INTRODUCTION — Anaphylaxis is a potentially fatal disorder. The rate of occurrence is increasing in industrialised countries. Anaphylaxis is not always recognised as such because it can mimic other conditions and is variable in its presentation.
This topic will review the recognition and treatment of anaphylaxis by healthcare professionals working in emergency department (ED.
DEFINITION AND DIAGNOSIS — Anaphylaxis is defined as a serious allergic or hypersensitivity reaction that is rapid in onset and may cause death. The diagnosis of anaphylaxis is based primarily upon clinical symptoms and signs, as well as a detailed description of the acute episode, including antecedent activities and events occurring within the preceding minutes to hours.
Anaphylaxis is under recognised and undertreated. This may partly be due to failure to appreciate that it can present without obvious skin symptoms and signs and without shock. Anaphylaxis is a much broader syndrome than “anaphylactic shock,” and the goal of therapy should be early recognition and treatment with adrenaline to prevent progression to life-threatening respiratory and/or cardiovascular symptoms and signs, including shock.
Diagnostic criteria — Diagnostic criteria for anaphylaxis were published by a multidisciplinary group of experts in 2005 and 2006. These criteria were intended to help clinicians recognise the full spectrum of symptoms and signs that comprise anaphylaxis.
There are three diagnostic criteria, each reflecting a different clinical presentation of anaphylaxis. Anaphylaxis is highly likely when any ONE of the following three criteria is fulfilled:
Criterion 1 — Acute onset of an illness (minutes to several hours) involving the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at least one of the following:
- Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia).
OR
- Reduced blood pressure (BP) or associated symptoms and signs of end-organ dysfunction (eg, hypotonia [collapse] syncope, incontinence). (See ‘Criterion 3′ below.)
Note: Skin symptoms and signs are present in up to 90 percent of anaphylactic episodes. This criterion will therefore frequently be helpful in making the diagnosis.
Criterion 2 — Two or more of the following that occur rapidly after exposure to a LIKELY allergen for that patient (minutes to several hours):
- Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula).
- Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia).
- Reduced BP or associated symptoms and signs (eg, hypotonia [collapse], syncope, incontinence).
- Persistent gastrointestinal symptoms and signs (eg, crampy abdominal pain, vomiting).
Note: Skin symptoms or signs are absent or unrecognised in up to 20 percent of anaphylactic episodes. Criterion 2 incorporates symptoms and signs in other organ systems and is applied to patients with exposure to a substance that is a likely allergen for them.
Criterion 3 — Reduced BP after exposure to a KNOWN allergen for that patient (minutes to several hours):
- Reduced BP in adults is defined as a systolic BP of less than 90 mmHg or greater than 30 percent decrease from that person’s baseline
- In infants and children, reduced BP is defined as low systolic BP (age specific)* or greater than 30 percent decrease in systolic BP
Note: Criterion 3 is intended to detect anaphylactic episodes in which only one organ system is involved and is applied to patients who have been exposed to a substance to which they are known to be allergic, for example, hypotension or shock after an insect sting.
There will occasionally be patients who do not fulfill any of these criteria, but for whom the administration of adrenaline is appropriate. As an example, it would be appropriate to administer adrenaline to a patient with a history of near-fatal anaphylaxis to peanut who presents with urticaria and flushing that developed within minutes of a known unintentional ingestion of peanut.
Symptoms and signs — Anaphylaxis may present with various combinations of approximately 40 potential symptoms and signs.
Common symptoms and signs of anaphylaxis include the following:
- Skin symptoms and signs, which occur in up to 90 percent of episodes, including generalized hives, itching or flushing, swollen lips-tongue-uvula, periorbital edema, conjunctival swelling.
- Respiratory symptoms and signs, which occur in up to 70 percent of episodes, including nasal discharge, nasal congestion, change in voice quality, sensation of throat closure or choking, stridor, shortness of breath, wheeze, cough.
- Gastrointestinal symptoms and signs, which occur in up to 45 percent of episodes, including nausea, vomiting, diarrhea, and crampy abdominal pain.
- Cardiovascular symptoms and signs, which occur in up to 45 percent of episodes, including hypotonia (collapse), syncope, incontinence, dizziness, tachycardia, and hypotension.
The factors that determine the course of anaphylaxis in an individual patient are not fully understood. At the onset of an anaphylactic episode, it is not possible to predict how severe it will become, how rapidly it will progress, and whether it will resolve promptly and completely or become biphasic or protracted.
Death from anaphylaxis usually results from asphyxiation due to upper airway edema or respiratory failure due to bronchial obstruction, and less commonly, from cardiovascular collapse.
Time course — Anaphylaxis is usually characterized by a defined exposure to a potential trigger, followed by rapid onset, evolution, and resolution of symptoms and signs within minutes to hours.
TRIGGERS — Most anaphylaxis episodes are triggered through an immunologic mechanism involving IgE. Foods are the most common trigger in children, while medications and insect stings are more common triggers in adults than in children.
CONTRIBUTORY FACTORS — Comorbidities and concurrent medications may impact the severity of symptoms and signs and response to treatment in patients with anaphylaxis.
Comorbidities — Asthma and cardiovascular disease are the most important risk factors for a poor outcome from anaphylaxis. Other disorders may also increase risk.
- Persistent asthma is a risk factor for anaphylaxis. Asthma is also associated with increased risk of death from anaphylaxis, especially in adolescents and young adults with poorly controlled disease.
- Cardiovascular disease is an important risk factor for death from anaphylaxis in middle-aged and older individuals.
- Other respiratory diseases, eg, chronic obstructive pulmonary disease (COPD), interstitial lung disease, or pneumonia are also risk factors for severe or fatal anaphylaxis in older adults.
Concurrent medications — Concurrent administration of certain medications, such as beta-adrenergic blockers, angiotensin-converting enzyme inhibitors, and alpha-adrenergic blockers may increase the likelihood of severe or fatal anaphylaxis, and may also interfere with the patient’s ability to respond to treatment and with the patient’s compensatory physiologic responses.
- Beta-adrenergic blockers, administered orally, parenterally, or topically (eg, eye drops) are sometimes associated with severe anaphylaxis and may also potentially make anaphylaxis more difficult to treat by causing unopposed alpha-adrenergic effects. They also can worsen hypotension, as well as reduce the bronchodilator and cardiovascular response to the beta-adrenergic effects of endogenous or exogenous adrenaline.
- Alpha-adrenergic blockers may decrease the effects of endogenous or exogenous adrenaline at alpha-adrenergic receptors, potentially making anaphylaxis less responsive to the alpha-adrenergic effects of adrenaline.
- ACE inhibitors are of particular importance in regards to patients who have experienced anaphylaxis to Hymenoptera venom.
LABORATORY TESTS — The clinical diagnosis of anaphylaxis can sometimes be supported by documentation of elevated concentrations of serum or plasma total tryptase or plasma histamine. It is critical to obtain blood samples for measurement of these mast cell and basophil mediators soon after the onset of symptoms, because elevations are transient.
- Serum or plasma total tryptase – The standardized assay for measurement of total serum or plasma tryptase is widely available in clinical laboratories (normal range 1 to 11.4 ng/mL, Phadia AB, Uppsala, Sweden). In infants under age six months, normal baseline total tryptase concentrations are higher than they are in older infants, children, and adults. Optimally, the blood sample for tryptase measurement needs to be obtained from 15 minutes to 3 hours of symptom onset. A tryptase level that is within normal limits cannot be used to refute the clinical diagnosis of anaphylaxis.
Serial measurements of total tryptase in serum or plasma over several hours may increase the sensitivity and the specificity of the tests.
- Plasma histamine – Plasma histamine levels typically peak within 5 to 15 minutes of the onset of anaphylaxis symptoms, and then decline to baseline by 60 minutes due to rapid metabolism by N-methyltransferase and diamine oxidase. Elevated plasma histamine levels correlate with anaphylaxis symptoms and signs, and are more likely to be increased than are total serum tryptase levels.
DIFFERENTIAL DIAGNOSIS — Approximately 40 other diseases and conditions might need to be considered in the differential diagnosis of anaphylaxis. The most common disorders in the differential diagnosis include acute generalized urticaria and/or angioedema, acute asthma exacerbations, syncope/faint, and anxiety/panic attacks
IMMEDIATE MANAGEMENT — Prompt assessment and treatment are critical in anaphylaxis, as respiratory or cardiac arrest and death can occur within minutes. The cornerstones of initial management are the following:
- Removal of the inciting antigen, if possible (eg, stop infusion of a suspect medication)
- Call for help (summon a resuscitation team in a hospital setting, or call 999 or an equivalent emergency medical services number in a community setting)
- Intramuscular injection of adrenaline. IM into the mid-outer aspect of the thigh.
- Placement of the patient in the supine position with the lower extremities elevated, or if dyspneic or vomiting, placement of the patient semi-recumbent with lower extremities elevated
- Supplemental oxygen (8-10 liters by face mask)
- Volume resuscitation with intravenous fluids
- Two large-bore intravenous catheters (ideally 14 to 16 gauges for most adults) should be inserted in preparation for rapid administration of fluids and medications.
- In normotensive adults, isotonic (0.9 percent) saline should be infused at a rate of 125 mL per hour to maintain venous access.
- Continuous electronic monitoring of cardiopulmonary status, including blood pressure, heart rate, and respiratory rate, and monitoring of oxygen saturation by pulse oximetry is required for the duration of the episode.
- Intubation should be performed immediately if marked stridor or respiratory arrest is present.
Intravenous fluids — Intravenous access should be obtained in case fluid resuscitation is required. Massive fluid shifts can occur rapidly in anaphylaxis due to increased vascular permeability, with transfer of up to 35 percent of the intravascular volume into the extravascular space within minutes.
The following principles should guide therapy:
Fluid resuscitation should be initiated immediately in patients who present with orthostasis, hypotension, or incomplete response to intramuscular adrenaline.
- Adults should receive 1 to 2 liters of normal saline at a rate of 5 to 10 mL/per kilogram in the first minutes of treatment. Large volumes of fluid (eg, up to 7 liters) may be required.
- Children should receive normal saline in boluses of 20 mL per kilogram, each over 5 to 10 minutes, and repeated as needed. Large volumes of fluid (up to 100 mL per kilogram) may be required.
Normal saline is preferred over other solutions in most situations, because other solutions have potential disadvantages:
- Lactated Ringer’s solution can potentially contribute to metabolic acidosis
- Dextrose is rapidly extravasated from the circulation into the interstitial tissues
- Colloid solutions (eg, albumin or hydroxyethyl starch) confer no survival advantage in patients with distributive shock and are more costly [71]
PHARMACOLOGIC TREATMENTS —
Adrenaline — Adrenaline is the drug of choice for anaphylaxis. The pharmacologic actions of this agent address the pathophysiologic changes that occur in anaphylaxis better than any other medication. It decreases mediator release from mast cells. Moreover, it is the only medication that prevents or reverses obstruction to airflow in the upper and lower respiratory tracts, and prevents or reverses cardiovascular collapse.
Therapeutic actions and adverse effects — The therapeutic actions of adrenaline include the following:
- Alpha-1 adrenergic agonist effects: increased vasoconstriction, increased peripheral vascular resistance, and decreased mucosal edema (eg, in the upper airway).
- Beta-1 adrenergic agonist effects: increased inotropy and increased chronotropy.
- Beta-2 adrenergic agonist effects: increased bronchodilation and decreased release of mediators of inflammation from mast cells and basophils.
Dosing and administration —
- Intramuscular injection — Intramuscular injection is recommended over subcutaneous injection because it consistently provides a more rapid increase in the plasma and tissue concentrations of adrenaline. The adrenaline dilution for intramuscular injection contains 1 mg per mL and may also be labeled as 1:1000.
For adults, the recommended dose of adrenaline (1 mg per mL) is 0.3 to 0.5 mg per single dose, injected intramuscularly into the mid-outer thigh (vastus lateralis muscle). Based on clinical experience and consensus opinion, this dose may be repeated at 5 to 15 minute intervals. Typically, only one or two additional doses are needed.
For infants and children, the recommended dose of adrenaline (1 mg per mL) is 0.01 mg per kilogram (up to 0.5 mg per dose in a child weighing 50 kg or more), injected intramuscularly into the mid-outer thigh (vastus lateralis muscle). The dose should be drawn up using a 1 mL syringe. This treatment may be repeated at 5 to 15 minute intervals.
- Intravenous infusion and indications — Patients who do not respond to intramuscular injection of adrenaline and fluid resuscitation may not be adequately perfusing muscle tissues, as most commonly occurs in individuals presenting with profound hypotension or symptoms and signs suggestive of impending shock (dizziness, incontinence of urine and/or stool). Such patients should receive adrenaline by SLOW intravenous infusion, with the rate titrated according to response and the presence of continuous hemodynamic monitoring.
- The adrenaline dilution for intravenous infusion contains 0.1 mg/mL and may also be labeled 1:10,000.
- For adults, the initial dose for intravenous adrenaline infusion is 2 to 10 micrograms per minute, titrated to effect on blood pressure with continuous noninvasive monitoring.
- For infants and children, the dose for intravenous infusion of adrenaline is 0.1 to 1 microgram per kilogram per minute, titrated to effect on blood pressure with continuous noninvasive monitoring.
Situations requiring caution — There are NO absolute contraindications to adrenaline use in anaphylaxis.
Subgroups of patients might theoretically be at higher risk for adverse effects during adrenaline therapy. Formal risk-benefit analyses are not possible.
- Patients with cardiovascular diseases: reluctance to administer adrenaline due to fear of adverse cardiac effects should be countered by the awareness that the heart is a target organ in anaphylaxis. In the healthy human heart, mast cells are present throughout the myocardium and in the intima of coronary arteries. In patients with coronary artery disease, mast cells are found in atherosclerotic lesions and contribute to atherogenesis. Anaphylaxis can unmask subclinical coronary artery disease, and myocardial infarction and/or arrhythmias can occur during anaphylaxis, even if adrenaline is not injected. Moreover, anaphylaxis itself can cause vasospasm, arrhythmias, and myocardial infarction in patients, including children, with healthy hearts as confirmed by normal electrocardiograms, echocardiography, and other studies after resolution of anaphylaxis.
- Patients receiving monoamine oxidase inhibitors (which block adrenaline metabolism), or tricyclic antidepressants (which prolong adrenaline duration of action).
- Patients with certain preexisting conditions, such as recent intracranial surgery, aortic aneurysm, uncontrolled hyperthyroidism or hypertension, or other conditions that might place them at higher risk for adverse effects related to adrenaline.
- Patients receiving stimulant medications (eg, amphetamines or methylphenidate used in the treatment of attention deficit hyperactivity disorder) or abusing cocaine that might place them at higher risk for adverse effects from adrenaline.
Adjunctive agents — Adjunctive therapies for the treatment of anaphylaxis include antihistamines, bronchodilators, glucocorticoids, and other vasopressors in addition to adrenaline.
H1 antihistamines —
- H1 antihistamines relieve itch and hives. These medications DO NOT relieve upper or lower airway obstruction, hypotension or shock, and in standard doses do not inhibit mediator release from mast cells and basophils. For parenteral treatment, only first-generation agents are available:
H2 antihistamines — There is minimal evidence to support the use of H2 antihistamines in conjunction with H1 antihistamines in the emergency treatment of anaphylaxis.
If used, ranitidine (50 mg in adults) (12.5 to 50 mg [1 mg per kilogram] in children), may be diluted in 5 percent dextrose to a total volume of 20 mL and injected intravenously over five minutes.
Bronchodilators — For the treatment of bronchospasm not responsive to adrenaline, inhaled bronchodilators, such as salbutamol should be administered by nebulizer/compressor as needed.
Glucocorticoids — The onset of action of glucocorticoids takes several hours; therefore, these medications do not relieve the initial symptoms and signs of anaphylaxis. The rationale for giving them is to prevent the biphasic or protracted reactions.
CARE UPON RESOLUTION — To reduce the risk of recurrence, patients who have been successfully treated for anaphylaxis subsequently require confirmation of the anaphylaxis trigger, as well as anaphylaxis education.
Observation — There is no consensus regarding the optimal observation period for a patient who has been successfully treated for anaphylaxis in a healthcare facility. The following are suggested:
- Patients with moderate anaphylaxis who do not respond promptly to adrenaline, and all patients with severe anaphylaxis, should be admitted to an observation unit or to a hospital.
- For patients with anaphylaxis that resolved promptly and completely with treatment, we suggest a minimum observation period of a few hours, and prefer a period of 8 to 10 hours, if possible. We also suggest that if patients are sent home after only a few hours, they should be trained to use an adrenaline autoinjector.
SUMMARY AND RECOMMENDATIONS
- Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.
- There are three clinical criteria for the diagnosis of anaphylaxis, which reflect the different ways in which anaphylaxis may present.
- Recognition is not always easy, because anaphylaxis can mimic many other disorders and can be variable in its presentation.
- Patients and healthcare professionals commonly fail to recognize and diagnose anaphylaxis in its early stages, when it is most responsive to treatment.
- Anaphylaxis most often results from an IgE-mediated allergic reaction. Common triggers include foods, insect stings, and medications.
- The clinical diagnosis of anaphylaxis may or may not be confirmed by measurement of elevated concentrations of plasma histamine or serum or plasma total tryptase. Elevations in these mediators are transient. Serum tryptase is seldom elevated in food-triggered anaphylaxis or in normotensive patients with anaphylaxis.
- Prompt recognition and treatment are critical in anaphylaxis. In fatal anaphylaxis, median times to cardiorespiratory arrest are 5 minutes in iatrogenic anaphylaxis, 15 minutes in stinging insect venom-induced anaphylaxis, and 30 minutes in food-induced anaphylaxis.
- Adrenaline is lifesaving in anaphylaxis. It should be injected as early as possible in the episode in order to prevent progression of symptoms and signs. There are no absolute contraindications to adrenaline use, and it is the treatment of choice for anaphylaxis of any severity.
- For adults, the dose of adrenaline is 0.3 mg to 0.5 mg, injected intramuscularly into the mid-outer thigh. This treatment may be repeated at 5 to 15 minute intervals.
- For infants and children, the dose of adrenaline is 0.01 mg per kilogram up to 0.5 mg per dose, injected intramuscularly into the mid-outer thigh. This treatment may be repeated at 5 to 15 minute intervals.
- Massive fluid shifts can occur in anaphylaxis, and all patients with orthostasis, hypotension, or incomplete response to adrenaline should receive large volume fluid resuscitation with normal saline.
- Supplemental oxygen should be administered.
Check out the NICE Guidelines on Anaphylaxis CG134 Anaphylaxis
Few important points from the NICE Guidelines
- Food is a particularly common trigger in children, while medicinal products are much more common triggers in older people.
- One in 1333 of the population of England has experienced anaphylaxis at some point in their lives
- Approximately 20 deaths from anaphylaxis reported each year in the UK
- Document the acute clinical features (airway, breathing, circulation, associated skin and mucosal symptoms)
- Record the time of onset of the reaction
- Record possible trigger factor.
- Take blood sample for mast cell tryptase (1st sample straight after receiving emergency treatment and 2nd sample after 1-2 hrs after starting the symptoms)
- Adult and young people (16, 17yrs) should observe for 6-12 hrs from the onset of symptoms depending on the response to treatment.
- Paediatric patient need to be admitted for longer observation.
- At discharge all suspected anaphylaxis patient should have 1) referral to allergy services, 2) adrenaline injector and 3) patient information on anaphylaxis.
Source: Uptodate, eMedicine, NICE Guidelines
HMP 1: Anaphylaxis: Rapid recognition and Treatment
