaphylaxis at subsequent anaesthetics. Changes in blood pressure during anaesthesia related to histamine release can be blocked with H~ and H2 receptor antagonists (Moss et al, 1981; Philbin et al, 1981; Schoning et al, 1982; Hosking et al, 1988; Lorenz et al, 1994). These events may happen in up to 26% of anaesthetics where Haemaccel is given, but the routine use of H~ and H2 receptor antagonists has not become common practise (Lorenz et al, 1994). The role of direct histamine release in major reactions is less clear. Histamine can be the only mediator in severe reactions, especially in betablocked patients with cardiac disease, but direct release is usually transient. Persistent high levels have not been recorded during severe reactions but late haemodynamic improvement with the use of H2 blockers suggest that this may occur. Persistent severe reactions usually involve the release of the other mediators. It should be assumed that all reactions lasting greater than 10 minutes are immune-mediated.

Anaphylaxis during anaesthesia: incidence The incidence of anaphylaxis to a specific substance is a fraction in which the denominator is the number of cases in which the substance has been given and the numerator is the number of associated cases of anaphylaxis. Both of these numbers are difficult to gather accurately. Problems in recognition, reporting and testing make the numerator difficult to estimate, and there is no direct way of obtaining detailed information on numbers exposed to risk in the population from which reactions are reported, so the denominator is unknown. The largest study is a multicentre French study which showed an incidence of 1:6000. (Laxcnaire ct al, 1990). All the published data are encompassed by the Boston Collaborative Drug Surveillance study (Beard and Jick, 1985) which showed an incidence of 1:900 to 1:20000. To establish accurately an incidence of severe anaphylaxis with 5% confidence limits, about 30 million patients would have to be studied (Fisher and Baldo, 1994); it is therefore apparent that incidences of reactions for specific drugs are likely to be even less meaningful and specific numbers difficult to obtain.

Drugs producing anaphylaxis The drugs producing anaphylaxis over a 22-year period are shown in Table 2.

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Table 2. Cause of life-threatening clinical anaphylaxis during anaesthesia 1974-1997 (N= 604). Induction agents Thiopentone Althesin Propanidid Methohexitone Propofol Midazolam

N = 86 46 29 6 1 3 1

Induction agent and relaxant Thiopentone/Suxamethonium Thiopentone/Alcuronium Thiopentone/Atracurium

N = 3* 1 1 1

Muscle relaxants N = 350 Alcuronium Suxamethonium Atracurium d-Tubocurarine Gallamine Pancuronium Mivacurium Vecuronium Rocuronium Suxamethonium/Atracurium Suxamethonium/Gallamine Suxamethonium/Alcuronium Suxamethonium/Vecuronium Suxamethonium/d-Tubocurarine

124 107 37 21 16 11 1 15 1 1* 2* 4* 1* 1*

Reactions to two NMBDS on separate occasions dtc/Alcuronium 3 Decarnethonium/Suxamethonium 1 Pancuronium/Alcuronium 1 Gallamine/Alcuronium 1 Suxamethonium/Pancuronium 1 Alcuronium/Vecuronium 1 Colloid solutions

N = 34

Haemaccel Dextran 70 Dextran 40 SPPS NSA Plasma Other drugs N = 26 Protamine Contrast media Neostigmine Atropine Platelets Ondansetron Latex Gortex Patent Fragmin Ergometrine Blood Antibiotics N = 3 7 Cephalothin Cephamandole Cephazolin Cefotaxime Cefotetan Penicillin Ampicillin FlucloxaciUin Vancomycin Ampicillin/flucloxacillin#

24 6 1 1 1 1 9 4 1 2 2 1 2 1 1 1 1 1

Local anaesthetics N= 5 Prilocaine/Lignocaine Bupivacaine Lignocaine

Narcotics N = 15 Morphine Fentanyl Omnopon Pethidine

No drug detected

N= 48

11 1 7 2 4 2 3 4 2 1

* Both drugs received prior to reaction and positive skin and or RAST tests. t Two reactions on separate occasions.

It 2 2

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Neuromuscular blocking drugs It can be seen from Table 2 that neuromuscular blocking drugs (NMBDs) are the commonest causes of anaphylactic reactions, as in all large series. Suxamethonium is the most common culprit everywhere except in Australia, where alcuronium was commonest (Fisher and Baldo, 1983), although suxamethonium is currently the most common cause of death due to anaesthetic anaphylaxis in Australia. Pancuronium and vecuronium appear inherently safer than other NMBDs, but in France changing patterns of usage to reduce the use of suxamethonium have been associated with an increasing incidence of reactions to vecuronium (Laxenaire et al, 1990). Usage is the major factor in rate of reactions. However, examination of the incidence of positive skin tests to NMBDs in reactors (Table 3) suggests that some NMBDs are associated with a higher risk than others due to prevalence of sensitivity. Cross-sensitivity occurs in 60% of reactors, with the most common pairings of suxamethonium and gallamine, alcuronium and d-tubocurarine, and pancuronium and vecuronium (Fisher and Munro, 1983; Moneret-Vautrin et al, 1990) Cisatracurium and atracurium are antigenically identical, and there appears a high incidence of cross-sensitivity between rocuronium and vecuronium but, surprisingly, not pancuronium (Fisher M, unpublished data). Table 3. Percentage of patients allergic to neuromuscular blocking drugs allergic to individual drugs by skin testing.

Alcuronium Suxamethonium d-Tubocurarine Atracurium Gallamine Vecuronium Pancuroniurn

Positive

Number tested

Positive (%)

154 142 111

321 322 264

48% 44% 42%

67 47 25 37

201 163 197 315

33% 29% 13% 12%

Thiopentone Thiopentone remains a significant cause of life-threatening allergy and is often suspected in delayed reactions, although a cause and effect relationship is hard to establish. Two studies suggest that the incidence is in the order of 1:20 000. (Evans and Keogh, 1977; Beamish and Brown, 1981). Multiple uneventful exposures usually occur before the abnormal reaction but rarely it may occur on the first exposure. There is variable crosssensitivity with other barbiturates.

Cremophor-based drugs Previously used anaesthetic drugs althesin and propanidid, and initially propofol, were dissolved in Cremophor EL and had a very high incidence of anaphylaxis of up to 1:900. These allergic reactions were usual in that they caused complement activation by the classical and alternative path-

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ways. Skin testing produced positive results, suggesting IgE involvement (Fisher, 1976, 1984). The precise roles in anaphylaxis of the active drug and the solvent were not elucidated.

Propofol After changing the solvent to intralipid, life-threatening reactions to propofol still occurred, though to a lesser extent (Laxenaire et al, 1992), but the exact incidence is still unknown. Positive skin tests and radioimmunoassay tests have been documented. There is no evidence in the literature to support the relationship between allergy to eggs and allergy to the solvent causing anaphylaxis. Six patients have been referred to our clinic who developed late onset (20 minutes) bronchospasm and rash after administration of propofol to which lignocaine had been added, but none of these patients had an elevation in mast cell tryptase levels. Other induction agents Reactions to ketamine, midazolam, etomidate and methohexitone have been described but are extremely rare. Opioids Reactions to morphine, codeine phosphate, pethidine, omnopon and fentanyl have all been described but these are also rare. Less than 20 cases have been reported in the literature (Fisher et al, 1991). Antibiotics Antibiotics account for between 2 and 6% of reported anaphylactic reactions, with cephalosporins being the most common culprit (Fisher and Baldo, 1998). The incidence is increasing in Australia (Fisher and Baldo, 1998) and France (Laxenaire, pers. comm.). Cross-reactivity between cephalosporins is unusual as the antigenicity is usually related to side-chains rather than to the beta-lactam group. Crosssensitivity to penicillin through the beta-lactam group is probably overestimated and their is no evidence of cross-sensitivity between penicillin and 2nd, 3rd and 4th generation cephalosporins (Anne and Reisman, 1995). Cephalexin has a common side-chain with ampicillin with some cross-over in allergy, while ceftazidine (without the common side-chain) does not (Audicana et al, 1994). A recent study has shown that up to 25% of patients undergoing major surgery had non-immune non-histamine-mediated reactions to antibiotics (Kuennecke et al, 1996). Protamine Reactions to protamine may involve a number of mechanisms including IgE, IgG, and complement (Lakin et al, 1978; Sharath et al, 1985; Weiss et

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A N D M. M. F I S H E R

-al, 1989). Two different types of reaction may occur, a classical anaphylactic reaction and a syndrome producing pulmonary hypertension and right heart failure (Horrow, 1985). A prolonged and persistent capillary leak post-bypass has been attributed to protamine and plasma products, although no direct cause and effect has been shown (Horrow, 1985). Fish allergy and vasectomy have been suggested as predisposing factors to protamine anaphylaxis, but there is no convincing association.

Colloids and blood products All synthetic colloids have been shown to produce clinical anaphylaxis and there is no major evidence that one particular colloid has a higher incidence than another. As previously described, these reactions are rare during shock and there is little evidence that IgE is involved in the reactions. Pre-treatment with high-molecular-weight dextrans reduces the incidence of reactions to dextrans (Messmer et al, 1980), but anaphylaxis has occurred prior to the pretreatment and after the pre-treatment. Reactions to blood products are well documented but are surprisingly infrequently reported to our unit.

Latex Allergy to latex is becoming more of a problem to both health care workers and to patients in the operating theatre. Multiple glove changes are now required with the institution of universal precautions in hospitals and in dental clinics. This has led to a 5-17% risk of latex allergy in health care workers, most showing signs of contact dermatitis (type IV) but some develop bronchospasm at work which reverses on leaving the hospital environment. Latex allergy in the general population is more common in those who have atopy, who reportedly have a 4.4 times higher incidence. Children with spina bifida or congenital urological abnormalities have a 20-65% chance of having a latex allergy, which may arise from repeated surgical exposure and a need for multiple catheterization. In the general population the incidence of latex allergy is thought to be very low, about 0.37%. Cross-reactivity between latex and foods such as kiwi fruit, banana, avocado and chestnut have been found, all antigenically similar to latex (Kam et al, 1997). As well as type IV reaction, type I hypersensitivity reactions also occur and a large number of case reports describe life-threatening reactions to latex from urinary catheters (Zerin et al, 1996), surgical gloves (Barakat et al, 1992; Laxenaire and Moneret-Vautrin, 1994; Sussman and Beezhold, 1995), anaesthetic equipment, rubber stoppered vials (Kam et al, 1997) and balloons on thermodilution catheters (Gosgnach et al, 1995). The onset of anaphylaxis is usually delayed from the start of anaesthesia by 15 minutes and becomes progressively worse over the next 5-10 minutes and so is difficult to distinguish from reactions to other drugs. Most have positive prick tests (Laxenaire and Moneret-Vautrin, 1994) and elevated mast cell tryptase level (Volcheck and Li, 1994), suggesting an IgE-mediated reaction. Latex allergy is an increasing problem in anaesthetists. (For

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valuable information on epidemiology and prevention of reactions the reader is referred to the web site: http://www.latexallergy/com/.) Local anaesthetics

Anaphylactic reactions to local anaesthetics are extremely rare. Of the 208 patients referred to our unit, with a history of allergy to local anaesthetics, only four had severe anaphylaxis to local anaesthetics, four reacted to additives and four had delayed reactions. The commonest 'reactions' seen were psychological in 102 patients (Fisher and Bowey, 1997b). Some of the reactions may be related to the additives in local anaesthetics (Kajimoto et al, 1995), but this is difficult to prove as the tests for preservatives are unreliable and so where this cannot be excluded these solutions should be avoided. In three other published studies only 10 of 443 patients with a history of local anaesthetic allergy had positive skin tests to local anaesthetics (Fisher and Bowey, 1997b).

Clinical features of anaphylaxis Reactions may occur at any time during anaesthesia, but they are most common after induction (90%). Reactions may be well established before they are noticed. Table 4 shows the first clinical feature noted in 589 patients. Table 4. First clinical feature noted during anaphylaxic reactions in 589 patients. Symptom

Number

Subjective Cough No pulse No bleeding Swelling Difficult to inflate ECG abnormality Rash Flush Urticaria Other Desaturation

9 40 153 2 7 140 13 25 107 11 19 63

Total records

589

The most common initial features in the last few years have been difficulty in lung inflation and desaturation. Difficulty in inflation often leads the anaesthetist to change the tube which has led to subsequent accusations by 'expert' witnesses that the reaction was due to oesophageal intubation. The manifestations of oesophageal intubation usually appear later than in anaphylaxis. The clinical features in 555 patients are shown in Table 5. The table shows that cardiovascular manifestations are the most common feature, that

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T. WHITTINGTON AND M. M. FISHER Table 5. Clinical features of anaesthetic anaphylaxis in 555 patients. Number of cases

Sole feature

Worst feature

Cardiovascular collapse

490

61

434

Bronchospasm transient asthmatics

207 84 91

32

100

Cutaneous rash erythema urticaria more than one

73 264 45 32

Angioedema

135

7

18

2

3

Generalized oedema

37

Pulmonary oedema

13

Gastrointestinal

38

any system may be the only system involved and that the full constellation of symptoms does not occur in every patient. Cardiovascular collapse is associated with vasodilatation and supraventricular tachycardia. It is the only feature in approximately 10% of cases, which may lead to the reaction being attributed to other causes. Asthmatic patients who develop anaphylaxis invariably get bronchospasm. This is the most difficult feature to treat when severe. The pulmonary oedema is a low-pressure membrane oedema due to leaky capillaries and is associated with a volume deficit. Factors which increase severity are a history of asthma, use of I]-adrenoceptor antagonists and epidural anaesthesia. All of these states are associated with reduced efficiency of endogenous catecholamine response, which may make the reaction worse. Other allergic or anaphylactoid manifestations of mediator release occur. Delayed rashes (4 hours to 2 weeks) and periorbital oedema are not uncommon. These delayed reactions (type III and IV) usually occur in relation to thiopentone. Treatment There is a wide spectrum of severity of reaction and efficacy of response to treatment. Some patients respond to crystalloid and steroids, both of which are ineffective in severe cases, and others die in spite of excellent early management. There are no controlled trials of treatment in humans. Non-specific measures • • •

Give 100% oxygen. Stop the administration of the suspected antigen. Call for help and stop surgery if possible.

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• • •

• •

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Large bore intravenous access. Secure the airway. Adrenaline should be given i.v. if ECG and blood pressure are monitored, but i.m. for less severe reactions and if no monitoring is available. The route of adrenaline administration is controversial. Intravenous adrenaline may produce cardiac arrhythmias, infarction and severe hypertension, particularly if the diagnosis is incorrect or in unmonitored patients. While adrenaline should not be withheld until the patient is monitored, i.m. adrenaline may be a safer route and effective early. External cardiac massage if patient is pulseless. Intermittent positive pressure ventilation (IPPV) if necessary.

Specific treatment

Cardiovascular collapse Treatment should involve sympathomimetic vasoconstrictor drugs and intravenous fluids. What evidence there is favours the use of colloid solutions in preference to crystalloid (Fisher, 1977; Waldhausen et al, 1987) and adrenaline as the sympathomimetic since it has both vasoconstrictor and bronchodilator effects. German workers suggest that colloid fluid alone is preferable to using adrenaline because of the risk of adverse effects (Waldhausen et al, 1987). In our studies sympathomimetic drugs appear to enable more rapid stabilization. Adrenaline usually stops the progression of angioedema (Fisher, 1991). In monitored patients with severe reactions 3-5 ml of 1 in 10 000 (100 ~tg/ml) adrenaline should be given intravenously followed by a rapid infusion of 1-2 1 of colloid solution (Fisher, 1986). In over 90% of patients this will produce a rapid response but some patients, particularly those with epidurals, taking ~-adrenoceptor antagonists or with cardiac disease may not respond. In patients taking ~-adrenoceptor antagonists it may be advisable to use drugs with mainly an ~-adrenergic effect such as noradrenaline or metaraminol (Fisher, 1986). Glucagon has been used successfully but is often difficult to find in operating theatre suites. In refractory cases noradrenaline should be tried, and we now have seen a number of refractory cases where there was improvement with H2 receptor antagonists (De Soto and Turk, 1989). Anaphylactic shock only rarely involves the heart as a target organ although patients with cardiac disease may develop cardiac failure and are more likely to develop arrhythmias. If the heart becomes a target organ, severe global myocardial depression may require aortic balloon counterpulsation (Raper and Fisher, 1988).

Bronchospasm Bronchospasm, when it occurs, is often the most difficult problem to treat. Intravenous adrenaline is the first line drug. Continuous nebulization of ~2-adrenoceptor agonists such as salbutamol, and steroids (e.g.

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1 g methylprednisolone) should be given. Volatile anaesthetic agents may be of benefit. Isofluorane is the agent of choice with an adrenaline infusion. Ketamine may produce a dramatic response, especially in children. The main aim of ventilation is to maintain oxygenation and to avoid barotrauma, so slow rates (less than 6 breaths per minute) should be used. Hand ventilation may be better than IPPV. Provided that the arterial blood pH is greater than 7.0 and oxygenation is adequate, then the absolute level of carbon dioxide is unimportant. Aiding expiration by squeezing the lateral chest wall may be lifesaving when the airway's resistance is greater than the chest wall and lung elasticity (Fisher et al, 1989). Obviously, pneumothorax is a major concern in this situation and if their is any sudden deterioration then chest drains should be inserted. If all else fails and mechanical ventilation is impossible, barotrauma has occurred and cardiac arrest is imminent, then consideration should be given to cardiopulmonary bypass if available.

Angioedema In patients who develop angioedema intubating the patient's trachea is mandatory if dyspnoea is progressing. Adrenaline usually stops the process, and H~ receptor antagonists should be given. When a leak occurs around the endotracheal tube in a patient who is awake and spontaneously breathing, the patient can be extubated (Fisher and Raper, 1992).

Pulmonary oedema Pulmonary oedema in this situation is best controlled by positive end expiratory pressure (PEEP) until capillary leakage is controlled and the saturation improved. Diuretics are not useful in this situation as it is a lowpressure oedema and the patient has a volume deficit. In rare reactions following cardiopulmonary bypass large volumes of high-protein oedema fluid may occur. This needs invasive monitoring and massive fluid replacement. If PEEP is used the fluid may leak through the lung surface into the thoracic cavity, causing tamponade of the lungs and heart. This requires the insertion of chest drains (Olinger et al, 1980).

Diagnosis The diagnosis of anaphylaxis during anaesthesia is important not only to prevent subsequent reactions, but also for epidemiological and medicolegal reasons. The goals of diagnostic testing are to determine the cause of the event and the drug responsible for the event, to detect other drugs which may produce a similar event, and to determine those drugs which are safe to use in future anaesthetics. Patients should be referred for investigation when there is a high index of suspicion. Reactions affecting only one system or those of intermediate severity may be overlooked. The history is very important. If, for example,

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a patient develops severe bronchospasm, erythema and cardiovascular collapse after a single injection of propofol, and all the investigations are negative, it is still important to give a written warning suggesting that the drug should not be administered subsequently and explain the seriousness of the situation to the patient. One patient who presented with a note saying 'allergy to suxamethonium', died after being given thiopentone, which was the other drag given in the previous anaesthetic. Another uninvestigated patient who was labelled allergic to thiopentone reacted fatally to suxamethonium. Minor reactions restricted to the skin, reactions of short duration and intermediate severity and delayed reactions are difficult to investigate, and the available tests provide little help. We have not yet been able to document a case in which a minor reaction has led to, or preceeded, a severe reaction.

Investigation of an anaphylactic reaction The investigation during or shortly after the reaction aims to establish whether the reaction is immunologically mediated. The agent may be identifiable at the time with radio-immunoassay (RIA) tests for drugspecific antibodies.

Histamine assays. Raised concentrations of plasma histamine implicate histamine in the reaction. High levels do not establish the cause, but concentrations above 20 nmol per litre are suggestive that histamine is involved, and very high levels suggest that the reaction is anaphylactic (Levi et al, 1982; Laroche et al, 1988, 1991, 1992a). The converse is not true. No elevation in plasma histamine levels does not mean that histamine is not involved as local release may be implicated. Histamine assays have limited value as the rise is usually transient and sampling must occur within 10 minutes (Laroche et al, 1991), often at a time when resuscitation is a priority. Meticulous and complicated handling of the specimens is necessary.

Urinary methyl histamine Measurement of methyl histamine has an advantage over direct histamine levels because it has a more prolonged rise and provides a simpler assay. It is not a very accurate test, and studies have shown that it reached pathological levels in only 4 of 10 patients who had adverse reactions to anaesthesia, with 10 of 10 having high plasma histamine and nine of 10 with elevated mast cell tryptase (Laroche et al, 1992a).

IgE levels Alterations in serum total IgE levels after a reaction have been suggested as evidence that IgE is involved in such reactions. The IgE in these reactions

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is bound and so serum levels logically would not elevate. Drug-specific IgE -taken during the reaction usually (but not always) correlates with those of subsequent investigation (Laroche et al, 1992b).

Complement levels Changes in serum complement levels and activation of the classical and alternative pathways have been demonstrated after clinical anaphylaxis, particularly when due to althesin, contrast media and protamine (Best et al, 1983; Lasser et al, 1980; Cogen et al, 1979; Watkins et al, 1976). These changes have also been shown in IgE-mediated reactions where no complement activation is required and may represent activation secondary to shock or an independent process. Complement activation may occur without clinical manifestations, especially after cardiopulmonary bypass when heparin-protamine complexes may activate complement (Best et al, 1984). With these non-anaphylactic activations complement levels are likely to have a limited value, although there are insufficient data published to enable a valid assessment to be made. Activation rather than complement fractions should be measured, due to the dilutional effects during anaphylaxis (Fisher et al, 1984). This test, however, does not help to detect the drug responsible but is useful in confirming that some immunological event has occurred.

Mast cell tryptase Measurement of mast cell tryptase has proven to be an important advance in the diagnosis of anaphylactoid reactions during anaesthesia. Tryptase is a neutral protease in mast cell granules and is released during their activation (Enander et al, 1991). In anaphylactic reactions the levels are elevated for 1-5 hours after the onset of the reaction (Schwartz et al, 1989), enabling resuscitation to occur before the need for blood sampling. The assay is robust, easy to transport and requires no special handling of the blood samples. It is not affected by haemolysis (no tryptase in blood cells) and reliable samples can be obtained at post-mortem (Yunginger et al, 1991; Fisher and Baldo, 1993b). Although, in reactions to anaesthetic drugs, mast cell tryptase appears to be highly specific and sensitive for anaphylaxis, severe reactions may occur in which there is evidence of IgE involvement by skin testing or RIA testing, even when serum taken at an appropriate time does not show elevated tryptase levels. Laroche et al (1992a) postulated an allergic mechanism where the mediators of anaphylaxis are released from basophils which do not contain tryptase. Tryptase is also released during direct histamine release. Table 6 shows the incidence of positive skin and RIA tests associated with elevated mast cell tryptase. Although the association of elevated mast cell tryptase levels and positive tests is high, the severity of reactions means that skin testing is still necessary when mast cell tryptase levels are not elevated (Fisher and Baldo, 1997).

317

ANAPHYLACTIC AND ANAPHYLACTOID REACTIONS Table 6. Incidence of IgE involvement in patients with elevated mast cell tryptase (MCT). (Data taken from Fisher and Baldo, 1997). Group MCT not elevated Appropriate sample MCT elevated P value (chi square) MCT equivocal

Number of patients

ID positive/ performed

RAI positive/ performed

IgE detected

182 143 158

11/98 6/87 108/113 < 0.0001 0/6

9/96 4/81 72/101 < 0.0001 0/2

14/154 7/137 125/158 < 0.0001 0/6

10

Investigations after a reaction

Skin testing Skin testing is performed 4-6 weeks after the reaction (Fisher, 1984) but it detects only those reactions due to IgE, and possibly IgG. Testing, however, gives a high yield of results in published series, reflecting the high incidence of IgE involvement in severe reactions. Two forms of skin testing are used--intradermal and prick testing. Intradermal tests involve diluting the drug and injecting it into the dermis, and in prick testing the undiluted drug is introduced into the dennis by pricking the patient's skin through a drop of the drug to be tested. It is usual to use controls such as histamine and/or high concentrations of an opioid to determine that histamine response and release is normal (Fisher, 1984; Leynadier et al, 1987a). The great advantages of skin tests are that they have the highest yield of positive results and can be performed by anyone, and cross-sensitivity determined by skin testing usually enables safe decisions to be made as to subsequent anaesthesia (Fisher, 1984; Thacker and Gibbs, 1984; Fisher and Baldo, 1985; Leynadier et al, 1987b; Moneret-Vautrin et al, 1987; Moscicki et al, 1990). Prick testing has the advantages of less trauma to the skin, easier preparation, cost and safety. It is also more likely to be Successfully completed in children. Intradermal tests may produce more false positives and so may be slightly safer in that respect. The two tests have a greater than 90% agreement in the drug implicated (Leynadier et al, 1987a; Fisher and Bowey, 1997a) but agreement in determining cross-sensitivity with NMBDs is less reliable. The diagnostic yield is improved by performing both tests (Fisher and Bowey, 1997a). Skin tests are of little value in reactions to colloids, contrast media and blood products. Local anaesthetic allergy is so rare that the aim is to exclude allergy. In this case skin testing alone is inadequate and so without a clear-cut history suggestive of anaphylaxis and a positive Wheal and flare reaction to local anaesthetic at 1:100 dilution of 0.5% local anaesthetic the dose should be increased to 2 ml of undiluted local. Before the skin testing the patient should be tested with 2 ml of saline which often reproduces the symptoms. Deaths have occurred during skin testing (although not to anaesthetic drugs). In over 1000 intraderrnal tests we have had only two

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easily treatable reactions but resuscitation facilities should always be present. Radio-immunoassay tests

This is the most recent tool in testing for circulating IgE on the assumption that it reflects IgE bound to mast cells. An antigen, which is either the drug or an analogue is coupled to a solid support. The antigen-support complex is then incubated with the patient's serum so that any antibodies will bind to the supported antigen. The serum is then washed away and the complex incubated with radio-labelled anti-IgE and then measured by radioactive counting. This test needs drug-specific antibodies in the support and so is performed in only a few specialist laboratories. Use of these tests in over 300 patients has shown the following: (a) Radio-immunoassay tests will detect the drug responsible for a reaction less often than skin tests and are not available for all drugs. (b) A combination of radio-immunoassay tests and skin tests will increase the detection of responsible drugs by about 5%. (c) There is generally agreement between the tests for the drugs responsible, but a 50% disagreement for tests to other NMBDs when a battery of tests is performed. Cross-sensitivity as determined by radioimmunoassay is greater than by skin testing, giving both false-positive radio-immunoassy and false-negative skin tests. (d) There is significant in vitro cross-sensitivity between thiopentone and NMBDs by radio-immunoassay tests which is not shown clinically. Similarly, patients who react to NMBDs have a high incidence of positive RIAs to morphine which is not significant clinically and is probably related to the single quaternary group on morphine binding to the receptor on the antibody to NMBDs which bind by their quaternary or tertiary groups (Fisher and Baldo, 1983). In patients positive by one test the specificity of an alternative test increases. In practice, if any one test is positive then the patient should avoid that drug. Other tests

Leukocyte and basophil histamine release tests have been used in specialized laboratories and give similar results to radio-immunoassay. Evidence suggests that significant histamine release from blood cells is highly suggestive of an immune mechanism (Genovese et al, 1996). The disadvantage of these tests is that there are few laboratories that perform them and that the patient needs to go to the laboratory rather than simply supply a blood specimen. When skin and RIA tests have been negative we have not found that positive histamine release tests determined the drug responsible. In severe reactions the current range of tests will find an identifying agent in 95% of patients, and in those in which no agent is identified other forms of anaesthesia should be considered.

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PRE.OPERATIVE TESTING While some authors have suggested a role for pre-operative testing of either all or perceived high-risk patients with RIA testing, the efficacy and availability of such testing suggests that it has no valid role (Fisher and Baldo, 1994). In 68 patients we pre-operatively tested because of a family history of a reaction, multiple allergies, or alleged environmental chemical sensitivity syndrome; we found two weak positive skin tests. The recent French studies showing a high incidence of positive skin tests in the population (see above) present a challenge to anaesthetists. To prick test patients preoperatively with the drugs drawn up for use may be a valid, and virtually cost-free, method of preventing anaphylaxis in areas where the apparent risk is high. Adoption of the practice, however, may make the anaesthetist who does not test and whose patient reacts, medicolegally vulnerable.

Desensitization and blocking Thomas et al (1988) used the monoquaternary compound tiemmonium to block allergy to NMBDS by binding to the quaternary receptor. French workers have used other monoquaternary compounds to block reactions (Moneret-Vautrin et al, 1995). H, and H2 antihistamines in combination with steroids and adrenaline should also at least modify and possibly block reactions, but this has not been shown in practice.

Documentation Allergic patients should be encouraged to wear a warning device stating the drugs implicated by the testing. This is not sufficient on its own to ensure safe subsequent exposure. They should also be given a letter stating which drugs were given, what happened, which tests were performed, the results of those tests and the conclusion. Subsequent anaesthetists should add details of anaesthesia which is uneventful, or otherwise, to the letter. Anaesthetic allergy has been shown to persist for up to 27 years, and few patients lose their sensitivity (Fisher and Baldo, 1992). With this method of testing and follow-up we have seen five subsequent allergic reactions in 320 subsequent exposures. Two were related to falsenegative tests to alternative relaxants, two were related to using relaxants not tested, and one was probably due to latex allergy. Of 69 patients, 68 who were diagnosed as not anaphylactic have had uneventful subsequent anaesthesia and one has had a second prolonged block.

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