Anytime a patient receives a drug or is exposed to a chemical substance, an adverse reaction or an allergic reaction is possible. During the perioperative period, patients can be exposed to a wide variety of drugs. The anesthetic team must be vigilant for reactions and be ready to diagnose and treat reactions quickly. In some cases, reactions to medications can be severe or even life threatening. Anesthesia technicians must be ready to provide prompt assistance and technical support to the anesthesia team during a crisis.

Reactions to drugs and chemical substances can be categorized by the mechanism of the reaction. An adverse drug reaction is one that is known to be associated with the use of the drug, and the effect follows a predictable course. Some examples of adverse drug reactions include relative drug overdose, drug being given too rapidly producing exaggerated effects, known side effects such as nausea, and topical mechanical or chemical irritation from skin exposure. It is important to understand the difference between an adverse drug reaction and a true allergic reaction to a drug or substance because the etiology, mechanism of the reaction, and the treatment are different for the two types of reactions. Adverse drug reactions are not true drug allergies. True allergy to a drug or substance involves an immune reaction.

The most serious allergic reaction to a drug or chemical substance is called anaphylaxis. This chapter covers the following important aspects of an anaphylactic reaction:

Anaphylaxis is an immune reaction to a drug or foreign substance that is rapid in onset, unpredictable in severity, and unanticipated and can be life threatening. It is a systemic immune reaction against a foreign substance, or antigen. This reaction involves specific immune system proteins referred to as antibodies. The antibodies attach to the foreign antigen, which then triggers a cascade of inflammatory responses within the body. Proinflammatory and inflammatory mediators are released into the bloodstream, which can rapidly result in the clinical syndrome of anaphylaxis: skin rash, hemodynamic instability and hypotension, airway compromise from tissue swelling, bronchospasm with oxygenation and ventilation difficulties, possible cardiac depression, and dysrhythmias. True anaphylaxis is a medical emergency. The anesthetic team must be prepared to recognize, diagnose, and rapidly treat these reactions and provide supportive care, without delay, for the best patient outcome.

Anaphylaxis is a specific type of allergic reaction that involves immunoglobulin E (IgE) antibodies interacting with a foreign antigen, causing mast cell and basophil degranulation. An antibody is a specific protein that can recognize and bind to a specific antigen. An antigen is a molecule (or molecule-protein complex) that is capable of stimulating an immune response. An initial exposure to an antigen (e.g., various drugs, latex, prep solutions) is needed to produce sensitization, which is the production of specific antibodies to this specific antigen by cells called plasma cells. These IgE antibodies attach to the surface of specific immune cells called mast cells (in the tissues) and basophils (in the circulation). On reexposure to this foreign antigen, these specific IgE antibodies on the immune cells bind to the antigen. Cross-linking of the IgE antibodies
occurs, causing the mast cells and basophils to degranulate, and release preformed inflammatory mediators, such as histamine, tryptase, and chemotactic factors. This degranulation activates a systemic inflammatory cascade with further release of leukotrienes, prostaglandins, kinins, and cytokines. These released mediators cause the systemic clinical manifestations of anaphylaxis.

There are other immune reactions to antigens that can occur that do not involve IgE antibodies, but do involve release of histamine and other inflammatory mediators from mast cells. This is called non-IgE-mediated histamine release (anaphylactoid) and can involve other types of antibodies (IgG, IgM) and inflammatory mediators (complement). It is also possible for a drug, without an antibody interaction, to directly interact with the mast cell and cause histamine release. The amount of histamine released is related to the total dose of the drug and how rapidly it is given. An example of a drug that can do this is vancomycin. This effect for some drugs can be lessened by giving the drug slowly and carefully by using a timed infusion pump.

The physiologic response to the release of the mediators of anaphylaxis includes smooth muscle spasm in the respiratory bronchial tree and in the gastrointestinal tract; increased mucous production and airway edema; increased vascular permeability, with capillary leak and tissue edema resulting in intravascular volume loss (in some cases up to 30% of the circulating blood volume); and vasodilation. The vasodilation and intravascular fluid loss result in decreased venous return of blood to the heart. The effect of these physiologic changes can produce hypotension with poor tissue perfusion (shock), cardiac dysfunction, life-threatening arrhythmias, and bronchospasm with oxygenation and ventilation difficulties. The clinical syndrome produced by anaphylactic and anaphylactoid reactions can be similar; however, anaphylactic reactions tend to be far more severe.

The clinical manifestations of anaphylaxis can vary. In an awake patient, the patient may complain of respiratory symptoms, such as difficulty breathing, nasal congestion, and chest discomfort; skin rash, and itching, or cardiovascular symptoms such as dizziness and a sense of impending doom. Patients may have nausea or vomiting and abdominal cramps. Vital signs may show tachycardia, hypotension, and a rapid respiratory rate with noisy labored breathing. Objectively, the patient may have skin flushing and/or a rash. There may be difficulty breathing from laryngeal edema or wheezing from bronchospasm.

Under anesthesia, however, the initial signs of anaphylaxis may be cardiovascular collapse, with low blood pressure and either a rapid or slow heart rate. These early signs are frequently attributed to other causes leading to confusion in the actual diagnosis. Bronchospasm may occur, making ventilation difficult, with subsequent hypoxia. The end-tidal carbon dioxide level will increase, causing a respiratory acidosis. Both acidosis and hypoxia in combination with hypotension and poor perfusion can lead to myocardial depression and cardiovascular collapse. Cutaneous signs of allergy, such as urticarial rash or skin flushing, may not be present or appreciated under anesthesia, as an anesthetized patient cannot report itching, and the patient is covered by drapes.

It is important to appreciate there is a spectrum of clinical presentation associated with anaphylaxis. A patient may not present with all of these symptoms, and the severity of symptoms may vary. The most life-threatening presentation is hypotension and cardiovascular collapse. The incidence of anaphylaxis under anesthesia is hard to estimate, but ranges from 1/3,500 to 1/20,000, with a mortality rate between 3% and 6%. The most common clinical features of anaphylaxis under anesthesia were cardiovascular symptoms (74%), cutaneous symptoms (70%), and bronchospasm (44%).

During the course of anesthetic care, multiple drugs are given over a relatively short period of time. With the induction of general anesthesia, it is not uncommon for five or more drugs from different classes, with different chemical structures and mechanisms of action, to be given together in succession. The majority of anaphylactic reactions will occur within the first 10 minutes after the drug is given. The patient is at the highest risk for an anaphylactic reaction
just after the induction of general anesthesia, at a time when there is a lot of distracting activity in the operating room. Other conditions can present with similar symptoms, such as a relative anesthetic overdose with hypotension, wheezing after intubation from light anesthesia, or a vasovagal reaction. These conditions are known and anticipated and treated routinely by the anesthesia provider. It is when the usual adjustments and medications are not correcting the situation readily, and the hypotension or bronchospasm is persistent, that the anesthetic team must consider the diagnosis of anaphylaxis and quickly initiate the treatment.

After an anaphylactic reaction, it is often unclear which drug was the offending agent. Patients can be referred later to allergy centers to be tested for antibodies to specific drugs that were given perioperatively. This allergy testing referral system is fairly developed in Europe and less developed in the United States. According to the European literature, based on information gathered from preoperative allergy testing centers, the most common triggers of anaphylaxis under anesthesia are muscle relaxants (69%), latex exposures (16%-20%), and antibiotics (15%). Known triggers of anaphylaxis in the perioperative period include the following: