Anesthesia for the Pregnant Patient with Immunologic Disorders

Stephen H. Halpern

Margaret Srebrnjak

Introduction

The role of the immune system is to rid the body of foreign material such as bacteria, viruses, and other foreign matter. However, in predisposed individuals, an overreaction to foreign antigens can occur, resulting in a wide variety of pathologic states and syndromes. Some immunologically mediated disorders are acute and life-threatening, such as anaphylaxis, while others are chronic, such as rheumatoid disease and allograft rejection. None of these preclude pregnancy.

Immunologic responses are divided into two major divisions, the innate immune response and the adaptive immune response. The innate immune system is a non-specific and immediate reaction to a foreign allergen and does not change regardless of how many times an infectious agent is encountered. It includes physical barriers, such as the epidermis and mucous, as well as elements of the immune system such as natural killer cells, phagocytes, cytokines, and complement. Complement factors are a group of serum and cell surface proteins, which cause an amplifying series of enzymatic reactions when activated; they can cause direct cell lysis, facilitate phagocytosis of the foreign cell, or cause the release of mediators (1).

Higher organisms have also developed an antigen-specific immunologic reaction called adaptive immunity that works in concert with innate immunity. Specifically, an individual will respond, more rapidly and robustly, to specific antigens on subsequent exposure, using T and B cells. It is a reaction with “memory,” since it relies on an initial exposure (2).

When an antigen is presented and recognized by antigen-specific T cells and B cells, priming, activation, and differentiation occur. B cells proliferate and differentiate into antigen-specific memory cells and plasma cells. Plasma cells secrete antibodies, such as immunoglobulin (Ig) A, G, or E, whose role is to neutralize toxins, activate complement, and facilitate phagocytosis of foreign cells. Only IgG crosses the placenta (1). T cells also proliferate and differentiate into memory cells as well as effector T cells.

There are four classic hypersensitivity reactions that lead to tissue injury. Similar mechanisms also cause autoimmune diseases. For the purpose of this chapter, the classification works well for both (Table 38-1). Recently, several subcategories under Type IV hypersensitivity have been included as our understanding of immune reactions has expanded (2).

Type I Hypersensitivity (IgE-mediated Reactions)

Immediate hypersensitivity or anaphylaxis is a reaction that requires the recognition of antigens by membrane-bound IgE on mast cells in the tissues and basophils in blood. A single cell may be armed with specific IgE molecules for many different antigens. When an allergen is re-encountered, a change in the shape of the cell membrane occurs resulting in degranulation and the release of vasoactive peptides and chemotactic factors. The immediate reaction is mostly carried out by mast cells with basophils being activated and recruited a few hours later (2).

Inhalation of antigens and subsequent mediator release leads to bronchoconstriction and mucous secretion; ingestion of antigens causes diarrhea and vomiting; and subcutaneous antigens produce urticaria and angioedema. With intravascular antigen exposure, systemic activation occurs, causing increased capillary permeability, hypotension, tissue swelling, and smooth muscle contraction (Fig. 38-1) (2).

Anaphylaxis Terminology

Defining anaphylaxis is a challenge. Some interpret it as a broad term describing a severe, life-threatening, generalized hypersensitivity reaction, while others define it as a specific IgE-mediated reaction (3,4). Recently, National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network proposed clinical criteria for the diagnosis (Table 38-2).

Anaphylactoid reactions appear similar to IgE-mediated hypersensitivity, but do not involve antibodies or a previous exposure. Mechanisms include, non-specific complement activation and direct histamine release. For example, most muscle relaxants and opioids release histamine directly from mast cells. Unlike anaphylaxis, many anaphylactoid reactions can be attenuated with antihistamines, corticosteroids, and the slow administration of drugs. Most drugs can cause both types of reactions (5).

Type II Hypersensitivity (Antibody-mediated Cytotoxic Reactions)

The antibody-mediated cytotoxic immune response is initiated by the binding of circulating IgM or IgG antibodies with cell surface or tissue-matrix antigens, which have been modified to make the antigen foreign. The antigens may be normal red blood cell antigens like those in autoimmune hemolytic anemia or they may be altered such as when penicillin attaches to red blood cells and initiates a drug-induced hemolytic anemia (1,2).

Once antibodies bind to the cells, the complement cascade is initiated. Activated complements C3 and C5, also known as anaphylatoxins, work directly to cause mast cell degranulation. Some complement factors enhance phagocytosis of the targeted cell by macrophages, neutrophils, and eosinophils; others form a membrane-attack complex that perforates the cell membrane causing cell lysis and death. This mechanism is responsible for disorders such as erythroblastosis fetalis, immune thrombocytopenia, and myasthenia gravis (1,2).

Table 38-1 Major Types of Immune-mediated Hypersensitivity Reactions

Mechanism	Antigen	Effector Mechanism	Examples
Type I Hypersensitivity (Immediate)	Soluble allergen	Mast cell–bound IgE Histamine, tryptase, carboxypeptidase, serotonin, PAF	Anaphylactic shock Allergic rhinitis Angioedema Urticaria
Type II Hypersensitivity (Cytotoxic)	Cell-surface Ag Tissue-matrix Ag	IgG or IgM Phagocytes, NK cells Complement	Hemolytic transfusion reactions Erythroblastosis fetalis ITP Graves’ disease
Type III Immune complex mediated	Soluble Ag	IgG Phagocytes, NK cells Complement	SLE SBE
Type IV Delayed-type hypersensitivity	Soluble Ag Soluble Ag Cell-associated Ag	T_H 1 cell Release cytokines to attract macrophages T_H 2 cell Release cytokines to attract eosinophils and stimulate B cells T_C cell	Tuberculin test Contact dermatitis RA (in part) Multiple sclerosis Chronic rhinitis Chronic asthma Allograft rejection (in part)
Ag, antigen; IgE, immunoglobulin E; IgG, immunoglobulin G; IgM, immunoglobulin M; PAF, platelet activating factor; ITP, immune thrombocytopenic purpura; SLE, systemic lupus erythromatosus; SBE subacute bacterial endocarditis; T_H 1, Type I helper T cell; T_H 2, Type II helper T cell; T_C, cytotoxic T cell; RA, rheumatoid arthritis Adapted from: Salmon JE. Mechanisms of immune-mediated tissue injury. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, PA: Saunders Elsevier; 2008:266–270.

Figure 38-1 Mechanisms of IgE-mediated reactions.

Table 38-2 Clinical Criteria for Diagnosing Anaphylaxis

Anaphylaxis is highly likely when any one of the following three criteria are fulfilled:

Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips–tongue–uvula)
AND AT LEAST ONE OF THE FOLLOWING
1. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
2. ↓BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
1. Involvement of the skin–mucosal tissue (e.g., generalized hives, itch-flush, swollen lips–tongue–uvula)
2. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
3. ↓ BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)
4. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
↓ BP after exposure to known allergen for that patient (minutes to several hours)
- Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline

PEF, Peak expiratory flow; BP, blood pressure
Data from: Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391–397.

Type III Hypersensitivity (Immune Complex Diseases)

Immune complex diseases occur when small, soluble antigen–antibody complexes deposit in vascular beds, glomerular and pulmonary basement membranes, and serous cavities. Complement is activated and inflammation occurs. The prototypical Type III autoimmune disease is systemic lupus erythematosus (SLE). Patients with SLE develop circulating IgG against native cellular elements such as DNA (2).

Type IV Hypersensitivity (Delayed-type Reactions)

Delayed hypersensitivity is mediated by antigen-specific effector T cells that require 1 to 3 days to respond. These T cells include antigen-specific T helper cells and cytotoxic T cells. Cytotoxic T cells directly attack foreign cells while antigen-specific T helper cells release cytokines. In the tuberculin test or contact dermatitis, Type I T helper cells release cytokines to signal macrophages to the site of reaction. Rheumatoid arthritis and multiple sclerosis are thought to be caused in part by a Type I T helper cell–mediated reaction. With chronic asthma and chronic allergic rhinitis, Type II T helper cells use cytokines to facilitate antibody production from B cells and to attract eosinophils to carry out tissue inflammation. Chronic allograft rejection is largely due to cytotoxic T cell function (2).

Type I Hypersensitivity (Ige-Mediated Reactions)

Allergy to Anesthetic and Non-anesthetic Agents

Epidemiology

The incidence of perioperative immediate hypersensitivity is poorly defined because of variations in reporting accuracy and completeness. However, the incidence of all immediate hypersensitivity reactions associated with anesthesia is about 1:5,000, while the incidence of allergic anaphylaxis is about 1:10,000. The associated mortality is between 3% and 9% (6). Neuromuscular blockers are most frequently implicated as a cause of perioperative anaphylaxis, followed by latex, and antibiotics (Fig. 38-2).

There are no specific risk factors for allergy to medications. However, patients who have had a previous, uninvestigated severe reaction during anesthesia are at increased risk of recurrence (7). It is unrelated to atopy, a history of multiple allergies, genetics, allergy to non-anesthetic drugs, or a history of multiple chemical sensitivities (8). Although asthma does not increase the incidence of anaphylaxis during anesthesia, it is a risk factor for severe respiratory symptoms (7).

Presentation

In general, agents that have been used for long, continuous periods before the onset of an acute reaction are less likely a cause of hypersensitivity than agents recently introduced (9). Intravenously administered medications cause symptoms rapidly. Drugs given rectally elicit symptoms over 15 to 30 minutes and chlorhexidine allergy often takes 10 minutes or longer to manifest depending on the route of administration (10).

Figure 38-2 Causes of anesthetic-related anaphylaxis.

Figure 38-3 Grading of the severity of the clinical signs of immediate hypersensitivity.

Presentation of anaphylaxis is variable but if symptoms occur rapidly, it is more likely the reaction will be severe and life-threatening (11). In addition, anaphylaxis produces more severe symptoms than anaphylactoid reactions (12). A four-point grading scale may be useful to describe the severity of the reaction (Fig. 38-3) (13).

The awake patient may complain of pruritus around the lips, tongue, ear canal, eyes, palms, and genitalia. They also complain of a metallic taste in the mouth, headache, and a feeling of impending doom. Gastrointestinal symptoms include nausea, vomiting, and abdominal cramps. With progressive angioedema, they may have hoarseness, dysphonia, shortness of breath, chest pain, and eventual cardiovascular collapse. Female patients may also complain of uterine cramps (11).

During general anesthesia, common initial features include pulselessness, desaturation, and difficulty with ventilation (7). Low oxygen saturation can occur as a result of mucus plugging, bronchospasm, or impaired circulation. Skin manifestations are less helpful since draping can obscure urticaria and angioedema, and in severe cases, cardiovascular collapse may occur before skin signs appear. Overall, cutaneous symptoms can be absent in 33% of patients (14) but some of these appear after blood pressure is restored. Cardiovascular symptoms typically include tachycardia and hypotension but in 10% of cases, bradycardia is a prominent feature due to profound hypovolemia (4,7). In very severe cases, the patient may also develop disseminated intravascular coagulation (DIC) (11).

Management

Management of the parturient should include: (1) Remove or discontinue the offending agent, (2) administer 100% oxygen and maintain an open airway, (3) call for help and administer epinephrine for Grade III and IV reactions, and (4) maintain venous return by displacing the uterus to the left or positioning the patient in the full left lateral position. Pharmacologic treatment is discussed in Table 38-3.

It is important to administer intravenous epinephrine and maintain intravascular volume. While epinephrine is not used for Grade I reactions, it is indicated for Grade III or IV reactions. Electrocardiographic monitoring is needed since epinephrine can provoke ventricular arrhythmias. Patients on β blockers can have a blunted response to epinephrine, often requiring large volumes of fluid, high doses of epinephrine, and glucagon. Other resuscitative drugs should be considered in epinephrine-resistant anaphylaxis, such as dopamine, norepinephrine, or vasopressin. In Grade IV cases, as much as 35% to 50% of the intravascular fluid can transfer to the extravascular space within 10 minutes; large volumes of colloid or crystalloid may be required and therapy should be initiated early (7).

Histamine receptor blocking drugs and corticosteroids may be useful adjuncts. Antihistamines are particularly effective for angioedema and urticaria but the value of corticosteroids for reducing the risk of a recurrence has not been proven. Corticosteroids decrease late swelling of the pharynx and larynx. Salbutamol or albuterol are indicated for bronchoconstriction, but should not replace epinephrine in instances of severe bronchospasm and cardiovascular collapse (7). Patients have also been given tranexamic acid when anaphylaxis has been associated with DIC (11).

Anaphylaxis usually resolves in 2 to 8 hours in the absence of secondary pathology (4), but continued vigilance is mandatory since reactions may recur 1 to 72 hours after onset, in up to 23% of patients (11).

Specific Considerations in the Pregnant Patient

During anaphylaxis, the fetus is not exposed to maternal toxic inflammatory mediators such as histamine, as they are metabolized by the placenta. Since maternal IgE does not cross the placenta, an immune reaction should not occur in the fetus. However, the fetus is vulnerable to inadequate placental perfusion secondary to maternal hypotension. While epinephrine may cause uterine artery vasoconstriction, it should be used in effective doses to terminate the anaphylactic reaction. The use of ephedrine is controversial (15), as it may not effectively correct maternal hypotension.

Left uterine displacement should be used after 20 weeks’ gestation to avoid aortocaval compression. The American Heart Association advocates that critically ill parturients who are at risk for cardiac arrest should be placed in the full lateral position to maintain venous return, blood pressure, cardiac output, and fetal oxygenation (16).

For an urgent or emergency cesarean delivery, regional anesthesia can be considered if the patient is hemodynamically stable and the fetus is not in distress. If the patient experienced oropharyngeal or laryngeal edema, immediate airway management may be indicated. Observation for airway obstruction should continue for several hours in case relapse occurs (11).

Specific Allergies

Local Anesthetic Agents

Many patients experience adverse reactions to local anesthetics (LAs) but only less than 1% are due to immune hypersensitivity reactions (17). When patients are referred for LA allergy testing, other allergens such as chlorhexidine or latex are found much more frequently to be responsible for the reaction (18). Both Type I and Type IV hypersensitivity reactions occur, with delayed-type hypersensitivity being more common (17).

Immediate hypersensitivity caused by LAs, presents with the typical symptoms of anaphylaxis within minutes of injection. Delayed-type hypersensitivity manifests as contact
dermatitis from topical preparations or localized edema from dental injections. Type IV reactions appear within 1 to 3 days but some occur as soon as 2 hours, causing difficulty in differentiating them from a Type I immediate reaction (17).

Table 38-3 Pharmacologic Management of Anaphylaxis in the Parturient

Ephedrine	Grade II reactions (moderate): BOLUS: 10 mg IV every 1–2 min Switch to epinephrine if there is no response or severity increases
Epinephrine	Grade II reactions (moderate): BOLUS: 10–20 μg IV Sc/im 200–500 μg (lateral thigh) every 5 min until IV obtained Grade III reactions (severe): BOLUS: 100–200 μg IV every 1–2 min INFUSION: 1–4 μg/min Grade IV reactions/Cardiac Arrest: BOLUS: 1–3 mg IV over 3 min (3–5 mg over next 3 min) INFUSION: 4–10 μg/min
Fluid	IV crystalloid 5–10 mL/kg over 5 min 1,000–2,000 mL, after 30 mL/kg switch to colloids
Diphenhydramine	25–50 mg IV (Grade II–IV reactions require epinephrine first)
Ranitidine	50 mg IV (Grade II–IV reactions require epinephrine first)
Salbutamol or Albuterol	Inhalation: 2.5–5 mg in 3 mL saline nebulized BOLUS: Salbutamol 100–200 μg INFUSION: Salbutamol 5–25 μg/min
Glucocorticoids	Hydrocortisone hemisuccinate 200 mg IV every 6 h (Grade II–IV reactions require epinephrine first)
Other vasopressors: Dopamine: 2–20 μg/kg/min Glucagon: 1–5 mg IV over 5 min, then 5–15 μg/min Consider early with patient on β blockers Norepinephrine: 5–10 μg/kg/min Vasopressin: Bolus: 2–10 IU IV until response
IV, intravenous; μg, micrograms; sc, subcutaneous; im, intramuscular.

Local anesthetics are divided into two groups, based on their chemical structure. The benzoic acid or ester LAs (Group I) includes drugs such as benzocaine, chloroprocaine, and tetracaine. Allergy in Group I is much more common due to the metabolite, para-aminobenzoic acid, or preservatives such as methylparaben or metabisulfites (19). The amide group (Group II) includes bupivacaine, lidocaine, and ropivacaine, and reports of true hypersensitivity allergy are rare. Cross-reactivity among ester LAs is common, but not with amides. There is little evidence that ester LAs cross-react with amide LAs (7).

Ideally, the pregnant patient who has experienced an adverse response to LAs should be seen prior to pregnancy for testing. However, pregnant patients can undergo skin testing for LAs, after informed consent if clinically indicated. After a comprehensive history, a common protocol for diagnosing LA allergy includes the administration of skin tests followed by a provocative challenge (12); a summary appears in Table 38-4. If the offending agent is unknown, the challenge should consist of LAs likely to be used in labor and delivery such as preservative-free bupivacaine and lidocaine.

Table 38-4 Approach to the Parturient with a History of Adverse Reactions to Local Anesthetics

1.	History Determine nature of reaction and LA implicated If the history is suggestive of immediate LA allergy Consultation from allergist if possible Identify if LA is ester or amide Weigh risks and benefits of skin and challenge testing Obtain informed consent if testing is considered Perform test near term or when patient presents for delivery
2.	Which LA agent? If LA is known: Test with LA with other structure, or another amide If LA is unknown: Test with LA to be used for labor and delivery
3.	Perform challenge tests Perform test in area with resuscitative facilities and monitoring Intravenous catheter should be placed and the patient fasted Notify obstetrical and neonatal team

If the offending LA is known, it is best to use an LA with the other chemical structure. However, since substantial cross-reactivity among amides has not been well documented, another amide can also be considered if the suspicion of LA allergy is low (20).

General Anesthetic Agents

Induction Agents

Propofol is currently mixed with a solution vehicle including soy and egg lecithins (extracted from egg yolks). There had been concern that patients allergic to soy or eggs may have reactions to propofol administered intravenously. However, in a small study of 25 egg-allergic patients, all propofol skin tests were negative (19). More commonly, propofol causes direct mast cell activation especially with higher doses (11,21). The estimated incidence of anaphylaxis with propofol is 1 in 60,000 (19). The incidence of thiopental allergy is estimated at 1 in 30,000 administrations. Etomidate, ketamine, and benzodiazepines are exceedingly rare causes for IgE-mediated anaphylaxis (19). There are no reported cases of anaphylaxis to inhalational anesthetics (4).

Neuromuscular Blockers

Neuromuscular blocking agents are among the most common agents to cause perioperative anaphylaxis and may cause a reaction on first exposure. This may be due to the structural similarity between neuromuscular blocking agents and certain chemicals found in toothpastes, detergents, cough medicines, and shampoos. Succinylcholine is the most common neuromuscular blocker implicated (4). The incidence of cross-reactivity among muscle relaxants lies between 60% and 70% (7).

Opioids

Most reactions to opioids such as morphine, codeine, and meperidine are secondary to direct mast cell mediator release from skin mast cells rather than IgE mechanisms. As a result, skin tests are invariably positive, even in normal control subjects. However, fentanyl, sufentanil, and remifentanil do not directly stimulate skin mast cells, so skin tests may be helpful. The incidence of cross-reactivity is unknown, although cases have been described in which meperidine, and methadone have cross-reacted with morphine antibodies, despite having different chemical structures (21).

Non-anesthetic Drugs

Oxytocin

Synthetic oxytocin has rarely been implicated in severe anaphylactic reactions (22). The test itself must be interpreted cautiously, since oxytocin can be irritating to the skin (23). Latex allergy should always be considered when symptoms of anaphylaxis occur soon after the administration of oxytocin since oxytocin may facilitate the development of symptoms in latex-allergic patients (24).

Antibiotics

Penicillins and cephalosporins elicit approximately 70% of the allergic reactions to antibiotics (7). With the recent Group B streptococcus infection prevention guidelines, it has become a more pressing issue in the parturient. Early cephalosporins were known to contain trace amounts of penicillin and cross-reactivity was often demonstrated. However, current drug preparations have a low level of cross-reactivity (11). A cross-sensitivity rate of 8% to 10% is often quoted; however, many of these reactions are related to skin rashes that are not immunologic in origin (19). First generation cephalosporins are more likely to cross-react with penicillin than third generation agents (7).

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs are increasingly recognized as a cause of anaphylactoid reactions due to the inhibition of cyclooxygenase and the generation of excessive leukotrienes. The onset is usually 10 minutes after intravenous administration, 30 minutes after rectal dosing and up to 1 hour after oral administration (10). Since aspirin and NSAIDs do not initiate specific IgE antibodies, allergy can only be established by an oral challenge (21). Cross-reactions occur between aspirin and most of the NSAIDs (5).

Chlorhexidine

Chlorhexidine is increasingly recognized as a cause for both Type I and Type IV hypersensitivity reactions. It is often overlooked as a cause of anaphylaxis, since reactions are delayed up to 10 minutes. Reactions can be triggered by cutaneous, mucosal, or parenteral application (21).

Synthetic Colloids

Synthetic colloids, such as hydroxyethyl starch, gelatins, and dextran-containing colloids cause 3% of all perioperative hypersensitivity reactions (25). The vast majority of reactions occur after 30 minutes and are non-allergic in nature (10). Gelatins and dextrans cause more reactions than hetastarch (25) with estimates of IgE-mediated anaphylaxis, ranging from 0.06% to 0.35% (7).

Allergy to Latex

Epidemiology

The introduction of universal precautions in the 1980s increased the use of latex-containing gloves and medical equipment, with a subsequent increase in the incidence of latex allergy and sensitivity to 1.4% and 7%, respectively (25). More recently, latex avoidance in the workplace and the restriction of powdered latex gloves may be reducing the incidence of allergy (26,27).

Latex sensitivity is defined as the presence of positive skin tests or positive in vitro tests to latex; patients are frequently asymptomatic until a threshold of exposure triggers an allergic reaction. Latex allergy is defined as the presence of allergic symptoms when there is contact with latex in a latex-sensitive person (9). The most dramatic presentation for latex allergy is the IgE-mediated reaction, although Type IV allergic contact dermatitis is four times more common (28).

Three high-risk groups for latex allergy have been identified— health care workers, workers with occupational exposure, and children with spina bifida and genitourinary abnormalities (11). Among health care workers, the prevalence of latex sensitivity ranges from 12.5% to 15.8% with the majority being asymptomatic (29). Exposure is most often from latex-contaminated aerosolized cornstarch powder that is added to latex gloves to make them easier to put on. Latex proteins from the gloves attach to the cornstarch during processing and storage, and eventually disperse with manipulation (30).

Latex allergy and sensitivity may affect over half of the patients with spina bifida. Interestingly, studies show they are allergic to different latex proteins than hospital workers probably as a result of parenteral and mucous membranes exposure rather than through inhalation (30).

There are other risk factors for latex allergy including specific food allergies and atopy. Fruits such as chestnuts, bananas, kiwis, and avocados may have peptides that cross-react with latex (25,30). Atopic patients are also at high risk for latex sensitivity if they have occupational exposure (27).

Presentation

The clinical manifestations of latex anaphylaxis can differ depending on whether exposure is outside or inside the hospital setting. Typical histories outside the surgical suite include oral itching, facial redness, or swelling to latex toy balloons or during dental examinations (30). Vaginal symptoms occur with the use of condoms. Contact urticaria on the hands is commonly described when wearing latex gloves, and bronchospasm and rhinoconjunctivitis typically occurs
with exposure to latex glove powder (9). Severe reactions may result in cardiovascular collapse (11).

In the hospital, symptoms of vaginal pruritus and swelling have been described at the time of examination, delivery, or immediately peripartum. Airborne exposure can lead to rhinitis, conjunctivitis, and bronchospasm, rarely leading to cardiovascular collapse and fetal distress (31). The signs and symptoms of anaphylaxis due to latex may occur from 20 minutes to an hour after exposure, making it difficult to differentiate from intravenously administered agents (11).

Pregnancy itself may be associated with higher rates of latex sensitivity (24). During cesarean delivery, symptoms of latex anaphylaxis may follow the intravenous injection of oxytocin, leading to misdiagnosis. It is possible that latex proteins released from surgical gloves during the skin and uterine incision enter the circulation after the administration of oxytocin. The contracting placental site provides the portal of entry causing symptoms. Alternatively, the reaction may occur because oxytocin has structural similarity to latex, or oxytocin may form part of the epitope of the latex antigen.

Management

Many hospitals have formulated policies and procedures for detection and management of patients with latex allergy or sensitivity. They have also taken the initiative to decrease the risk of latex sensitivity among their staff. Suggestions regarding the management of latex allergy patients appear in Table 38-5.

Testing for latex allergy can be difficult because numerous different latex proteins have been implicated in IgE-mediated immunologic reactions. In addition, skin test extracts are not commercially available. “Home-made” preparations have been produced, however due to the wide variability of glove protein content; latex skin tests have a limited sensitivity and specificity. Serologic tests that identify latex IgE are available but not sufficiently sensitive for screening purposes (11).

Table 38-5 Recommendations for the Management of Latex-sensitive and Latex-allergic Patients

Identify and Prioritize	Identify the latex sensitive patient Arrange in vivo and in vitro testing if possible Notify the entire health care team Arrange list so patient is first of the day Place sign on operating/labor room door “Latex Allergy”
Patient Preparation	Antihistamines and corticosteroids not recommended Prepare all medication and equipment with non-latex gloves A latex-free cart with supplies should be available Cotton wrappings to protect skin from latex based blood pressure cuffs or tubing Avoid latex esmarchs, tapes, tourniquets, drains, and urinary catheters
Gloves	NO low protein latex gloves Use alternatives: Styrene, styrene-butadiene, neoprene, and polyvinylchloride
Syringes	Glass or non-natural latex syringes are preferred Regular syringes are acceptable providing that drugs are freshly drawn and administered (within 6 h)
Medications	Glass ampoules Remove rubber stopper from vial or one puncture through fresh vial
Intravenous sets	Tape over injection ports and use stopcocks. Avoid buretrols Regular intravenous bags or minibags may be used Add medications through port to be spiked

Elective procedures on known latex-sensitive individuals should be carried out in a “latex-free” environment and should be performed at the start of the day (9). Airborne latex may persist in significant quantities, particularly on scrub suits (32). Synthetic gloves should be used when preparing equipment for the medical procedure in a latex-sensitive patient (4). Ideally, all latex products should be avoided but in reality, certain latex devices are more apt to cause a reaction than others, depending on the method of manufacture. Dry natural rubber, such as that used for syringe plungers and vial stoppers contain much less protein than surgical gloves made from latex concentrate and are less likely to cause reactions (30). Since it is not mandatory to identify the latex content of vial stoppers, guidelines advocate removal of the stopper or restrict use to a single puncture (33).

Hand Dermatitis

Hand dermatitis, both allergic contact dermatitis and common irritant dermatitis, are known risk factors for IgE-mediated latex reactions. The abraded skin may provide a portal of entry into the bloodstream for a variety of latex allergens (27).

Allergic contact dermatitis (Type IV hypersensitivity) is caused by a hypersensitivity to the various chemicals added to the latex mixture during manufacture, rather than the latex proteins themselves. The reactions appear 24 to 48 hours after a repeated exposure. Signs and symptoms include erythematous or scaling patches with blistering (30).

Irritant dermatitis is caused by moisture under the gloves, other workplace chemicals, and repeated hand washing. It is a non–immune-mediated reaction, characterized by pruritus, irritation, scaling, and cracking at the site of contact. It appears minutes to hours after exposure (9).

Investigation of Anaphylaxis

Acute Assessment

If anaphylaxis is suspected, patients should be referred to an allergist to confirm that anaphylaxis has occurred and to identify the offending agent. Blood for serum tryptase levels should be drawn immediately and within 2 hours of symptoms, and again at 24 hours.

Histamine can be tested in the blood and urine. Since elevations in plasma histamine return to baseline within 60 minutes, samples must be drawn quickly (34). Similar to tryptase, it is elevated in both allergic and non-allergic mechanisms and its absence does not preclude an anaphylactic reaction (7). In addition, false negative values have been identified in pregnancy (12).

Allergy Testing

When allergy tests are performed after a reaction, many centers advocate waiting 4 to 6 weeks from the event before skin and in vitro tests are administered. It allows the levels of immunoglobulins and mediators to return to prereaction levels (7).

Skin Testing

Skin prick tests and intradermal testing involve exposing mast cells in the skin to specific antigens (in drugs or products). Both are performed on the upper back or the volar surface of the forearm. If specific IgE on the mast cells encounters the corresponding antigen, a skin reaction occurs, confirming a Type I reaction (5). It is more sensitive than in vitro testing and is the diagnostic procedure of choice for detecting IgE-mediated allergies (11). Appropriate positive (histamine or codeine) and negative (saline) controls should be used.

There is difficulty in studying some anesthetic agents, such as opioids and neuromuscular blockers, since standard solutions cause direct histamine release. Guidelines have been developed for the appropriate dilution of drugs for skin tests (12).

Skin prick tests are performed using a hypodermic needle which is passed through a drop of testing reagent at a 45-degree angle to the skin. The skin is gently lifted, causing a small break in the epidermis and a minute amount of allergen penetrates and interacts with the mast cells. The site is compared to positive and negative controls after 15 minutes. The mean diameter of the wheal (calculated by adding the longest diameter to the diameter at 90 degrees divided by 2) should be at least 3 mm more than the negative control (35).

Table 38-6 Suggested Protocol for Skin Prick Tests and Progressive Challenge for Local Anesthetics

Initial Test	Skin Prick Test: Undiluted LA^a
Step	Route	Volume (mL)	Dilution
1	Subcutaneous	0.1	Undiluted LA^a
2	Subcutaneous	0.5	Undiluted LA
3	Subcutaneous	1.0	Undiluted LA
4	Subcutaneous	2.0	Undiluted LA
	^a15 min interval in between Positive challenge test: Presence of local wheal and erythema or systemic anaphylactic symptoms
^aConsider dilutions of 1:100 or 1:1,000 with a history of severe reactions (Thyssen JP, Menne T, Elberling J, et al. Hypersensitivity to local anaesthetics-update and proposal of evaluation algorithm. Contact Derm 2008;59:69–78.) LA, local anesthetic.