【分享】Anaphylaxis and Adverse Drug Reactions
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Anaphylaxis and Adverse Drug Reactions
Levy, Jerrold H M.D.
From: Levy: ASA Refresher Courses in Anesthesiology, Volume 33(1).2005.155-163
Any substance that patients are exposed to in the perioperative period, including drugs, blood products, or environmental antigens such as latex, can produce anaphylaxis. All of these 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 in fact represent different immune and nonimmune responses.1 There is confusion in the literature about the term anaphylaxis, and a multitude of descriptive terminologies have been reported to describe the spectrum of reactions. Based on current concepts, anaphylaxis is best defined as a clinical syndrome characterized by acute cardiopulmonary collapse after antigen (foreign substance) exposure. This Refresher Course defines the spectrum of anaphylactic and adverse drug reactions an anesthesiologist may encounter.
Adverse Drug Reactions
Adverse drug reactions are common; however, only 6% to 10% are immunologically mediated.2 Although some drug-induced allergic reactions may be classified into one of the four Gell and Coombs hypersensitivity categories, many others cannot be classified because of our lack of mechanistic information. Theoretically, any drug can induce an immune response.1–4 However, some drugs are more likely to elicit clinically relevant immune responses than are others. 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 (for example, opioid-related nausea). However, some drugs have direct effects on inflammatory cells (for example, drug-mediated histamine release from mast cells or biologic response modifiers). Unfortunately, patients often refer to any adverse drug effects as being allergic in nature. Anesthetic drugs also have the potential to produce direct effects on the cardiovascular system (for example, propofol-induced vasodilation) complicating the diagnosis of perioperative adverse drug reactions. Unlike most adverse 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-threatening responses.1
Life-threatening Allergic Reactions (Anaphylaxis)
Because any parenterally administered agent can cause death from anaphylaxis, anesthesiologists must diagnose and treat the acute cardiopulmonary changes that can occur. Recent studies from Europe suggest that perioperative drug-induced anaphylaxis may be increasing. 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 after a second challenge with a foreign antigen.5 When life-threatening allergic reactions mediated by antibodies or immune mechanisms occur, they are defined as “anaphylaxis.” Multiple other terms are used in the literature to describe life-threatening reactions that are not immune-mediated. Through the years, these terms have created major confusion because one cannot distinguish the etiology of reactions based on clinical observation. Much of the confusion about anaphylaxis in the literature is because many older anesthetic agents could directly degranulate mast cells.
Pathophysiology of Anaphylaxis
Antigen binding to IgE antibodies initiates 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 the respiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria in the cutaneous system.1 Cardiovascular collapse during anaphylaxis results from the effects of multiple mediators on the heart and vasculature.6–9 The vasodilation seen clinically can result from a spectrum of different mediators that interact with vascular endothelium and/or vascular smooth muscle.1,8
Vasodilatory Shock and Anaphylaxis
Vasodilatory shock occurs in anaphylaxis resulting from multiple mechanisms, including the excessive activation of vasodilator mechanisms, including unregulated nitric oxide synthesis that activates soluble guanylate cyclase and produces cGMP, and prostacyclin synthesis that activates soluble adenylate cyclase and produces cAMP, both causing dephosphorylation of myosin and hence vasorelaxation.1,8 Nitric oxide synthesis and metabolic acidosis activate the potassium channels in vascular smooth muscle. The resulting vascular hyperpolarization prevents calcium from entering the cell. Hypotension and vasodilatation persist, despite catecholamine therapy.10 Other mediators that are released by non-IgE mechanisms may also produce shock by different mechanisms (for example, protamine induced acute pulmonary vasoconstriction) are 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 in a sensitized individual usually produces immediate clinical manifestations of anaphylaxis, but the onset may be delayed 2 to 20 minutes.3,6,9 Individuals vary in the manifestations and course of anaphylaxis because of exposure (oral versus parenteral). A spectrum of reactions exists, ranging from minor clinical changes to acute cardiopulmonary collapse, leading to death 1 (Table 1). The enigma of anaphylaxis is the unpredictability of occurrence, the severity of the attack, and the lack of an allergic history.1
Table 1. Recognition of Anaphylaxis during Anesthesia
--------------------------------------------------------------------------------
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) activation can occur after complement activation by immunologic (antibody-mediated: IgM, IgG–antigen activation) or nonimmunologic (heparin–protamine, endotoxin, cardiopulmonary bypass) pathways.11–14 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. In addition, C5a interacts with specific high-affinity receptors on white blood cells and platelets, causing leukocyte chemotaxis, aggregation, and activation.13 Aggregated leukocytes embolize to various organs producing microvascular occlusion and liberation of inflammatory products, including oxygen-free radicals, lysosomal enzymes, and arachidonic acid metabolites (that is, prostaglandins and leukotrienes). Antibodies of the IgG class directed against antigenic determinants or granulocyte surfaces can also produce leukocyte aggregation.15 These antibodies are called leukoagglutinins. Investigators have associated polymorphonuclear leukocyte activation in producing the clinical manifestations of transfusion reactions,15 pulmonary vasoconstriction after protamine reactions,16 and transfusion-related acute lung injury (TRALI).17 Studies currently are examining the potential of C5a inhibition by monoclonal antibodies (Pexelizumab; Alexion Pharmaceuticals Inc., Cheshire, CT) to prevent the adverse effects of complement generation in perioperative settings, and other complement inhibiting strategies are being developed.
Nonimmunologic Release of Histamine
Many diverse molecular structures administered during the perioperative period degranulate mast cells to release 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 with intravascular volume administration and/or catecholamines, the responses in different individuals may vary.1 The newer neuromuscular-blocking agents (for example, rocuronium and cisatracurium) are devoid of histamine-releasing effects but can produce direct vasodilation and false-positive cutaneous responses that can confuse allergy testing and interpretation.22,23 The mechanisms involved in nonimmunologic histamine release represent degranulation of mast cells but not basophils through 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 produce anaphylaxis.1 Therefore, a plan for the treatment of anaphylactic reactions must be established before the event.1 Airway maintenance, 100% oxygen administration, intravascular volume expansion, and epinephrine are essential to treat the hypotension and hypoxia that results from vasodilation, increased capillary permeability, and bronchospasm 6–9,24–26 Table 2 lists a protocol for management of anaphylaxis during general anesthesia, with representative doses for a 70-kg 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 used 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 Novel therapeutic 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 needed when hypotension persists despite therapeutic interventions as listed. When available, the use of transesophageal echocardiography in an intubated patient can be useful in diagnosing the cause of acute or persistent cardiovascular dysfunction. All patients after anaphylactic reaction should be admitted to an intensive care unit for 24 hours of monitoring because they may develop recurrence of manifestations after successful treatment.1 Based on the efficacy of vasopressin in vasodilatory shock, it should also be considered in the treatment of anaphylactic shock not responding to more traditional therapy.8,29
Table 2. Management of Anaphylaxis
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Pretreatment for Allergic Reactions
The anesthesia literature suggests life-threatening hypersensitivity reactions are more likely to occur in patients with a history of allergy, atopy, or asthma. However, this does not make it mandatory to pretreat these patients with antihistamines and/or corticosteroids. There is no data in the literature to suggest that pretreatment is effective for true anaphylactic reactions. Most of the literature on pretreatment is from studies evaluating patients with previous radiocontrast media reactions that are nonimmunologic mechanisms. Although attempts to pretreat patients for anaphylaxis to latex are growing in clinical practice, there is no data to support this as an effective preventative measure. In fact, pretreatment may lull physicians into a false sense of security. Furthermore, even when large doses of corticosteroids have been administered, life-threatening anaphylactic reactions have occurred.1,25
Management of the Allergic Patient
Patients presenting with an allergic history need to be carefully evaluated. Often, patients will complain of allergy when the reaction was a predictable adverse drug reaction. However, for practical and medicolegal purposes, that class of drug should be avoided when the history or records are consistent with an allergic reaction and preservative-free alternatives should be chosen. The problem occurs whenever multiple drugs are simultaneously administered or when patients present with muscle-relaxant reactions because of the risk of crossreactivity to the bisquaternary ammonium ions in the molecule. In this situation, skin testing may be required to see what can be administered safely.1
Epidemiology of Anaphylaxis: Agents Implicated
Many agents administered in the perioperative period have the potential to produce allergic reactions on reexposure. However, the agents most often reported to cause a perioperative anaphylactic reaction are antibiotics, blood products, latex (rubber), muscle relaxants, and polypeptides (protamine or aprotinin). A recent epidemiologic study reported from 1999 to 2001 from France reported 789 reactions.31 Anaphylaxis, diagnosed on the basis of clinical history, skin tests, and/or specific immunoglobulin E assay, was found in 518 cases (66%) and nonimmune reactions in 271 cases (34%). The most common causes of anaphylaxis were neuromuscular-blocking agents (NMBAs) (n = 306, 58.2%), latex (n = 88, 16.7%), and antibiotics (n = 79, 15.1%). Rocuronium (n = 132, 43.1%) and succinylcholine (n = 69, 22.6%) were the most frequently incriminated NMBAs. The positive predictive value of tryptase for the diagnosis of anaphylaxis was 92.6%; the negative predictive value was 54.3%.
Latex Allergy
Latex represents an environmental agent often implicated as an important cause of perioperative anaphylaxis. Healthcare workers, children with spina bifida and urogenital abnormalities, and certain food allergies have also been recognized as individuals at increased risk for anaphylaxis to latex.31–36 Brown reported a 24% incidence of irritant or contact dermatitis and a 12.5% incidence of latex-specific IgE positivity in anesthesiologists.34 Of this group, 10% were clinically asymptomatic although IgE-positive. A history of atopy was also a significant risk factor for latex sensitization. Brown suggests these individuals are in their early stages of sensitization and perhaps, by avoiding latex exposure, their progression to symptomatic disease can be prevented.34 Patients allergic to both tropical fruits (for example, bananas, avocados, and kiwis) and stone fruits have also been reported to have antibodies that crossreact with latex.35–37 Multiple attempts are being made to reduce latex exposure to both healthcare workers and patients. If latex allergy occurs, then strict avoidance of latex from gloves and other sources needs to be considered following recommendations as reported by Holzman.33 Because latex is such a widespread environmental antigen, this represents a daunting task. Despite recognizing latex anaphylaxis, multiple other agents, including antibiotics, induction agents, muscle relaxants, nonsteroidal antiinflammatory drugs, protamine, colloid volume expanders, and blood products represent additional etiologic agents often responsible for anaphylaxis in surgical patients.1
Neuromuscular-Blocking Agents
NMBAs have several unique molecular features that make them potential allergens. All NMBAs are functionally divalent and are thus capable of crosslinking cell-surface IgE and initiating mediator release from mast cells and basophils without binding or haptenizing to larger carrier molecules.1 NMBAs have also been implicated in epidemiologic studies of anesthetic drug-induced anaphylaxis.38–40 Epidemiologic data from France suggest that NMBAs are responsible for 62% to 81% of reactions, depending on the time period evaluated.31,38 Rocuronium is currently the NMBA most reported from France. We and others have reported previously that aminosteroidal compounds as well as benzylisoquinoline-derived agents produce positive weal and flare responses when injected intradermally.19,22,42 Estimates of anaphylactic reactions in anesthesia vary, but data suggests that false-positive skin tests may overestimate the incidence of rocuronium-induced anaphylactic reactions.19,22,41,42 The differences noted in the incidence of reactions may reflect the potential for false-positive weal and flare responses.41,42 NMBAs can also produce direct vasodilation by multiple mechanisms, which include calcium channel blockade. The false-positive skin tests that were reported to be biopsy-negative for mast cell degranulation clearly confound interpreting skin tests in patients who have had life-threatening cardiopulmonary collapse. Dilute solutions of NMBAs need to be used when skin testing for potential allergic reactions to these agents. However, the exact concentration that should be used is unclear. Because skin-testing procedures are important in evaluating potential drug allergies, the threshold for direct vasodilating and false-positive effects must be determined whenever subjects are skin-tested for a particular drug.
Polypeptides and Blood Products
Polypeptides are larger molecular-weight molecules that pose greater potential to be antigenic and include aprotinin, latex, and protamine. Diabetic patients receiving protamine containing insulin as neutral protamine Hagedorn (NPH) or protamine insulin have a 10- to 30-fold increased risk for anaphylactic reactions to protamine when used for heparin reversal, with an absolute risk of 0.6% to 2% in this patient population.25,26 Because protamine is often administered concomitantly with blood products, prot-amine is often implicated as the causative agent in adverse reactions, especially in cardiac surgical patients. Platelet and other allogeneic blood transfusions can produce a series of adverse reactions by multiple mechanisms, and blood products have a greater potential for allergic reactions compared with protamine.1 Although antigen avoidance is one of the most important considerations in preventing anaphylaxis, this is not always possible, especially with certain agents in which alternatives are not available. Protamine is an important example of when alternatives are under investigation, but not currently available. Aprotinin, a bovine derived, ~6,512 dalton molecular weight protein used to reduce bleeding, has had anaphylactic reactions after reexposure for cardiac surgery.43 There were 248 reexposures to aprotinin in 240 patients: 101 adult and 147 pediatric cases. The time between the first and second aprotinin exposures was 344 (interquartile range 1,039) days, and seven reactions to aprotinin were reported (2.8%) that ranged from mild to severe. Patients with an interval less than 6 months since the previous exposure had a statistically higher incidence of adverse reactions than patients with a longer interval (five of 111 or 4.5% versus two of 137 or 1.5%, P < 0.05).43
Suggested web sites: AnaphylaxisWeb.com , Bronchospasm.com .
References
1. Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd ed. Stoneham: Butterworth-Heinemann Publishers; 1992.
2. Gruchalla RS: Drug allergy. J Allergy Clin Immunol 2002; 111(suppl):S548–59. Bibliographic Links
3. Kemp SF, Lockey RF: Anaphylaxis: A review of causes and mechanisms. J Allergy Clin Immunol 2002; 111(suppl):S548–59.
4. Porter J, Jick H: Drug-induced anaphylaxis, convulsions, deafness, and extrapyramidal symptoms. Lancet 1977; 1:587–8.
5. Portier MM, Richet C: De l'action anaphylactique de certains venins. C R Soc Biol 1902; 54:170–2. [Context Link]
6. Pumphrey RS, Roberts IS: Postmortem findings after fatal anaphylactic reactions. J Clin Pathol 2000; 53:273–6. Ovid Full Text Bibliographic Links [Context Link]
7. Prussin C, Metcalfe DD: IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2002; 111(suppl):S486–94. Bibliographic Links [Context Link]
8. Landry DW, Oliver JA: The pathogenesis of vasodilatory shock. N Engl J Med 2001; 345:588–95. [Context Link]
9. Delage C, Irey NS: Anaphylactic deaths: A clinicopathologic study of 43 cases. J Forensic Sci 1972; 17:525–40. Bibliographic Links [Context Link]
10. Levy JH: Cardiovascular changes during anaphylactic reactions in man. J Clin Anesth 1989; 1:426–30. Ovid Full Text Bibliographic Links [Context Link]
11. Levy JH, Tanaka KA: Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003; 75:S715–20. Ovid Full Text Bibliographic Links [Context Link]
12. MacGlashan D: Histamine: A mediator of inflammation. J Allergy Clin Immunol 2003; 112(suppl):S53–9. Bibliographic Links [Context Link]
13. Walport MJ: Complement. N Engl J Med 2001; 344:1058–66 (part 1); 344:1140–4 (part 2). [Context Link]
14. Jacob HS, Craddock PR, Hammerschmidt DE, Moldow CFR: Complement-induced granulocyte aggregation—An unsuspected mechanism of disease. N Engl J Med 1980; 302:789–94. Ovid Full Text Bibliographic Links [Context Link]
15. Kopko PM, Popovsky MA, MacKenzie MR, et al.: HLA class II antibodies in transfusion-related acute lung injury. Transfusion 2001; 41:1244–8. [Context Link]
16. Morel DR, Zapol WM, Thomas SJ, et al.: C5a and thromboxane generation association with pulmonary vaso- and broncho-constriction during protamine reversal of heparin. Anesthesiology 1987; 66:597–604. Bibliographic Links [Context Link]
17. Popovsky MA, Abel MD, Moore SB: Transfusion related acute lung injury associated with passive transfer of antileukocyte antibodies. Am Rev Respir Dis 1985; 128:185–9. Ovid Full Text Bibliographic Links [Context Link]
18. Levy JH, Brister NW, Shearin WA, et al.: Wheal and flare responses to opioids in humans. Anesthesiology 1989; 70:756–60. Ovid Full Text Bibliographic Links [Context Link]
19. Veien M, Szlam F, Holden JT, et al.: Mechanisms of nonimmunological histamine and tryptase release from human cutaneous mast cells. Anesthesiology 2000; 92:1074–81. Ovid Full Text Bibliographic Links [Context Link]
20. Levy JH, Adelson D, Walker B: Wheal and flare responses to muscle relaxants in humans. Agents Actions 1991; 34:302–8. [Context Link]
21. Levy JH, Kettlekamp N, Goertz P, Hermens J, Hirshman CA: Histamine release by vancomycin. A mechanism for hypotension in man. Anesthesiology 1987; 67:122–5. Ovid Full Text Bibliographic Links [Context Link]
22. Levy JH, Davis GK, Duggan J, Szlam F: Determination of the hemodynamics and histamine release of rocuronium (Org 9426) when administered in increased doses under N20/O2–sufentanil anesthesia. Anesth Analg 1994; 78:318–21. Bibliographic Links [Context Link]
23. Levy JH, Gottge M, Szlam F, Zaffer R, McCall C: Weal and flare responses to intradermal rocuronium and cisatracurium in humans. Br J Anaesth 2000; 85:844–9. Ovid Full Text Bibliographic Links [Context Link]
24. Lee JM, Greenes DS: Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000; 106:762–6. Bibliographic Links [Context Link]
25. Levy JH, Zaidan JR, Faraj B: Prospective evaluation of risk of protamine reactions in NPH insulin-dependent diabetics. Anesth Analg 1986; 65:739–42. [Context Link]
26. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weintraub WS: Evaluation of patients at risk for protamine reactions. J Thorac Cardiovasc Surg 1989; 98:200–4. Ovid Full Text Bibliographic Links [Context Link]
27. Caplan RA, Ward RJ, Posner K, Cheney FW: Unexpected cardiac arrest during spinal anesthesia: A closed claims analysis of predisposing factors. Anesthesiology 1988; 68:5–11. [Context Link]
28. Levy JH: New concepts in the treatment of anaphylactoid reactions. Ann Fr Anesth Reanim 1993; 12:223–7. Bibliographic Links [Context Link]
29. Tsuda A, Tanaka KA, Huraux C, et al.: The in vitro reversal of histamine-induced vasodilation in the human internal mammary artery. Anesth Analg 2001; 93:1453–9. Ovid Full Text Bibliographic Links [Context Link]
30. Huraux C, Makita T, Montes F, Szlam F, Levy JH: A comparative evaluation of the effects of multiple vasodilators on human internal mammary artery. Anesthesiology 1998; 88:1654–9. Ovid Full Text Bibliographic Links [Context Link]
31. Mertes PM, Laxenaire MC, Alla F, et al.: Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology 2003; 99:536–45. [Context Link]
32. Gold M et al: Intraoperative anaphylaxis: An association with latex sensitivity. J Allergy Clin Immunol 1991; 87:662–6. Ovid Full Text Bibliographic Links [Context Link]
33. Holzman RS: Latex allergy: An emerging operating room problem. Anesth Analg 1993; 76:635–41. Buy Now Bibliographic Links [Context Link]
34. Brown RH, Schauble JF, Hamilton RG: Prevalence of latex allergy among anesthesiologists: Identification of sensitized but asymptomatic individuals. Anesthesiology 1998; 89:292–9. Ovid Full Text Bibliographic Links [Context Link]
35. Lavaud F, Prevost A, Cossart C, et al.: Allergy to latex, avocado, pear, and banana: Evidence for a 30 kd antigen in immunoblotting. J Allergy Clin Immunol 1995; 95:557–64. Bibliographic Links [Context Link]
36. Blanco C, Carrillo T, Castillo R, et al.: Latex allergy: Clinical features and cross-reactivity with fruits. Ann Allergy 1994; 73:309–14. Bibliographic Links [Context Link]
37. Lebenbom-Mansour MH, Oesterle JR, Ownsby DR, et al.: The incidence of latex sensitivity in ambulatory surgical patients: A correlation of historical factors with positive serum immunoglobulin E levels. Anesth Analg 1997; 85:44–9. Ovid Full Text Bibliographic Links [Context Link]
38. Moneret-Vautrin DA, Mouton C: Anaphylaxie aux myorelaxants: valeur prédictive des intradermoréactions et recherche de l'anaphylaxie croisée. Ann Fr Anesth Réanim 1985; 4:186–91. Bibliographic Links [Context Link]
39. Fisher MM, Munro I: Life threatening, anaphylactoid reactions to muscle relaxants. Anesth Analg 1983; 62:559–64. Ovid Full Text Bibliographic Links [Context Link]
40. Laxenaire MC: Drugs and other agents involved in anaphylactic shock occurring during anaesthesia. A French multicenter epidemiological inquiry. Ann Fr Anesth Reanim 1993; 12:91–6. [Context Link]
41. Dhonneur G, Combes X, Chassard D, et al.: Skin sensitivity to rocuronium and vecuronium: a randomized controlled prick-testing study in healthy volunteers. Anesth Analg 2004; 98:986–9. Ovid Full Text Bibliographic Links [Context Link]
42. Levy JH: Anaphylactic reactions to neuromuscular blocking drugs: Are we making the correct diagnosis? Anesth Analg 2004; 98:881–2. Ovid Full Text Bibliographic Links [Context Link]
43. Dietrich W, Spaeth P, Ebell A, Richter JA: Incidence of anaphylactic reactions to aprotinin: Analysis of 248 reexposures to aprotinin. J Thorac Cardiovasc Surg 1997; 113:194–201. Bibliographic Links [Context Link]
Anaphylaxis and Adverse Drug Reactions
Levy, Jerrold H M.D.
From: Levy: ASA Refresher Courses in Anesthesiology, Volume 33(1).2005.155-163
Any substance that patients are exposed to in the perioperative period, including drugs, blood products, or environmental antigens such as latex, can produce anaphylaxis. All of these 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 in fact represent different immune and nonimmune responses.1 There is confusion in the literature about the term anaphylaxis, and a multitude of descriptive terminologies have been reported to describe the spectrum of reactions. Based on current concepts, anaphylaxis is best defined as a clinical syndrome characterized by acute cardiopulmonary collapse after antigen (foreign substance) exposure. This Refresher Course defines the spectrum of anaphylactic and adverse drug reactions an anesthesiologist may encounter.
Adverse Drug Reactions
Adverse drug reactions are common; however, only 6% to 10% are immunologically mediated.2 Although some drug-induced allergic reactions may be classified into one of the four Gell and Coombs hypersensitivity categories, many others cannot be classified because of our lack of mechanistic information. Theoretically, any drug can induce an immune response.1–4 However, some drugs are more likely to elicit clinically relevant immune responses than are others. 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 (for example, opioid-related nausea). However, some drugs have direct effects on inflammatory cells (for example, drug-mediated histamine release from mast cells or biologic response modifiers). Unfortunately, patients often refer to any adverse drug effects as being allergic in nature. Anesthetic drugs also have the potential to produce direct effects on the cardiovascular system (for example, propofol-induced vasodilation) complicating the diagnosis of perioperative adverse drug reactions. Unlike most adverse 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-threatening responses.1
Life-threatening Allergic Reactions (Anaphylaxis)
Because any parenterally administered agent can cause death from anaphylaxis, anesthesiologists must diagnose and treat the acute cardiopulmonary changes that can occur. Recent studies from Europe suggest that perioperative drug-induced anaphylaxis may be increasing. 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 after a second challenge with a foreign antigen.5 When life-threatening allergic reactions mediated by antibodies or immune mechanisms occur, they are defined as “anaphylaxis.” Multiple other terms are used in the literature to describe life-threatening reactions that are not immune-mediated. Through the years, these terms have created major confusion because one cannot distinguish the etiology of reactions based on clinical observation. Much of the confusion about anaphylaxis in the literature is because many older anesthetic agents could directly degranulate mast cells.
Pathophysiology of Anaphylaxis
Antigen binding to IgE antibodies initiates 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 the respiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria in the cutaneous system.1 Cardiovascular collapse during anaphylaxis results from the effects of multiple mediators on the heart and vasculature.6–9 The vasodilation seen clinically can result from a spectrum of different mediators that interact with vascular endothelium and/or vascular smooth muscle.1,8
Vasodilatory Shock and Anaphylaxis
Vasodilatory shock occurs in anaphylaxis resulting from multiple mechanisms, including the excessive activation of vasodilator mechanisms, including unregulated nitric oxide synthesis that activates soluble guanylate cyclase and produces cGMP, and prostacyclin synthesis that activates soluble adenylate cyclase and produces cAMP, both causing dephosphorylation of myosin and hence vasorelaxation.1,8 Nitric oxide synthesis and metabolic acidosis activate the potassium channels in vascular smooth muscle. The resulting vascular hyperpolarization prevents calcium from entering the cell. Hypotension and vasodilatation persist, despite catecholamine therapy.10 Other mediators that are released by non-IgE mechanisms may also produce shock by different mechanisms (for example, protamine induced acute pulmonary vasoconstriction) are 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 in a sensitized individual usually produces immediate clinical manifestations of anaphylaxis, but the onset may be delayed 2 to 20 minutes.3,6,9 Individuals vary in the manifestations and course of anaphylaxis because of exposure (oral versus parenteral). A spectrum of reactions exists, ranging from minor clinical changes to acute cardiopulmonary collapse, leading to death 1 (Table 1). The enigma of anaphylaxis is the unpredictability of occurrence, the severity of the attack, and the lack of an allergic history.1
Table 1. Recognition of Anaphylaxis during Anesthesia
--------------------------------------------------------------------------------
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) activation can occur after complement activation by immunologic (antibody-mediated: IgM, IgG–antigen activation) or nonimmunologic (heparin–protamine, endotoxin, cardiopulmonary bypass) pathways.11–14 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. In addition, C5a interacts with specific high-affinity receptors on white blood cells and platelets, causing leukocyte chemotaxis, aggregation, and activation.13 Aggregated leukocytes embolize to various organs producing microvascular occlusion and liberation of inflammatory products, including oxygen-free radicals, lysosomal enzymes, and arachidonic acid metabolites (that is, prostaglandins and leukotrienes). Antibodies of the IgG class directed against antigenic determinants or granulocyte surfaces can also produce leukocyte aggregation.15 These antibodies are called leukoagglutinins. Investigators have associated polymorphonuclear leukocyte activation in producing the clinical manifestations of transfusion reactions,15 pulmonary vasoconstriction after protamine reactions,16 and transfusion-related acute lung injury (TRALI).17 Studies currently are examining the potential of C5a inhibition by monoclonal antibodies (Pexelizumab; Alexion Pharmaceuticals Inc., Cheshire, CT) to prevent the adverse effects of complement generation in perioperative settings, and other complement inhibiting strategies are being developed.
Nonimmunologic Release of Histamine
Many diverse molecular structures administered during the perioperative period degranulate mast cells to release 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 with intravascular volume administration and/or catecholamines, the responses in different individuals may vary.1 The newer neuromuscular-blocking agents (for example, rocuronium and cisatracurium) are devoid of histamine-releasing effects but can produce direct vasodilation and false-positive cutaneous responses that can confuse allergy testing and interpretation.22,23 The mechanisms involved in nonimmunologic histamine release represent degranulation of mast cells but not basophils through 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 produce anaphylaxis.1 Therefore, a plan for the treatment of anaphylactic reactions must be established before the event.1 Airway maintenance, 100% oxygen administration, intravascular volume expansion, and epinephrine are essential to treat the hypotension and hypoxia that results from vasodilation, increased capillary permeability, and bronchospasm 6–9,24–26 Table 2 lists a protocol for management of anaphylaxis during general anesthesia, with representative doses for a 70-kg 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 used 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 Novel therapeutic 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 needed when hypotension persists despite therapeutic interventions as listed. When available, the use of transesophageal echocardiography in an intubated patient can be useful in diagnosing the cause of acute or persistent cardiovascular dysfunction. All patients after anaphylactic reaction should be admitted to an intensive care unit for 24 hours of monitoring because they may develop recurrence of manifestations after successful treatment.1 Based on the efficacy of vasopressin in vasodilatory shock, it should also be considered in the treatment of anaphylactic shock not responding to more traditional therapy.8,29
Table 2. Management of Anaphylaxis
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Pretreatment for Allergic Reactions
The anesthesia literature suggests life-threatening hypersensitivity reactions are more likely to occur in patients with a history of allergy, atopy, or asthma. However, this does not make it mandatory to pretreat these patients with antihistamines and/or corticosteroids. There is no data in the literature to suggest that pretreatment is effective for true anaphylactic reactions. Most of the literature on pretreatment is from studies evaluating patients with previous radiocontrast media reactions that are nonimmunologic mechanisms. Although attempts to pretreat patients for anaphylaxis to latex are growing in clinical practice, there is no data to support this as an effective preventative measure. In fact, pretreatment may lull physicians into a false sense of security. Furthermore, even when large doses of corticosteroids have been administered, life-threatening anaphylactic reactions have occurred.1,25
Management of the Allergic Patient
Patients presenting with an allergic history need to be carefully evaluated. Often, patients will complain of allergy when the reaction was a predictable adverse drug reaction. However, for practical and medicolegal purposes, that class of drug should be avoided when the history or records are consistent with an allergic reaction and preservative-free alternatives should be chosen. The problem occurs whenever multiple drugs are simultaneously administered or when patients present with muscle-relaxant reactions because of the risk of crossreactivity to the bisquaternary ammonium ions in the molecule. In this situation, skin testing may be required to see what can be administered safely.1
Epidemiology of Anaphylaxis: Agents Implicated
Many agents administered in the perioperative period have the potential to produce allergic reactions on reexposure. However, the agents most often reported to cause a perioperative anaphylactic reaction are antibiotics, blood products, latex (rubber), muscle relaxants, and polypeptides (protamine or aprotinin). A recent epidemiologic study reported from 1999 to 2001 from France reported 789 reactions.31 Anaphylaxis, diagnosed on the basis of clinical history, skin tests, and/or specific immunoglobulin E assay, was found in 518 cases (66%) and nonimmune reactions in 271 cases (34%). The most common causes of anaphylaxis were neuromuscular-blocking agents (NMBAs) (n = 306, 58.2%), latex (n = 88, 16.7%), and antibiotics (n = 79, 15.1%). Rocuronium (n = 132, 43.1%) and succinylcholine (n = 69, 22.6%) were the most frequently incriminated NMBAs. The positive predictive value of tryptase for the diagnosis of anaphylaxis was 92.6%; the negative predictive value was 54.3%.
Latex Allergy
Latex represents an environmental agent often implicated as an important cause of perioperative anaphylaxis. Healthcare workers, children with spina bifida and urogenital abnormalities, and certain food allergies have also been recognized as individuals at increased risk for anaphylaxis to latex.31–36 Brown reported a 24% incidence of irritant or contact dermatitis and a 12.5% incidence of latex-specific IgE positivity in anesthesiologists.34 Of this group, 10% were clinically asymptomatic although IgE-positive. A history of atopy was also a significant risk factor for latex sensitization. Brown suggests these individuals are in their early stages of sensitization and perhaps, by avoiding latex exposure, their progression to symptomatic disease can be prevented.34 Patients allergic to both tropical fruits (for example, bananas, avocados, and kiwis) and stone fruits have also been reported to have antibodies that crossreact with latex.35–37 Multiple attempts are being made to reduce latex exposure to both healthcare workers and patients. If latex allergy occurs, then strict avoidance of latex from gloves and other sources needs to be considered following recommendations as reported by Holzman.33 Because latex is such a widespread environmental antigen, this represents a daunting task. Despite recognizing latex anaphylaxis, multiple other agents, including antibiotics, induction agents, muscle relaxants, nonsteroidal antiinflammatory drugs, protamine, colloid volume expanders, and blood products represent additional etiologic agents often responsible for anaphylaxis in surgical patients.1
Neuromuscular-Blocking Agents
NMBAs have several unique molecular features that make them potential allergens. All NMBAs are functionally divalent and are thus capable of crosslinking cell-surface IgE and initiating mediator release from mast cells and basophils without binding or haptenizing to larger carrier molecules.1 NMBAs have also been implicated in epidemiologic studies of anesthetic drug-induced anaphylaxis.38–40 Epidemiologic data from France suggest that NMBAs are responsible for 62% to 81% of reactions, depending on the time period evaluated.31,38 Rocuronium is currently the NMBA most reported from France. We and others have reported previously that aminosteroidal compounds as well as benzylisoquinoline-derived agents produce positive weal and flare responses when injected intradermally.19,22,42 Estimates of anaphylactic reactions in anesthesia vary, but data suggests that false-positive skin tests may overestimate the incidence of rocuronium-induced anaphylactic reactions.19,22,41,42 The differences noted in the incidence of reactions may reflect the potential for false-positive weal and flare responses.41,42 NMBAs can also produce direct vasodilation by multiple mechanisms, which include calcium channel blockade. The false-positive skin tests that were reported to be biopsy-negative for mast cell degranulation clearly confound interpreting skin tests in patients who have had life-threatening cardiopulmonary collapse. Dilute solutions of NMBAs need to be used when skin testing for potential allergic reactions to these agents. However, the exact concentration that should be used is unclear. Because skin-testing procedures are important in evaluating potential drug allergies, the threshold for direct vasodilating and false-positive effects must be determined whenever subjects are skin-tested for a particular drug.
Polypeptides and Blood Products
Polypeptides are larger molecular-weight molecules that pose greater potential to be antigenic and include aprotinin, latex, and protamine. Diabetic patients receiving protamine containing insulin as neutral protamine Hagedorn (NPH) or protamine insulin have a 10- to 30-fold increased risk for anaphylactic reactions to protamine when used for heparin reversal, with an absolute risk of 0.6% to 2% in this patient population.25,26 Because protamine is often administered concomitantly with blood products, prot-amine is often implicated as the causative agent in adverse reactions, especially in cardiac surgical patients. Platelet and other allogeneic blood transfusions can produce a series of adverse reactions by multiple mechanisms, and blood products have a greater potential for allergic reactions compared with protamine.1 Although antigen avoidance is one of the most important considerations in preventing anaphylaxis, this is not always possible, especially with certain agents in which alternatives are not available. Protamine is an important example of when alternatives are under investigation, but not currently available. Aprotinin, a bovine derived, ~6,512 dalton molecular weight protein used to reduce bleeding, has had anaphylactic reactions after reexposure for cardiac surgery.43 There were 248 reexposures to aprotinin in 240 patients: 101 adult and 147 pediatric cases. The time between the first and second aprotinin exposures was 344 (interquartile range 1,039) days, and seven reactions to aprotinin were reported (2.8%) that ranged from mild to severe. Patients with an interval less than 6 months since the previous exposure had a statistically higher incidence of adverse reactions than patients with a longer interval (five of 111 or 4.5% versus two of 137 or 1.5%, P < 0.05).43
Suggested web sites: AnaphylaxisWeb.com , Bronchospasm.com .
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