History
The word anaphylaxis originally derived from the Greek prefix ana, meaning against, and root word phylaxis, meaning protection. Anaphylaxis was first described in 1902 by scientists Portier and Richet while trying to yield a tolerance to sea anemone venom in dogs. They expected the dogs’ immune systems would generate protection, but instead caused a rapid onset of near-fatal symptoms. Their research concluded that the immune system becomes sensitized by an allergen over several weeks, and if that allergen is reintroduced, it may result in a severe reaction.
Allergic Reaction
An allergic reaction is a broad term used to describe an acute, local hypersensitivity reaction. The most common signs associated with allergic reactions are cutaneous in nature, with no other systemic signs. These include erythema (reddening of the skin), pruritus (itchy skin), urticaria (hives), and angioedema (swelling under the skin). It’s thought that cutaneous signs could be potential precursors to the development of systemic signs associated with anaphylaxis. Causes of a local hypersensitivity reaction include food, insect bites, vaccines, or other drug agents.
Anaphylaxis
Anaphylaxis can be defined as an acute, severe life-threatening systemic hypersensitivity reaction. This means that besides the cutaneous signs associated with allergic reactions, there is an additional systemic component. Additional body systems affected during anaphylaxis include gastrointestinal, cardiovascular, respiratory, neurological, and ocular. Anaphylaxis is the result of a massive, generalized release of mediators, primarily histamine.
The Immune System
The function of the immune system is to protect the body from anything that could cause harm, damage, or disease. An antigen is any foreign substance that when introduced to the body, stimulates an immune response. When the body detects an antigen that threatens its health, it employs various mechanisms to destroy it. An antibody (also known as an immunoglobulin) is a Y-shaped protein used by the immune system in response to an antigen. The antibody’s role is to neutralize the antigen by binding to it and making the antigen inactive. In relation to allergic reactions and anaphylaxis, the two primary antibodies involved are immunoglobulin-E (IgE) and immunoglobulin-G (IgG).
Pathophysiology
The two common immunologic pathways of anaphylaxis are either IgE receptor-mediated (the common pathway) or IgG receptor-mediated (the alternative pathway). The classic pathway of anaphylaxis starts when exposure to an antigen results in a sensitivity. IgE antibodies are produced in response to the sensitivity and bind and coat mast cells and basophils. This initial phase of the classic pathway is silent, meaning no clinical signs manifest. Upon repeated exposure of the antigen, the IgE antibodies located along the cell cross-link with the antigen. Once cross-linked, the cell (mast or basophil) undergoes degranulation and releases inflammatory mediators, primarily histamine. Histamine release is rapid, with measurable concentrations in plasma found within 1 minute of an anaphylaxis event. Histamine is a mediator and acts through receptors (histamine-1 [H1], histamine-2 [H2], and histamine-3 [H3]) to promote circulatory shock. H1 receptors mediate coronary artery vasoconstriction and cardiac depression. H2 receptors mediate gastric acid production, systemic vasodilation, and increased heart rate and contractility. H3 receptors mediate inhibition of endogenous (innate) norepinephrine release, which inhibits the body’s normal compensatory response. This type of reaction can be caused by insect bites, reptile envenomation, food, plants, or certain medications.
The alternative pathway of anaphylaxis does not require previous exposure or sensitization to an antigen. Upon exposure, IgG antibodies are produced and bind to mast cells and macrophages. The cell (mast or macrophage) then undergoes degranulation and primarily releases platelet activating factor (PAF). PAF is a potent bronchoconstrictor, causing decreased inotropy, decreased coronary artery blood flow, peripheral vasodilation, and hypotension. PAF also promotes platelet aggregation and is proinflammatory. This type of reaction can be caused by blood production transfusions, activation of coagulation system, or autoimmune disorders.
The non-immunologic pathway of anaphylaxis occurs independently of immunoglobulins but still results in mast cell and basophil degranulation. This type of reaction can be caused by physical factors (exposure to heat, exposure to cold, exposure to water, exercise) or certain medications (i.e., opioids, NSAIDs, ethanol, radiocontrast agents, chemotherapeutic agents).
Clinically, the anaphylaxis pathways (IgE-mediated, IgG-mediated, non-immunologic) are indistinguishable and are, therefore, treated identically.
Clinical Signs
The key difference between anaphylaxis reactions and allergic reactions is a systemic (multi-organ system) component. The three most commonly affected systems are gastrointestinal (GI), cardiovascular, or respiratory. However, neurologic and ocular signs can sometimes be present. Manifestation of clinical signs vary depending on species and route of antigen exposure. In canines, cutaneous and GI signs predominate; in felines, GI and respiratory signs predominate.
The GI signs associated with anaphylaxis result from a combination of the high number of mast cells present within the GI tract, the effect of histamine release into the hepatobiliary system (in canines), and activation of H2 receptors within the GI tract. When histamine is released into the hepatic portal vein from the GI tract, it leads to hepatic vein congestion (hepatic venous outflow obstruction) which increases hepatic vascular resistance. The cardiovascular signs associated with anaphylaxis result from changes in cardiac output. Vasoconstriction of coronary arteries leads to decreased inotropy and myocardial dysfunction. Additionally, generalized erythema and acute shock states contribute to widespread vasodilation and hypotension. The respiratory signs associated with anaphylaxis result from bronchoconstriction and upper airway obstruction (secondary to laryngeal/pharyngeal edema and increased mucous production).
Diagnosis
Successful diagnosis of an anaphylactic reaction is dependent on a thorough patient history, comprehensive physical exam, and observation of clinical manifestations. It is important to document historical information through communication with the client/owner. Information that should be collected include any history of previous hypersensitivity reactions, duration of symptoms, any recent time outdoors prior to onset of symptoms, or any known acute exposure to an antigen. It is valuable to try to establish a timeline (exposure—onset of clinical signs—progression of signs) and document in the medical record.
To evaluate cardiovascular function, perform cardiac auscultation, palpate pulse quality, check mucous membrane (mm) color and capillary refill time (CRT), obtain a blood pressure (BP), and collect an electrocardiogram (ECG) strip. To evaluate respiratory function, you should perform respiratory auscultation, evaluate any respiratory effort (RE), observe if there are any noises associated with respiration, and obtain a pulse oximeter reading. To evaluate the GI system, you should inspect the oral cavity, perform abdominal palpation, and include a rectal exam. To evaluate neurological function, you should evaluate mentation and ambulation.
Biomarkers
A study published in 2009 focused on investigating the hepatobiliary parameters (alanine transaminase [ALT] and gallbladder changes) in canine patients experiencing anaphylaxis. ALT is a hepatic enzyme that is specifically an indicator of hepatocyte leakage. The ALT enzyme is a very sensitive marker of hepatic dysfunction (as seen in anaphylaxis), so an elevation can be considered a diagnostic indicator. A scanning abdominal ultrasound should be performed to evaluate the intraabdominal components (GI tract, liver, gallbladder). In a normal patient, the gallbladder is thin and poorly visualized during imaging. During anaphylaxis, there is hepatic congestion and portal hypertension (which both affect venous drainage of the gallbladder). As a result, gallbladder wall changes (i.e., wall thickening, “halo” or double rim effect, multiple wall striations) are more prominently seen; these changes are indicative of the animal’s impaired hepatobiliary function. The study’s results concluded that elevation of ALT and an abnormal gallbladder wall were both markers associated with anaphylaxis.
Treatment
Patients suffering from anaphylaxis present in a mixed distributive-hypovolemic shock state. Shock can be defined as the failure of the circulatory system to maintain perfusion and distribute oxygen to tissues. Histamine decreases systemic vascular resistance, which is responsible for maintaining vascular tone. This results in profound vasodilation and peripheral pooling of blood, leading to a maldistribution of vascular volume. Histamine also increases vascular permeability (the vessel’s ability to remain intact). These “leaky” vessels result in a relative hypovolemia due to excessive fluid losses and shifts of intravascular fluid to the extravascular space. Treatment should center on the patient’s presenting status and severity of clinical signs. Supportive therapies include fluid therapy, oxygen, epinephrine, antihistamines, and adjunctive measures.
Venous access is essential to be able to administer fluids and medications. Ideally, a large bore IV catheter should be placed to allow for higher volumes of fluid therapy. IV catheters should also be placed in the cephalic vein to allow for easier IV access, reduce the likelihood of contamination from GI losses and to prevent mal-positioning or occlusion. Isotonic crystalloid solutions should be administered rapidly in shock dose aliquots (90 ml/kg canine, ¼ aliquot doses; 50 ml/kg feline, ¼ aliquot doses). Reassessment of resuscitation endpoints should be used to guide fluid therapy. If the patient is experiencing profound GI losses, it’s essential to keep up with ongoing losses to prevent continued or worsened hypovolemia and dehydration. This can be done by quantifying the losses (vomit, diarrhea) every 4 hours and replacing with an additional “bolus” bag of isotonic crystalloids.
Oxygen should be provided to any patient experiencing respiratory signs. Oxygen can be delivered by flow-by face mask during stabilization measures. Once stabilized, oxygen therapy can continue supportively as either nasal cannula or oxygen cage delivery. Reevaluation of respiratory parameters, specifically RR, RE, and pulse oximeter, should be used to determine if the patient is still in need of oxygen or if they can be weaned and/or discontinued.
Epinephrine is the cornerstone in treatment for anaphylactic events. Epinephrine is a catecholamine, with its main effects being on the cardiovascular system and vascular smooth muscle. Epinephrine supports arterial blood pressure (causes vasoconstriction), relaxes smooth muscle in the bronchi (relieves bronchoconstriction), improves cardiac contractility and heart rate (by direct heart stimulation), and inhibits further mast cell degranulation (thus antagonizing the effects of histamine). Epinephrine administration should start with a single IV or IM dose. When giving IV, epinephrine should be given slowly, titrating to effect, as rapid infusion can result in more negative side effects. An IV constant rate infusion (CRI) should be considered when multiple boluses are required to maintain cardiovascular stability. Ideally, a CRI should be setup on a syringe pump to allow for more accurate titrating and adjusting of dosage.
Antihistamines block histamine release and the negative effects from the activation of H1 and H2 receptors. H1 blockers (i.e., diphenhydramine) reduce pruritus, erythema, and other cutaneous and nasal signs. H2 blockers (i.e., famotidine) reduce gastric acid secretions.
Bronchodilators (i.e., albuterol, terbutaline) may also be considered in cases with severe or continued respiratory distress despite oxygen therapy. Bronchodilators dilate the bronchial smooth muscle to decrease airway resistance, increase airflow to the lungs and relieve bronchospasm. In severe cases of respiratory distress, it may be necessary to intubate. Vasopressors (i.e., dopamine) may be indicated if there’s no cardiovascular improvement with fluid resuscitation and epinephrine therapy. Vasopressors are potent vasoconstrictors used to increase blood pressure. It’s important to note that vasopressors shouldn’t be considered until the patient has been fully fluid resuscitated (received full shock dose of crystalloids). Contradictory to their use in allergic reactions, there is no clinical evidence to support the use of glucocorticoids in anaphylaxis. While glucocorticoids can help alleviate the inflammatory response, the beneficial effects of use are not seen for up to 4–6 hours. Due to their delayed effects, they should never be used as a first-line drug.
Nursing Care
Monitoring of the anaphylactic patient is essential for patient care and outcome. Often times, these patients are dedicated cases for the first several hours. During stabilization therapies, it is primarily the veterinary nurse assessing the patient and recording vital signs. Important parameters to be include HR, pulse rate, BP, mm color, CRT, RR, RE, and overall mentation. For the first few hours, vitals should ideally be done every 30–60 minutes; as they become less critical, vitals can decrease to every 1–4 hours.
Depending on the patient’s initial BP reading, frequent measurements (initially every 30–60 minutes) are indicated. To ensure consistency, the same limb and cuff size should be used each time. As BP stabilizes, frequency of measurements can be reduced to every 1–4 hours. A continuous ECG should be used to monitor for changes in HR or development of arrhythmias. A continuous ECG should be used until heart rate and rhythm have normalized, then ECG monitoring can be reduced to intermittent recordings. A pulse oximeter should also be used to monitor the patient’s oxygenation status and response to oxygen therapy (if employed). If oxygen therapy is provided, pulse oximeter readings should be taken on and off oxygen; this allows for a comparison of the patient’s oxygenation ability. Once normal readings off oxygen are recorded, oxygen therapy can begin to be weaned and/or discontinued.
More often than not, these patients are recumbent for several hours. It is, therefore, important to provide recumbent care (passive range of motion exercises, limb massage, rotation of hips) to prevent pressure sores and discomfort. Maintaining patient cleanliness is also a main part of good nursing care. Diaper pads can be used to cover patient bedding and as a means of being able to quantify GI losses. If possible, a gram scale can be used to weigh soaked diaper pads, as one gram is equivalent to one ml. Using diaper pads is also a way to help keep the patient cleaner by having them not lay in their losses. Accurate recording of a patient’s losses is necessary when it comes to quantifying GI replacement fluids.
Lastly, careful monitoring is also indicated to watch for a biphasic reaction. A biphasic reaction is a secondary reaction that can occur 8–72 hours after initial stabilization. Generally, the same organ systems involved in the initial reaction also re-occur during the biphasic (secondary) reaction.
Conclusion
Anaphylaxis is a true life-threatening emergency. It is also a condition that’s difficult to define and can be challenging to diagnose. Appropriate recognition, prompt stabilization, and dedicated nursing care are all vital to positive patient outcome.
References
1. Silverstein DC, ed. Small Animal Critical Care Medicine. St. Louis, MO: Elsevier; 2015.
2. Scalf R, ed. Study Guide to the AVECCT Examination. San Antonio, TX: AVECCT; 2014.
3. Battaglia AM, Steele AM, Battaglia AM, eds. Small Animal Emergency and Critical Care for Veterinary Technicians. St. Louis, MO: Elsevier; 2016.
4. Norkus CL. Veterinary Technicians Manual for Small Animal Emergency and Critical Care. Hoboken, NJ: Wiley; 2019.