II ALLERGIC REACTIONS IN ANAESTHESIA A. Criado *, A. Seiz *, JR. Ortiz ** * Department of Anesthesiology and Reanimation. Hospital Universitario "La Paz". Madrid.

** Department of Anesthesiology and Reanimation. Clínica Universitaria de Navarra. Pamplona. INTRODUCTION Anesthesiology delivers a special drug in the practice of medicine. Most drugs used are non-therapeutic, potentially lethal and have a margin or th erapeutic index / toxic narrow. In addition, they all have a potential to cause adverse reactions. Many of the drugs used in anesthesia, other than inhalation a gents can induce histamine release and be responsible for allergic reactions. Th ese responses may be due to an adverse drug reaction (anaphylactoid reaction), o r an immune mechanism mediated by IgE antibodies, which require prior exposure t o the molecule responsible for the sensitization (anaphylactic reaction). Clinic ally the most important mediator in anaphylactoid reactions is histamine, while the true anaphylactic reactions, the contact of the sensitizer molecule (hapten) with IgE antibodies formed by previous exposure, can trigger a large release of mediators (leucotrienios , prostaglandins, serotonin, etc.).. Anaphylactic reac tions are usually the most severe and serious (1). The incidence of severe aller gic reactions in anesthesia is 1/3.500 anesthesia with a mortality of 5-6%. 60% are anaphylactic. Its diagnosis can only be done by immunoallergic studies (2,3) . 19 A. Criado, A. Seiz, JR. Ortiz DRUG REACTIONS Adverse reactions The risk of an adverse reaction is an inevitabl e consequence of the proper administration of the drug. Some studies show that u p to 30% of medical patients admitted, develop some type of adverse drug reactio n during their hospitalization. These adverse reactions in 80% of cases are pred ictable, and are due to action of the drug itself. They tend to be dose-dependen t and correspond with the side effects described for each drug. Allergic reactio ns account for 20% of drug reactions. Usually are not predictable, nor are dosedependent, or associated with the pharmacological action of the drug. They are u sually related to an individual's immune response. When the allergic reaction is called antibody-mediated anaphylactic. When antibodies are not responsible for the reaction or may not be shown are known as anaphylactoid. Clinically it is im possible to distinguish the two reactions and the diagnosis must be made in immu noallergic techniques. According to these criteria, allergic reactions are class ified as anaphylactic reactions and IgE-mediated anaphylactoid reactions not med iated by IgE (leukocyte activation, release of histamine). IgE anaphylactic reac tion is required prior contact of antigen with the body, causing sensitization w ith IgE antibody production that will be located in mast cells and basophilic ce lls. In a subsequent contact Ag-Ab complex causes leukocyte activation with rele ase of histamine and numerous chemical mediators (leucotrienios, prostaglandins, kinins, etc..) From the granules of mast cells and basophils develop anaphylact ic table. The severity and onset of symptoms is related to the specificity of th e mediators in the target organs (cardiovascular, pulmonary and cutaneous). Ther e are individual variations in clinical manifestations and severity of anaphylax is. Allergic reactions are not IgE mediated Some mechanisms can trigger release of mediators and cause similar clinical symptoms to anaphylactic: * Activation o f neutrophil leukocytes may occur through the activation of complement by immune mechanism (IgM, IgG) or non-immunological (endotoxins , heparin-protamine compl ex, etc.).. The fractions of complement C3 and C5, also known as anaphylatoxins, are capable, when activated, to cause the release of histamine from mast cells and basophilic cells that produce increased 20

Allergic reactions in anesthesia capillary permeability and smooth muscle contraction. The fraction C5a causes ac tivation and aggregation of leukocytes and platelets, which aggregate trigger re lease of various mediators. These mechanisms have been attributed to reactions t o transfusions and protamine.€* Histamine release by non-immune Many drugs admin istered perioperatively release histamine in relation to dose and without the in volvement of immunological mechanisms. Have been implicated in the onset of degr anulation of mast cells without activation of basophils and the participation of some opioid receptors. The administration of morphine, atracurium, and vancomyc in can release histamine producing vasodilation and urticaria along the vein adm inistered. Effect on outpatient anesthesia up to 10% of patients will complain of any aller gies to any drug and are particularly attributed to antibiotics (40-50%) and pai n (15-25%). Only 10% is referred to anesthetics. However, Allergy studies perfor med in these patients, indicate that most of the pictures described are due to a dverse drug reactions and that only 3-10% are true allergic reactions (4-12). Pr obably the incidence of allergic reactions in anesthesia is the 0.5-2% and in se vere anaphylactic frame 1/3.000 to 1/10.000 anesthesia (1,12). There are predisp osing factors that increase the risk of anaphylactic reactions (Table I). Table I Risk factors for allergic Age between 30-50 years Females: 4:1 History o f atopy States hiperansiedad Repeated exposure to allergens 1. Age: more common in young people between 30-50 years. Are less common in chil dren because of the immaturity of the immune system and the lower probability of previous exposures. 2. Sex: they are four times more common in women than in me n, perhaps because of increased exposure to allergens (dyes, detergents, rubber gloves, etc.).. 3. History of atopy (asthma, hay fever, food allergy, etc.).. 4. Anxiety states. 5. Repeated exposure to drugs or allergens, especially with int ervals of more than two weeks. 21 A. Criado, A. Seiz, JR. Ortiz In any case, in these risk groups there is no indication of Allergy exhaustive s tudies, provocation test, even prophylaxis against the risk of possible reaction s not found. There are factors or situations when the allergic reaction associat ed with increasing severity, as in patients treated with beta-blockers, reaction s in the course of an epi or spinal anesthesia for sympathetic blockade added, a nd bronchial asthma in which unreasonably increases the degree of bronchospasm. Virtually all drugs used in anesthesia, both anesthetics, and other common use ( antibiotics, colloids, blood products, latex, etc..) Have been implicated in all ergic reactions (Tables II and III). In these reactions, 30% were anaphylactic ( specific IgE-mediated), 45% is non-specific histaminoliberación and 25% did not identify the mechanism (11). Table II allergic reactions in anesthesia. Epidemiological study in France (Laxe naire2) 1984-9 muscle relaxing agent Latex Colloids Antibiotics Other Opioids Hy pnotics n = 821 81% 0.5 11 3 0.5 2 2 1990-1 n = 813 70% 12.5 6 1.7 4 6 2.6 2.6 n = 1030 1992-3 60% 19 8 3.5 5 3.1 1.4 Table III Muscle relaxants and suxamethonium anaphylaxis Atracurium Vecuronium Pancuronium alcuronium 42% 23% 21% 8% 6% The highest incidence of allergic reactions xants (60%), especially when suxamethonium, its distribution is due to the frequency of -sensitivity between relaxants in 60-80% of to anesthetics is due to muscle rela atracurium and vecuronium, although use of each. It has been found cross patients due to their common chemica

l structure of the ammonium ion. Many cosmetics, detergents, dyes and quaternary ammonium compounds have in their composition and can act as sensitizers, which explains anaphylactic reactions at first exposure to muscle relaxants and their greater incidence in women (6,12,15,16). Among the barbiturates have been observ ed cross-reactivity between them and the previous exposure is a predisposing fac tor. 22 Allergic reactions in anesthesia Allergy to local anesthetics has been described for the ester group (procaine), but are exceptional for the amide group (lidocaine and bupivacaine MEPI). Its in cidence is very low (0.5%) and sometimes the reactions have been attributed to p reservatives and additives (methylparaben and metabisulfite). There is no crossreactivity between both groups (10-17). The incidence of latex allergy has incre ased in recent years especially in people with chronic history of contact with m aterials that have latex in patients with multiple interventions (spina bifida a nd genitourinary malformations) among health workers and between workers of oper ating rooms rubber (18-20).€Should always be suspected in patients reporting all ergies to fruits (chestnut, banana, kiwi, avocado) or contact dermatitis to rubb er products. Its real incidence is underestimated, because many of its clinical intraoperative go unnoticed or undiagnosed. CLINICAL clinical symptoms is often independent of the reaction mechanism, altho ugh anaphylactic reactions (IgE immunologic mechanism) does not depend on the do se administered, and the reaction can become self-perpetuating indicating greate r amount of adrenaline to block the activation circle of mediators. Anaphylactoi d reactions tend to be self-limiting (the cessation of administration of the ant igen), the short half-life of histamine. Symptoms usually appear within minutes of drug administration. When there are more late in the maintenance phase of ane sthesia, we must suspect a reaction to latex. Some reactions have been described at the end of orthopedic surgery after the release of the tourniquet and are du e to the antibiotics used to disinfect the wound. The first signs of anaphylaxis occur in areas with higher concentrations of mast cells, as in skin and mucous membranes, lungs, cardiovascular system and digestive tract. Muco-cutaneous sign s appear in 70% of reactions, the involvement circulatory (hypotension and tachy cardia) in 85% and 35% bronchospasm. In less severe forms predominantly hypotens ion and tachycardia with cutaneous preferably in the chest, but can be generaliz ed quickly. In severe forms can be triggered an anaphylactic shock box where mor tality is 5-6% (7,11,13,14). Generally, with the administration of epinephrine, reverts to the clinic after 1 hour without sequelae, but in some cases the shock is refractory to epinephrine, especially in patients treated with beta-blockers , requiring significant time infusion of fluids and high doses of adrenaline. Pr ogress will depend on how early and effectiveness of treatment initiated. The cl inical signs of hypotension, tachycardia, laryngospasm can persist for hours des pite treatment. Anaphylactic shock can be replayed within 24 hours to 20% of pat ients, so it must remain guarded in a reanimation unit. 23 A. Criado, A. Seiz, JR. Ortiz DIAGNOSIS (Table IV) Table IV diagnostic Guideline IMMEDIATE anaphylaxis XXXX XX 1 TIME 6-8 WEEKS Serum tryptase, plasma histamine Metilhistamlna urinary specific IgE skin tests Ac X X The first objective is to show the mechanism involved in the reaction, confirmin

g a diagnosis of anaphylaxis, by evidence confirming the degranulation of mast c ells. Basically we measured: 1. Serum tryptase. It is a protease present in mast cells is higher after degranulation, reaches the peak hour, decreased at 10 hou rs and returned to baseline levels (<1 ng / ml) at 24 hours of the reaction. It is also detectable postmortem. 2. Plasma histamine. It stands at 5 minutes of re action and goes quickly to 15 to 20 minutes, except when the shock is severe, si nce their metabolism is slowed. Concentrations above 100 ng / ml suggest a diagn osis of allergic reaction. 3. Metilhistamina urine. It is the main metabolite of histamine. It is detected in the first void and remains elevated at 24 h of rea ction. It is a good indicator of histamine release in plasma. In case you can no t make these determinations must immediately freeze samples of serum, plasma and urine at -20 ° C, for further studies. The second objective is to identify diag nostic agents responsible. This study was performed delayed 6-8 weeks by: 1. Tit ration of specific IgE. This is done by radioimmunoassay (RAST) incubating patie nt sera with IgE antibodies on a solid phase fixed leading cause of potential an tigens. There are currently marketed for muscle relaxants kit, latex, thiopental , propofol, morphine, pethidine, protamine, gelatin and antibiotics. This test h as a high sensitivity and specificity and correlates well with skin tests. 2. Sk in tests. Should be performed on non-pigmented skin and next to the target subst ance, it makes a positive control with histamine and negative saline. The readin g was performed at 15 minutes. Usually performed two types of tests: a) Prick te st. It consists of inoculating the undiluted drug in the forearm. It is consider ed positive when the edema of the skin is> 2 mm or more than 50% of positive con trol.€When epidermal puncture allergen does not pass into the bloodstream, there being no risk of anaphylaxis or sensitization. b) skin test. Is usually done in the back by intradermal injection of 0.05 to 1 ml of various dilutions of the s ubstance or drug. It conside24 Allergic reactions in anesthesia ra positive a wheal> 9 mm. There may be false positives with histamine-releasing drugs. Skin tests can identify the causative agent in 75-90% of cases. The sens itivity to muscle relaxants is up 98%. Challenge tests are almost discouraged, e xcept for local anesthetics (1,12,17). Allergy diagnosis always has a core suppo rt in the medical record in the sequence of events and their causality. The test s in vivo or in vitro used to confirm clinical diagnoses. In all cases, patients must provide a full report of the officers responsible, the type of reaction an d alternative or safe drugs. Initial treatment should be aimed at identifying the responsible agent (anesthet ic, colloids, blood, latex, etc..), To suppress his administration and stabilize the cardiovascular and respiratory symptoms. (Table V). Table V INITIAL identify and suppress antigen administration Maintain airway and 100% O2 expansion volume (2-4 L crystalloid if hypotension) Adrenaline: 5-10 mg bolus if hypotension 0.1-0.5 mg iv if cardiovascular collapse anesthetic agents SECONDARY Remove from 0.25 to 1 g of hydrocortisone methylprednisolone 1-2 g of bicarbonate (0.5-1 mEq / kg) hypotension and acidosis adrenaline infusion: 0.1 to 1 mg / kg / min effect as bronchodilators: aminophylline iv and / or salbutam ol aerosol Antihistamines: 0.5-1 mg / kg diphenhydramine assess airway after ext ubation Corticosteroids: Treatment of anaphylactic reaction The volume replacement should be fast and energetic (crystalloids and colloids) to offset the sharp drop in peripheral vascular resistance. Place the patient in Trendelenburg position may facilitate venous return. Epinephrine is the drug of choice for the treatment of hypotension, bronchospasm and angioedema. Occasiona lly when the shock is refractory associate is needed infusion of noradrenaline ( 0.1-1 mg / kg / min) to preserve cerebral and coronary risk. Patients with sympa thetic blockade by epi or spinal anesthesia, require for their control, very hig h doses of catecholamines and aggressive replacement of blood volume. 25

A. Criado, A. Seiz, JR. Ortiz Arrhythmias are usually secondary to hypoxemia, hypercapnia, catecholamine treat ment or the presence of a cardiopathy. Your treatment will be symptomatic, attem pting to eliminate the triggers and the most appropriate antiarrhythmic. Calcium antagonists may be indicated by its antagonistic effect of arrhythmias caused b y histamine. Bronchospasm can be a complication difficult to treat if not improv ed with adrenaline. Salbutamol and aminophylline are used, halogenated anestheti c agents be a good therapeutic alternative. Corticosteroids, although perhaps in the acute phase are not too effective, they have very useful to inhibit the lat e components of the reaction. Occasionally some signs and symptoms such as hypot ension, right ventricular dysfunction, pulmonary hypertension, airway obstructio n and stridor persist for 5-30 hours while maintaining treatment. Recurrences ma y also occur, so it is advisable to maintain surveillance of these patients at l east 24 hours in the reanimation unit (1.2 l). PROPHYLAXIS IN PATIENTS ALLERGIC The only really effective measure to prevent an anaphylactic reaction in allergic patients is to avoid contact with the offendi ng agent, hence the importance of a careful history to exclude previous reaction s, or to investigate cross-allergies in patients with intolerance to cosmetics, dyes, detergents, and certain fruits. It is very important to distinguish previo us allergic reactions to certain drugs intolerance which reflect their own pharm acological effects or side effects. Serious hypersensitivity reactions occur mor e frequently in patients with a history of allergy, atopy or bronchial asthma, h owever, has been shown that premedication with corticosteroids in these patients is not effective to prevent the possible occurrence of perioperative anaphylact ic reactions. The preparation with steroids and antihistamine, is used in patien ts allergic to complement activating substances or histamine-releasing, as with iodinated contrast.€It has also been recommended for patients with latex allergy because of the difficulty in the operating room to ensure an environment free o f this allergen, despite the precautions are taken. Because latex allergy has in creased in recent years, it is recommended to always have special equipment avai lable in the surgical area of material including: circuit respirator, gloves, tr acheal tubes, masks, serums systems, syringes, nasogastric tubes and bladder pre ssure cuffs Stethoscopes and containing no latex in its composition, and avoid a ny medication or multidose vial with a rubber stopper sera that should be tapped . Drug prophylaxis (Table VI) may give a false sense of security, and that has n ot been proven to prevent the occurrence of intraoperative anaphylaxis (22). In diabetic patients receiving insulin-protamine (NPH), have a risk of 10-30 26 Allergic reactions in anesthesia Table VI Preoperative prophylaxis in patients at risk allergic Diphenhydramine Ranitidine Prednisone 1-2 mg/kg/24 h (three doses) 4 mg/kg/24 h (4 doses) 3 mg / kg / 24 h (3 doses) Start prophylaxis prophylaxis 24 hours before 24 hours postoperatively Continue anaphylactic reaction times when given protamine to reverse heparin. However, th e incidence of severe reactions less than 2% (23). Antihistamines are advisable to prevent the release of histamine, but do not prevent anaphylactic reactions A g-Ab immune. Currently there are no effective drugs to prevent the synthesis of histamine, but the cromoglicolato sodium (Intal ®) inhibits mast cell degranulat ion. The most effective are antihistamines that block H1 receptors (Atarax ®, Tr iludan ® and Hismanal ®). The use of anti H2 (cimetidine or ranitidine) is more controversial because of its effects bronchial and by inhibition of hepatic micr

osomal enzyme system. In hiperansiedad states that favor the release of histamin e, we recommend adequate premedication with benzodiazepines. Prophylaxis with co rticosteroids is controversial. Only commonly used in allergy to iodinated contr ast media and occasionally to latex. In patients at risk should be preferred his taminoliberación inhalants and anesthetics less histamine (Table VII). Table VII Halogenated inhalational anesthetics bit histaminoliberadores Hypnotic s: etomidate, propofol and benzodiazepines morphine: fentanyl and alfentanil Neu roleptics: droperidol relaxants: vecuronium and pancuronium amide local anesthet ics: lidocaine and bupivacaine Locoregional anesthetic techniques are a good alternative for patients allergic to or predisposing factors. Epidural anesthesia has been recommended in combinat ion with general, interventions that require muscle relaxation in patients with allergy to muscle relaxants. REFERENCES l. Laxenaire MC, Moneret-Vautrin DA. Risk of allergy in anesthesia and resuscita tion. Ed Masson SA Barcelona 1993. 27 A. Criado, A. Seiz, JR. Ortiz 2. Laxenaire MC. Anaphylaxis: Incidence, diagnosis and investigation. ESA Abstra cts 4th Annual Congress. London, 1996. 3. Levi JH. Anesthesia anaphylactic react ions in an Intensive Care. 2nd ed. Stoneham. Butterworth-Heinemann Publ. 1992. 4 . Escolano F, Sierra P. Allergic reactions during anesthesia. Rev Esp Anest Rean 1996, 43, 17-26. 5. Currie M, Webb RK, Williamson JA, Russell WI, Mackay P. Cli nical anaphylaxis: an analysis of 2000 incident reports. Anaesth Intens Care, 19 93, 21, 621-625. 6. Fisher MM, Baldo BA. The incidence, and clinical features of anaphylactic reactions in Australia During anesthesia. Ann Fr Anesth Reanim, 19 93, 12, 97-104. 7. Facon A, Grzybowski M, Divry M, Tsicopoulus A, Scherpereel Ph . L'allergie aux agents anesthesiques: Analyse de 96 observations recentes. Cah Anesthesiol 1988, 36, 97-100. 8. Hungs OR, Bands C, Laney G, Drover, Stevens S, Mac Sween M. Drug allergies in the surgical Population. Can J Anaesth 1994, 41, 1149-1155. 9. Laxenaire MC. Agent and Other Drug Involved in anaphylactic shock occurring During anesthesia. A French multicenter epidemilogical inquiry. Ann Fr Anesth Reanim 1993, 12, 91-96. 10. Anderson JA. Allergic reactions to drugs and biological agents. JAMA 1992, 268, 2845-2857. 11. J. Watkins Adverse reaction t o neuromuscular bloquers: Frequency, investigation and epidemiology. Acta Anaest hesiol Scand 1994, 38 (suppl 10), 6-10. 12. Fisher M, Baldo BA. Anaphylaxis Duri ng Anaesthesia: current Aspects of diagnosis and prevention. Eur J Anaesthesiol 1994, 11: 263-284. 13. Laxenaire MC, Charpentier C, Feldman L. Reactions anaphyl actoides colloidaux aux substituts du plasma: Incidence, facteurs de risque, Mec anismes. Ann Fr Anesth Reanim 1994, 13, 301-310. 14. Watkins J, Wild G.€Improved diagnosis of anaphylactoid reactions by Measurement of serum tryptase and urina ry methylhistamine. Ann Fr Anesth Reanim 1993, 12, 169-172. 15. Withngton DE. Al lergy, anaphylaxis and anesthesia. Can J Anaesth 1994, 41, 1133-1139. 16. Baldo BA, Fisher MM. Diagnosis of IgE - dependent anaphylaxis to neuromuscular blockin g drugs, thiopentone and opioids. Ann Fr Anesth Reanim 1993, 12, 173-181. 17. Es colano F, Aliaga L, Alvarez J, Alcon A, Olive A. Allergic reactions to local ane sthetics. Rev Esp Anestesiol Reanim 1990, 37, 172-175. 18. Leynadier F, Pecquet C, Dry J. During surgery Anaphylaxis to latex. Anaesthesia 1989, 44, 547-550. 19 . McKinstry LJ, Fenton WJ, Barrett P. Anaesthesia and the patient with latex all ergy. Can J Anaesth 1992, 39, 587-589. 20. Ortiz JR, García J, Archilla J, Criad o A. Latex allergy in anesthesiology. Rev Esp Anestesiol Reanim 1995, 42, 169-17 4. 21. McKinnon RP, Wildsmith JA. Histamine reactions in anesthesia. Br J Anaest h 1995, 74, 217-228. 22. Setlock MA, Cotter TP, Rosner D. Latex allergy: failure of prophylaxis to Prevent Severe reaction. Anesth Analg 1993, 76, 650-652. 23. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weintraub WAS. Evaluation of Patient

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