• Embed Doc
  • Copy Link
  • Readcast
  • Collections
  • CommentGo Back
Download
 
Anaphylaxis and Adverse Drug ReactionsJerrold H. Levy, M.D. Atlanta, Georgia
310Page 1
INTRODUCTION
Any substance that patients are exposed to in the perioperative period including drugs, blood products, or environmental antigens such as latex can produce anaphylaxis. Pharmacologic agents also have the potential to produce predictable and unpredictable adverse reactions. The most life-threatening form of an adverse reaction isanaphylaxis
,
however, the clinical presentation of anaphylaxis may represent different immune and nonimmuneresponses.(1) There is confusion in the literature about the term anaphylaxis, and a multitude of descriptiveterminologies have been reported to describe the spectrum of reactions. This presentation will define the spectrumof anaphylactic and adverse drug reactions an anesthesiologist may encounter.
ALLERGY, ATOPY, AND ANAPHYLAXIS
The term "allergy" was first described in 1906 to suggested that in hypersensitivity reactions, antigens(molecules functioning as foreign substances) had induced changes in reactivity. The idea was that allergy should be considered an "uncommitted" biologic response, that could eventually lead either to immunity (a beneficialeffect) or allergic disease (a harmful effect) (2). The terms "drug allergy," "drug hypersensitivity," and "drugreaction" are often used interchangeably. Drug reactions encompass all adverse events related to drugadministration, regardless of etiology. Drug hypersensitivity is defined as an immune-mediated response to a drugagent in a sensitized patient. Drug allergy is restricted specifically to a reaction mediated by IgEThe term "atopy" (derived from Greek atopos, meaning out of place) is also often used to describe IgE-mediated diseases (2). Atopic individuals have a genetic predisposition to produce IgE antibodies against commonenvironmental allergens and have one or more atopic diseases including allergic rhinitis, asthma, and atopiceczema
1
. Other allergic diseases, including contact dermatitis develop through other complex non IgE mechanismsincluding cell mediated immune responses, and are considered nonatopic allergic conditions. Hypersensitivityreactions are considered untoward physiologic events mediated through immune mechanisms (2).Richet and Portier first used the word anaphylaxis (ana -against, prophylaxis - protection) to describe the profound shock and resulting death that sometimes occurred in dogs immediately following a second challenge witha foreign antigen. (5) Several task forces have defined
anaphylaxis
as an “immediate systemic reaction caused byrapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral basophils (3,4).” Themost common causes of anaphylaxis depend on the patient population that clinicians manage. For allergists, thisincludes food, antibiotics, insect stings, and environmental antigens. Sampson suggests anaphylactic reactions aredistinguished from
anaphylactoid reactions,
which “mimic signs and symptoms of anaphylaxis, but are due to non-IgE-mediated release of potent mediators from mast cells and basophils(3,4).” Unfortunately, these definitions arenot useful to most anesthesiologists. Based on current concepts, anaphylaxis is best defined as a clinical syndromecharacterized by acute cardiopulmonary collapse following antigen (foreign substance) exposure. Much of theconfusion about anaphylaxis in the literature is because many older anesthetic agents could directly degranulate mastcells or activate complement independent of immune mechanisms. This presentation will define the spectrum of anaphylactic and adverse drug reactions an anesthesiologist may encounter.
ADVERSE DRUG REACTIONS
Adverse drug reactions are common, however, only 6-10% are immunologically mediated.(1) Althoughsome drug-induced allergic reactions may be classified into one of the four Gell and Coombs hypersensitivitycategories, many others cannot be classified because of our lack of mechanistic information. Theoretically, any drugcan induce an immune response, although some drugs are more likely to elicit clinically relevant immune responsesthan are others. (1-4) Most serious predictable adverse drug reactions are toxic and related to either the amount of drug in the body (overdosage), unintended administration route, or known side effects (i.e., opioid related nausea).However, some drugs have direct effects on inflammatory cells (i.e., drug-mediated histamine release from mastcells, or biologic response modifiers). Unfortunately, patients often refer to any adverse drug effects as beingallergic in nature. Anesthetic drugs also have the potential to produce direct effects on the cardiovascular system(eg, propofol induced vasodilation) complicating the diagnosis of perioperative adverse drug reactions. Unlike mostadverse drug reactions, allergic drug reactions are unpredictable and are dose-independent because small amounts of the antigen including that amount eluted off latex gloves during latex anaphylaxis can produce life-threateningresponses. (1) When clinicians have severe adverse drug reactions, they should consider reporting them to the Foodand Drug Administration at http://www.fda.gov/medwatch/.
 
 310Page 2
PATHOPHYSIOLOGY OF ANAPHYLAXIS
 Antigen binding to IgE antibodies causes anaphylaxis. Prior exposure to the antigen or to a substance of similar structure is required to produce sensitization, although an allergic history may be unknown to the patient.On reexposure, 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 produce acute cardiopulmonary dysfunction.(6-9) The released mediators produce a symptom complex of bronchospasm and upper airway edema in therespiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria inthe cutaneus system.(1) Cardiovascular collapse during anaphylaxis results from the effects of multiple mediatorson the heart and vasculature.(6-9) The vasodilation seen clinically can result from a spectrum of different mediatorsthat interact with vascular endothelium and/or vascular smooth muscle.(1,8)
VASODILATORY SHOCK AND ANAPHYLAXIS
Vasodilatory shock occurs in anaphylaxis due to multiple mechanisms, including the excessive activationof 
 
vasodilator mechanisms including unregulated nitric oxide synthesis that activates
 
soluble guanylate cyclase and produces cGMP, and prostacyclin synthesis that activates soluble adenylate cyclase and producing cAMP, bothcausing dephosphorylation
 
of myosin and hence vasorelaxation. (1,8) Nitric oxide
 
synthesis and metabolic acidosisactivate the potassium channels
 
in vascular smooth muscle.
 
The resulting vascular hyperpolarization preventscalcium from entering the cell. Therefore, hypotension
 
and vasodilatation persist, despite catecholamine therapy.(10)Other mediators that are released by non IgE mechanisms may also produce shock by different mechanisms (eg, protamine induced acute pulmonary vasoconstriction) will be discussed in non IgE mediated reactions.(1)
 
RECOGNITION OF ANAPHYLAXIS
 The onset and severity of the reaction relate to the mediator's specific end organ effects. Antigenic challenge ina sensitized individual usually produces immediate clinical manifestations of anaphylaxis, but the onset may bedelayed 2-20 minutes.(3,6,9) Individuals vary in the manifestations and course of anaphylaxis because of exposure(oral vs. parenteral). A spectrum of reactions exist, ranging from minor clinical changes including urticaria tocardiopulmonary collapse including severe bronchospasm, vasodilatory shock, and even pulmonary vascular injuryin certain cases, leading to death as shown below.(1) The enigma of anaphylaxis is the unpredictability of occurrence, the severity of the attack, and the lack of a prior allergic history.(1)Signs and symptoms in anaphylaxis develop rapidly, often within seconds or minutes following antigen exposureand include any combination of the following:
Symptoms
: difficulty breathing, wheezing, throat swelling, confusion, palpitations, light-headedness, dizziness,generalized itching/hives, anxiety, nausea, vomiting, diarrhea, abdominal pain or cramping (more common withfood allergens), nasal congestion, coughing, sneezing.
Signs: Respiratory;
wheezing increased airway secretions, angioedema of airway, increased airway pressuresduring positive pressure ventilation, difficulty ventilating.
Cardiovascular;
arrhythmias (supraventricular,ventricular, and asystole), hypotension, cardiac arrest, vasodilatory shock (low systemic vascular resistance) and pulmonary vasoconstriction.
NON-IgE MEDIATED REACTIONS
 Other immunologic and nonimmunologic mechanisms release inflammatory mediators independent of IgE,creating a clinical syndrome identical to anaphylaxis.(11-17) Polymorphonuclear leukocyte (neutrophil) activationcan occur following complement activation by immunologic (antibody mediated: IgM, IgG-antigen activation) or non-immunologic (heparin-protamine, endotoxin, cardiopulmonary bypass) pathways.(11-14) Complementfragments 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. In addition, C5a interacts with specifichigh-affinity receptors on white blood cells and platelets, causing leukocyte chemotaxis, aggregation, andactivation.(13) Aggregated leukocytes embolize to various organs producing microvascular occlusion and liberationof inflammatory products including oxygen-free radicals, lysosomal enzymes and arachidonic acid metabolites (i.e. prostaglandins and leukotrienes). Antibodies of the IgG class directed against antigenic determinants or granulocytesurfaces can also produce leukocyte aggregation.(15) These antibodies are called leukoagglutinins. Investigatorshave associated polymorphonuclear leukocyte activation in producing the clinical manifestations of transfusion
 
 310Page 3reactions, (15) pulmonary vasoconstriction following protamine reactions, (16) and transfusion related acute lunginjury (TRALI). (17)TRALI is a life-threatening adverse effect of transfusion and is the leading cause of transfusion-relateddeath (17). TRALI and anaphylaxis are both temporally related to the transfusion of blood components. However,different mechanisms may be responsible. The first is an antibody-mediated event produced by transfusing IgGantibodies as described against anti-HLA class I, class II, or antigranulocyte antibodies into patients whoseneutrophils share these antigens (17). The other is a sequential event model where the clinical condition of the patient produces pulmonary endothelial activation and leukocyte sequestration, and the second event is thetransfusion of a biologic response modifier (including lipids or antibodies) that further activates these polymorphonuclear leukocytes to adhere, resulting in endothelial damage, capillary leak, and TRALI(17).
NONIMMUNOLOGIC RELEASE OF HISTAMINE
Many diverse molecular structures administered during the perioperative period degranulate mast cells torelease histamine in a dose-dependent, nonimmunologic fashion.(18-21) Intravenous administration of morphine,atracurium, or vancomycin can release histamine, producing vasodilation and urticaria along the vein of administration.(18) Although the cardiovascular effects of histamine release can be treated effectively withintravascular volume administration and/or catecholamines, the responses in different individuals may vary.(1) Thenewer neuromuscular blocking agents (e.g., rocuronium and cisatracurium) are devoid of histamine releasing effects but can produce direct vasodilation and false-positive cutaneous
 
responses that can confuse allergy testing andinterpretation.(22,23) The mechanisms involved in nonimmunologic histamine release represent degranulation of mast cells but not basophils via cellular activation and stimulation of phospholipase activity in mast cells. (19)
TREATMENT PLAN
 Most anesthetic drugs and agents administered perioperatively have been reported in the literature to produceanaphylaxis.(1) Therefore, a plan for the treatment of anaphylactic reactions must be established before theevent.(1) Airway maintenance, 100% oxygen administration, intravascular volume expansion, and epinephrine areessential to treat the hypotension and hypoxia that results from vasodilation, increased capillary permeability, and bronchospasm. (6-9,24-26) Table 1 lists a protocol for management of anaphylaxis during general anesthesia, withrepresentative doses for a 70-kilogram adult. Therapy must be titrated to desired effects with careful monitoring.Severe reactions require aggressive therapy. The route of administration of epinephrine and the dose depends on the patient's condition. (1)Rapid and timely intervention with common sense must be utilized to treat anaphylaxis effectively.(27)Reactions may be protracted with persistent hypotension, pulmonary hypertension and right ventricular dysfunction,lower respiratory obstruction, or laryngeal obstruction that persist 5 to 32 hours despite vigorous therapy.(24) Noveltherapeutic approaches for anaphylactic shock and/or right ventricular failure are currently under investigation.(28-30) During general anesthesia patients may have altered sympathoadrenergic responses to acute anaphylactic shock.In addition, the patient during spinal or epidural anesthesia may be partially sympathectomized, needing earlier intervention with even larger doses of epinephrine and other catecholamines.(27)Additional hemodynamic monitoring including radial and pulmonary artery catheterization may be neededwhen hypotension persists despite therapeutic interventions as listed. When available, the use of echocardiography,either transesophageal in an intubated patient, or transthoracic can be useful in diagnosing the cause of acute or  persistent cardiovascular dysfunction. All patients following anaphylactic reaction should receive corticosteroids,and be admitted to an intensive care unit or other similar setting for an observational time as they may developrecurrence of manifestations following successful treatment. (1) Based on the efficacy of vasopressin invasodilatory shock, it should also be considered in therapy of anaphylactic shock not responding to therapy (8,29).Table 1.
Management of anaphylaxis
 Initial therapy1. STOP ADMINISTRATION OF ANTIGEN2. MAINTAIN AIRWAY WITH 100% OXYGEN3. DISCONTINUE ALL ANESTHETIC AGENTS4. START INTRAVASCULAR VOLUME EXPANSION5. GIVE EPINEPHRINE (5-10 mcg IV initial bolus with hypotension, titrate as needed; 0.1 to 0.5 mg IV withcardiovascular collapse)
of 00

Leave a Comment

You must be to leave a comment.
Submit
Characters: ...
You must be to leave a comment.
Submit
Characters: ...