Anaphylaxis: quick reference for emergency management

Basic principle

Anaphylaxis is a rapidly developing systemic hypersensitivity reaction that can cause life-threatening compromise of the airway, breathing or circulation. Skin symptoms may be absent, and circulatory shock does not have to be present for the condition to be serious [1].

Intramuscular adrenaline (epinephrine) is the first-line treatment and must be given early when anaphylaxis is suspected. Do not wait for a complete diagnosis or for grading. Antihistamines, corticosteroids, inhaled bronchodilators and nebulised adrenaline never replace intramuscular adrenaline [1,2].

Delayed administration of adrenaline is associated with more severe and more protracted reactions, biphasic courses and fatal outcome. At the same time, serious adverse effects are uncommon when the correct dose is given intramuscularly [2,3].

When should anaphylaxis be suspected?

Anaphylaxis is a clinical diagnosis. Treat as anaphylaxis in any of the following:

1. Acute onset of skin or mucosal symptoms, for example generalised urticaria, itching, flushing or angio-oedema, together with at least one of the following:

   • airway compromise
   • respiratory compromise
   • circulatory compromise
   • severe gastrointestinal symptoms, particularly after exposure to a drug, insect venom or another non-food allergen

2. Acute airway, respiratory or circulatory compromise after exposure to a known or probable allergen, even if skin symptoms are absent [1,4].

Typical warning symptoms are:

• hoarseness, stridor, swelling of the tongue or throat
• dyspnoea, hypoxia, bronchospasm or severe cough
• hypotension, collapse, impaired consciousness or new-onset marked weakness
• rapidly progressive symptoms from several organ systems
• severe abdominal pain or repeated vomiting after probable allergen exposure
• sudden hypotension or severe bronchospasm during anaesthesia, a drug infusion or the administration of contrast medium

Skin symptoms are absent in approximately 10 to 20 percent of anaphylactic reactions. The absence of urticaria must therefore not be used to exclude the diagnosis [1].

Isolated urticaria, localised angio-oedema or itching without compromise of the airway, breathing or circulation is usually an allergic reaction but not in itself anaphylaxis. The patient must nonetheless be observed, since the reaction can progress.

Practical grading

There are several grading systems, and no grading replaces immediate clinical assessment. The updated international grading comprises five levels, with mild skin and mucosal reactions in the lower grades and marked airway, respiratory or circulatory compromise in the higher ones [5].

For acute clinical use the following simplification can be used:

The grade can change within minutes. Treat the current physiological threat, not the grading label.

The first minute

1. Stop the exposure if this can be done immediately.

   • Stop a suspected drug infusion or contrast medium.
   • Remove a visible bee sting.
   • Never delay adrenaline in order to identify or remove the allergen.

2. Give adrenaline 1 mg/ml intramuscularly into the middle third of the anterolateral thigh.

   • Dose 0.01 mg/kg, corresponding to 0.01 ml/kg.
   • The maximum single dose is 0.5 mg, corresponding to 0.5 ml.
   • Adults are usually given 0.5 mg. In a smaller adult, or with a milder initial picture, 0.3 mg can be used.
   • Document the time and the dose.

3. Call for help.

   • In hospital: activate the emergency call and contact anaesthesia or intensive care early in a severe reaction.
   • Outside hospital: call the local emergency number. The patient must not drive or be transported in a private car.

4. Position the patient correctly.

   • Patient with circulatory compromise: flat supine, preferably with the legs raised.
   • Marked respiratory compromise: the patient may need a semi-sitting position, but the legs should be kept elevated if possible.
   • Unconscious patient breathing spontaneously: recovery position.
   • Pregnant patient: left lateral position or manual left displacement of the uterus.
   • Do not let the patient suddenly sit up, stand up or walk.

5. Assess and treat according to A to E.

   • Secure a patent airway.
   • Give high-flow oxygen in respiratory compromise, hypoxia, hypotension or when repeated doses of adrenaline are needed.
   • Attach pulse oximetry, blood pressure monitoring and ECG as soon as this can be done without delaying adrenaline.
   • Insert one or more large-bore peripheral cannulas in a severe reaction.
   • Prepare airway equipment and be ready for cardiopulmonary resuscitation.

6. Repeat intramuscular adrenaline after 5 minutes if airway, respiratory or circulatory compromise persists or recurs. If the reaction is still inadequately treated after two doses it should be regarded as potentially refractory [2].

About 8 percent of anaphylactic reactions are treated with more than one dose of adrenaline. Among food- and venom-triggered reactions that received adrenaline the proportion is higher. Only a small minority persist despite two doses, which makes a lack of response an important marker of severity [6].

Intramuscular adrenaline dosing

Use adrenaline 1 mg/ml. Do not confuse this concentration with the more dilute preparations intended for intravenous use.

Weight thresholds for adrenaline auto-injectors vary somewhat between products and summaries of product characteristics. Within health care, drawing up a weight-based dose allows more precise dosing. In larger adolescents and adults, an auto-injector containing 0.3 mg can give a lower dose than the recommended maximum dose of 0.5 mg [2,7].

In small children the benefit of immediate treatment must be weighed against the fact that an auto-injector containing 0.15 mg can deliver more than 0.01 mg/kg. The potential overdose is as a rule less dangerous than untreated anaphylaxis or the delay involved in drawing up the drug. Hold the child's leg firmly during the injection to reduce the risk of needle injury [8].

Technique of administration

• Give the injection into the middle third of the anterolateral thigh, not into the upper arm.
• The injection can if necessary be given through thin clothing, but avoid pockets, seams and objects.
• Subcutaneous administration should not be used, because absorption is slower and less predictable.
• Do not massage a markedly swollen injection site.
• Record every dose and time clearly.
• Do not switch to intravenous bolus doses because an intramuscular dose has not had an immediate effect.

There is no absolute contraindication to intramuscular adrenaline in anaphylaxis. This applies also in old age, pregnancy, ischaemic heart disease and tachycardia. Serious cardiovascular adverse effects are linked above all to intravenous bolus doses, dosing errors and too high a concentration [9].

Positioning

Incorrect positioning can contribute to circulatory collapse. A patient with hypotension or a feeling of faintness must not sit or stand. An upright position has repeatedly been described in connection with fatal anaphylaxis [3].

• Hypotension or presyncope: flat position with the legs raised.
• Severe breathlessness without hypotension: cautiously semi-sitting with the legs elevated.
• Vomiting or unconsciousness with preserved breathing: recovery position.
• Pregnancy: left lateral position, or supine with manual left displacement of the uterus.
• Infants: flat or semi-recumbent in the carer's arms. Avoid holding the child fully upright.

The patient must not be allowed to walk to the toilet, the shower or a means of transport until the reaction is stable and the circulatory risk has been judged to be low.

Airway and breathing

Upper airway compromise

Hoarseness, stridor, swelling of the tongue or throat, drooling and a rapidly increasing change in voice indicate a threatened upper airway.

• Give intramuscular adrenaline immediately.
• Call anaesthesia and ENT early.
• Give high-flow oxygen.
• Prepare for early intubation. Do not wait until marked oedema has made intubation impossible.
• Nebulised adrenaline can be given as an adjunct in stridor or laryngeal oedema according to the local dosing protocol.
• Nebulised adrenaline does not replace intramuscular adrenaline.

Bronchial obstruction

For bronchospasm persisting after the first dose of adrenaline:

• give inhaled salbutamol or terbutaline via a spacer
• in severe respiratory compromise, give the bronchodilator by oxygen-driven nebuliser
• repeat according to the clinical response and the local asthma protocol
• consider an inhaled anticholinergic bronchodilator in severe obstruction

An inhaled beta-2 agonist treats bronchospasm but not laryngeal oedema, vasodilatation, capillary leak or shock. Persisting respiratory compromise is therefore an indication for further intramuscular adrenaline, not merely for more inhalations [2].

Exhaustion, a falling level of consciousness, a silent chest, hypoxia despite oxygen and rising carbon dioxide indicate impending respiratory failure.

Circulation and fluid treatment

Anaphylactic shock has both distributive and hypovolaemic components. Marked vasodilatation and rapid capillary leak can substantially reduce the effective circulating volume within a short time. Adrenaline may work less well if the circulating volume is not restored at the same time [2].

In hypotension, shock or an inadequate response to the first dose of adrenaline:

1. Insert one or more large-bore peripheral cannulas.
2. Give a balanced crystalloid rapidly.
3. Reassess blood pressure, pulse, peripheral perfusion, level of consciousness and chest findings after each bolus.
4. Repeat if hypoperfusion persists.

Large volumes of fluid may be needed in refractory anaphylaxis. Fluid treatment must, however, be titrated with particular care in known heart failure, severe renal failure or signs of a cardiogenic component.

In cardiac arrest, the usual guidelines for cardiopulmonary resuscitation apply. Adrenaline is then given intravenously or intraosseously according to the cardiac arrest algorithm, not according to the dosing for intramuscular treatment of anaphylaxis.

Second-line drugs

Second-line drugs are given only once adrenaline, correct positioning, oxygen and, where needed, fluid have been dealt with.

Antihistamines

Antihistamines have no documented effect on hypotension, bronchospasm, laryngeal oedema or survival. The Cochrane review found no randomised trials that could demonstrate a clinical benefit in anaphylaxis [10].

Antihistamines can be used for persisting itching and urticaria once acute problems with the airway, breathing and circulation have been treated. Choose in the first instance an oral, non-sedating H1 antihistamine. Sedating antihistamines can make assessment more difficult by causing drowsiness, and rapid intravenous administration of some preparations can cause hypotension.

Corticosteroids

Corticosteroids should not be given routinely as acute treatment or with the aim of preventing a biphasic reaction. Systematic reviews have not identified controlled trials showing that corticosteroids improve the acute course or prevent recurrence [11,12]. Later observational data have likewise not provided convincing support and have raised the suspicion of an increased burden on health care, although the influence of indication bias cannot be excluded [2,13].

A corticosteroid can be considered as third-line treatment in:

• marked concurrent asthma
• protracted bronchial obstruction
• refractory anaphylaxis after adequate adrenaline and fluid have been given
• another concurrent condition with a separate indication for a steroid

Betamethasone or another corticosteroid must never delay a repeat dose of adrenaline.

Refractory anaphylaxis

The reaction should be regarded as potentially refractory if airway, respiratory or circulatory compromise persists despite two adequate intramuscular doses of adrenaline, correct positioning and initial fluid treatment [14,15].

Immediate measures

1. Call anaesthesia and intensive care.
2. Continue intramuscular adrenaline every 5 minutes while an infusion is being prepared.
3. Ensure oxygen, ventilation and readiness for advanced airway management.
4. Give further rapid crystalloid according to the clinical response.
5. Check that the triggering infusion or other allergen really has been removed.
6. Reconsider differential diagnoses and concurrent causes of shock.
7. Start a dilute intravenous adrenaline infusion according to the local intensive care or anaesthesia protocol.
8. Attach continuous ECG, blood pressure and oxygen saturation monitoring. Consider an arterial line and ultrasound assessment of the heart and volume status.

Intravenous adrenaline should preferably be given as a titrated infusion. Intravenous bolus doses carry a greater risk of severe hypertension, arrhythmia, myocardial ischaemia and dosing errors. The exceptions are cardiac arrest and certain perioperative situations where an experienced anaesthetist gives small titrated doses under full monitoring [2,14].

If hypotension persists despite an adrenaline infusion and adequate fluid, an additional vasopressor may be needed. There is insufficient evidence to identify noradrenaline (norepinephrine), vasopressin or any other vasopressor as generally superior. Treatment should be directed by an intensive care or anaesthesia specialist [14].

Beta blockers and glucagon

Beta blockers can reduce the response to adrenaline. In persisting shock in a patient taking a beta blocker, intravenous glucagon can be considered, since its inotropic and chronotropic effects are not dependent on beta-adrenergic receptors.

Several international guidelines state 1 to 5 mg intravenously slowly for adults, followed by a titrated infusion if an effect is seen. The evidence consists mainly of case reports, and dosing should follow the local protocol. Be prepared for nausea, vomiting, aspiration, hyperglycaemia and electrolyte disturbance [14].

Biphasic and protracted anaphylaxis

A biphasic reaction means that symptoms recur after complete initial resolution without further allergen exposure. The pooled frequency is around 5 percent, considerably lower than older estimates of up to 20 percent [2].

Recurrence can occur after several hours. In a meta-analysis the median time was 11 hours, with a wide spread. Hypotension during the first reaction and an unknown trigger were associated with a higher risk [16].

Other risk markers are:

• severe initial anaphylaxis
• the need for more than one dose of adrenaline
• a delayed first dose of adrenaline
• persisting or protracted symptoms
• severe asthma or marked bronchospasm
• continued absorption of the allergen, for example after food intake
• a previous biphasic reaction
• an unknown trigger
• a long distance to emergency care or inadequate supervision after discharge

Antihistamines and corticosteroids do not reliably prevent biphasic anaphylaxis [12].

Observation time

The observation time is counted from the point at which symptoms have resolved completely, not from arrival or from the first dose of adrenaline. There is no observation period that captures all biphasic reactions. A meta-analysis in adults showed that one hour of observation after resolution of symptoms gave a negative predictive value of about 95 percent, while at least six hours gave about 97 percent [17].

Use a risk-based assessment:

Children, pregnant women, frail elderly patients and patients with significant cardiac or pulmonary disease may need longer observation. The same applies late in the evening or at night, with a long journey home, in the absence of a working adrenaline auto-injector or with uncertain ability to manage a recurrence.

Swedish local care protocols may specify other minimum times and should be followed where they are more cautious.

Tryptase and acute sampling

A tryptase sample must never delay adrenaline or other resuscitation. The test does not confirm the diagnosis acutely but can later support that mast cell activation has occurred.

In a severe, unclear, drug-triggered or perioperative reaction:

1. Take an acute serum tryptase as soon as the patient has been stabilised, preferably within 1 to 2 hours of symptom onset.
2. A sample taken within 1 to 4 hours is still useful.
3. Take a baseline sample no earlier than 24 hours after complete resolution of symptoms, or alternatively at a later allergy workup.
4. Compare the acute value with the patient's own baseline.

An acute rise in tryptase above 1.2 times the baseline value plus 2 micrograms/L supports mast cell activation. A normal value does not exclude anaphylaxis, particularly not in food-triggered reactions in children [1,20].

A raised baseline tryptase may indicate mast cell disease or hereditary alpha-tryptasaemia and warrants specialist assessment, particularly after severe insect venom-triggered or idiopathic anaphylaxis [4].

Differential diagnoses and pitfalls

Important differential diagnoses

• vasovagal syncope
• an acute asthma attack
• a foreign body or other mechanical airway obstruction
• a panic attack or hyperventilation
• hereditary or drug-induced bradykinin-mediated angio-oedema
• sepsis or other distributive shock
• bleeding or hypovolaemia
• pulmonary embolism
• acute coronary syndrome
• an epileptic seizure
• hypoglycaemia
• food protein-induced enterocolitis syndrome in children
• acute urticaria without anaphylaxis
• a reaction to the infusion rate, for example direct mast cell activation by certain drugs

A brief syncope with pallor and bradycardia that improves rapidly in a flat position suggests a vasovagal reaction. Anaphylaxis more often produces tachycardia, persisting hypotension, urticaria, angio-oedema, bronchospasm or gastrointestinal symptoms. Bradycardia can, however, also occur in severe anaphylactic shock.

Common pitfalls

• Waiting for skin symptoms. Anaphylaxis can be present without urticaria.
• Waiting for hypotension. Hypotension is often a late sign, particularly in children.
• Giving an antihistamine first. This can delay adrenaline without treating the life-threatening process.
• Giving a corticosteroid to prevent recurrence. The effect is not established.
• Giving adrenaline subcutaneously or into the upper arm. Give it intramuscularly into the thigh.
• Waiting 10 to 15 minutes before the next dose. With persisting serious symptoms a further dose should be given after 5 minutes.
• Giving intravenous adrenaline as a routine bolus. This increases the risk of overdose and cardiovascular complications.
• Letting the patient stand up. This can precipitate sudden circulatory collapse.
• Giving a bronchodilator alone for anaphylactic bronchospasm. Inhalation does not treat the other components of the reaction.
• Forgetting fluid in shock. Capillary leak and reduced venous return can be marked.
• Interpreting a normal tryptase as excluding anaphylaxis.
• Forgetting to document times, doses and possible triggers.

Underuse of adrenaline and poor auto-injector technique are well-documented problems. Practical training should therefore be prioritised over verbal instruction alone [18,19].

Special situations

Infants

Infants can have classic symptoms such as urticaria, angio-oedema, cough, wheezing and vomiting, but also non-specific changes in behaviour. Sudden irritability, clinginess, stopping play, tongue thrusting, pulling at the ear or unusual tiredness must be assessed in their clinical context [8].

Hypotension can be a late sign. Tachycardia, pallor, floppiness, repeated vomiting and altered behaviour can be early expressions of systemic involvement. The treatment principle is the same as for older children: adrenaline 0.01 mg/kg intramuscularly.

Pregnancy

Adrenaline must be given immediately in pregnancy as well. Inadequately treated maternal hypotension and hypoxia are more dangerous for the fetus than a correct intramuscular dose of adrenaline.

• Place the patient in the left lateral position or displace the uterus to the left.
• Give high-flow oxygen.
• Treat hypotension aggressively with crystalloid and adrenaline.
• Start continuous fetal monitoring when the gestational age allows it.
• Contact an obstetrician and anaesthesia early.
• Consider emergency delivery in persisting maternal circulatory failure, according to obstetric and anaesthetic protocol [23].

Perioperative anaphylaxis

Perioperative anaphylaxis can present with isolated hypotension, bronchospasm, rising airway pressure, desaturation or a falling end-tidal carbon dioxide. Skin symptoms can be hidden by drapes or appear only once perfusion has been restored.

An experienced anaesthetist can use titrated intravenous adrenaline under full monitoring, since venous access and continuous monitoring are already in place. An early infusion is preferred when the response to small titrated doses is poor. Large volumes of fluid may be needed [21].

After stabilisation:

• suspected exposures and exact times must be documented
• acute and later baseline tryptase must be taken
• the anaesthetic record, drugs, infusion fluids, disinfectants, latex exposure and implant materials must be preserved for the investigation
• the patient must be referred for a formal allergological workup

All suspected perioperative reactions should be investigated, since incorrectly identifying the trigger can lead both to renewed exposure to the true allergen and to unnecessary future drug restrictions [22].

Cardiovascular disease and chest pain

Anaphylaxis can itself cause coronary spasm or an acute coronary syndrome, sometimes called Kounis syndrome. Chest pain, ischaemic ECG changes or arrhythmia should therefore not automatically be interpreted as an adverse effect of adrenaline.

Give intramuscular adrenaline in anaphylaxis and add an ECG, troponin and cardiological assessment. Intravenous doses of adrenaline should be avoided outside a monitored specialist setting [9].

Before the patient goes home

Perform a structured discharge check.

Adrenaline auto-injector

Patients at risk of further anaphylaxis from food, insect venom or another exposure that is hard to avoid should be given an adrenaline auto-injector. Usually prescribe two auto-injectors when a second dose may be needed or when access to emergency care is limited. About one in ten adrenaline-treated reactions requires more than one dose [6].

Ensure that:

• the strength is appropriate for the current weight
• the patient or carer can demonstrate the correct technique with a trainer device
• the indication for use is understood
• the auto-injectors are to be carried accessibly, not left in a distant cupboard
• expiry dates and storage have been gone through
• the patient knows that a second dose is given after about 5 minutes if symptoms persist
• the emergency number is called in a severe reaction, with persisting symptoms, when a repeat dose is needed or in case of uncertainty

Not everyone who has had drug-triggered anaphylaxis needs an adrenaline auto-injector if the drug is only given within health care and can reliably be avoided. The decision is individualised [18].

Written action plan

Give a written anaphylaxis plan with:

• the suspected trigger
• the symptoms that should prompt adrenaline
• the strength of the auto-injector and how it is used
• when the second dose should be given
• when the emergency number should be called
• advice on positioning
• how to make contact for follow-up

Medication after discharge

A routine three-day course of a corticosteroid after anaphylaxis is not recommended, since a benefit in preventing a biphasic reaction lacks reliable support [2,11,12].

A non-sedating antihistamine can be given for a short period if itching or urticaria persists. It must not be described as protection against further anaphylaxis.

Referral and documentation

• Refer for an allergological workup when the trigger is unclear, when re-exposure is likely or when specific prevention may become relevant.
• Document symptoms, severity, the suspected exposure, cofactors, all doses of adrenaline, the volume of fluid given, the response to treatment and the observation time.
• Flag the record with a warning in suspected drug-triggered anaphylaxis, but state that the diagnosis is provisional until the investigation is complete.
• In a perioperative reaction, all drugs and materials given must be documented, not only the substance that was first suspected.
• Optimise asthma treatment.
• After a systemic reaction to a bee or wasp sting, an allergist should assess the need for venom-specific immunotherapy, which is the only treatment that effectively prevents further systemic reactions in confirmed insect venom allergy [24].
• Consider investigation for mast cell disease in recurrent idiopathic anaphylaxis, a severe insect venom reaction or a raised baseline tryptase [4].

Repeated practical training is needed. Patients and relatives often forget the technique, even if they have been instructed previously [19,25].

Short emergency algorithm

1. Suspect anaphylaxis in acute airway, respiratory or circulatory compromise after probable allergen exposure.
2. Give adrenaline 1 mg/ml intramuscularly into the thigh, 0.01 mg/kg, maximum 0.5 mg.
3. Lay the patient flat. Do not let the patient stand or walk.
4. Call for help, give oxygen, monitor and insert a large-bore cannula.
5. Give a rapid crystalloid bolus in hypotension, shock or an inadequate response.
6. Repeat intramuscular adrenaline after 5 minutes if symptoms persist.
7. After two inadequate doses: treat as refractory anaphylaxis, call anaesthesia or intensive care and prepare an adrenaline infusion.
8. Give a bronchodilator only as an adjunct for bronchospasm.
9. Give an antihistamine only for persisting skin symptoms after stabilisation.
10. Do not give a corticosteroid routinely.
11. Decide the observation time according to severity and the risk of recurrence.
12. Ensure an adrenaline auto-injector, an action plan, training, documentation and an allergy referral before discharge.

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