1. The definition of anaphylaxis adopted in this chapter refers to all immediate hypersensitivity reactions, irrespective of the underlying immunological mechanism, emphasising their similar clinical presentation and same immediate management.
2. Presentation, time course and response to treatment depend on the trigger agent, its route and rate of administration, the nature of the patient’s hypersensitivity and the state of health of the patient.
3. There has been a rising incidence of reactions to antibiotics and latex while the proportion of anaphylaxis due to neuromuscular blockers has been falling.
4. The only certain way to avoid anaphylaxis-related mortality and morbidity is avoidance of the triggering agents.
5. It is mandatory during preoperative assessment to systematically review the potential for a hypersensitivity reaction and to identify high-risk patients who need to undergo allergy testing. These are summarised in the section ‘Patients at high risk of anaphylactic reactions during anaesthesia’.
6. While prophylactic administration of H1 and or H2 antihistamines and steroids does not guarantee protection from anaphylaxis, it may diminish the incidence and severity of bronchospasm and hypotension in reactions due to non-specific histamine release.
Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction (Johansson et al., 2001). It is characterised by rapidly developing life-threatening airway and/or breathing and/or circulation problems usually associated with skin and mucosal changes.
In the definition adopted by the European Academy for Allergology and Clinical Immunology (Ewan et al., 2010), anaphylaxis refers to all immediate hypersensitivity reactions irrespective of the underlying immunological mechanism, including both IgE-mediated and non-IgE-mediated reactions. The definition emphasises that anaphylactic reactions share similar clinical presentation and warrant the same immediate management. Anaphylactic reactions are divided into allergic and non-allergic anaphylaxis after specialist testing is undertaken. Allergic anaphylaxis refers to anaphylaxis mediated by an immunological mechanism such as IgE, IgG or complement activation by immune complexes.
This definition has not been universally accepted, and some organisations still use the term ‘anaphylactoid’ with reference to non-IgE-mediated reactions, reserving the term ‘anaphylaxis’ for IgE-mediated reactions (Sampson et al., 2006).
Anaphylaxis may present with hypotension, tachycardia or bradycardia, cutaneous flashing, rash or urticaria, bronchospasm, angioedema and cardiac arrest. Anaphylactic reactions appear to share similar characteristics irrespective of the underlying mechanism. Nonetheless some studies indicate that allergic anaphylaxis tends to be more severe than non-allergic anaphylaxis. Analysis of anaesthesia-related anaphylaxis in France between 1 January 1999 and 31 December 2000 showed that cardiovascular collapse and bronchospasm were more common in allergic anaphylaxis, and cardiac arrest occurred only in allergic anaphylaxis (Mertes & Laxenaire, 2004). On the other hand, cutaneous signs were more common in non-allergic anaphylaxis.
Anaphylaxis is not a homogeneous entity; its presentation, time course and response to treatment depend on the trigger agent, its route and rate of administration, the nature of the patient’s hypersensitivity and the state of health of the patient. In general, onset of the reaction is related to the route of administration. Reaction to intravenously administered antibiotics or neuromuscular blockers tends to occur within minutes of injection, while reaction to latex occurs 30–60 minutes after the beginning of surgery, although it may occur immediately (Dewachter, Mouton-Faivre & Emala, 2009; Guideline, 2009).
Incidence of anaphylaxis to anaesthetic agents and other drugs and substances to which a patient is exposed during surgery was reported to be 1 in 13,000 in France and between 1 in 10,000 to 1 in 20,000 in Australia (Ewan et al., 2010). Incidence of anaphylaxis in the UK is uncertain; it is likely to be significantly underreported and accuracy and completeness of reporting have been suboptimal (Guideline, 2009). Occurrence of anaphylactic reactions is expected to rise due to increasing exposure to antibiotics and analgesics together with increasing sensitivity to latex.
Severity of anaphylactic reactions ranges from mild to life threatening. The commonly used clinical severity scale system uses five grades of anaphylaxis of increasing severity (Mertes & Laxenaire, 2004). Grade I corresponds with cutaneous signs such as erythema, urticaria and the presence or absence of angioedema. Grade II describes moderate multi-organ involvement, with cutaneous signs, hypotension, severe tachycardia and bronchial hyper-reactivity, including cough and wheeze. Grade III denotes severe life-threatening multi-organ involvement that requires specific treatment: collapse, tachycardia or bradycardia, cardiac arrhythmias and bronchospasm. Grade IV equates to circulatory and/or respiratory arrest, while grade V signifies death.
The mortality rate from anaphylaxis during anaesthesia was reported as ranging from 3.5 per cent to 4.7 per cent (Ewan et al., 2010) and 3 per cent to 9 per cent (De Hert et al., 2011). Death resulted even when reactions were appropriately treated. Allergic reactions in patients with known risk were the cause of death in 1 per cent of cases (Lienhart et al., 2006). Risk of death is increased in those with asthma, particularly when it is poorly controlled (Pumphrey & Gowland, 2007). Another unfavourable outcome from anaphylaxis is severe hypoxic brain injury, which was reported in an additional 2 per cent of cases (Fisher & Baldo, 1993).
The main causal agents of anaphylaxis during anaesthesia recorded during the study period between 1999 and 2000 in France were: neuromuscular blockers (58% of all cases), latex (16.7%), antibiotics (15.1%), hypnotics (3.4%), colloids (4%), opioids (1.3%) and other agents (7%) (Mertes & Laxenaire, 2004). The distribution of anaphylactic reactions between these substances appears to be identical in different countries (Mertes et al., 2005).
With the increasing number of surgeries and changes in anaesthetic practice, there has been a rising incidence of reactions to antibiotics and latex while the proportion of anaphylaxis due to neuromuscular blockers fell from two thirds of all reactions reported previously to about one third of anaphylaxis cases (Ewan et al., 2010).
Neuromuscular blocking agents (NMBAs) are responsible for 60 per cent of anaphylactic reactions and anaphylaxis is twice as likely to occur in anaesthesia when NMBA are administered (Laxenaire, Mertes & des Réactions Anaphylactoïdes, 2001).
Amongst NMBAs, the likelihood of reaction was the highest with rocuronium and suxamethonium, lower with vecuronium and the lowest with atracurium, although atracurium was associated with a high incidence of skin reactions (Mertes & Laxenaire, 2004). Fifty-six per cent of these reactions were triggered by rocuronium (45/80), 21 per cent by succinylcholine (17/80), 11 per cent by vecuronium (9/80), 9 per cent by atracurium (7/80) and 3 per cent by mivacurium (2/80). There were no reported events triggered by pancuronium or cisatracurium (Sadleir et al., 2013).
A previous history of specific drug exposure is not necessary. Conversely, an uneventful exposure may sensitise an individual to subsequent administration of a drug. There is some evidence that pholcodine-based cough medicines that contain quaternary ammonium groups cause sensitisation to quaternary ammonium of NMBAs, which may account for anaphylaxis to NMBAs without a previous exposure to NMBAs (Crilly & Rose, 2014).
Cross-sensitivity between different NMBAs is relatively common. If anaphylaxis to an NMBA is suspected, the patient should undergo skin-prick testing (SPT) with all the NMBAs in current use. If SPT is positive to an NMBA, the patient should be warned against future exposure to all NMBAs if possible. If use of an NMBA during anaesthesia is required, it would seem appropriate to use an NMBA which has a negative skin test, accepting that a negative skin test does not guarantee that anaphylaxis will not occur.
Self-reporting is important, although only a minority of patients who report allergy to antibiotics have a true allergy. Skin testing is only approximately 60 per cent predictive of clinical hypersensitivity. Penicillins and cephalosporins, which share the b-lactam ring, are responsible for approximately 70 per cent of antibiotic-induced anaphylaxis.
Patients who are allergic to penicillin or amoxicillin have a higher incidence of allergic reactions to first-generation cephalosporins and cefamandole, with which they share the structure of the side chains attached to the b-lactam ring, but not to other cephalosporins.
Allergy to local anaesthetics is exceptional. Preservatives such as methyl-paraben or metabisulphites may be responsible in some cases. It is suggested that reported adverse reactions relate to inadvertent intravascular injection, resulting in excessive concentration of local anaesthetic or systemic absorption of epinephrine. Reactions occurring in the dental chair may also be associated with idiopathic angioedema or latex allergy.
Opioids are an uncommon cause of anaphylaxis. Morphine, pethidine and codeine cause non-specific histamine release, which precludes diagnostic skin testing. Hence the diagnosis of anaphylactic reaction relies on a careful history and the exclusion of other possibilities. Challenge testing may be appropriate in some cases, but may be performed only in specialist centres.
Anaphylaxis to propofol is very uncommon. There is no evidence to support the suggestion that patients with egg or soy allergy should avoid propofol. Anaphylaxis to thiopental is extremely uncommon and probably a result of the decline in its use. A small number of cases of midazolam anaphylaxis have been reported.
Incidence of reactions due to modified gelatines and dextrans is similar. Intravenous gelatine solutions should be avoided in patients with a history of allergy to gelatine-containing vaccines. Anaphylaxis to hydroxyethyl-starch is rare.
Antiseptics and Disinfectants
Chlorhexidine may cause reactions ranging from contact dermatitis to life-threatening anaphylaxis. Anaphylaxis has occurred when chlorhexidine was used as an antiseptic for urological and gynaecological procedures as well as insertion of central venous and epidural catheters. The chlorhexidine coating of certain central venous catheters was found to cause anaphylactic reaction. It is prudent to allow skin disinfectant to completely dry before beginning an invasive procedure. Anaphylaxis to polyvinylpyrrholidine as povidone-iodine is rare.
Other substances which can induce anaphylaxis during anaesthesia include: NSAID, contrast media and dyes, protamine, aprotinine and chlorhexidine. No anaphylactic reaction to inhaled anaesthetics has been published.
Patients at High Risk of Anaphylactic Reaction during Anaesthesia
The only certain way to avoid anaphylaxis-related mortality and morbidity is avoidance of the triggering agents. It is mandatory during preoperative assessment to systematically review the potential for hypersensitivity reaction and to identify high-risk patients who need to undergo allergy testing. These include patients with documented or possible reactions (De Hert et al., 2011):
– patients with previous anaphylaxis documented by specialised investigation to any of the drugs or materials which are likely to be administered or used during anaesthesia;
– patients with a history of undiagnosed adverse events during previous anaesthetic with symptoms suggesting a possible allergic reaction;
– patients with a history of clinical symptoms suggesting a possible latex allergy, irrespective of the circumstance (for example, workers exposed to latex, including healthcare providers, patients exposed to prolonged latex urinary catheterisation, patients having undergone multiple surgeries and patients with eczema and contact allergy with rubber and adhesive tape);
– patients with spina bifida and myelomeningocele, as these conditions are a risk factor for development of latex allergy;
– patients with mastocytosis, a condition which predisposes to anaphylaxis to certain drugs (Ewan et al., 2010).
– patients with a history of clinical symptoms suggesting allergy to vegetables, fruits or cereals known to have frequent cross-reactivity with latex; these include kiwi, banana, papaya, avocado, chestnut and buckwheat (Malinovsky et al., 2008).
Other groups of patients that should raise caution are patients with a history of cutaneous sensitivity to cosmetics, detergents or rash from cough medicines that contain pholcodine or quaternary ammonium groups, which may be a source of cross-sensitivity to opioids and muscle relaxants. It has been shown that pholcodine induces the production of IgE antibodies to quaternary ammonium groups, therefore being an alternative source of sensitisation to neuromuscular blocking agents. Anaesthetists should be aware of this potential cross-reactivity, and the pre-anaesthetic evaluation should assess exposure to pholcodine during the past 12 to 24 months, as sensitisation declines within 1 or 2 years in exposed patients. This recommendation is particularly valid in countries where the pholcodine consumption is expected to be high, such as France and the UK. Anaesthetists should specifically ask about the use of pholcodine-containing cough suppressants as patients may not volunteer this information as these medications are sold over the counter.
Anaphylaxis to amoxicillin and cephalosporins is commonest in asthmatic smokers who have previously had multiple courses of these antibiotics without reacting; respiratory symptoms of anaphylaxis such as bronchospasm in such patients are not uncommonly and perhaps understandably initially misinterpreted as caused by asthma rather than anaphylaxis (Guideline, 2009).
Risk of anaphylactic reaction mandates allergy testing; on the other hand there is no evidence to support benefits from routine allergy testing in someone with no positive history. Similarly, allergy testing is not indicated in asthmatic or atopic individuals with reactions to agents which are not going to be administered or come into contact with the patient during anaesthesia.