Anaphylaxis

Anaphylaxis

ACUTE MEDICINE II Anaphylaxis Key points Neil H Young C The diagnosis of anaphylaxis is not always obvious C Anaphylaxis should therefore be co...

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ACUTE MEDICINE II

Anaphylaxis

Key points

Neil H Young

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The diagnosis of anaphylaxis is not always obvious

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Anaphylaxis should therefore be considered in any patient with rapid-onset deterioration in respiratory function, or hypotension or an acute airway problem

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Both the presentation and the causative factor can vary depending on the clinical situation

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Adrenaline (epinephrine) is the treatment of choice and should be given without delay if any life-threatening problems are present

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All patients need appropriate immediate and long-term followup

Graham R Nimmo

Abstract Acute anaphylaxis has been described as ‘a serious allergic reaction that is rapid in onset and may cause death’. It is becoming more common and is underdiagnosed. Even when anaphylaxis is recognized, it tends to be undertreated. All clinical staff should maintain a high level of awareness of anaphylaxis in order to recognize, assess and manage it optimally. In this article, we have concentrated equally on treatment and on recognition with assessment. The patient who exhibits the full range of manifestations of anaphylaxis may be readily diagnosed, but many present with only one or two of the features, thereby increasing diagnostic uncertainty and leading to delays in definitive treatment with adrenaline (epinephrine).

Keywords Adrenaline; anaphylaxis; critical care; hypersensitivity Assessing severity-initial resuscitation An early assessment of severity is essential to decide whether adrenaline (epinephrine) is necessary and whether the support of a doctor skilled in advanced airway management and circulatory is needed (Table 2). Patients with any of the major manifestations (airway, breathing or circulatory problems) should immediately be given adrenaline. In addition to adrenaline, the mainstays of initial resuscitation in anaphylaxis include administration of a high inspired concentration of oxygen and a rapid fluid bolus. The Resuscitation Council (UK) guideline for the management of anaphylaxis2 is reproduced in Figure 1.

Acute anaphylaxis is a medical emergency that presents in many guises and can occur anywhere from the community to the variety of in-hospital clinical settings. It has been described as ‘a serious allergic reaction that is rapid in onset and may cause death’,1 and is becoming more common. Because of the variability in presentation, it can be difficult to recognize and diagnose.

Recognition and assessment Making the diagnosis There are a few important questions to ask when considering the diagnosis (Table 1):  Is there a trigger/cause? (this may not always be apparent).  Is there significant past history? (e.g. atopy, previous reactions).  Is there multisystem involvement (respiratory/cardiovascular/skin/gastrointestinal)?  Is the patient taking a b-adrenoceptor blocker? (these can prevent the innate adrenergic response to an allergic reaction, resulting in an increased severity of reaction, and can cause catecholamine resistance, making treatment more difficult). A diagnosis of anaphylaxis should be considered in any illness of acute onset involving otherwise unexplained respiratory or cardiovascular compromise.

Patient positioning A number of guidelines recommend lying the patient flat and raising their legs. In the presence of upper airway swelling, bronchospasm or pulmonary oedema, this is potentially dangerous and can cause severe respiratory distress and respiratory arrest. We strongly counsel against this practice if airway or respiratory compromise is a prominent feature of the presentation. Our applied clinical practice is to keep the patient in a semi-recumbent position to optimize airway management, even in the presence of significant hypotension. Features Stridor is an inspiratory, high-pitched sound caused by partial obstruction of the laryngeal inlet. The condition is potentially lethal, even in the absence of bronchospasm, pulmonary oedema or shock. Tachypnoea is usual, often accompanied by a paradoxical (see-saw) breathing pattern. High-concentration humidified oxygen and systemic adrenaline should be given, and an emergency call for advanced airway expertise made. It may be impossible to secure the airway by conventional endotracheal intubation, and emergency front of neck airway access may be necessary and life-saving. Early administration of adrenaline can reverse the upper airway oedema causing the stridor. Adrenaline acts at a1-adrenergic receptors to cause vasoconstriction, thus increasing blood pressure and decreasing mucosal oedema. It

Neil H Young MB ChB MRCP(UK) FRCA DICM FFICM is a Consultant in Intensive Care Medicine and Anaesthesia at the Royal Infirmary of Edinburgh, Edinburgh, UK. Competing interests: none declared. Graham R Nimmo MB ChB MD (Edin) EdD (Stirling) FRCP(Edin) FFARCSI FFICM is a Consultant in Intensive Care Medicine and Clinical Education at the Western General Hospital, Edinburgh, UK. Competing interests: none declared.

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intramuscularly. In some cases, a doctor experienced in the use of intravenous adrenaline for circulatory support may titrate adrenaline intravenously in boluses of up to 50 micrograms. There is some evidence that a delay in the administration of adrenaline increases mortality.

Differential diagnosis of anaphylaxis C

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Stridor: infection (epiglottitis, croup, abscess), tumour, foreign body, smoke or toxin inhalation Wheeze: asthma; chronic obstructive pulmonary disease, pulmonary oedema, smoke or toxin inhalation Pulmonary oedema: left ventricular failure, acute respiratory distress syndrome, smoke or toxin inhalation Rash (acute generalized urticaria) Gastrointestinal symptoms: scombroid poisoning (decayed fish), monosodium glutamate Hereditary angioedema: classic symptom triad of abdominal pain, peripheral oedema and laryngeal oedema in the absence of urticaria Angioedema caused by an ACE inhibitor: this can occur because ACE inhibitors alter the degradation of bradykinin

Bronchospasm is caused by the effects of histamine, leukotrienes and cytokines on bronchial smooth muscle, and may be profound. Tachypnoea and accessory respiratory muscle activity are common; paradoxical breathing, bradypnoea and bradycardia signify a life-threatening situation, heralding imminent respiratory arrest. Immediate administration of high-concentration humidified oxygen and intramuscular adrenaline plus high-dose corticosteroids intravenously and nebulized salbutamol (in that order) is often beneficial. Second-line bronchodilators such as aminophylline can be effective but should be administered carefully under expert supervision. Early access to advanced airway expertise is important, remembering that intubation of the trachea (and the drugs used to facilitate it) can worsen bronchospasm and cause circulatory collapse. Slow rates of mechanical ventilation with prolonged expiratory times are employed, and side-to-side manual compression of the chest to encourage exhalation has been described as a useful rescue therapy. Repeated doses of adrenaline or an intravenous adrenaline infusion may be required.

ACE, angiotensin-converting enzyme.

Table 1

also acts at b1-adrenergic receptors to increase force and rate of cardiac contraction, and b2-adrenergic receptors to cause bronchodilatation and a decrease in mediator release. The initial recommended adult dose of adrenaline/epinephrine in anaphylaxis is 500 micrograms (0.5 ml of 1:1000 solution)

Pulmonary oedema is generated by capillary leak in the pulmonary microcirculation. In addition to oxygen and adrenaline, continuous positive airways pressure or mechanical ventilation may be essential to maintain adequate oxygenation. Both bronchospasm and pulmonary oedema can take many hours to improve.

Major and minor manifestations of anaphylaxis Major manifestations C C C C C C

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Hypotension, shock and circulatory collapse result from a combination of vasodilatation and capillary leak. The onset can be impressively fast, even over a couple of minutes, especially in reactions secondary to intravenous drug administration. Vasodilatation is caused by histamine, bradykinin and cytokines, and mediated through nitric oxide production. This causes hypotension through relative hypovolaemia in which the circulating blood volume is inadequate to fill the increased vascular ‘space’. Capillary leakage then results in absolute hypovolaemia with plasma loss into the tissues, which compounds the hypotension. Both tachycardia and bradycardia have been described clinically, but the latter often signifies imminent cardiac arrest. Highconcentration oxygen should be given with adrenaline as described above. Rapid intravenous fluid administration is required so large-bore vascular access is necessary; this can be difficult because of tissue oedema. Intraosseous access to the circulation is a potential alternative. A fluid bolus of 500 ml to 1 litre should be administered as quickly as possible. Given the increasing evidence that colloids have no benefits over crystalloids in critically ill patients, we recommend crystalloid as the initial fluid resuscitation of choice. Repeated doses of adrenaline or an adrenaline infusion may be required, but should be given in a critical care setting and guided by invasive haemodynamic monitoring.

Orofacial swelling with airway compromise Laryngeal swelling, manifesting as stridor Bronchospasm, manifesting as wheeze Pulmonary oedema Shock Cardiovascular collapse with faintness, palpitations, loss of consciousness Cardiac arrest

Treatment C C

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Stabilization and reversal of the process Stop or remove any cause: stop intravenous infusions of drugs, plasma expanders and blood products Give immediate oxygen and adrenaline (epinephrine)

Minor manifestations e the importance of these relates to their role in pointing to the diagnosis C C

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Upper respiratory tract features: rhinitis, conjunctivitis Skin rashes/colour changes: angioedema, urticaria, erythema, pallor, itch Gastrointestinal symptoms: abdominal pain, nausea and vomiting

Table 2

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Figure 1

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Myocardial dysfunction associated with anaphylaxis is increasingly described.3 The pathophysiology of this is interesting, both anaphylaxis-induced myocardial ischaemia (Kounis syndrome) and Takotsubo cardiomyopathy being possible manifestations. Takotsubo cardiomyopathy is associated with elevated catecholamine concentrations; both endogenous catecholamines and the exogenous catecholamines used to treat anaphylaxis may be contributory. Anaphylaxis in patients given concurrent b-adrenoceptor blockers can present significant challenges to cardiovascular management. There may be a reduced response to adrenaline; in this situation glucagon can be considered. However, there is also a risk of unopposed a-effects of any adrenaline administered, and continuous invasive blood pressure monitoring is mandatory in this situation.

Clinical features of anaphylaxis in 502 patients reacting to parenteral drugs perioperatively

Bronchospasm Transient From asthmatics Pulmonary oedema Cardiovascular collapse Cutaneous features Rash Erythema Urticaria >1 feature Angioedema Generalized oedema Gastrointestinal features

Recognition in patients under anaesthesia or intubated and ventilated In this situation, a history is unavailable so symptoms cannot be elicited. The following may be the only clinical features (in any combination or in isolation):  airway compromise, including high airway pressures  inability to ventilate, including an abnormal end-tidal CO2 trace  wheeze  desaturation  hypotension  skin changes. Table 3 summarizes the clinical features of 502 patients who reacted to drugs perioperatively.

Sole feature

Worst feature

191 76 85 13 447

18

91

2 5

3 400

6

17

65 233 42 30 125 36 36

Source: Fisher M. Fortnightly review: treatment of acute anaphylaxis. Br Med J 1995; 311: 731e33.

Table 3

potential causes of anaphylaxis in critical care and theatre environments.4

Preventing further deterioration and early biphasic recurrence A second anaphylactic episode can result from the original allergen, a so-called biphasic response (Figure 2). This is well recognized, but the exact frequency is debated, with a quoted range as wide as 1e37% of anaphylactic reactions. The timing of these is also uncertain, with documented recurrences of anaphylaxis of 1e72 hours after the index event. Administration of adrenaline can reduce the occurrence of biphasic reactions. The utility of corticosteroids and antihistamines is unproven. The early administration of systemic corticosteroids (intravenous in these cases) has two purposes, which have a biologically plausible basis: first, to dampen down the acute inflammatory process, and second, to reduce the risk or intensity of a secondary or biphasic anaphylactic reaction. Whereas adrenaline works almost immediately via cell surface receptors and a rapid enzymatic process, corticosteroids take significantly longer to have their effect. They must first cross the cell wall, move to the nucleus and alter protein synthesis, before the resulting proteins can mediate their anti-inflammatory effects. This takes several hours. Systematic review reveals no randomized trials supporting the use of corticosteroids in anaphylaxis. However, given the relatively low incidence of adverse effects, they will probably remain in national and international guidelines as it is very difficult to conduct welldesigned randomized controlled trials in anaphylaxis. It should be emphasized that corticosteroids are second line, and should not impede or delay the administration of adrenaline. Antihistamines have traditionally been included in the stabilization treatment package because of their propensity to dampen down the histamine-related features of itch and angioedema,

Causes The likely cause of an anaphylactic reaction varies by the clinical setting. The causative agent can also vary with age, with foods being more common in children and medications being more common in middle-aged and elderly adults. Drug causes The most commonly reported drugs causing anaphylaxis are penicillins and cephalosporins, probably because of their immunogenicity and frequency of use. Reactions tend to be more rapid and severe when the drug is administered parenterally. There may be no previous history of drug exposure. Nonsteroidal anti-inflammatory drugs and aspirin are also commonly implicated. Drugs in elective and emergency anaesthesia in theatre, emergency department and critical care: neuromuscular blocking agents cause around 60% of anaphylactic reactions in this context. The antigen is the quaternary ammonium group that is found in other drugs, food, cosmetics and hair products, so a reaction can occur without previous exposure to the drug itself. The most commonly found cause in a large French study was rocuronium, followed by suxamethonium. In the same study, after neuromuscular blocking drugs, latex was found to be the next most common causal agent (16.7%), followed by antibiotics (15.1%), colloids (4%) and hypnotics (3.4%). Chlorhexidine skin preparations and chlorhexidine-impregnated central venous catheters should also be considered as

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No. of cases

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Figure 2

individuals who have emergency treatment for anaphylaxis should be referred to a specialist allergy service; and anyone with a systemic reaction to a wasp or bee sting should be referred to a specialist allergy service for assessment for venom immunotherapy. While awaiting allergy clinic review, patients or their relatives or carers must be carefully counselled regarding the risks of biphasic reactions, avoidance of suspected triggers, symptoms and signs that can herald a further episode of anaphylaxis, and the need for emergency care in the event of another episode. A

with the H1 anti-histamine chlorphenamine being included in UK guidelines.2 A Cochrane systematic review found no evidence to support their use and recommended that a randomized trial be conducted. In some countries, national guidelines include the administration of H2-blockers in addition to chlorphenamine, but they do not feature in UK guidance.

Follow-up and prevention Blood should be drawn immediately (without delaying resuscitation), at 1e2 hours after clinical onset and at 24 hours (or in convalescence) to allow measurement of serum tryptase. These measurements indicate whether an anaphylactic reaction has indeed occurred. Serial tryptase measurement has been shown to have a sensitivity of 73% and specificity of 98% in the diagnosis of anaphylactic reactions. A decision must be made about the length of time the patient should be kept under immediate observation. This has important practical implications, and there is wide variation in both practice and recommendations; local policies will have been developed to support practice. There is an increased risk of a biphasic reaction in patients who have suffered major manifestations, especially if adrenaline administration has been delayed. It is usual for patients to be observed for 6e12 hours (National Institute of Health and Care Excellence (NICE) guidance). In March 2016, NICE produced a quality standard for anaphylaxis, with the goals of contributing to improvements in documenting the incidence of anaphylaxis, admission rates for anaphylactic episodes and mortality from anaphylactic episodes.5 The quality statements included that the following: patients requiring emergency treatment for anaphylactic reactions should be prescribed, and given training to use, an adrenaline autoinjector before hospital discharge, and be given continuing training in its use; all

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KEY REFERENCES 1 Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report e Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med 2006; 47: 373e80. 2 Resuscitation Council (UK). Emergency treatment of anaphylactic reactions: guidelines for healthcare providers. https://www.resus. org.uk/anaphylaxis/emergency-treatment-of-anaphylacticreactions/ (accessed 30 Nov 2016). 3 Cha YS, Kim H, Bang MH, et al. Evaluation of myocardial injury through serum troponin I and echocardiography in anaphylaxis. Am J Emerg Med 2016; 34: 140e4. 4 Sharp G, Green S, Rose M. Chlorhexidine-induced anaphylaxis in surgical patients: a review of the literature. ANZ J Surg 2016; 86: 237e43. 5 National Institute for Health and Clinical Excellence. Anaphylaxis: assessment to confirm an anaphylactic episode and the decision to refer after emergency treatment for a suspected anaphylactic episode. Clinical guideline no. 134. 2011. London: NICE. Available from: https://www.nice.org.uk/guidance/qs119 (accessed 30 Nov 2016).

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FURTHER READING Bayer O, Reinhart K, Kohl M, et al. Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: a prospective sequential analysis. Crit Care Med 2012; 40: 2543e51. Fisher M. Fortnightly review: treatment of acute anaphylaxis. Br Med J 1995; 311: 731e3.

Lee S, Sadosty AT, Campbell RL. Update on biphasic anaphylaxis. Curr Opin Allergy Clin Immunol 2016; 16: 346e51. McLean-Tooke APC, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatment of anaphylaxis: what is the evidence? Br Med J 2003; 327: 1442e5.

TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.

Question 1

B.

A 56-year-old man who was in the high-dependency unit 6 days after a total gastrectomy required a central venous catheter to facilitate total parental nutrition. He had been physiologically stable prior to this. Immediately after insertion of the line, he became tachypnoeic and flushed. His respiratory rate increased to 34 breaths/minute, with wheeze throughout his chest, and his blood pressure decreased to 85/38 mmHg.

C. D. E.

What is the most appropriate next step in his management? A. Give 500 micrograms of intramuscular adrenaline B. Give 50 micrograms of intramuscular adrenaline C. Give 500 micrograms of intravenous adrenaline D. Commence an intravenous adrenaline infusion E. Give 50 micrograms of intra-osseous adrenaline

Question 3 A 47-year-old woman developed an urticarial skin rash while on the haematology ward. She had been admitted with neutropenic sepsis following treatment for acute myeloid leukaemia. Treatment for the sepsis was with intravenous gentamicin and piperacillinetazobactam. She had a previous history of paroxysmal atrial fibrillation. On clinical examination her airway and breathing were normal and she was cool peripherally. Heart rate was 145e165 beats/ minute, Blood pressure was 75/43 mmHg, An ECG showed new atrial fibrillation.

Question 2 A 29-year-old woman presented to the emergency department with facial swelling and stridor after being stung by a bee. She was treated in the emergency department with intramuscular adrenaline (epinephrine), intravenous chlorphenamine and intravenous hydrocortisone. She was admitted to the medical assessment unit for a period of observation, and 8 hours later was well with no symptoms or signs suggestive of a biphasic reaction.

Which of the following treatments would be of most benefit? A. 500 micrograms of intramuscular adrenaline (epinephrine) B. 50 mg of oral metoprolol C. 5 mg of intravenous metoprolol D. 500 micrograms of intravenous digoxin. E. 500 ml of intravenous sodium chloride

What is the correct follow-up for this patient? A. She should receive an adrenaline autoinjector; referral to a specialist allergy service is unnecessary in view of the clear precipitant

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She should receive an adrenaline autoinjector and be referred to a specialist allergy service for consideration of venom immunotherapy She should be referred to a specialist allergy service and take daily antihistamines in case she is stung again She does not need any further follow-up, but should be counselled to avoid bees She should be referred to a specialist allergy service for a decision regarding the need for an adrenaline autoinjector

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