Anaphylactic and Anaphylactoid Reactions

Jerrold H. Levy

CASE SUMMARY

A 73-kg, 27-year-old, otherwise healthy office worker with a history of frank reflux, who suspects he may have reacted to a sulfa drug as a child, presents for knee ligament reconstruction. After application of monitors, determination of baseline vital signs, and preoxygenation, his anesthetic was induced with sodium thiopental 350 mg, fentanyl 100 µg, and succinylcholine 100 mg in a rapid sequence induction utilizing cricoid pressure. Endotracheal intubation was easily accomplished and confirmed, and 1 g of cephalothin was given for infection prophylaxis while N₂O and isoflurane were initiated.

The circulating nurse notices red splotchiness on the patient’s thorax. The heart rate increased from 68 to 92 bpm, and the blood pressure decreased from 132/78 to 95/60 mmHg. A repeat blood pressure was 60/43 mmHg, and the patient manifests a suggestion of wheezing not noted earlier. The next blood pressure determination cycled without success, and the pulse oximeter stopped functioning. The electrocardiogram (ECG) was sinus tachycardia. A pulse could not be palpated. The anesthesiologist administered 200 µg of epinephrine. The intravenous (IV) rate was wide open. Another 500 µg of epinephrine was administered, and the pulse was again not palpable, with the pulse oximeter reading 100%.

How Is Anaphylaxis Defined?

Anaphylaxis was first reported in 1902 by Portier and Richet when immunizing animals against jellyfish toxins with Actinia extract.¹ Instead of transferring immunity or pro (for) phylaxis (protection), some of the animals developed marked shock, which resulted in death. They first used the word anaphylaxis (ana-against, prophylaxis– protection) to describe this clinical syndrome. Anaphylaxis produces multiorgan system dysfunction, including shock.² The target organs include the respiratory, cardiovascular, cutaneous, and gastrointestinal systems, all of which contain large quantities of inflammatory cells called mast cells. Because of the complex effects of the mediators present and the target end organs, the presentation of anaphylaxis is often unpredictable, with variable signs and symptoms.² In 2004 and 2005, the National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network sponsored a multidisciplinary “Symposium on the Definition and Management of Anaphylaxis”. This consortium brought together physicians from various medical specialties that deal with anaphylaxis to review current knowledge and to discuss features of a common definition, common treatment strategies, and areas in need of future research.³,⁴

In 1998, the Joint Task Force on Practice Parameters defined anaphylaxis as an “immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and basophils.”⁵ The most common causes of anaphylaxis depend on the patient population that clinicians manage. For allergists, this includes food, certain medications such as antibiotics, insect stings including fire ant and hymenoptera, and environmental antigens. Sampson et al. suggest anaphylactic reactions are distinguished from anaphylactoid reactions, which “mimic signs and symptoms of anaphylaxis, but are caused by the non-IgE-mediated release of potent mediators from mast cells and basophils.”³,⁴ Unfortunately, these definitions are not useful to most
anesthesiologists, surgeons, or intensivists managing a patient with acute life-threatening cardiopulmonary collapse following drug or blood product administration. In the perioperative period, certain agents are at an increased risk to produce anaphylaxis.

Agents most often associated with causing anaphylaxis include drugs, blood products, and environmental antigens such as latex.² Pharmacologic agents also have the potential to produce predictable and unpredictable adverse reactions. The most life-threatening form of an adverse reaction is anaphylaxis; however, the clinical presentation of anaphylaxis may represent different immune and nonimmune responses.² As stated in the preceding text, there is confusion in the literature about the term, anaphylaxis. On the basis of current concepts, anaphylaxis is best defined as: a clinical syndrome characterized by acute cardiopulmonary collapse following antigen (foreign substance) exposure. This chapter will describe the spectrum of anaphylactic and adverse drug reactions an anesthesiologist may encounter.

What Definitions Are Used in the Genre of Anaphylaxis?

The term allergy was first described in 1906 by von Pirquet, who suggested that in both immunity and hypersensitivity reactions, antigens induced changes in reactivity.⁶ Over time, the term, allergy, was used to describe immunoglobulin E (IgE)-mediated allergic disease. It was von Pirquet’s intent that the term be considered an “uncommitted” biologic response that could eventually lead either to immunity (a beneficial effect) or allergic disease (a harmful effect).⁶

The term, atopy, (from the Greek atopos, meaning out of place) is also often used to describe IgE-mediated diseases.⁶ Persons with atopy have a hereditary tendency to produce IgE antibodies against common environmental allergens, and have one or more atopic diseases (e.g., allergic rhinitis, asthma, and atopic eczema).⁶ Some allergic diseases, including contact dermatitis and hypersensitivity pneumonitis, develop through other complex non-IgE mechanisms, including cell-mediated immune responses, and are considered nonatopic allergic conditions. Hypersensitivity reactions are considered untoward physiologic events mediated through immune mechanisms.

What Is the Pathophysiology of Anaphylaxis?

Antigen binding to IgE antibodies causes anaphylaxis.²,⁷,⁸ Prior exposure to the antigen or a substance of similar structure is needed to produce sensitization, although an allergic history may be unknown to the patient. On reexposure, the antigen binds to bridge two immunospecific IgE antibodies on the surfaces of mast cells and basophils to release a complex series of inflammatory molecules that can be sufficient to produce acute cardiopulmonary dysfunction.⁸ The released mediators produce a symptom complex of bronchospasm and upper airway edema in the respiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria in the cutaneous system.²,⁹ Cardiovascular collapse during anaphylaxis results from the effects of multiple mediators on the heart and vasculature.¹⁰,¹¹ The vasodilation seen clinically can result from a spectrum of different mediators that interact with the vascular endothelium and/or vascular smooth muscle.²,¹²

What Are the Mechanisms of Vasodilatory Shock in Anaphylaxis?

Vasodilatory shock occurs in anaphylaxis because of multiple mechanisms, including the excessive activation of vasodilator mechanisms.¹² The increased synthesis of nitric oxide (NO) contributes to the hypotension and resistance to catecholamines that occur in anaphylactic shock. NO production is increased because of increased expression of the inducible form of NO synthase that occurs in vascular smooth muscle cells and endothelial cells.¹² The mechanisms increasing the inducible NO synthase are suggested to be cytokines (such as interleukin-1β, interleukin-6, tumor necrosis factor α, and adenosine) and other inflammatory mediators. Increased NO synthesis contributes to vasodilatation in shock. The vasodilating action of NO in vasodilatory shock is mediated mainly by the activation of myosin light-chain phosphatase; however, NO may also cause vasodilatation by activating potassium channels in vascular smooth muscle cells.¹² The vascular hyporeactivity to catecholamines that occurs in anaphylactic shock can be ameliorated by arginine vasopressin.¹²

In addition to the increased NO synthesis that activates soluble guanylate cyclase and produces cyclic guanosine monophosphate (cGMP), prostacyclin synthesis also contributes to vasodilation. It activates soluble adenylate cyclase and produces cyclic adenosine monophosphate (cAMP), both causing dephosphorylation of myosin, and hence vasorelaxation. Although multiple mediators, including arachidonic acid metabolites and kinins, are responsible for vasodilation, histamine also exhibits a major role in acute cardiovascular collapse.¹² Stimulation of endothelial H₁ receptors releases NO and prostacyclin.¹³ Unfortunately, specific blockade of the target enzyme of NO pathway may not attenuate vasodilation because of the other simultaneous mechanisms that also produce vasodilation.¹³

Why Is Anaphylaxis in the Operating Room Difficult to Diagnose?

The clinical diagnosis of intraoperative anaphylaxis is problematic because most anesthetics, including propofol, cause vasodilation, hypotension, and potentially cardiopulmonary dysfunction because of their direct and indirect effects on sympathoadrenergic responses, the heart, and the vasculature.¹⁴ Patients with cardiovascular disease and hypovolemia may even be more acutely affected by the changes that occur after anesthetic induction. The onset and severity of the reaction relate to the mediators’ specific end organ effects. The antigenic challenge in a sensitized individual usually produces immediate clinical manifestations of anaphylaxis, although the onset may be delayed by 2 to 20 minutes. Individuals vary in the expressions and course of anaphylaxis because of the route of exposure (oral vs. parenteral).¹⁵ A spectrum of reactions exist, ranging from minor clinical changes such as urticaria, to cardiopulmonary collapse, as well as severe bronchospasm, vasodilatory shock, and in certain cases, even pulmonary vascular injury, eventually leading to death.²,⁴ The enigma of anaphylaxis is its unpredictability of occurrence, the severity of the attack, and the lack of a prior allergic history.²

What Are the Signs and Symptoms of Anaphylaxis?

In most patients, the signs and symptoms of anaphylaxis can be variable,²,¹¹,¹⁶,¹⁷ and include those listed in Table 50.1.

TABLE 50.1 Signs and Symptoms of Anaphylaxis

CUTANEOUS: Itching, flushing, urticaria (hives), angioedema (perioral), and sweating

OPHTHALMIC: Itching, tearing, periorbital edema

NOSE AND MOUTH: Sneezing, runny nose, nasal congestion, metallic taste, swelling

RESPIRATORY TRACT: Difficulty in breathing, sensation of choking, wheezing, increased airway secretions, swelling of the upper throat, hoarseness; patients may have wheezing, increased airway pressures during positive pressure ventilation

CARDIOVASCULAR SYSTEM: Palpitations, arrhythmias (supraventricular, ventricular, and asystole), hypotension, and cardiac arrest; patients may also display vasodilatory shock (low systemic vascular resistance) and pulmonary vasoconstriction

GASTROINTESTINAL SYSTEM: Nausea, vomiting, abdominal cramps, bloating, and diarrhea

NERVOUS SYSTEM: Dizziness, weakness, fainting, a sense of impending doom, and seizures

What Mechanisms Produce Anaphylactoid Reactions?

▪ NON-IgE-MEDIATED REACTIONS

Multiple inflammatory pathways, including immunologic and nonimmunologic mechanisms, can release vasoactive mediators independent of IgE, creating a clinical syndrome identical with anaphylaxis.²,¹⁸,¹⁹,²⁰ Septic shock and the resulting vasodilatory shock is a primary example of this response.¹² Endothelial activation with release of vasoactive compounds is mostly responsible for this cardiovascular manifestation.²

Other important pathways include activation of polymorphonuclear leukocytes (neutrophils) that can occur following complement activation by immunologic (antibody-mediated: IgM, IgG-antigen activation) or nonimmunologic (heparin-protamine, endotoxin, cardiopulmonary bypass) pathways.²¹,²² Complement fragments of C3 and C5 (C3a and C5a) are called anaphylatoxins because they release histamine from mast cells and basophils, contract smooth muscle, and increase capillary permeability.²¹,²² In addition, C5a interacts with specific high-affinity receptors on white blood cells and platelets, causing leukocyte chemotaxis, aggregation, and activation.²¹,²² Aggregated leukocytes embolize to various organs and produce microvascular occlusion and liberation of inflammatory products, including oxygenfree radicals, lysosomal enzymes, and arachidonic acid metabolites (i.e., prostaglandins and leukotrienes).²¹,²² Investigators have associated polymorphonuclear leukocyte activation with producing the clinical manifestations of transfusion reactions and pulmonary vasoconstriction following protamine reactions.²

Transfusion-related acute lung injury (TRALI) is a life-threatening adverse effect of transfusion and the leading cause of transfusion-related death.²³ Anaphylaxis and TRALI share a common definition because both are temporally and mechanistically related to the transfusion of blood components. Two different etiologies have been proposed. The first is a single antibody-mediated event involving the transfusion of anti-human leukocyte antigen (HLA) class I and class II or antigranulocyte antibodies into patients whose leukocytes express the cognate antigens.²³ The second is a two-event model: the first event is the clinical condition of the patient resulting in pulmonary endothelial activation and neutrophil sequestration, and the second event is the transfusion of a biologic response modifier (including lipids or antibodies) that activates these adherent polymorphonuclear leukocytes, resulting in endothelial damage, capillary leak, and TRALI.²³

▪ NONIMMUNOLOGIC RELEASE OF HISTAMINE

Histamine release can occur from multiple agents, including drugs and endogenous neurokinins (i.e.,
substance P).¹⁸,²⁰,²⁴,²⁵ Different drugs administered during the perioperative period degranulate mast cells, but not basophils, to release histamine in a dose-dependent, nonimmunologic manner.²,¹⁸,²⁵,²⁶ The IV administration of morphine, atracurium, or vancomycin can release histamine, producing vasodilation, redness, and urticaria along the vein of administration. This nonimmunologic histamine release has classically been considered to be the cause of many anaphylactoid reactions. Usually, the hypotensive effects of histamine release can be treated with temporary pressor support or intravascular volume administration; however, the responses in different individuals may vary. The newer neuromuscular blocking agents (NMBAs), for example, rocuronium and cisatracurium lack the histamine-releasing effects, but can produce direct vasodilation and false-positive cutaneous responses that can confound allergy testing and interpretation.²⁰ The mechanisms involved in nonimmunologic histamine release represent the degranulation of mast cells, but not basophils, through cellular activation and stimulation of phospholipase activity in mast cells.²⁰,²⁴

Only gold members can continue reading. Log In or Register to continue