Anaphylaxis during the perioperative period.

The incidence of anaphylaxis during anesthesia has been reported to range from 1 in 4000 to 1 in 25,000. Anaphylaxis during anesthesia can present as cardiovascular collapse, airway obstruction, and/or skin manifestation. It can be difficult to differentiate between immune and nonimmune mast cell-mediated reactions and pharmacologic effects from the variety of medications administered during general anesthesia. In addition, cutaneous manifestations of anaphylaxis are less likely to be apparent when anaphylaxis occurs in this setting. The evaluation of IgE-mediated reactions to medications used during anesthesia can include skin testing to a variety of anesthetic agents. Specifically, thiopental allergy has been documented by skin tests. Neuromuscular blocking agents such as succinylcholine can cause nonimmunologic histamine release, but there have also been reports of IgE-mediated reactions in some patients. Reactions to opioid analgesics are usually caused by direct mast cell mediator release rather than IgE-dependent mechanisms. Antibiotics that are administered perioperatively can cause immunologic or nonimmunologic reactions. Protamine can cause severe systemic reactions through IgE-mediated or nonimmunologic mechanisms. Blood transfusions can elicit a variety of systemic reactions, some of which might be IgE-mediated or mediated through other immunologic mechanisms. The management of anaphylactic reactions that occur during general anesthesia is similar to the management of anaphylaxis in other situations.

INTRODUCTION

The term “anaphylaxis” was coined by Nobel prize recipients Portier and Richet[1] in 1902, when they described a dog that had tolerated a previous injection of actinotoxin, a jellyfish toxin, but reacted with bronchial spasm, cardiorespiratory arrest, and death to a smaller dose 14 days later. Whereas prophylaxis in Greek means “protection,” anaphylaxis means “opposite protection” or “against protection”.[2] Anaphylaxis generally occurs on re-exposure to a specific antigen and requires the release of proinflammatory mediators, but it can also occur on first exposure, because there is cross-reactivity among many commercial products and drugs.

Immune-mediated allergic reactions are classified, according to their mechanism, on the basis of the Gell and Coombs classification. Whereas anaphylaxis is a Type I immunoglobulin (Ig)E-mediated hypersensitivity reaction involving mast cells and basophils, contact dermatitis is a Type IV T-lymphocyte cell-mediated delayed-type hypersensitivity reaction. Other immune-mediated reactions include Type II reactions in which IgG, IgM, and complement mediate cytotoxicity and Type III reactions in which immune-complex formation and deposition leads to tissue damage.[3] Anaphylactoid reactions occur through a direct nonimmune-mediated release of mediators from mast cells and/or basophils or result from direct complement activation, but they present with clinical symptoms similar to those of anaphylaxis.[34]

Surgeons perform major operations under general anesthesia. During anesthesia and pre and post anesthesia period the patient is given wide variety of drugs, colloids and exposed to natural latex rubber. Anesthesiologist routinely administers multiple agents, namely anesthetic drugs, antibiotics, polypeptides, and blood products etc, perhaps too rapidly and in quick succession. Majority of these have the potential to produce severe, at times fatal hypersensitive reactions, which contribute for perianesthetic morbidity and mortality. Many of these drugs can elicit adverse drug reactions that fall apart into two major types. First, reactions that are usually dose dependent and related to the pharmacological properties of the drug and/or its metabolites. Second, reactions that are unrelated to the drug's pharmacological characteristics and that are less dose dependent. These reactions comprise drug intolerance, idiosyncratic reactions and drug-induced immune-mediated allergic and nonimmune-mediated so-called pseudo-allergic or anaphylactoid reactions.[5] Hence, it is quite essential for the surgeon to identify anaphylaxis reaction and anesthesiologist to be able to prevent them preoperatively, diagnose and treat them intraoperatively and investigate them further postoperatively.

Various studies have proven that many anesthetic drugs, natural latex rubber and antibiotics and analgesics can induce life-threatening anaphylaxis reactions. It is important for surgeon to have detailed knowledge of anaphylaxis including diagnosis and treatment. The correct management of anaphylaxis during anesthesia requires a multidisciplinary approach with prompt recognition and treatment of the acute event by the attending anesthesiologist, and subsequent determination of the responsible agent(s) with strict avoidance of subsequent administration of all incriminated and/or cross-reacting compounds. However, correct identification of the causative compound(s) and safe alternatives is not always straightforward and, too often, not done. Diagnosis of anaphylaxis during anesthesia is not always straight forward. It can be hampered as a broad spectrum of different drugs can elicit heterogeneous allergic and nonallergic reactions with distinct and sometimes unclear pathological mechanisms.[5]

The terms anaphylactic and anaphylactoid, however, have been used inconsistently in the literature. Therefore, the nomenclature task force set up by the European Academy of Allergy and Immunology (EAACI) has proposed that anaphylactic-type reactions should be reclassified into allergic anaphylaxis and nonallergic anaphylaxis.[6] Allergic anaphylaxis being further subdivided in IgE-mediated and non-IgE-mediated reactions.[67] During general anesthesia, anaphylactic and anaphylactoid reactions cannot be distinguished clinically, according to Mertes and coworkers.[8] However, in that study, in which a classification of symptom severity was applied, it was found that clinical manifestations seemed to be more severe in patients with documented anaphylaxis than in individuals presenting with an anaphylactoid reaction. Cutaneous manifestations were more frequent in anaphylactoid reactions, but they were not confined to that setting; cardiovascular and broncho-obstructive events, on the other hand, were more frequent during anaphylaxis. In the case of cardiovascular and respiratory complications, clinical symptoms may also occur as isolated events, which can easily be misdiagnosed, according to those authors, if we consider all diseases presenting identical clinical manifestations.[8]

The pathological processes involving the IgE-mediated release of vasoactive substances after exposure to an antigen to which there has been previous exposure and sensitization are known as anaphylactic reactions. An anaphylactoid reaction is clinically indistinguishable but occurs by a different, nonimmune mechanism. These pseudoallergic reactions are caused by the release of histamine and, probably, other mediators. The histamine-releasing effect depends on the dose of the medication and the most potent medications are morphine and almost all muscular relaxants. Regrettably, the legion case reports of severe drug reactions use these terms loosely and interchangeably. This only causes confusion when trying to establish the cause and mechanism of reactions to different drugs.[910] Laxenaire's group, who are the French experts on anaphylaxis during anesthesia, has proposed that all reactions should be described as anaphylactoid unless an immune mechanism has been demonstrated.[8]

Incidence

The incidence of anaphylaxis and anaphylactoid reactions during anesthesia is very difficult to estimate but has been calculated to range from 1 in 3500 to 1 in 13,000 cases.[1213] Another report from Australia estimated the incidence to be between 1 in 10,000 and 1 in 20,000.[14] Another recent report, from Norway, estimated the incidence to be 1 in 6000.[15] Muscle relaxants are associated with the most frequent incidence of anaphylaxis, and over the last two decades, natural rubber latex (NRL) has emerged as the second most common cause of anaphylaxis.[1617]

The incidence of anaphylaxis after administration of muscle relaxants has been assessed at 1 in 6500 procedures in which such a relaxant was administered.[18] Mortality can be high (3.4%) and anaphylactic deaths can account for as many as 4.3% of all deaths occurring during general anesthesia.[1920] In vitro studies of the effects of increasing concentrations of different anesthetics on the release of preformed and de novo mediators from human basophils and mast cells isolated from lung parenchymal, skin and heart tissue have demonstrated that most general anesthetics are able to induce histamine and tryptase release from human basophils and mast cells.[2122]

The prevalence of bronchial hyper-reactivity is approximately 10% and this condition is an important risk factor for perioperative bronchospasm, a potentially life-threatening event whose incidence in anesthesia practice varies from relatively low rates of 0.17% or 4.2%[2324] to higher ones of about 7%[25] or 20%.[26] Obstructive bronchial reactions tend to increase in proportion to the proximity of the latest asthma attack in relation to the date of surgery.[232627] Tracheal intubation also constitutes a high risk factor for intraoperative bronchospasm[232627] and diagnostic approaches such as bronchoscopy and endobronchial biopsy may aggravate respiratory symptoms in children with asthma.[28] Increased bronchial symptoms in the week following bronchoscopy have also been reported in children.[28]

The degree of severity varies and does not allow differentiation between an IgE-mediated or non-IgE mediated reaction resulting from nonspecific mediator release[17] The mortality from these reactions is in the range from 3% to 6%, and an additional 2% of patients experience significant residual brain damage.[14] An IgE-mediated mechanism has been confirmed in 40% to 70% of cases.[29] Severe adverse reactions are infrequent during surgery, and IgE-mediated allergic reactions are the main contributors to morbidity and mortality in this kind of reaction during surgery.[30] Serious problems are unusual during surgery (0.4% of cases), but anesthesia contributes to a third of these cases. Allergic reactions are among the major factors that contribute to morbidity and mortality during an anesthetic and to changes in postoperative care. A recent review of serious intraoperative problems highlighted a case of fatal anaphylactic shock and suggested that preventive strategies are needed for anaphylaxis.[30]

Pathophysiology

Anaphylactoid reactions are derived from the activation of the complement and/or bradykinin cascade and the direct activation of mast cells and/or basophils. Clinical manifestations of anaphylactoid reactions are indistinguishable from anaphylactic reactions. These reactions are rapid in onset and start within seconds to minutes of exposure to the allergen. Symptoms progress rapidly and can affect most organ systems, including the skin (pruritus, flushing, urticaria, and angioedema) and eyes (conjunctivitis), the upper (rhinitis and angioedema) and lower (bronchoconstriction with wheezing and dyspnea, and cyanosis) airway, the intestinal tract (abdominal pain, nausea, vomiting, and diarrhea), and the cardiovascular system (tachycardia, hypotension, and shock), and can lead to cardiovascular collapse and death.[4]

Regardless of the initiating trigger and mechanism, cellular events involving activation of tyrosine kinases and calcium influx in mast cells and basophils result in rapid release of granule associated preformed mediators such as histamine, tryptase, carboxypeptidase A3, chymase, and proteoglycans. Downstream activation of phospholipase A2, COXs, and lipoxygenases leads to production of arachidonic acid metabolites, including prostaglandins and leukotrienes and synthesis of the platelet-activating factor. In addition, an array of cytokines and chemokines are synthesized and released, including IL-6, the newly recognized IL-33 and TNF-a, which is both a late-phase mediator and a preformed mediator. The opening of the endothelial barrier through endothelial Gq/G11-mediated signaling has been identified as a critically important process leading to anaphylaxis symptoms in many body organ systems.[31]

Recognition of anaphylaxis during general anesthesia

The lack of an adequate diagnosis could lead to a potentially fatal re-exposure to the same agent. The common findings that clinical manifestations of intraoperative reactions differ from those of anaphylactic reactions outside of anesthesia might be explained by the fact that patients are draped during anesthesia and cannot complain of cutaneous symptoms such as pruritus or a sense of flushing.[17] Moreover, concomitantly administered drugs may alter the expression and degree of clinical manifestations. The difficulty in recognizing anaphylactic symptoms in anesthetized subjects may also be explained by the need to exclude various other clinical conditions.[32]

Alertness in recognition is essential, because reactions may be well established before they are noticed. The most commonly reported initial features are pulselessness, difficulty in lung inflation and desaturation.[33] A decreased etCO2 value is also of valuable diagnostic interest. If the signs appear later, during the maintenance of anesthesia, they suggest an allergy to latex or volume expander. Latex allergy should also be considered when gynaecological procedures are performed. Particles from obstetricians’ gloves, which accumulate in the uterus during obstetrical manoeuvres, could suddenly be released into the systemic blood flow following oxytocin injection. Anaphylactic reactions to antibiotics have also been reported following removal of tourniquet during orthopaedic surgery.[34]

Etiology

The two primary causes of true anaphylaxis in the patient under anesthesia are muscle relaxants and latex allergy. The muscle relaxants indicated in clinical studies most responsible for reactions include succinylcholine, atracurium, vecuronium, and pancuronium.[35]

Neuromuscular blocking agents

The most common cause of anaphylaxis during general anesthesia or postoperatively is neuromuscular blocking agents (muscle relaxants), which are responsible for 60% to 70% of episodes of anaphylaxis occurring during this period.[8363738394041424344] All NMBA can elicit anaphylaxis and there is an agreement that the short-acting depolarizing succinylcholine poses the greatest risk, despite its close structural homology to acetylcholine.[454647] Neuromuscular blocking agents can induce two types of reactions. One is driven by an immunological mechanism and is IgE-dependent with the quaternary ammonium (NH4 +) structures as main antigenic epitope,[4748] while the second one, particularly described with benzylisoquinolinium-type NMBA such as mivacurium, atracurium, and d-tubocurarine, results from nonspecific stimulation of mast cells.[49505152] Cross-reactivity between NMBA is said to be common because of ubiquitous ammonium groups in these drugs. The estimated prevalence of cross-reactivity between NMBA is about 65% by skin tests and 80% by radioimmuno assay (RIA) inhibition tests.[5]

Most of the muscle relaxants cause direct release of mast cell histamine without the requirement for specific antibody. However, life-threatening reactions usually are IgE- mediated.[53] The tertiary or quaternary ammonium group, common to all muscle relaxants, is likely the immunodominant determinant recognized by IgE.[47] The antigenicity of the shared ammonium structures may be responsible for cross-reactivity among the muscle relaxants. Cross-reactivity occurs most consistently between pancuronium and vecuronium.[54] Cross-reactions also may occur between muscle relaxants and other classes of pharmaceuticals, based upon in vitro inhibition of specific-IgE binding to the muscle relaxants. Agents that potentially cross-react with muscle relaxants include: Acetylcholine, choline, morphine, neostigmine, and pentolinium. Cross-inhibition suggests that previous exposure to these nonanesthetic drugs may sensitize individuals to muscle-relaxing agents, resulting in reactions among patients without prior anesthesia.[5556]

Natural rubber latex

Latex allergy is an important cause of anaphylaxis during anesthesia.[817] Latex sensitization is due to IgE-mediated reactivity to any number of antigens from Hevea brasiliensis, the source of latex. Sensitization occurs in up to 12% of health care workers, up to 75% of patients with spina bifida and in patients undergoing multiple surgical procedures.[575859] IgE-mediated NRL allergy has become a well-defined condition with recognized risk groups, established diagnostic tools, and adequate prevention strategies.[60] In 1984, Turjanmaa et al.[61] described the first cases of NRL-associated intraoperative anaphylaxis. The at-risk individuals for perioperative anaphylaxis from NRL can be subdivided into those genetically predisposed (i.e., atopics) and those with significant exposure such as healthcare workers and children requiring multiple or repetitive surgical and medical interventions (e.g., neural tube defects, spinal cord trauma, and urogenital malformations) that need chronic bladder care with repeated insertion of NRL catheters or chronic indwelling catheters.[5] In contrast, adult patients with spinal cord injury and repeated latex exposure seem not at risk for latex allergy.[5]

It is important to distinguish this from contact dermatitis to chemicals used in the manufacture of rubber, which is a different disorder with different implications and requiring less stringent avoidance during surgery. Contact dermatitis causes slow-onset eczematous reactions, is not life threatening and caused by a type IV reaction and thus IgE antibodies are not involved.[62] Allergic reactions to latex occur intraoperatively as time is needed to absorb the allergen through the mucosa or peritoneum.

A systemic reaction is unlikely to occur within a few minutes of latex exposure. If latex allergy is suspected, skin prick test SPTs and serum-specific IgE tests should be undertaken. SPTs are superior to serum assays[2063] with a greater sensitivity and specificity than specific IgE. If latex allergy is strongly suspected and skin test and serum-specific IgE is negative, glove challenge (exposing the patient to latex by wearing a latex glove for increasing periods while monitoring for objective signs of an allergic reaction) should be undertaken. If glove challenge is negative, a buccal challenge should be undertaken.[62]

With exposure, sensitized individuals may develop urticaria, angioedema, allergic rhinitis, asthma, and anaphylaxis. Latex-induced anaphylaxis from powdered latex gloves, as well as other sources, may present in the operating room in patients, surgeons, nurses or anesthesiologists. Latex has been reported to account for up to 17% of intraoperative anaphylaxis.[63]

The features of intraoperative anaphylaxis may differ considerably from anaphylaxis not associated with surgical procedures. While cutaneous, hypotensive and respiratory events occur in both, hypotensive cardiovascular collapse is a feature of reactions to latex during surgery while dizziness or syncope is found largely in anaphylaxis induced by nonsurgical procedures.[6465]

Latex-induced anaphylaxis may occur in a variety of situations, all involving direct contact with latex, usually gloves, or instruments, or with aerosolization of latex antigen adherent to the cornstarch powder of latex gloves. Thus, latex reactions can occur during operative procedures, when gloves are donned. Latex reactions may occur immediately with latex contact or may be delayed from 30 to 60 min. Intraoperative latex anaphylaxis may be related to the administration of drug through a latex port prior to surgery, or during the surgical procedure itself. Latex reactions have also been reported to occur during dental procedures from latex gloves or dams, during obstetrical or gynecologic examinations and during latex condom use. Spina bifida patients are potentially at risk during each surgical procedure because of the numbers of procedures they undergo.[5665]

For the sensitized health care worker, latex gloves should not be worn and the worker's colleagues should wear nonpowdered latex gloves or nonlatex gloves. The workplace should be “latex safe” with all nonglove latex devices replaced by nonlatex devices. A “latex free” emergency cart should be available to treat reactions. Rubber stoppered vials should be avoided.[56]

Antibiotics

Penicillin, cephalosporins, and other-lactam antibiotics

These are the most commonly used antibiotics during the perioperative period and perhaps some of the most commonly used drugs overall. Penicillin is the most common cause of anaphylaxis in the general population. The antibiotics most commonly implicated in reactions during this period are b- lactam antibiotics and vancomycin.[66] Taken together, penicillins and cephalosporins elicit approximately 70% of perioperative anaphylactic reactions elicited by antibiotics.[813]

After muscle relaxants and latex allergy, antibiotics are targeted as the third leading cause of anaphylactic reactions in the surgical patient.[17] Sulfonamide allergy is also fairly common in surgical patients. Keeping the incidence of drug-allergy-induced anaphylaxis in the surgical patient in perspective, up to 2% of the population is allergic to penicillin, but approximately only 0.01% of penicillin administration results in an anaphylactic reaction.[11] In patients with a history of a prior reaction to penicillin, one review of the literature found that only 10% to 20% of patients who report a penicillin allergy have a documented allergy.[67] A review of this subject found that patients with an allergy to penicillin were more likely (threefold) to experience an anaphylactic reaction to any other drug.[68] Although some experts state that it is safe to administer cephalosporins to penicillin-allergic patients and that penicillin skin tests are not indicated[68] others have recommended avoidance of cephalosporins in those with positive penicillin skin tests or anaphylaxis.[676970]

Goodman et al.[70] performed a retrospective chart review of intraoperative anesthesia records over a 14-month period and demonstrated that cephalosporins can be given to patients who claim to be allergic to penicillin. However, a limitation of this study is that patients who reported anaphylaxis to penicillin were excluded.

Vancomycin is a glycopeptide antibiotic selectively used for treatment of resistant organisms and for use in individuals with penicillin allergy. It is commonly used for antibiotic prophylaxis in the surgical and it is commonly associated with anaphylactoid reactions consisting of pruritus, erythema of the head and upper torso, and arterial hypotension. Administration, especially when it is rapid, may result in life-threatening, non-IgE-mediated anaphylaxis.[717273] Direct histamine release and direct myocardial depression partially explain this phenomenon.[74] These nonimmunologic reactions to vancomycin can be reduced or eliminated by administering this drug as a dilute solution, dissolved in at least 200 mL, and infused over at least a 2-h period.

Other antibiotics that are often used in the operating room and that may rarely trigger an anaphylactic reaction include clindamycin, gentamicin, and metronidazole. Clindamycin is used against Gram-positive and anaerobic bacteria and usually causes a contact dermatitis. No specific IgE antibody has been found, and skin prick and intradermal skin tests are negative. Gentamicin is a broadspectrum aminoglycoside often used in patients at risk for endocarditis, whereas metronidazole is a nitroimidazole derivative used against anaerobic infections. IgE-mediated hypersensitivity, although previously reported, is extremely rare in both cases.[75]

Plasma volume expanders (colloids)

Today, colloids have been recognized to cause up to 4% of all perioperative anaphylactic reactions.[81376] These reactions were severe in 20% of the cases and generally occurred 20 min after start of infusion. Fatalities to colloids have been reported.[77] For a comprehensive review of anaphylactoid reactions to colloids, the reader is referred elsewhere.[78]

Dextran and hydroxyethyl starch (HES), large-molecularweight polysaccharides, may be used as a nonblood, highoncotic fluid replacement during surgery. These agents are infrequently associated with adverse reactions and anaphylaxis. Estimates of reaction rates are 0.008% to 0.08% for dextran and 0.08% for HES.[79] The incidence of allergic reactions to colloids seems to be increasing. Whereas earlier reports from the 1980s described an incidence of 0.03% for dextran and hetastarch[8081] a French study from 1994 demonstrated an overall frequency of 0.22%. Gelatins (0.34%) and dextrans (0.27%) were more likely to cause an allergic reaction than albumin (0.1%) or hetastarch (0.06%). Individuals with prior drug allergies were three times more likely to develop anaphylaxis, and males were more likely than females to develop an allergic reaction.[82] Egg allergy does not appear to be a contraindication to the use of albumin, because the principal egg protein, ovalbumin (45 kd), is different from human serum albumin (67 kd).[83] A report from France demonstrated that 2.9% of intraoperative anaphylaxis cases were due to colloids.[16]

Intravenous drugs used for anesthetic induction

It can cause perioperative anaphylaxis. More than 290 cases of anaphylaxis are reported in the literature from the use of barbiturates, especially thiopental. The incidence of anaphylaxis to thiopental is estimated to be 1 in 30,000 administrations, and previous exposure and female sex are associated with an increased incidence.[84] However, the reaction rate with barbiturates is only 1:25,000, with the reported occurrence of reactions reflecting the common use of these compounds. Women are three times more likely to have reactions from thiopental than men.[8586]

Propofol is a nonbarbiturate induction agent that is potentially useful if sensitivity to barbiturates is a concern[87] IgE-mediated reactions from propofol may occur,[8889] however, most adverse reactions to propofol are nonimmunologic. Propofol may directly stimulate histamine release, and this effect may be greater when administered with muscle relaxants.[90] Propofol (2,6-diisopropylphenol) is currently formulated in a lipid vehicle containing soybean oil, egg lecithin, and glycerol. The incidence of anaphylactic reactions with the new formulation is 1 in 60,000, although it has been reported to cause 1.2% of cases of perioperative anaphylaxis in France.[91] A more recent report from the same group in France demonstrated that 2.1% of cases of intraoperative anaphylaxis are due to propofol.[16]

Benzodiazepines

Diazepam is more likely than midazolam to cause an anaphylactic reaction because of the propylene glycol solvent that replaced Cremophor EL. The active metabolite desmethyldiazepam may be responsible for the cross-reactivity with other benzodiazepines.[92] Midazolam is a safe drug, because it does not have any active metabolites. Although anaphylactoid reactions to midazolam have been reported, no serologic or cutaneous testing was performed[75] In addition, midazolam has been used safely for the induction of anesthesia in patients with drug allergy.[9394]

Narcotics used in perioperative period are a common cause of flushing and urticaria following intravenous administration. Anaphylaxis, in contrast, is very rare.[959697] Morphine is a tertiary amine that causes nonimmunological histamine release, and meperidine causes nonimmunological histamine release more often than any other opioid.[75] There are reported cases of IgE-mediated reactions to these opioids.[129798]

Dermal mast cells express opioid receptors that bind to the narcotic and stimulate histamine release. Other populations of mast cells do not express this receptor. Cutaneous flushing and hives often occur after intravenous morphine administration, but with rare exceptions, the amount of histamine release does not result in hypotension or bronchospasm. Reducing the rate of opioid administration usually limits the severity of these reactions. Fentanyl does not directly stimulate histamine release by way of the mast-cell opioid receptor.[99] There are reports of anaphylaxis to morphine and fentanyl.[98]

Local anesthetic agents readily induce cell-mediated immunologic reactions when applied topically to the skin, but humoral immune responses are rare. Adverse effects from local anesthetics are not uncommon, but immunologically mediated reactions following parenteral administration are very unusual. Anaphylactic reactions to amide local anesthetics are extremely rare, and true allergic reactions to esters account for 1% of all drug reactions to local anesthetics.[100101102] The most common immune-mediated reaction to local anesthetics is a delayed hypersensitivity reaction (Type IV reaction), or contact dermatitis.[102] Challenge tests remain the gold standard, or rather reference test to diagnose anaphylaxis from local anesthetics and different protocols exist.[103104105106]

Povidone-iodine

Povidone-iodine (betadine) is the most common topical antiseptic solution use. Allergic contact dermatitis, a Type IV cell-mediated hypersensitivity reaction, is more common with povidone-iodine. Patch testing to diagnose this type of reaction is best done with dried 10% povidone iodine solution, because long exposure to povidoneiodine in the aqueous state may yield a false-positive result due to direct skin irritation.[107]

Chlorhexidine

Chlorhexidine is widely used all over the world as a skin disinfectant before surgery or invasive procedures and in the general population in mouthwash or for disinfecting minor scratches. Therefore, patients may become sensitized before a surgical procedure. A report in the literature describes four patients with a history of minor rashes or faints in connection with previous chlorhexidine exposure who developed severe hypotension requiring epinephrine after subsequent exposure. Skin testing (prick test with 0.5% or intradermal test with 0.0002% chlorhexidine) was positive for chlorhexidine, Evidence for an IgE-mediated hypersensitivity to chlorhexidine was first provided in 1984[110] and hapten inhibition studies have shown the entire chlorhexidine molecule to be complementary to the IgE antibody binding sites and the 4-chlorophenol, biguanide, and hexamethylene structures together constitute the allergenic determinant.[111112]

Symptoms of chlorhexidine anaphylaxis have been attributed to cutaneous, percutaneous, mucosal, and parenteral application. Life-threatening reactions with profound hypotension, ventricular fibrillation and cardiac ischaemia are generally associated with mucosal or parenteral exposure as might occur during application of urethral gels, implanted antimicrobial surgical mesh, and insertion of chlorhexidine-coated central venous catheters respectively. Severe, potentially life-threatening anaphylaxis from simple cutaneous application such as perioperative skin disinfection and wound cleansing remains anecdotal and probably underestimated. In a recent survey, chlorhexidine accounted for 27% of the overlooked perioperative hypersensitivity reactions.[113]

Nonsteroidal anti-inflammatory drugs

Aspirin and NSAIDs are the second most common cause of drug-induced anaphylaxis (after antibiotics).[113] Anaphylactic reactions to NSAIDs are unrelated to other reactions caused by these drugs, such as respiratory reactions and exacerbations of chronic idiopathic urticaria.[114] True anaphylactic reactions to NSAIDs appear to be medication specific in that some patients who have had an anaphylactic reaction to one NSAID are able to tolerate structurally unrelated NSAIDs, but this is largely based on clinical experience rather than large scale challenge studies.[113] NSAIDs, including aspirin, can cause reactions, by inhibition of cyclo-oxygenase, resulting in generation of leukotrienes.[115116] NSAIDs are increasingly recognized as a cause of non-IgE-mediated anaphylactic reactions. They may be given rectally towards the end of surgery, i.v., or sometimes with premedication, depending on the procedure. The onset of reaction is usually up to 10 min after i.v. administration, 15-30 min from rectal administration and 30-60 min after oral administration. If the onset of reaction is at the end of surgery, this immediately excludes the induction agents, and the main differential diagnosis is an NSAID given rectally late during the procedure, latex allergy or a reaction to colloid. There are no reliable diagnostic tests for NSAID intolerance and this is essentially a clinical diagnosis, having excluded other potential causes (such as NMBAs and latex rubber). However, the diagnosis can be confirmed by provocation, but this should only be considered if there is doubt from the history.[117]

Causes of severe adverse events during anesthesia[62]

Exaggerated pharmacological effect, e.g., hypotension during extradural anesthesia or with propofol; bradycardia and hypotension after opiates

Anaphylaxis to one of the i.v. NMBAs or anesthetic drugs

Adverse reaction to another administered drug e.g., drug with premedication; antibiotic with induction; analgesic, e.g., NSAID rectally or opiate intraoperatively

Latex rubber allergy

Reaction to intravenous infusion, for example colloid, blood, plasma

Allergy to other substance given, e.g., chlorhexidine or a diagnostic dye

Problem with anesthetic technique, for example intubation

Autonomic parasympathetic effects, e.g., during laparoscopy, peritoneal traction, arthroscopy, squint surgery, dental surgery

Blood loss

Medical (non-allergic) cause, for example septicaemia; cardiac; severe asthma, pneumothorax; air embolus

Malignant hyperthermia

Clinical features

The clinical manifestations are more severe and longer lasting in reactions of immunologic origin than in pharmacologic reactions. The clinical signs do not always fully exist and they may be misleading. The most common clinical features of anaphylaxis during anesthesia are cardiovascular and cutaneous signs and symptoms.[1] However, cutaneous signs can be difficult to identify, because the patient is draped.[17] Additionally, while the patient is under anesthesia, there is an absence of symptoms that the patient is experiencing an anaphylactic reaction. The absence of cutaneous signs does not exclude the diagnosis of anaphylaxis. The diagnosis of anaphylaxis depends in large part on the patient's ability to describe the event, and the patient cannot describe symptoms because they are unconscious or not fully conscious. Cardiovascular collapse may be the sole manifestation of anaphylaxis and may be confused with other causes of cardiovascular collapse in this setting. The majority of surgical anaphylaxis occurs during the induction period when muscle relaxants, sedatives, and opiates are administered.

In anaphylaxis, the clinical features are to some extent dependent on the cause and route of administration of allergens. Allergy to a drug given i.v. as a bolus is of rapid onset, usually within minutes of administration and predominantly causes cardiovascular collapse 120. In contrast, with a rectally administered drug, there is usually a delay of 15-30 min to onset, and urticaria, angio-oedema or asthma is common. Similarly, an i.v. infusion of gelatin usually takes 15-30 min to cause a reaction. In latex rubber allergy, where the allergen is absorbed through the peritoneum, mucosa or skin, a mixed clinical picture is seen, and the onset may be >30 min from first contact. Common initial clinical features seen by the anesthetist are loss of pulse, fall in arterial pressure, difficulty in inflating the lungs and flushing.[14] The timing in relation to drug administration is important, and gives a clue to the aetiology. If anaphylaxis occurs within minutes of induction then Intravenous anesthetics, Intravenous opiate, and Intravenous antibiotic are the culprits. And if anaphylaxis occurs intraoperatively then the likely cilprits are IV NSAIDs, opiods, antibiotics. And if anaphylaxis occurs towards end of surgery or during recovery then latex allergy, rectal NSAID and IV opiods are the cause.[62]

Management of patient with suspected anaphylaxis during anesthesia

Stop administration of all agents likely to have caused the anaphylaxis.

Call for help.

Maintain airway, give 100% oxygen and lie patient flat with legs elevated.

Give epinephrine (adrenaline). This may be given intramuscularly in a dose of 0.5 mg to 1 mg (0.5 to 1 mL of 1:1,000) and may be repeated every 10 min according to the arterial pressure and pulse until improvement occurs. Alternatively, 50 to 100 μg intravenously (0.5 to 1 mL of 1:10,000) over 1 min has been recommended for hypotension with titration of further doses as required.

Never give undiluted epinephrine 1:1000 intravenously. In a patient with cardiovascular collapse, 0.5 to 1 mg (5 to 10 mL of 1:10,000) may be required intravenously in divided doses by titration. This should be given at a rate of 0.1 mg/min stopping when a response has been obtained. Paediatric doses of epinephrine depend on the age of the child.

Intramuscular epinephrine 1:1000 should be administered as follows

>12 years 500 μg IM (0.5 mL)

6-12 years 250 μg IM (0.25 mL)

>6 months-6 years 120 μg IM (0.12 mL)

<6 months 50 μg IM (0.05 mL)

Start rapid intravenous infusion with colloids or crystalloids.

Adult patients may require 2 to 4 L of crystalloid.

Secondary therapy

Give antihistamines (chlorpheniramine 10-20 mg by slow intravenous infusion).

Give corticosteroids (100 to 500 mg hydrocortisone slowly iv).

Bronchodilators may be required for persistent bronchospasm.

Strategies for prevention

The prevention of anaphylaxis after administration of general anesthetics would require the identification of patients at risk, but this approach is not easy to implement considering the large number of drugs, diagnostic reagents, devices containing latex, antiseptics, and blood products that are all routinely used in anesthesia. The low accuracy of diagnostic tests also plays a part. Sufficient knowledge of pathogenic mechanisms involved in systemic reactions to general anesthetics is essential to optimize prevention strategies. It is widely recognized that anaphylactic (immunoglobulin-E-mediated) events usually occur after repeated administration of sensitizing agents (especially general anesthetics and, in some cases, contrast media). These events are somewhat predictable in high-risk patients or in subjects who have had anaphylactic reactions previously.

If patient interviews, medical history taking, or previous diagnostic tests are able to identify a culprit agent or agents, an alternative product must be used. If the reaction is attributed to a neuromuscular blocking drug, there is risk from other such agents and consequently it is proper to use a regional blocking agent or volatile anesthetics if such techniques are suitable. Each reaction occurring during general anesthesia should be entered into a patient's medical record by the anesthesiologist in order to prevent future reactions. Investigations such as skin prick test, intradermal test and tryptase tests can be carried out to rule out allergies in suspected patients.

CONCLUSION

Anaphylaxis is life threatening condition, more so in operating theater due to lack of cutaneous symptoms because patient is unconscious or semiconscious and he is draped so cutaneous signs are not discovered early. Adverse drug reactions or side effects are usually expected, are dose dependent, and occur at therapeutic doses. Anaphylactic and anaphylactoid reactions are unexpected and dose independent and can occur at the first exposure to drugs used during anesthesia. Any drug can induce a life-threatening and sometimes fatal anaphylactic or anaphylactoid event even in the absence of any evident risk factor in the patient's medical history. Although anaphylaxis is a rare intraoperative event, most drugs used in the perioperative period can lead to anaphylaxis. The documentation of anaphylaxis is often lacking because the cause and effect relationship is often hard to prove and because the diagnosis is not easy to make with the patient under anesthesia. And fatal or near-fatal events may be induced by diagnostic or surgical procedures usually considered as routine and carried out in patients suffering from less severe disorders. Muscle relaxants and NRL are the most common anesthetic drugs or substances that may lead to anaphylaxis. Prevention is the most important component to decrease the incidence of anaphylaxis. Documentation of anaphylaxis during anesthesia, referral to an allergist for identification of the causative drug, and appropriate labeling of the patient are essential to prevent future episodes of anaphylaxis. Patient must be fully informed about anaphylaxis, its cause, signs and symptoms and causative agent. And he must be instructed to give thorough history whenever he reports to any hospital for treatment be it minor or major. He can be instructed to wear bracelet or carry card with him detailing which drugs he is allergic to. What is needed is improved accuracy in assessment of the rate of occurrence of anaphylaxis, and rapid, specific, sensitive in vitro test or panel of tests to confirm the clinical diagnosis of acute anaphylaxis.