REVIEW ARTICLE

Latex : An Update

David L. Hepner, MD*, and Mariana C. Castells, MD, PhD† Departments of *Anesthesiology, Perioperative, and Pain Medicine and †Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

he rate of sensitization has been increasing NRL: Description, Proteins, and since its first recognition in 1979, and anesthesi- Biochemistry T ologists encounter patients with a diagnosis of more and more often (1). Latex is a ubiq- NRL (cis-1,4-polyisoprene) is a milky fluid obtained uitous material that is found in balloons, , primarily from the Hevea brasiliensis tree (6). Latex and many surgical and nonsurgical products. Anes- and by-products are substances found thesiologists, like many other types of physicians who in many products present in hospital and home envi- often wear latex gloves, may also become sensitized to ronments. Since the 1980s, the increase in the inci- latex (2,3), and there are cases of disability of health dence of latex has been associated with care professionals because of latex allergy (4,5). Latex the increased use of latex gloves because of Universal anaphylaxis may lead to significant morbidity, and Precautions. The use of Universal Precautions pro- deaths have been reported (4,5). It is essential to rec- moted by the Centers for Disease Control and Preven- ognize which patients and colleagues are sensitized to tion to decrease the spread of the human immunode- latex to provide appropriate treatment and to establish ficiency virus and hepatitis B and C viruses has lead to adequate prevention. a 25-fold increase in the use of latex-containing surgi- The purpose of this article is to review recent find- cal gloves (7). Over the last two decades, latex has emerged as the second most common cause of ana- ings and developments on latex allergy. This article phylaxis in surgical suites (16.6% of cases) (8). How- reviews the general concepts of latex allergy in the ever, a recent French report (9) found that the inci- perioperative setting and specifically addresses natu- dence of cases of latex anaphylaxis is decreasing as a ral rubber latex (NRL) proteins, reactions associated result of the identification of at-risk patients, im- with NRL, and high-risk groups for developing latex proved testing, and preventive measures. In addition, allergy. In addition, we discuss the diagnosis, man- many manufacturers are decreasing latex in a variety agement, and prevention of latex allergy and conclude of products (10). There is currently no cure for latex with a discussion of future therapies. allergy, and avoidance of latex-containing products is The literature was searched using Medline from mandatory for affected individuals. 1966 until July 2002. A literature search with the key Latex gloves are the major source of latex proteins words anesthesia, anesthesiology, operating room and are implicated in most cases of latex-mediated (OR) or surgery, and latex, latex allergy, or latex hy- reactions (11,12). Latex gloves contain proteins that persensitivity produced 80 articles. The references of are subject to hydrolysis and denaturation during pro- these manuscripts were reviewed to identify other cessing. Latex particles are generally insoluble in wa- relevant articles. Finally, additional references were ter but are made more soluble in the presence of identified from reviews and abstracts on latex allergy ammonia, which is used to stabilize and preserve com- from the allergy and clinical literature mercial latex. Ammonia has been implicated in the from the last 5 yr. rupturing of organelles (i.e., lutoids) present in the latex with the release of soluble material (B-serum). B-serum fragments of latex protein result in low mo- lecular weight polypeptides (13). Hevea brasiliensis latex contains several well-characterized proteins (14– Accepted for publication November 21, 2002. 18). The rubber elongation factor of rubber trees (He- Address correspondence and reprint requests to David L. Hepner, MD, Department of Anesthesiology, Perioperative, and Pain Medicine, vea brasiliensis or Hev b) is the major in latex Brigham and Women’s Hospital, Harvard Medical School, 75 Francis (18) and there are 11 Hev b proteins (Hevb1toHev St., Boston, MA 02115. Address e-mail to [email protected]. b 11) of which latex profilin (Hev b 5, 18–20 kd) and DOI: 10.1213/01.ANE.0000050768.04953.16 hevein (Hev b 6.02, 4.7 kd) are common examples

©2003 by the International Anesthesia Research Society 0003-2999/03 Anesth Analg 2003;96:1219–29 1219 1220 REVIEW ARTICLE HEPNER AND CASTELLS ANESTH ANALG LATEX ALLERGY 2003;96:1219–29

(14,18). In addition, others have reported a 14-kd com- and Type IV mediated (24). Another ponent as being an important allergen in latex (15–17). reaction associated with latex, but not caused by latex Hev b 5 sensitization is common among health care itself, is irritant . workers. Irritant Contact Dermatitis. The most common reac- The increased demand for gloves also led to a de- tion associated with latex is an irritant contact derma- crease in processing time, and this in turn has led to an titis that may develop minutes to hours after exposure increase in latex proteins. Different manufacturers of to latex-powdered gloves or chemicals. It may occur gloves use different methods, standards, and process- on the first exposure, is usually benign, and not life ing times. There is a 3000-fold difference in latex con- threatening. It looks similar to a localized powder tents in 10 different brands of gloves (11). There are no abrasion with a loss of the epidermoid skin layer, government regulations that require companies eventually leading to soreness, pruritus, and redness. to label the protein content. Cornstarch, used as a The extent of the reaction depends on physical factors donning agent for gloves, acts as a carrier for latex such as the duration of exposure and skin tempera- by binding to latex proteins. The cornstarch- ture. The alkaline pH of most powdered gloves is the latex particles are released into the air and inhaled and most likely cause of this reaction (25). may lead to respiratory symptoms (3). Allergic Contact Dermatitis or Type IV Cell-Mediated Frequently used products that contain latex include Hypersensitivity Reaction. This is a delayed onset im- urinary catheters, tourniquets, rubber plunger of sy- munologic reaction and results from T-cell-mediated ringes, IV tubing, tape, and electrocardiogram pads sensitization to the additives of latex. It is not life (Table 1). It is very difficult to predict which device threatening, and it is far more common than a Type I and brand may contain latex without appropriate la- reaction. This is usually secondary to a reaction to beling. Starting on September 30, 1998, the Food and antioxidants and rubber accelerators such as thiurams, Drug Administration (FDA) mandated that the prod- carbamates, and mercapto compounds. On a repeated ucts that contain latex be labeled as such, including exposure, a reaction begins within 48–72 h of expo- packaging devices containing NRL that require labels sure, often leading to erythema with vesicles and such as “Caution: The Packaging of this Product Con- scales. One can diagnose this type of reaction with a tains Natural Rubber Latex Which May Cause Allergic patch test to one of these antioxidants or accelerators Reactions” (19). Labeling statements relating to hy- (26). poallergenicity are prohibited because the FDA has Type I IgE-Mediated Hypersensitivity Reaction. This received several reports of allergic reactions to medi- is the most severe reaction and may lead to significant cal gloves labeled as hypoallergenic. morbidity and mortality. It requires sensitization and Natural rubber includes all materials made from or containing natural latex. The production of latex in- the production of IgE antibodies. On first exposure, patients are sensitized and produce IgE specific for volves the use of natural latex in a concentrated col- ϩ loidal suspension. In contrast, dry natural rubber pro- Hev b. Hev b proteins act as , activate CD4 duction involves the use of coagulated natural latex T-helper cells Type II (Th2 cells), and induce B cells to dried or milled sheets. Dry natural rubber is less al- form specific Hev b IgE secreting plasma cells. The IgE lergenic than latex and carries a softer warning by the then binds to the surface of tissue mast cells and blood FDA as follows: “This Product Contains Dry Natural basophils. Upon reexposure, Hev b proteins cross-link Rubber” (19). However, dry natural rubber can cause membrane-bound IgE leading to degranulation of the allergic reactions and should not be used in a latex- sensitized mast cells and basophils. Preformed medi- allergic patient (20–23). It is of note that the FDA does ators, histamine, and proteases such as tryptase and not require manufacturers to recall nonlabeled devices newly generated arachidonic acid metabolites (prosta- already in interstate commerce before September 30, glandins and leukotrienes) are then released, leading 1998. to a reaction that ranges from local urticaria to a full-blown anaphylactic reaction. Latex proteins are absorbed slowly when the expo- sure is airborne, and symptoms usually develop ap- Reactions Associated with Latex proximately 30 min after exposure. Mild reactions in- Latex sensitization is defined as the presence of im- clude local urticaria, , and conjunctivitis and munoglobulin (Ig)E antibodies to latex but without are more likely to result via airborne exposure or clinical manifestations. Latex sensitization does not direct contact with the skin. Powdered gloves may always lead to latex allergy, even if there is further release airborne particles (cornstarch) with latex pro- contact with latex products. Latex allergy refers to any tein, which can lead to symptoms such as bronchocon- immune-mediated reaction to latex associated with striction, rhinitis, and conjunctivitis. Occupational ex- clinical symptoms, which include Type I mediated posure to latex is strongly correlated with allergic hypersensitivity reactions to the latex protein itself . Baur et al. (27) screened subjects working in ANESTH ANALG REVIEW ARTICLE HEPNER AND CASTELLS 1221 2003;96:1219–29 LATEX ALLERGY

Table 1. Latex Containing Products Used in the Operating Room and Postanesthesia Care Unit and Their Latex-Free Alternatives Latex products and safe alternatives available Frequently contain latex Latex-free alternatives Ace wraps Teds, pneumatic boots Airways Hudson airways, oxygen masks Ambu bag (black or blue reusable) Clear, disposable ambu bags Anesthesia circuits Neoprene circuits, bag (Vital Signs) Bandaids Sterile dressing with plastic tape or tegaderm Blood pressure cuff Dura-Cuf௡ Critikon Vital Answers or use over gown or stockinette Catheters, Silicone condom catheter (Mentor’s “Clear Advantage”) Catheters, indwelling Silicone Foley (Kendall, Argyle, Baxter) Catheter leg bags straps Use over cloth Catheter secure Use silk tape Catheters, straight Plastic (Mentor, Bard) Double, triple lumen (Bard, Rusch) Chux (washable rubber pads) Disposable underpads Dressings Moleskin, Micropore, Coban (3M) Tegaderm (3M), Steri-strips Elastic bandages, ace wrap TEDS, baxter elastic bandages Electrode pads 3M, baxter electrocardiogram pads Dantec surface electrocardiogram pads Endotracheal tubes Mallenckrodt, Sheridan, Portex tube styletes Laryngeal mask airway Gloves, latex nonsterile Sensicare gloves Gloves, sterile and exam surgical & medical Vinyl, neoprene gloves (Neolon, Tachylon, Tru-touch, Elastryn) Heplock-PRN adapter Use stopcock to inject meds Introducer sets Arrow central access tray and multi-lumen central IV tubing, injection ports Baxter, Abbott, Walrus tubing Walrus anesthesia sets are latex-free IV fluid Abbott IV fluid Jobst spandex products Jobst has a nonlatex material Masks Disposable mask should travel with patient throughout hospital. Medication vials Remove latex stopper OR caps with Elastic (bouffant) Caps with ties Oxygen tubing Nasal, face mask Penrose drains Jackson-Pratt silicone tubing Zimmer Hemovac (PVC) Spinal/epidural kits/single epidural catheters Baxter Weiss epidural tray 25 gauge Whitacre spinal kits (Abbott) Stethescope tubing Do not let tubing touch patient, cover with web roll Suction tubing Mallenckrodt, Yankauer, Davol suction catheters Swan-Ganz, pulmonary artery catheter Catheter with polyurethane balloon: American Biomed’s CLS thermodilution catheter (7F, 110 cm) Syringes Becton Dickinson angiocaths and syringes, Concord Portex, Bard syringes Vacutainer needle for phlebotomy Tape—cloth adhesive, paper Plastic, silk, 3M’s Microfoam, Blenderm, Durapore Theraband strips and tubes Cover with cloth Tourniquet Latex free tourniquet (blue)

These lists are offered as a general guideline. It is very difficult to obtain full and accurate information on the latex content of products, which may vary between companies and product series and also with time. Double checking the label before use with latex allergic individuals is strongly recommended. As of September 30, 1998, all products that contain natural rubber latex or dry natural rubber must be labeled as such. hospitals and ORs with different latex gloves used, and type of gloves (28). Long OR time, levels and demonstrated that sensitization and respi- large number of gloves used, and high-allergen- ratory symptoms were likely to develop if the level of containing gloves are associated with large aeroaller- latex was more than 0.6 ng/m3. Others gen levels (28). There is a recent report of a parturient have published data about aeroallergen levels in ORs at 32-wk gestation who developed dyspnea, wheez- depending on the use of the room, total number of ing, hypotension, and an urticarial , as well as 1222 REVIEW ARTICLE HEPNER AND CASTELLS ANESTH ANALG LATEX ALLERGY 2003;96:1219–29 fetal bradycardia after the removal of latex powdered High-Risk Groups gloves by a nurse (29). Severe reactions usually occur shortly after paren- Health care workers, nonhealth care workers with teral or mucous membrane exposure and include occupational exposure to latex such as hairdressers, flushing, vasodilatation, severe bronchospasm, and food-service workers, and police officers, patients increased vascular permeability with edema and car- with atopic backgrounds, and children with spina bi- diovascular collapse (9). A recent survey of anaphy- fida or genitourinary abnormalities who have under- laxis during anesthesia demonstrated that cardiovas- gone multiple surgeries are at increased risk for latex cular symptoms (73.6%), cutaneous symptoms (69.6%), sensitivity (37). , even in the absence of and bronchospasm (44.2%) were the most common clin- multiple surgical procedures, seems to be an indepen- ical features (9). Mild reactions such as urticaria and dent risk factor for latex sensitization (38). Adult pa- may be masked by the presence of surgical tients undergoing multiple surgeries have a less fre- drapes, whereas mild bronchoconstriction or hypoten- quent incidence of latex sensitization than children sion may be masked by the presence of other anesthetics with spina bifida, and latex-free precautions from or may be difficult to recognize because they may mimic birth in children with spina bifida are more effective in physiological reactions happening during anesthesia. preventing latex sensitization than the same precau- Therefore, only a severe reaction may be recognized, and tions instituted later in life (39). Hevb1isthemajor the only presenting sign may be cardiovascular collapse. allergen for children with spina bifida (39). Other conditions that may resemble anaphylaxis Occupational exposure to latex is common among should be considered. Histamine release, with skin man- health care workers such as nurses who work in the ifestations such as , may occur from frequently intensive care unit or postanesthesia care unit who used medications such as morphine and some nondepo- change gloves approximately 50–100 times per day larizing muscle relaxants. Bronchospasm may be sec- (personal communication between MCC and her ondary to an asthmatic attack, right mainstem obstruc- latex-allergic nurses). A survey conducted among an- tion, inadequate anesthesia, pneumothorax, mechanical esthesia faculty and residents at the Brigham and obstruction, endobronchial intubation, pulmonary aspi- Women’s Hospital, Boston, MA, demonstrated that ration, pulmonary edema, or pulmonary embolism. Sud- the average respondent changes their gloves approx- den cardiovascular collapse may be the result of an acute imately 15–20 times per day. The prevalence of latex myocardial infarction or a high spinal anesthetic. The sensitization is less than 1% in a nonatopic normal medical history, the timing of the event, and the clinical population, whereas the prevalence in health care presentation are essential to aid in the precise diagnosis. workers ranges from 3%–12% (37). The incidence of Anaphylaxis caused by something other than latex latex sensitization, as measured by IgE levels, in am- should also be considered. Allergic reactions to anes- bulatory surgical patients at one institution was as thetic drugs, such as propofol (30), nondepolarizing frequent as 6.7% (1). Although sensitization does not muscle relaxants, such as vecuronium (31), and opi- always lead to an anaphylactic reaction, continued oids, such as fentanyl (32), usually occur within 10 min exposure to latex will increase the possibility of such a of the drug exposure but can also occur later (30 min reaction. A health care worker who is atopic is at to several hours). In general, drugs that have been increased risk, and the risk is increased if they had a used for long, continuous periods of time before the previous surgery (40). Anesthesiologists have a 12.5% onset of an anaphylactic reaction are less likely to be and 2.4% prevalence of latex sensitization and allergy, the causative drug as opposed to a medication that respectively (2). Adult anesthesiologists change gloves was recently given (33). Sometimes it may be difficult more often than pediatric anesthesiologists and have to pinpoint the exact cause of the anaphylactic reaction been demonstrated to have an increased prevalence of either because of multiple medications being used or latex sensitization (41). There is no increased risk of because of the failure to consider a medication that latex allergy with age, race, or sex, and exposure is the could cause an allergic reaction. Because latex is often single most significant factor associated with latex not considered a medication, it is often not considered allergy (2,42). in the differential diagnosis of anaphylaxis, and this The use of powdered gloves in the United States has may lead to an erroneous diagnosis (34,35). There are been significantly reduced in recent years. The re- also reports of anaphylaxis where the practitioner was moval of powder from gloves is important and is part not aware that a device, such as a pulmonary artery of the continued evolution of improving the latex catheter, was made out of latex (36). Latex should products that we use today. Latex sensitivity and always be considered in the differential diagnosis latex-related symptoms such as urticaria, pruritus, when an episode of perioperative anaphylaxis occurs. asthma, and rhino-conjunctivitis have been shown to Failure to do so may lead to the wrong diagnosis or to decrease in health care workers by changing from another life-threatening episode if another exposure to high-protein powdered gloves to low-protein, powder- latex occurs. free gloves (43). The American Academy of Allergy, ANESTH ANALG REVIEW ARTICLE HEPNER AND CASTELLS 1223 2003;96:1219–29 LATEX ALLERGY

Asthma, and Immunology and the American College of Table 2. Diagnosis of Latex Sensitization Allergy, Asthma, and Immunology recommend the use Focused history and physical examination of powder-free latex gloves to decrease latex sensitivity Acute reaction among health care workers (44). A cost analysis of a Blood testing conversion to a latex safe environment (no latex content Serum tryptase at all) demonstrated that although there would be an Retrospective diagnosis initial increase in cost, it would be more than offset by Detection of specific latex IgE antibodies the costs of diagnosis and disability because of latex Radioallergosorbent test (RAST) Pharmacia ImmunoCAP (CAP blood testing) sensitivity (45). HY-TEC AlaSTAT Standardized Latex-Fruit Syndrome Depends on total IgE levels Some fruits, such as bananas and pears, con- Sensitivity around 60% tain cross-reacting proteins with latex (46). In one Specificity close to 90% study, fresh latex serum, latex gloves, avocado pears, Class 0–VI Class 0: negative and bananas shared a 30-kd (46). An interest- Class I: weakly positive ing finding from this study is that patients who were Class II–III: moderately positive allergic to latex but not to fruits lacked the 30-kd Class IV: highly positive protein band. In another study, IgE antibodies were Class V–VI: very highly positive detected for a 30-kd protein present in , Skin testing bananas, guavas, citrus fruits, and peaches (47). Latex Europe cross-sensitization with is common in South Ammoniated source of latex Nonammoniated source of latex Florida because of the ubiquity of trees in this United States area. Signs of allergic reactions to these fruits include Nonammoniated latex trials pruritus, tightness in the throat, breathing difficulty, Not Food and Drug Administration approved and hives. One study found that 21.1% (29 of 137) of IgE ϭ . patients with documented latex allergy had also . Fruits in that study included bananas, kiwis, Table 3. Risk Factors for Latex Allergy watermelons, and peaches (48). In another study, 86% (49 of 57) of fruit-allergic patients were also allergic to Contact dermatitis latex compared with 4% (2 of 50) of controls (49). Urticaria to melons, watermelons, peaches, bananas, Asthma cherries, and pears were common. Other foods often Rhinitis Atopic background cited as being cross-reactive with latex include avoca- Multiple surgical procedures (e.g. spina bifida and dos, chestnuts, papains, potatoes, and tomatoes (50). genitourinary anomalies) Whereas patients allergic to fruits have an 11% risk of Anaphylaxis during previous surgical procedures a latex reaction, patients allergic to latex have a 35% Health care workers or workers in frequent contact with risk of a reaction to fruits (51). latex Cross-reactivity with fresh fruits and nuts

Any of the above present in the history and physical examination should Diagnosis increase suspicion on clinical grounds for latex allergy. In the United States, the diagnosis of latex allergy is based on a focused history and physical examination presence of signs and symptoms suggestive of mast- followed by positive in vitro testing (52). A document cell activation and release of mediators. These include released by the American Society of Anesthesiologists hypotension, bronchospasm, laryngeal edema, flush- in 1999 states that a positive history or physical exam- ing, and urticaria. Other signs during an anesthetic ination and a positive in vitro test establish the diag- include difficult hand ventilation, increased peak in- nosis of latex sensitivity (53). Standards for the diag- spiratory pressure, expiratory wheezes, increased nosis of latex allergy in the United States rely on in end-tidal carbon dioxide with an up-sloping of the vitro serologic tests (Table 2). In vivo testing with am- tracing, tachycardia, and decreased blood pressure. moniated latex or from a nonammoniated source of Blood Testing. The retrospective diagnosis is based latex is often used in Europe. on serologic tests because skin testing is not currently The diagnosis of anaphylaxis induced by latex is not approved in the United States. B-tryptase is a neutral different than that induced by other drugs or aller- protease stored in mast-cell secretory granules, which gens. Table 3 outlines the components of the history correlates with the level of hypotension, and an in- and physical examination that should increase the creased serum level demonstrates that mast-cell acti- index of suspicion for latex allergy. It is based on the vation with mediator release has occurred (54,55). The 1224 REVIEW ARTICLE HEPNER AND CASTELLS ANESTH ANALG LATEX ALLERGY 2003;96:1219–29

level peaks at approximately 30 min and then gradu- latex sensitization (Ͻ1%) in the general population ally decreases (half-life is 2 h), but the more severe the (62). reaction, the larger the B-tryptase level. The level may Skin Testing. Skin testing should be performed 4–6 persist in the blood for many hours or even days after wk after the anaphylactic episode because of mast-cell the episode (54,55). Levels of total tryptases more than mediator depletion. There is the risk of inducing sys- 13 ng/mL or of ␤ tryptase more than 1 ng/mL are temic anaphylaxis, and therefore, these tests should specific for anaphylaxis because basophils possess only be performed by physicians with adequate resus- minimal amounts of tryptase (56). Histamine is not citative equipment and training. There are no com- measured routinely because of its short half-life of a mercially available latex extract skin testing reagents few minutes. Urine histamine collections can be per- in the United States, but there are reports of the use of formed for 24 h after the anaphylactic episode and minute extracts of latex gloves (37). The problem is may be increased depending on the magnitude of that different types of latex gloves contain different anaphylaxis. Histamine is not specific for mast cells, amounts of proteins (63). Even the same type of gloves and basophils have similar amounts (57). may contain different amounts of latex proteins be- Serologic Testing. Serology involves the quantita- cause of different storage conditions. Skin testing re- tive measurement of serum-specific IgE antibodies to agents in Europe are made from ammoniated latex, latex. Serologic tests can be performed while the pa- used in the manufacturing of latex gloves, or from a tient has extensive skin lesions, is on medications such nonammoniated source of latex (64). as antihistamines, or has presented with a recent epi- Hamilton and Adkinson (65) compared nonammo- sode of anaphylaxis. The FDA has approved three niated latex, ammoniated latex, and ex- different serum tests that use the RAST technique and tracts as skin testing reagents in nonlatex-allergic and include the Pharmacia ImmunoCAP (Pharmacia latex-allergic volunteers. They demonstrated that as AB, Uppsala, Sweden), the HY-TEC EIA system long as equivalent total protein amounts were used, (HYOCOR Biomedical, Irvine, CA), and the AlaSTAT equivalent diagnostic sensitivity and specificity were observed in all groups. The authors concluded that (Diagnostic Product, Inc, Los Angeles, CA) (58). RAST nonammoniated latex might be considered the reagent tests are highly specific, but their sensitivity is low. of choice on the basis of practical quality control and The ImmunoCAP and AlaSTAT tests have specificities reproducibility considerations (65). The same authors that range from 80%–87% and sensitivities that range went on to document the safety and diagnostic sensi- from 50%–90% (53). The results of these tests are di- tivity of a nonammoniated latex extract in 358 adults vided into seven classes and range from Class 0 to (66). The participants underwent serologic testing for Class VI. Class 0 demonstrates the absence of IgE the presence of latex-specific IgE (Pharmacia Cap) and antibodies, and Classes I to VI demonstrate the pres- skin testing. The skin-prick test was very sensitive and ence of serum-specific IgE antibodies to latex. specific, and none of the participants with a history of Whereas Classes I and II demonstrate a significant latex allergy developed an episode of systemic ana- increase, Classes V and VI demonstrate a very large phylaxis. Some of these patients did develop signs of increase of IgE antibodies. The rate of false-positive mild systemic reactions such as pruritus, rash, rhinitis, tests is mostly because of antibodies against carbohy- ocular itch, or urticaria after skin testing (66). More drates that cross-react with IgE antibodies to latex recently, Biagini et al. (67) performed skin testing of (59,60). The rate of false negative is frequent (25%), health care workers with native forms of the Hev b and negative IgE antibody results should be inter- allergens. Whereas skin testing with these allergens preted with caution, especially in the setting of a pos- identified most latex-allergic health care workers, it itive history for latex sensitivity. The HY-TEC assay was not as sensitive or as specific as the nonammoni- has a less frequent false-negative rate but at the ex- ated latex. pense of a 25% false-positive rate. The HY-TEC assay has increased sensitivity (close to 10% more than the other two tests) at the cost of a decreased specificity. Recent work demonstrated that these FDA-approved Management serologic tests failed in some cases to identify common Discontinuation of the potential trigger and of the allergenic latex such as Hev b 2, 4, 5, 6, and anesthetic drug is very important in the treatment of 7b, furthermore demonstrating the small diagnostic anaphylaxis. Gloves should be changed to nonlatex if sensitivity of these tests (61). It is not currently recom- anaphylaxis is suspected and latex gloves are being mended to screen patients for latex allergy before a used. Special attention should be given to a recent surgical procedure in the absence of a suggestive his- medication or blood product that was given, and their tory. Doing so may significantly overestimate the in- administration should be discontinued. No further cidence of latex sensitization because of the poor sen- medications, other than those required for the treat- sitivity of the RAST tests and the small prevalence of ment of anaphylaxis, should be given. ANESTH ANALG REVIEW ARTICLE HEPNER AND CASTELLS 1225 2003;96:1219–29 LATEX ALLERGY

Therapeutic options include airway maintenance with (72) on latex allergy in health care workers demon- 100% oxygen, IV fluids to sustain the blood pressure strated that although the skin-prick test remained pos- (25–50 mL/kg), and resuscitation medications. Epineph- itive 2 yr after latex avoidance, latex specific IgE levels rine is the most important medication for the treatment decreased in most patients. In addition, allergic symp- of anaphylaxis. Its ␣-agonist properties help sustain the toms decreased in most patients. blood pressure, whereas its ␤2 effect is effective in re- Dakin and Yentis (73) developed a strategy for man- lieving bronchoconstriction. The dose and route used agement of latex allergic patients that consists of a depends on the severity of the episode. Whereas the collection of information of medical equipment in- allergy literature recommends initial doses of 0.2–0.5 mg cluding latex-free and latex-containing items and latex subcutaneously or IM (54), the presence of an IV catheter containing items that could be used with modification. during an anesthetic and the faster systemic absorption These authors contacted the technical support division via the parenteral route suggest that an IV administra- of the different manufacturers of medical equipment tion is preferred during anesthesia. The recommended and posted these lists together with a protocol to dose is 5–10 ␮g IV (0.l ␮g/kg) as the initial bolus in the manage latex-allergic patients in a latex-free box in the presence of severe hypotension, followed by a titration OR and labor and delivery floor (73). A protocol to to maintain systolic blood pressure (68). In the presence manage latex-allergic patients consists of identifica- of cardiovascular collapse, 0.1–0.5 mg IV of epinephrine tion of at-risk groups, latex-free environment, and should be promptly administered (68). The experience of close coordination between all health care personnel one of the authors (DH) suggests that the cardiovascular involved in the management of these patients. collapse may be severe enough to warrant repeated The American Society of Anesthesiologists Task Force doses of epinephrine and that an infusion may be re- of Latex Sensitivity recommends that patients who are quired (69). latex allergic have a surgical procedure performed as the Other useful medications include antihistamines (di- first case in the morning, when the levels of latex aeroal- phenhydramine 0.5–1 mg/kg IV or IM), bronchodilators lergens are the smallest (53). If it is not possible to do the (albuterol and ipratropium bromide via nebulization), case first, it is recommended to wash hands especially H-2 blockers (ranitidine 150-mg IV bolus or cimetidine thoroughly to remove any traces of powder or latex. It is 400-mg IV bolus), and corticosteroids (methylpred- best to use nonpowdered gloves to avoid all latex aeroal- nisolone 0.5 mg/kg). Corticosteroids are not the first line lergens (74). The OR should be latex safe, and all medical of treatment because of their prolonged onset but are products should be made of nonlatex materials. A resus- beneficial for delayed and late reactions. Once the initial citation cart should be next to the OR, and the room event is treated and the patient is medically stable, a should be labeled (in a visible place) as a latex-free OR. serum tryptase should be drawn, and an allergy consul- Holzman (75) demonstrated that a latex-safe protocol tation should be obtained. was effective in preventing anaphylaxis in latex-allergic Pharmacological prophylaxis in the acute setting children. No prophylaxis was used in 267 anesthetics, with H-1 blockers (e.g., diphenhydramine), H-2 block- and there was only one episode of anaphylaxis. This ers (e.g., ranitidine), and steroids (e.g., methylpred- episode occurred in close temporal relation to the injec- nisolone) is currently not recommended for patients tion of a local anesthetic-opioid mixture from a syringe with a documented latex allergy undergoing a surgi- with a latex stopper. The mixture was prepared 1.5 wk cal procedure. These medications do not produce any before the injection, and the patient tolerated the same changes in the sensitized mast cells and basophils. mixture when prepared from a latex-free syringe (75). Prophylaxis can diminish the early immune response, Although glass syringes or syringes with latex-free may blunt the early signs of anaphylaxis, and occa- plungers (e.g., Becton Dickinson syringes, Becton sionally a very severe response such as cardiovascular Dickinson, Franklin Lakes, NJ) are the ideal approach, collapse may be the only presenting sign (70,71). drawing the medication immediately before use into a syringe with a rubber-tipped plunger has been re- ported without complications (76). However, there is a report of an allergic reaction to latex in a patient who Prevention received morphine that was drawn immediately be- Prevention is the cornerstone in the management of fore the administration in a syringe with a rubber- latex sensitization. Patients should be educated re- tipped plunger (77). The bottom line is that it is safer garding their condition and the means to protect to use glass syringes or those with latex-free plungers, themselves from future reactions by avoiding latex, especially in patients with known episodes of latex wearing a Medic-Alert bracelet that identifies latex anaphylaxis. If a syringe with a rubber tip plunger is allergy for emergency situations, and carrying an Epi- used, the contents of the syringe should be injected Pen at all times. Table 4 identifies latex-free products immediately after filling to decrease release available in the community. A recent follow-up study from the plunger. Premixed syringes of drugs should 1226 REVIEW ARTICLE HEPNER AND CASTELLS ANESTH ANALG LATEX ALLERGY 2003;96:1219–29

Table 4. Latex Products and Safe Alternatives Available in the Community Latex containing Latex free alternative Balloons Mylar balloons Plastic or cloth toys Balls, koosh ball Vinyl, thronton sport ball Belt for clothing Leather or cloth belts Beach shoes Cotton socks Bungee cords Rope or twine Cleaning/kitchen gloves Vinyl Condoms Polyurethane avanti for males Polyurethane reality for females Crib mattress pads Heavy cotton pads Crutches - axillary, hand pads (guardian) Cover with stockinette Elastic bands Paper clips or twine Elastic on legs, waist of clothing/ Elastic on disposable diapers or rubber pants Cloth, velcro closures Feeding nipples Silicone nipples Foam rubber lining on splints, braces Line with cloth, felt Gloves, household Alleden—cotton gloves Bluette—synthetic gloves Monkey grip—PVC heavy duty Nimble fingers—vinyl Task handlers—synthetic Halloween rubber masks Plastic mask or water based paints Pacifiers Plastic pacifier—“The first years” Silicone—Pur, Gerber, Soft-Flex Racquet handles Leather handles Rain rubbers Lean vinyl “rubbers” Raincoats/slickers Nylon or synthetic waterproof coats Rubber bands/stamps Bands/stamps without rubber Rugs with rubber backing Rugs without rubber backing Shoes with rubber bottoms Leather or synthetic bottoms Sneakers Leather shoes Swim fins Clear plastic fins Swimming goggle rims Clear plastic rims Telephone cords Clear cords Tongs sandals Leather sandals Tooth massagers Soft brushes Wheelchair cushions (Roho) Cover with cloth

These lists are offered as a guideline to individuals, families, and professionals. It is very difficult to obtain full and accurate information on the latex content of products, which may vary between companies and product series. Double-checking with suppliers before use with latex allergic individuals is strongly recommended. be avoided except in an emergency where the benefits should be kept upright and not shaken (78). This case of rapid treatment would outweigh the risk of addi- involved the use of a methylprednisolone vial that con- tional latex exposure. However, it is best to notify the tained two rubber stoppers and required the displace- pharmacy in high-risk cases so that freshly prepared ment of one of the stoppers to mix the solid and liquid syringes with emergency medications are available, parts of the medication (78). ideally prepared in latex-free syringes. Although it is safest to use IV tubing, fluids, and It is best to use medications from glass ampoules if injection ports that are latex-free, such as the Walrus available. If the formulation comes only in vials with anesthesia sets, latex-containing anesthesia sets have stoppers, it is best to use those not made of latex. How- been used and recommended in patients with known ever, it is our experience that it is very difficult to know latex sensitivity as long as the latex injection ports are and keep track of which stopper is made out of latex. not instrumented (76,78). Medications should be in- Furthermore, most stoppers contain latex. It has been jected IV with the use of a stopcock, and all injection recommended to avoid instrumentation of the rubber ports, including Y-sites, rubber boots, and T-pieces, stopper with a syringe but instead to remove the stopper should be covered with tape to prevent the accidental and then to draw up the medication (76–78). Because puncturing of these sites. Penetrating these sites may there is a report of an allergic reaction to latex from a vial lead to liberation of latex particles into the IV fluid stopper that was not punctured with a needle, the vial stream. Most injection sites are now latex free. ANESTH ANALG REVIEW ARTICLE HEPNER AND CASTELLS 1227 2003;96:1219–29 LATEX ALLERGY

It is important that hospitals purchase nonpow- in a radiology technician with occupational latex al- dered surgical and examination gloves with small la- lergy that was successful in minimizing respiratory tex protein content to prevent the sensitization of and cutaneous symptoms (85). The patient was given health care workers and of patients requiring multiple incremental injections of latex extract subcutaneously surgical or nonsurgical procedures. Most reports of until a local or systemic reaction was demonstrated. A positive skin-prick responses to latex glove extracts in maximum tolerated dose was calculated by the pa- latex sensitized individuals occur when the protein tient’s response and was given weekly to build up content is more than 100 ␮g/g, as measured by the tolerance. Although there was an improvement in modified Lowry method (79). Smaller levels of protein clinical symptoms, there was no significant change in exposure will reduce the risk for sensitization and the patient’s serum levels of IgE to latex, except for elicitation of symptoms. The European Commission’s a mild increase at the end of the immunotherapy Scientific Committee on Medicinal Products and Med- (85). Another randomized, double-blinded, placebo- ical Devices’ opinion of NRL allergy (80) was that the controlled trial study conducted in Europe with a modified Lowry method is useful to distinguish be- standardized latex extract on latex-allergic health care tween gloves containing small, moderate, and large workers demonstrated improvements in the incidence protein levels, is simple to perform, and can be used as and severity of rhinitis, conjunctivitis, and cutaneous a routine method for monitoring production. How- symptoms (86). However, severe side effects including ever, because the limit of sensitization is likely to be hypotension, bronchospasm, and pharyngeal edema close to or less than the quantification limit of the developed in some patients. The authors acknowl- assay, there are concerns about whether it can be used edged that further clinical trials with a smaller main- to define a safe protein level (80). It is of note that the tenance dose of latex extract are required before rec- FDA allows manufacturers of latex gloves to have a 50 ommending this therapy (86). In addition, the authors ␮g/g detection limit (81). There are concerted efforts caution that immunotherapy with latex allergen by glove manufacturers in Malaysia to reduce the should be performed by experts in the field of allergy protein content of latex gloves to less than 100 ␮g/g. in a center with resuscitation equipment. Although the threshold latex protein level for sensiti- More recently, five cases of desensitization to latex zation is unknown, the potential for allergenicity is were successfully performed by means of an original markedly decreased when the level is Ͻ100 ␮g/g. contact exposure protocol (87). Five health care work- ers with proven IgE-mediated latex allergy progres- sively increased their exposure to latex first by wear- ing latex gloves for 10 s/d on one hand. The goal was Future Therapies to reach a final exposure of 1 h in both hands twice a Many patients who have latex allergy may be forced to day at the end of a 1-yr period. All five subjects quit their jobs, and complete avoidance of latex is diffi- completed the protocol, no subject experienced side cult. Latex is found in many surgical products because it effects, the cutaneous reaction to latex was markedly is relatively cheap, durable, and resistant (53). The tactile decreased, and the latex-specific IgE levels decreased properties of latex are hard to replace, especially for after the desensitization. The authors caution that surgeons performing fine surgeries. Vinyl gloves can be these are preliminary reports and that future studies used as an alternative to latex, but durability and barrier with a larger number of patients are required before properties have been of concern (82,83). Latex-sensitive recommending this treatment (87). individuals may develop symptoms of rhinitis and con- Recently, Hev b 5, a major latex allergen, has been junctivitis when exposed to areas with increased levels modified at critical amino acid residues by site di- of latex aeroallergens. This is of particular concern to rected mutagenesis (88). This modification has re- health care workers, and it may be difficult to modify the sulted in decreased IgE binding activity, and new working environment. Recent work has demonstrated recombinant Hev b 5 proteins are being considered as that aerosol or particulate face masks were effective in candidates for immunotherapy (88). Modified latex reducing occupational exposure to latex (84). The use of proteins would induce little IgE binding on mast cells powder-free gloves throughout the working environ- and few or no adverse reactions upon exposure. In ment is a much easier and effective alternative than addition, hevein (Hev b 6.02) has been well character- wearing masks. ized as a three-dimensional structure and is consid- Immunotherapy, the controlled, standardized ad- ered as a good candidate for allergen specific immu- ministration of an allergen to a sensitive patient, has notherapy (89). Its terminal regions were modified proven effective in protecting patients with insect with single-point mutations that caused a decrease in venom allergy and anaphylaxis. Immunotherapy has IgE binding capacity. been considered in the setting of latex allergic health Humanized anti-IgE monoclonal antibodies have care workers. There is a report of subcutaneous de- been produced with a potential role in latex allergy sensitization treatment with standardized latex extract and anaphylaxis. Patients with asthma and allergies 1228 REVIEW ARTICLE HEPNER AND CASTELLS ANESTH ANALG LATEX ALLERGY 2003;96:1219–29

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