How to recognize and treat this medical emergency
Systemic anaphylaxis represents the most critical and potentially fatal event within allergic manifestations (1). The phenomenon has been described in ancient medical literature and the first documented episode of anaphylaxis is reported on a hieroglyph of 2640 b.c. describing the death of pharaoh Menes from the wisp of a wasp. Nevertheless, the term anaphylaxis has been introduced only in 1902, by Charles R. Richet e Paul J. Portier, two investigators that described anaphylactic reactions in the animal experimental model. The phenomenon was initially described by the greek term a-phylaxis meaning “lack of protection” becoming for euphonic reasons anaphylaxis, a term which rapidly spread all over the world. For their studies, Richet e Portier won the Nobel prize in 1913.
There is limited knowledge about the exact prevalence and incidence of anaphylaxis in the general population. Foods and drugs including contrast media administration represent the most common elicitors of severe anaphylactic episodes (1: 5.000) (2, 3). Recent studies indicate that prevalence rates of severe anaphylaxis (1-3: 10.000 subjects) may be higher in USA and Australia, characterized by 0,65%-2% fatal events, that is 1-3 in a million of patients (4).
Pathophysiology
Anaphylaxis stricto sensu is a type I immunological reaction mediated by the interaction between IgE antibodies and a bivalent or multivalent antigen. The interaction between IgE linked to high affinity receptors (FceRI) present on the surface of effectors cells of allergic reactions (tissue mast cells and basophils) and the antigen (allergen) induces the release of vasoactive mediators (histamine, tryptase, leukotrienes, prostaglandines, platelet activating factor ecc.) (5). In addition, there are cases with very similar clinical symptomatology of anaphylaxis where immunological sensitization is not detectable and which have been called anaphylactoid or pseudo-allergic reactions (6). The mechanisms of these reactions include direct activation of mast cells and basophils not mediated by IgE antibodies, activation of the complement or other plasma protein systems (coagulation, kallikrein-kinin) as well as neuro-psycogenic reflex mechanisms. For example, it is well known that psychological stress alone can lead to increased plasma histamine levels (7). Anaphylactoid reactions can be induced by administration of contrast media, destran, protamin or general anesthetics.
There is a broad spectrum of elicitors of anaphylactic or anaphylactoid reactions. The most common elicitors of anaphylaxis are foods, drugs, drug and food additives, latex, microbial and physical agents ( table 1)
| Table 1: Elicitors of anaphylactic and anaphylactoid reactions |
| Drugs (antibiotics, aspirin, ecc.)FoodsAdditivesLatex
Animal venoms
Aeroallergens
Allergen immunotherapy
Seminal fluid
Contact urticariogens
Physical agents (cold, heat, UV radiation)
Exercise
Echinococcal cyst
Underlying disease
Complement factor 1-inactivator deficiency
Systemic mastocytosis |
Clinical manifestations
Systemic anaphylaxis represents the most severe expression of an allergic reaction. The phenomenon represents a syndrome of different symptoms involving various organs which may develop either alone, simultaneously or subsequently. Most commonly:
- symptoms start in the skin (pruritus, flush, urticaria, angioedema) and the neighbouring mucous membranes (pruritus and paresthesia of palat, pharynx and/or genital mucosa)
- proceed to the respiratory tract (rhinorrhoea, sneezing, hoarseness, dysphonia, laryngeal oedema, cough, laryngeal obstruction, bronchospasm, respiratory arrest)
- may involve the gastrointestinal system (cramps, nausea, vomitus, defecation, diarrhoea) and also miction and uterus cramps may occur
- may be characterized by cardiovascular symptoms of different severity (tachycardia, blood pressure changes, arrhythmia, shock, cardiac arrest). Cardiac manifestations in anaphylaxis may be observed in ECG changes (T fluttering, supraventricular arrythmia, AV-block) (8,9).
Prodromic symptoms of anaphylaxis comprise paraesthesia on palms and soles, “fishy taste”, anxiety, headache or disorientation.
A grading scale for severity scoring of anaphylaxis is here illustrated (Table 2).
Table 2 Grading of anaphylactic reactions according to clinical symptoms severity
| Grade |
Skin |
Gastro-intestinal |
Respiratory |
Cardiovascular |
| I |
Pruritus Urticaria Angioedema |
|
|
|
| II |
Pruritus Urticaria Angioedema |
NauseaCramping |
Rhinorrhea Dyspnoea Hoarseness |
Tachycardia Arrythmia Blood pressure change |
| III |
Pruritus Urticaria Angioedema |
Vomitus Defecation Diarrhoea |
Laryngeal edema Bronchospasm Cyanosis |
Shock |
| IV |
Pruritus Urticaria Angioedema |
Vomitus Defecation Diarrhoea |
Respiratory arrest |
Cardiac arrest |
Principal targets of anaphylaxis are the skin, the respiratory tract, and the gastrointestinal and cardiovascular system that may be involved singularly or in combination. Thus, skin symptoms such as pruritus and flushing, considered as “minor manifestations” not always appear prior to the involvement of respiratory or cardiovascular systems. In some cases, typical signs as tachycardia -often considered a characteristic of systemic anaphylaxis allowing differentiation from vaso-vagal reaction- may not be present.
Diagnosis of anaphylaxis may be confirmed by measuring serum tryptase whose levels remain high for approximately six hours after the anaphylactic episode, following mast cell degranulation.
Even though the clinical symptoms of anaphylaxis are characteristic, some differential diagnoses have to be considered (Table 3).
| Table 3. Differential diagnoses of anaphylactic reactions |
| Adverse drug reactionsHyperventilation, status asmaticusVasovagal reactionGlobus hystericus
Syncope (cardial, cerebral)
Bolus aspiration
Carcinoid syndrome
Ereditary angioedema
Seizures
Pulmonary embolism
Myocardial infarction
Hypoglycaemia
Feocromocitoma
Fisical urticaria
Anaphylaxis factitia (Munchausen Syndrome) |
Why do people die from anaphylaxis?
In spite of our knowledge of the immunologic and non immunologic mechanisms mediating anaphylactic reactions, the exact mechanisms of amplification which allow a healthy individual to be killed by a few micrograms of an allergen within minutes are not yet understood.
Autopsy data from patients who died from anaphylaxis, reveal that fatal reactions are limited to a single system or area (such as cardiovascular or respiratory system) and shock occurred from different causes in older versus younger patients. In older patients shock is determined by arrhythmia, which is more commonly found in older hearts within pre-existing disease (10, 11). It is useful to add, that angina pectoris episodes with acute myocardial infarction is well documented during an allergic reaction (drugs, contract media, latex, foods). These types of angina and allergic myocardial infarction are referred as “Kounis syndrome, cited in major cardiovascular textbooks as a new cause of coronary artery spasm (12).
Respiratory arrest, a frequent cause of death from anaphylaxis, can be induced by bronchospam or oedema of the higher or lower respiratory tract.
Younger patients who die of anaphylactic shock tend to experience vasodilation with hypotension, leading to pulseless electrical activity and death (10, 11).
One practical point related to modes of death in fatal anaphylaxis relates to posture: in some cases patients die within seconds of a “change to a more upright position”. There is evidence that patients suffering from anaphylactic shock cannot tolerate the emptying of the vena cava that results when they are made to sit up or stand since it causes loss of left ventricular filling pressure, myocardial ischemia, pulseless electrical activity, and quickly, death (13).
Epidemiological studies in the United Kingdom (UK Anaphylaxis Death Register) suggest that there are about 20 anaphylactic deaths per year, which corresponds to one per year for each 3 million people. 50% of these fatalities is caused by iatrogenic causes whereas 25% by food allergy. Respiratory arrest and cardiac shock are the most common causes of death (the first associated to food allergy, the latter to drugs and sting insect venom). In fatalities due to iatrogenic causes the median time to death was 5 min, 15 minutes for sting insect venom and 30 minutes for food (10).
Approaches for the treatment of anaphylaxis
Anaphylaxis is a life-threatening allergic reaction. Therefore, the time for diagnosis and treatment is extremely limited. Generally speaking, the shorter is the time between allergen exposure and symptom appearance the more severe the symptoms are. In order to determine prognosis of an anaphylactic reaction, distance from the hospital and delay in treatment administration may be critical. Thus, symptoms must be promptly treated locally (i.e. medical/dental office) following additional management of anaphylaxis in a more specialized medical setting (hospital). (14, 15).
Emergency treatment of anaphylaxis is based on the ABC mnemonic (Airway, Breathing, Circulation):
A (Airway): Ensure and establish a patient airway by repositioning head and neck. Patient should be placed in a supine position and lower extremities must be elevated to facilitate heart blood filling. Patients in severe respiratory distress may be more comfortable in a sitting position.
B (Breathing): Asses adequacy of ventilation and provide the patient with sufficient oxygen (O2 saturation 91% as determined by pulse oximetry). Treat bronchospasm as necessary (see therapy). Equipment for endotracheal intubation should be available for immediate use in event of respiratory failure and is indicated for poor mentation, respiratory failure or stridor that does not respond to supplemental oxygen and epinephrine.
C (Circulation): Eliminate continued exposure to the causative agent by discontinuing the infusion, as with radio-contrast media, or by placing a venous tourniquet proximal to the site of injection or insect sting.. Establish IV access immediately with large bore (16-18G) catheter and administer an isotonic solution as normal saline established as peripheral venal collapse is possible and can make IV access difficult.
Adrenalin (epinephrine)
The most significant factor in anaphylaxis, from the pathophysiologic point of view, is the massive release of mediators leading to rapid and severe changes in the respiratory and cardiovascular systems. The effect of the release of histamine and other vasoactive mediators from mast cells and basophils induces a quick passage of liquids (up to 50% of the total volume in 10 minutes) from the intra-vascular to the extra-vascular space. These changes induce severe hypotension and collapse frequently associated to arrhythmias and myocardial ischemia, or respiratory failure due to broncho-constriction in the lower airway or oedema in the upper airway. Thus, in order to efficiently treat anaphylaxis, vascular permeability must be decreased, an adequate left ventricular perfusion must be maintained, cardiac function and sufficient oxygen levels must be ensured. (17).
Adrenalin (epinephrine) is the drug of choice for anaphylaxis. It stimulates both a- and ß- adrenergic receptors and acts by increasing intracellular cAMP. Adrenalin a1 adrenergic effects (vasoconstriction, reduction of mucosal oedema) and some ß 2 adrenergic effects (bronco dilation, suppression of mediator release from mast cells and basophils) can reverse anaphylactic shock (18). The recommended route of administration is intra-muscular (i.m) (into the muscle of the antero-lateral thigh) with immediate therapeutic effect whereas subcutaneous (s.c) administration is also recommended with a rapid administration on the external surface of the upper arm. The recommended dosage for adults is 200-300 µg (0,2-0,3 ml of a 1:1000 solution of adrenalin). For children, the recommended dosage is 0,01 mg/ kg of weight, maximum dosage 0,3 ml.
Adrenalin aims to increase systolic blood pressure to adequate levels (80-100 mmHg). Thus, blood pressure monitoring is very important during anaphylaxis. If , following the first administration of adrenalin, the patient does not respond (low blood pressure), adrenalin administration can be repeated after 10 minutes. Adrenalin has a very narrow therapeutic window. Common pharmacologic effects that occur at recommended doses via any route of administration include agitation, anxiety, headache, pallor, palpitations, tremulousness. Rarely, and usually associated with over-dosage, or overly rapid rate of intravenous (i.v.) infusion, adrenalin administration might contribute to or cause myocardial ischemia or infarction, pulmonary oedema, prolonged QTc interval, ventricular arrhythmias, accelerated hypertension, and intracranial hemorrhage in adults and children alike (18). Particularly vulnerable populations are those individuals at the extremes of age, and those with hypertension, peripheral vascular disease, ischemic heart disease, or untreated hyperthyroidism. Cocaine and amphetamines sensitize the myocardium to effects of adrenaline, thus increasing the risk of toxic effects. However , none of these circumstances poses an absolute contraindication to adrenalin administration for anaphylaxis (19).
Even if adrenaline is promptly administered, in some cases responses may be reduced or absent. This event may be due to a rapid progression of the anaphylactic episode, a limited effect of adrenaline due to pre-existing ß or a blockade, the use of ACE-inhibitors or allergy to meta-bisulfites present as preservatives in the adrenaline solution.
Oxygen supplementation
One of the main causes of death during systemic anaphylaxis- as previously mentioned-, is due to the acute and severe obstruction of upper and lower airways. Therefore, following adrenaline administration – with positive effects on bronchospasm and airway oedema- it is important to ensure an adequate oxygen (O2) level. O2 supplementation with mask 40-100% (2-5 l/min), is an optimal measure, able to maintain a pO2> 60 mm Hg. In addition, administration of inhaled ß2 agonists as Salbutamol (Ventolin®) or even inhaled adrenalin may be indicated.
In case of failure or incomplete response of these measures, intubation may be necessary, although difficult to perform in some cases due to oedema of the upper airways. Emergency cricothyroidotomy or assisted ventilation may be also performed.
Liquid e.v. administration
In order to control blood pressure and establish circulatory volumes, the administration of liquids e.v. is necessary. Isotonic saline solutions, in addition to adrenaline and oxygen supplementation is the first step therapy in case of anaphylactic shock.. Administration of other drugs (anti-histamines, corticosteroids, aminofillin) are considered as “secondary” measures, not indicated for the initial management of anaphylaxis. Infusion must be rapidly administered, up to 1000 ml every 20-30 minutes for adults and 20-30 ml/kg/hour for children. Saline solution effect may be short as solutes easily spread in the extra-vascular space. Therefore, in case of marked hypotension, colloids can be administered (destran). Colloids have an osmotic effect, inducing liquid perfusion from tissues to the vascular bed and establishing the circulatory volume. However, destran can induce anaphylactoid reactions. Alternatively, plasma or human albumin may be used (20).
Other adrenergic drugs
In treating specific symptoms of anaphylaxis, other adrenergic drugs- in addition to adrenalin- may be useful. For bronchospasm, inhaled short acting ß2 agonists (salbutamol, terbutaline, fenoterol) can be used (up to 10 puffs). Long lasting ß2-agonists (salmeterol, formoterol) should not be used to treat anaphylactic shock.
For marked hypotension noradrenalin may be administered (4 mg in 1000 ml, 0.5-3 ml/min) (21).
Patients receiving ß-blockers, could be treated with glucagone or isoproterenol in case of hypotension non responsive to adrenaline administration (21).
In case of heart failure, administration of dopamine (5-15 µg/kg/min) with a and ß adrenergic effects may be indicated.
Anthiistamines
The effects mediated by histamine in anaphylaxis are secondary to the activation of H1 and H2 receptors. Antihistamines (H1 and H2 antagonists) may be helpful once patient stabilizes. Slow e.v. administration (3-5 min) induces rapid effects whereas oral administration is efficacious after approximately 30 minutes, a time long enough to treat a medical emergency.
Diphenhydramine or hydroxizine (25-50 g i.m. or orally every 6-8 hours) or second generation antihistamines (cetirizine, loratadine, fexofenadine orally) and anti-H2 antihistamines as cimetidine (300 mg i.v. or orally every 6-8 hours) or ranitidine (100 mg i.v; 1,5 mg/kg in children) are largely administered.
Corticosteroids
Corticosteroids (CS) inhibit membrane phospholipases and production of prostaglandines, leukotrienes and PAF, mediators released by the primary effector cells of allergic reactions. As CS act after 1-4 hours following administration, they do not benefit acute anaphylaxis but may prevent relapse or protracted anaphylaxis. Recommended rout of administration is i.v. . (methylprednisolone 100-1000 mg i.v. o 2mg/kg in children; Hydrocortisone succinate 500-1000 mg i.v.) added in saline solutions.
Other drugs
In addition to the adrenergic agonists previously mentioned, theofilline is used for treatment of severe bronchospasm: 240 mg i.v. in 20-30 minutes in patients not yet treated with this drug. Maintainance dossage is 0,3-0,9 mg /kg/hour i.v. To note that therapeutic levels of theofillinemia are between 10 and 20 µg/ml and the most common adverse reactions are nausea, vomitus and arrhythmias.
Atropine may be indicated in case of marked bradycardia, A-V block, or bronchospasm or marked hypotension in patients receiving ß- blockers.
Treatment of anaphylactic reactions is here schematically illustrated (The diagnosis and management of anaphylaxis. J Allergy Clin Immunol 1998; 101:S465-S528) and in Table 4 e 5.
- Symptoms not immediately life-threatening may rapidly progress unless treated promptly
(a) Intramuscular or subcutaneous adrenalin (intramuscular preferred) .
Adults: 0,2 ml (2 mg) -0,5 ml (0,5 mg) of a 1:1000 adrenalin solution every 10-15 minutes if necessary, up to a maximum of 1 ml.
Children: 0.01 ml (0,01 mg/kg body weight up to a maximum of 0,5 ml (0,5 mg) per dose of 1:1000 dilution, repeated every 15 min for 2 doses, then every 4 hours as needed.
(b) Diphenhydramine: 1-2 mg/kg o 25-50 mg /dose may be given parenterally
(c) I.V. Corticosteroids (recommanded, but efficacy not clearly delineated)
- Immediate treatment of life threatening anaphylaxis includes:
(a) Adrenalin at dosage described above
(b) Adrenalin i.v. can be considered if the patient significantly worsens despite repeated doses of subcutaneous or intramuscular adrenalin; administered either by using a formulation of 1:10.000 (0,1 mg/ml = 1:100.000 (0,01 mg/ml) dilution initially titrated at 1 µg/min up to 2 µg/min as needed.
(c) Measures to restore circulation and respiration
(d) Vasopressors and i.v. fluids to treat hypotension
(e) Oxygen
(f) Inhaled bronchodilators for bronchospasm
(g) Constant monitoring of cardiac, respiratory and circulatory systems
3.A good clinical response indicates resolution of the anaphylactic reaction. Continued monitoring is indicated if (1) the response appears incomplete (2) biphasic anaphylaxis appears likely. Additional history and laboratory tests will add to diagnostic base.
Consider anti- H1 for urticaria/angioedema, and anti- H2 for epinephrine resistant hypotension.
- Additional treatment may be required for patients who:
(1) Are unresponsive to adrenalin due to ß-adrenergic blocking therapy (consider glucagon 1 mg i.v. as a bolus with continuous infusion 1-5 mg/h)
(2) For prominent respiratory symptoms (consider inhaled broncodilators)
(3) Need hospital admission for extended management or management of comorbid conditions.
- Monitor for late-phase reactions
(1) in a medical settino fora n extended period, for life threatening episodes, or
(2) at home if the reaction is mild
- Follow-up includes complete evaluation and a long-term treatment plan in consultation with an allergist/immunologist.
| Table 4. Treatment of anaphylactic shock |
|
| General measures |
Global clinical evaluationI.V. access with large bore catheterOxygen supplementation |
| Specific interventions |
Adrenalin (0,2-0,5 ml of 1:1000 dilution) i.m o s.c to repeat after 10-15 minuti, up to a maximum of 1 mlCorrection of hypotensionSupine position-lower extremities elevatedAdministration of liquids i.v.
Administration of vasoconstrictors i.v., anti H1 and anti-H2
Airway assessment
Oxygen supplementation
Neck extension
Inhaled adrenalin
Endotracheal Intubation
Tracheotomy
Teofilline i.v.
Inhaled broncodilators
Corticosteroids |
| Table 5. Checklist of equipments and drugs required for office management of systemic anaphylaxis as indicated by the WAO (World Allergy Organization): |
| -Stethoscope and sphygmomanometer-Tourniquets, syringes, needles (including large-bore 14-gauge)-Injectable adrenalin 1:1000
-Oral airway and endotracheal tubes
-Oxygen, and equipment to administer it
-Diphenhydramine (or similar) injectable anti-histamines
-Corticosteroids for i.v. injection
-Vasopressors (dopamine, noradrenaline)
-Glucagon
-Automatic Defibrillator |
Concluding remarks
Systemic anaphylaxis represents the most severe and unpredictable clinical event within allergic reactions. It represents a syndrome of different symptoms involving various organs which may develop either alone, simultaneously or subsequently. Recognize and treat the anaphylactic shock correctly and promptly is extremely important and can save patients lives. Treatment of anaphylaxis must guarantee airway assessment for a correct tissue oxygenation and ensure an adequate blood circulation for a regular heart activity. i.m. administration of adrenalin is the first choice treatment for anaphylactic shock, in association to oxygen supplementation and liquid infusion followed by administration of other drugs (adrenergics, cortisteroids, antihistamines ecc.) that represent a second line treatment.
Yet, it should be added that the best therapy for anaphylaxis is prevention and that it is important to carefully recognize patients at risk and establish adequate measures to prevent or attenuate the severity of an anaphylactic reaction.
REFERENCES
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18. Hoffman BB, 2001. “Cathecolamines, sympathicomimetic drugs, and adrenergic receptor antagonists. In Hardman JC, Limird LE, Gilman AG (eds) Goodman and Gilman’s the pharmacological basis of therapeutics. 10th edn, Mc Graw-Hill Companies Inc, New York, pp 215268.
19. Kemp SF, Lockey RF, Simons FER on behalf of the World Allergy Organization (WAO) ad hoc Committee on Epinephrine in Anaphylaxis, 2008. Epinephrine: the drug of choice for anaphylaxis. A statement of the WAO. Allergy; 63: pp 1061-1070.
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21. Muller U, Mosbech H, Blaauw P, Dreborg S, Malling HJ, Pryzbilla B et al. 1991. “Emergency treatment of allergic reactions to Hymenoptera stings”. Clin Exp Allergy 21: pp 281-288.
For information, contact:
Dr Caterina Detoraki (Aikaterini Detoraki)
Blog: allergolife.blogspot.it
Email: caterinadetoraki@hotmail.com
Brief profile
Dr Detoraki graduated in 1999 from the School of Medicine of the University of Naples Federico II where she also followed her residency in Allergy and Clinical Immunology. She attended the Asthma and Allergy Center of the Johns Hopkins University, Baltimore (USA) and after her residency, the Division of Allergic and Respiratory Diseases in the Department of Pediatrics -University of Naples Federico II, obtaining additional experience in the diagnosis and management of allergic diseases in children.
She attended various National and International Congresses and is co-author of scientific papers published by Italian and international journals.
In 2008 she received her Ph.D. degree in Clinical Physiology and Experimental Medicine from the University of Naples Federico II.
Since 2006 she works as a specialist in Allergy and Clinical Immunology, in the University Hospital Federico II of Naples.
