“Prehospital Pathophysiology” provides an opportunity for EMS providers to either refresh their knowledge related to the etiology of a certain disease or expand their knowledge base regarding common and not-so-common disease processes. This column is for both basic- and advanced-level prehospital care providers. The authors hope that through this column, EMS providers will gain a more thorough understanding of disease processes. If you would like to see a specific topic addressed in this column, send your request via e-mail to firstname.lastname@example.org.
Anaphylactic and anaphylactoid reactions are life-threatening events that result from an overreactive and misdirected immune response to a substance that is viewed by the body as foreign. This foreign substance is referred to as an antigen (see Table I for common antigenic substances). The reaction is systemic, which involves multiple organ systems, and is a direct result of the release of chemical mediators from mast cells and basophils. Specifically, the condition anaphylaxis requires the patient to be sensitized, and their reaction mediated through immunoglobin E (IgE) antibodies. An anaphylactoid reaction doesn’t need the presence of IgE antibodies for a hypersensitivity reaction to occur. Substances initiating the anaphylactoid reaction, such as radiopaque contrast media, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin (see Table II for other anaphylactoid substances), cause a direct breakdown of the mast cell and basophil membranes.
Thus, an anaphylactic reaction occurs only after the patient has been previously exposed at least once to the antigen and is sensitized; an anaphylactoid reaction can occur following a single, first-time exposure to certain agents in nonsensitized patients. Because anaphylactic and anaphylactoid reactions produce the same clinical manifestations and are treated exactly the same way, we use the term anaphylaxis to refer to both conditions.
Sensitization involves an immunologic process that occurs when the body views a substance as foreign. In response to the antigen, the body produces IgE antibodies to fight off the substance on reintroduction into the body. The IgE antibodies have a strong affinity for mast cells and basophils and subsequently attach to receptors on the cell membrane. Mast cells are located in connective tissue, especially near blood vessels, and in the mucosal layer in the lungs and the gut. Mast cells are filled with granules that release chemical mediators in an anaphylactic reaction. Basophils, which also contain granules, are polymorphonuclear leukocytes and are found circulating in the blood. Basophils, which are not well understood, become mast cells once they cross over into connective tissue. Once IgE antibodies are attached to the mast cells and basophils, the patient is considered to be sensitized, or primed for an anaphylactic reaction. The IgE antibodies can stay attached to the mast cells and basophils for seconds, minutes, days, weeks, months or years. The patient remains sensitized for an anaphylactic reaction as long as the IgE antibodies are attached to the mast cells and basophils.
Upon reintroduction of the antigen in the sensitized patient, the antigen attaches to several IgE antibodies located on the cell membranes of the mast cells and basophils. This linkage causes the cell membranes to break down or degranulate, releasing preformed chemical mediators from the cell granules into the extracellular fluid. Some mast cells or basophils may release the chemical mediators without degranulating, or may synthesize and release substances that are not preformed or stored in the granules. The chemical mediators that are released from the mast cells and basophils affect blood vessels, pulmonary bronchioles and other organs, leading to an increased vascular permeability, peripheral vasodilation, coronary vasoconstriction and smooth muscle contraction, especially in the bronchioles. This explains the etiology of many of the cutaneous (skin), pulmonary and cardiovascular signs and symptoms exhibited during an anaphylactic reaction.
Chemical mediators released from the mast cells and basophils are directly responsible for producing the clinical condition found in anaphylaxis. If chemical mediators were not released, there would be no end organ or tissue response and the patient would not suffer an anaphylactic reaction. Thus, it is these chemical mediators that produce the life-threatening vasodilation, increase in capillary permeability, bronchoconstriction, coronary artery vasoconstriction and other pathophysiologic responses.
Histamine is the predominant preformed chemical mediator released from the granules of the mast cells and basophils. Three classes of receptors—H1, H2 and H3—produce the organ and tissue response from circulating histamine. H1 receptor stimulation causes bronchoconstriction, systemic vasodilation, intestinal and uterine smooth muscle contraction, increased capillary permeability, increase in nasal mucus production and coronary artery constriction, producing many of the signs and symptoms exhibited in anaphylaxis. H2 receptor stimulation will increase the secretion of mucus and gastric acid, capillary permeability, and the force and rate of atrial and ventricular contractions, and may lead to bronchial smooth muscle and pulmonary vessel relaxation. H3 receptors, which are found in central nervous tissue and peripheral tissues, control the production and release of histamine. Two other preformed substances released by the mast cells during degranulation are neutrophil chemotactic factor and eosinophil chemotactic factor (ECF-A), which cause neutrophils and eosinophils, respectively, to be attracted to the site of inflammation.
Leukotrienes, once known as the slow-reacting substance of anaphylaxis (SRS-A), are synthesized and released by the mast cells and contribute to sustained effects of anaphylaxis. They have a slower onset, but are considered to be much more powerful and have a much longer duration than histamine in causing bronchoconstriction. Leuko-trienes also cause an increase in capillary permeability and mucus production. Prostaglandins are also synthesized and released by mast cells and produce an increase in vascular permeability and smooth muscle contraction.
Other substances released as a result of the anaphylactic reaction are platelet-activating factor (PAF) and bradykinin. PAF is released from mononuclear phagocytes, platelets and some endothelial cells in response to anaphylaxis. PAF causes the aggregation or clumping of platelets. PAF also results in a decrease in myocardial contractile force, coronary vasoconstriction and pulmonary edema. Bradykinin is the primary kinin produced by stimulation of the plasma kinin cascade. Bradykinin causes slow smooth muscle contraction, leading to bronchoconstriction and increased vascular permeability. Bradykinin is also thought to be much more powerful than histamine.
Almost all of the signs and symptoms of anaphylaxis can be primarily related to a few major pathophysiologic factors occurring during the reaction: 1) increase in vascular permeability; 2) vasodilation; and 3) bronchiole smooth muscle contraction. Signs, symptoms and etiology are listed as follows by organ system:
An increase in vascular permeability results in urticaria (hives), pruritis (itching) and angioedema (a deeper cutaneous swelling), especially around the mouth, eyes and to the extremities. Vasodilation will produce tingling, warmth, flushing and diffuse redness.
Upper Respiratory Tract
An increase in vascular permeability, vasodilation and stimulation of nerve endings will produce rhinitis and laryngeal edema. Signs and symptoms of rhinitis are nasal congestion, itchy nose, sneezing and rhinorrhea (nasal drainage). Laryngeal edema produces hoarseness, sensation of the throat tightening, dyspnea, stridor and excessive salivation.
Lower Respiratory Tract
Bronchiole smooth muscle contraction, which leads to bronchospasm, in addition to vasodilation and an increase in vascular permeability, affects the lower respiratory tract. The signs and symptoms are wheezing, cough, chest tightness, rhonchi, tachypnea, respiratory distress and cyanosis.
Circulatory collapse is produced as a result of an increase in vascular permeability with a loss of plasma volume out of the intravascular space, vasodilation and decreased cardiac output. Signs and symptoms include tachycardia, hypotension, weakness, syncope and light-headedness. The patient may also present with dysrhythmias.
Central Nervous System
Cerebral hypoxia results from a decrease in cerebral perfusion from the loss of intravascular volume associated with an increase in vascular permeability and vasodilation, and hypoxia resulting from laryngeal edema and bronchospasm. The patient becomes apprehensive and anxious, and may present with headache, confusion, altered mental status, seizures (rare) and coma.
GI signs and symptoms are caused by gut smooth muscle contraction and an increase in mucus secretion. Common signs and symptoms are diarrhea, abdominal cramping, nausea, vomiting and difficulty swallowing (dysphagia).
Other signs and symptoms that may occur include pelvic pain, vaginal bleeding and urinary incontinence from contraction of the smooth muscle in the uterus and bladder. Itchy, red, watery eyes result from stimulation of nerve endings.
Emergency care of a patient suffering from an anaphylactic reaction is geared toward supporting vital functions while eliminating the three primary factors (vasodilation, increased vascular permeability and bronchoconstriction) that are producing the pathophysiologic condition and the signs and symptoms. Aggressive airway management, ventilation, if necessary, and oxygenation must be performed immediately. Initiate at least one large-bore intravenous line of normal saline or lactated Ringer’s and run it according to the patient’s perfusion status. If the patient is hypotensive, run the fluids wide open. Place the patient on a continuous ECG monitor and pulse oximeter.
The drug of choice in anaphylaxis is epinephrine, which contains alpha and beta properties. The alpha properties will reverse vasodilation and vascular permeability; beta 1 will increase myocardial contractility; and the beta 2 properties will reverse the bronchoconstriction by promoting bronchiole smooth muscle dilation. Diphenhydramine (Benadryl) may also be administered to block the histamine receptors. Corticosteroids may be used to stabilize mast cell membranes and reduce release of chemical mediators.
- Dalton AL, Limmer D, Mistovich JJ, Werman HA. Advanced Medical Life Support: A Practical Approach to Adult Medical Emergencies, 2nd edition. Upper Saddle River, NJ: Prentice Hall, 2003.
- Guyton AC, Hall JE. Textbook of Medical Physiology, 10th edition. Philadelphia, PA: W.B. Saunders, 2000.
- Hamilton GC, Sanders AB, et al. Emergency Medicine: An Approach to Clinical Problem Solving, 2nd Edition. Philadelphia, PA: W.B. Saunders, 2003.
- Huether SE, McCance KL. Understanding Pathophysiology, 3rd edition. St Louis, MO: Mosby, 2004.
- Martini FH, Bartholomew EF, Bledsoe BE. Anatomy and Physiology for Emergency Care. Upper Saddle River, NJ: Pearson Education, 2002.
- Rodak BF. Hematology: Clinical Principles and Applications, 2nd edition. Philadelphia, PA: W.B. Saunders, 2002.
- Rosen P, Barkin RM, et al. Emergency Medicine Concepts and Clinical Practice, 5th edition. Mosby, 2002.
- Tintinalli JE. Emergency Medicine: A Comprehensive Study Guide. New York: McGraw-Hill, 2000.