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Bisulfite sensitivity manifesting as allergy to local dental anesthesia
Case report Bisulfite sensitivity manifesting as allergy to local dental anesthesia Howard J. Schwartz, M.D., and Theodore H. Sher, M.D. Cleveland, Ohio
A case of sulfite sensitivity first manifested as possible allergy to local anesthetics is described. Implications for the broad problem of local anesthetic reactivity are discussed and a possible approach by sulfite challenge of suspect patients is outlined. ( J ALLERGYCLIN1MMUNOL75:5257, 1985.)
Physicians and dentists are commonly faced by the problem patient who presents a history of hypersensitivity to local anesthetic agents but who further requires their use before a surgical or dental procedure. In many instances such a history requires that alternative methods of anesthesia be provided, with their inherent risks," 2 or the patient may have to undergo the procedure with no anesthesia at all. Although few true allergic reactions to local anesthetics have been documented," 2 the potential for serious medical and medicolegal consequences presented by a history of a prior adverse reaction is severe. The following case report offers a potential explanation for some of the adverse reactions to local anesthetics in describing a patient with sulfite sensitivity used as a preservative in the anesthetic to which she claimed to be allergic. Recognition of this possibility can lead to avoiding the more substantial hazards of general anesthesia for a limited surgical procedure without compromising patient care.
CASE REPORT E. G. is a 37-yr-old white woman with chronic vasomoter rhinitis, sinusitis, and nasal polyposis. Although she was nonatopic, she gave a history of drug intolerances, including penicillin and aspirin. Levels of serum IgG, IgA, IgM, and IgE were normal. In December 1982 she was administered injections of novocaine with epinephrine by her dentist in preparation for the repair of major dental caries. Within several minutes she From the Departments of Medicine and Pediatrics, Case Western Reserve University and University Hospitals, Cleveland, Ohio. Received for publication March 19, 1984. Accepted for publication Aug. 15, 1984. Reprint requests: Howard J. Schwartz, M.D., 1611 So. Green Rd., Cleveland, Ohio 44121.
developed a sense of flushing, warmth, and pruritus followed by scattered urticaria, dyspnea, and a sense of anxiety. The procedure was interrupted, and she was administered antihistamines by injection with resolution of her symptoms within one half hour. The dentist had used less than 2 ml (one Carpule) of this anesthetic injected into two sites within 1 min of each other. On examination vital signs were normal, and the general physical examination was unremarkable except for nasal mucous membrane swelling without polypoid changes. Laboratory examination revealed normal complete blood count, SMA-20, electrocardiogram, and pulmonary function. Skin testing in an effort to detect reactivity to local anesthetics was carried out by use of intradermal injection of several dilutions of procaine, prilocaine, mepivacaine, and lidocaine without vasoconstrictors." 2 These tests were entirely negative. A prick test with bisulfite (10 mg/ml) was negative. On another day the patient had oral bisulfite challenge (single blind), which was previously described, 3 with solutions of bisulfite. Thirty minutes after a blind oral dose of 10 mg of sodium bisulfite, the patient developed a sense of fullness in her head, nasal congestion, and a pruritic, erythematous urticarial blotchy eruption over her torso. She was treated for this with 50 mg of diphenhydramine hydrochloride (Benadryl; Parke-Davis, Morris Plains, N.J.) administered orally with resolution of all symptoms and signs within the hour. No pulmonary function abnormalities occurred throughout the challenge procedure. No lactose was present in the test materials. The patient subsequently was able to have the required dental repair uneventfully with the use of lidocaine by the dentist without vasoconstrictors (ASTRA pharmaceutical products). A subcutaneous challenge was declined by the patient.
DISCUSSION Reactions to local anesthetics are quite common, although only 1% of these adverse reactions are
525
526
Schwartz and Sher
J. ALLERGYCLIN. IMMUNOL. APRIL 1985
thought to be immunologically mediated. 4 Adverse drug reactions to local anesthetics have been classified into several categories, including toxic responses in normal individuals, idiosyncratic reactions, allergic or immunologic, and those unrelated to the primary drug used but caused by sympathetic stimulation, vasovagal reactions, or psychomotor stimulation. Symptoms and signs that have been attributed to local anesthetic "allergy" have included flushing, dyspnea, palpitations, hyperventilation, syncope, pruritus, urticaria, angioedema, nausea, vomiting, anxiety, seizure-like activity, and rhinitis. These complaints are most often attributed either to anxiety or to the effect of the vasoconstrictor (e.g., epinephrine) that is commonly present in these preparations. Several approaches to the patient who presents a history of local anesthetic sensitivity have been recommended.5.6 Skin testing with the local anesthetic in question has been used by several groups, although problems exist with this approach, including our lack of knowledge of the precise antigens involved in true anesthetic allergy and our lack of proved reliable skin test reagents. Skin tests have, however, been reported with local anesthetics, and subsequent clinical use of these drugs based on test results has been tolerated? One recommended approach to the patient who presents with suspected local anesthetic sensitivity is based on the chemical derivation of the anesthetic. Two structurally dissimilar groups are available: group 1 consists of synthetic para-amino benzoic esters (e.g., procaine, tetracaine [Pontocaine; Breon Laboratories, Inc., New York, N.Y.], and benzocaine) and group 2 that lacks the para-amino benzoic acid group (e.g., lidocaine and mepivacaine). It is believed that cross-reactivity does not exist between the two groups. If the history clearly indicated a reaction to an agent of one group, some authors have advocated the use of the agent in the other, structurally dissimilar group. Other approaches have used progressive skin testing, starting with prick testing when it is indicated with dilute solutions, and progressing to intradermal testing with increasing concentrations of the local anesthetic until full strength is reached. Provocative dose testing is then recommended by the subcutaneous route until full strength concentration is attained?. 6 Recently, several groups have reported on a variety of adverse reactions to sulfiting agents including anaphylaxis, gastrointestinal upset, urticaria, angioedema, hypotension, and respiratory distress. Major attention has been directed to the role of the sulfites in asthma. Reactions to the sulfites can follow both the inhalation and ingestion of foods and drugs containing sulfiting agents by sulfite-sensitive persons. 3. 7-9
Sulfiting agents are used as antioxidants in various pharmaceutical formulations and are to be found in many solutions containing sympathomimetic amines. Thus, bisulfite or metabisulfite is present in solutions of procaine, chloroprocaine, bupivacaine, lidocaine, mepivacaine, tetracaine, and etidocaine with vasopressors.l~ Concentrations of the sulfites may range up to 2.0 mg/ml. Parabens, which can be present in these local anesthetics, have been demonstrated on occasion to cause hypersensitivity reactions.It In our patient there was no indication of any paraben sensitivity. The alteration made in her anesthetic agent was the absence of vasopressors and sulfites in her second clinical exposure. It appears that vasoconstrictors have been used in solutions of local anesthetics in order to prolong the duration of anesthesia; sulfites stabilize the vasoconstrictors. J2 The mechanism of the reaction in our patient is unclear. Prenner and Stevens 7 have reported a case of anaphylaxis after ingestion of sodium bisulfite and were able to demonstrate type 1 immediate hypersensitivity. Stevenson and Simon 13 were unable to demonstrate reagin-mediated sensitivity in their study of metabisulfite-sensitive asthmatic patients and postulated either a nonreaginic anaphylactoid reaction, SO2 generation acting on irritant receptors, or sulfite metabolites combining with mast cells because of specific membrane defects. Recently, in a study of sulfitesensitive asthmatic patients, subcutaneous doses up to 10 mg were unable to elicit an asthmatic response, although both inhaled and ingested sulfite administration resulted in significant decreases in the FEVI. These doses were up to 10 times the amount in usual doses found in local anesthetics. ~4 In our patient the subsequent administration of the local anesthetic without sulfite was tolerated without incident. This patient may represent another group of sulfite-sensitive patients whose reaction is nonasthmatic and who are exquisitely sensitive to parenteral exposure. Our patient did not appear to suffer from an anxiety attack. The widespread use of sulfites inadvertently exposes large numbers of potentially sensitive persons. The authors suggest that reactions to these sulfites can explain many of the hitherto poorly understood reactions to local anesthetics. Further studies in these patients are in progress. Until more definitive data are available, patients who report a history of severe "allergy" to local anesthetic agents should be considered as potentially sulfite sensitive. A challenge test as has been described is the only method currently available to confirm this diagnosis. This should be used when the history indicates a serious hazard from read-
VOLUME 75 NUMBER 4
m i n i s t e r i n g the a g e n t s , a n d t h e s u r g e o n d e e m s the u s e of anesthetics with a vasoconstrictor (and hence cont a i n i n g sulfites) m a n d a t o r y . P r e t r e a t m e n t o f the p a t i e n t w i t h oral v i t a m i n B~2 m a y b e o f u s e in p r o p h y l a x i s o f r e a c t i o n s in s u l f i t e - s e n s i t i v e p e r s o n s . ~5 REFERENCES
1. DeSwarte, RD: Drug Allergy. In Patterson R, editor: Allergic diseases, diagnosis, and management. Philadelphia, 1980, JB Lippincott Co, p 557 2. Van Arsdel PP: Adverse drug reactions. In Middleton E, Reed CE, Ellis EF, editors: Allergy, principles and practice. St. Louis, 1978, The CV Mosby Co, p 1154 3. Schwartz HJ: Sensitivity to ingested metabisulfites: variations in clinical presentation. J ALLERGY CL[N IMMUNOL71:487, 1983 4. Verill PJ: Adverse reactions to local anesthetics and vasoconstrictive drugs. Practitioner 214:380, 1975 5. Incaudo G, Schatz M, Patterson R, Rosenberg M, Yamamoto F, Hamburger RN: Administration of local anesthetics to patients with a history of prior adverse reaction. J ALLERGYCLIN IMMUNOL61:339, 1978
Bisulfite s e n s i t i v i t y m a n i f e s t i n g as a l l e r g y
527
6. deShazo RD, Nelson HS: An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients. J ALLERGYCLm IMMUNOL63:387, 1979 7. Prenner BM, Stevens JJ: Anaphylaxis after ingestion of sodium bisulfite. Ann Allergy 37:180, 1976 8. Baker GJ, Collett P: Bronchospasm induced by metabisulfite containing foods and drugs. Med J Aust 2:614, 1981 9. Simon RA, Green L, Stevenson DD: The incidence of ingested metabisulfite sensitivity in an asthmatic population. J ALLERGY CLIN IMMUNOL69:118, 1982 10. Physicians desk reference. 1984 11. Nagel JE, Fuscaldo JT, Fireman P: Paraben allergy. JAMA 237:1594, 1977 12. Krantz JC Jr, Cart CR: The pharmacologic principles of medical practice, ed 2. Baltimore, 1951, Williams & Wilkins, p 347 13. Stevenson DD, Simon RA: Sensitivity to ingested metabisulrites in asthmatic subjects. J ALLERGYCLIN IMMUNOL68:26, 1981 14. Goldfarb G, Simon R: Provocation of sulfite-sensitive asthma. J Allergy Clin Immunol 73:135, 1984 15. Jacobsen DW, Simon RA, Singh M: Sulfite oxidase deficiency and cobalamin protection in sulfite-sensitive asthmatics (SSA). J ALLERGYCLIN IMMUNOL73:135, 1984
A case of sulfite sensitivity first manifested as possible allergy to local anesthetics is described. Implications for the broad problem of local anesthetic reactivity are discussed and a possible approach by sulfite challenge of suspect patients is outlined. ( J ALLERGYCLIN1MMUNOL75:5257, 1985.)
Physicians and dentists are commonly faced by the problem patient who presents a history of hypersensitivity to local anesthetic agents but who further requires their use before a surgical or dental procedure. In many instances such a history requires that alternative methods of anesthesia be provided, with their inherent risks," 2 or the patient may have to undergo the procedure with no anesthesia at all. Although few true allergic reactions to local anesthetics have been documented," 2 the potential for serious medical and medicolegal consequences presented by a history of a prior adverse reaction is severe. The following case report offers a potential explanation for some of the adverse reactions to local anesthetics in describing a patient with sulfite sensitivity used as a preservative in the anesthetic to which she claimed to be allergic. Recognition of this possibility can lead to avoiding the more substantial hazards of general anesthesia for a limited surgical procedure without compromising patient care.
CASE REPORT E. G. is a 37-yr-old white woman with chronic vasomoter rhinitis, sinusitis, and nasal polyposis. Although she was nonatopic, she gave a history of drug intolerances, including penicillin and aspirin. Levels of serum IgG, IgA, IgM, and IgE were normal. In December 1982 she was administered injections of novocaine with epinephrine by her dentist in preparation for the repair of major dental caries. Within several minutes she From the Departments of Medicine and Pediatrics, Case Western Reserve University and University Hospitals, Cleveland, Ohio. Received for publication March 19, 1984. Accepted for publication Aug. 15, 1984. Reprint requests: Howard J. Schwartz, M.D., 1611 So. Green Rd., Cleveland, Ohio 44121.
developed a sense of flushing, warmth, and pruritus followed by scattered urticaria, dyspnea, and a sense of anxiety. The procedure was interrupted, and she was administered antihistamines by injection with resolution of her symptoms within one half hour. The dentist had used less than 2 ml (one Carpule) of this anesthetic injected into two sites within 1 min of each other. On examination vital signs were normal, and the general physical examination was unremarkable except for nasal mucous membrane swelling without polypoid changes. Laboratory examination revealed normal complete blood count, SMA-20, electrocardiogram, and pulmonary function. Skin testing in an effort to detect reactivity to local anesthetics was carried out by use of intradermal injection of several dilutions of procaine, prilocaine, mepivacaine, and lidocaine without vasoconstrictors." 2 These tests were entirely negative. A prick test with bisulfite (10 mg/ml) was negative. On another day the patient had oral bisulfite challenge (single blind), which was previously described, 3 with solutions of bisulfite. Thirty minutes after a blind oral dose of 10 mg of sodium bisulfite, the patient developed a sense of fullness in her head, nasal congestion, and a pruritic, erythematous urticarial blotchy eruption over her torso. She was treated for this with 50 mg of diphenhydramine hydrochloride (Benadryl; Parke-Davis, Morris Plains, N.J.) administered orally with resolution of all symptoms and signs within the hour. No pulmonary function abnormalities occurred throughout the challenge procedure. No lactose was present in the test materials. The patient subsequently was able to have the required dental repair uneventfully with the use of lidocaine by the dentist without vasoconstrictors (ASTRA pharmaceutical products). A subcutaneous challenge was declined by the patient.
DISCUSSION Reactions to local anesthetics are quite common, although only 1% of these adverse reactions are
525
526
Schwartz and Sher
J. ALLERGYCLIN. IMMUNOL. APRIL 1985
thought to be immunologically mediated. 4 Adverse drug reactions to local anesthetics have been classified into several categories, including toxic responses in normal individuals, idiosyncratic reactions, allergic or immunologic, and those unrelated to the primary drug used but caused by sympathetic stimulation, vasovagal reactions, or psychomotor stimulation. Symptoms and signs that have been attributed to local anesthetic "allergy" have included flushing, dyspnea, palpitations, hyperventilation, syncope, pruritus, urticaria, angioedema, nausea, vomiting, anxiety, seizure-like activity, and rhinitis. These complaints are most often attributed either to anxiety or to the effect of the vasoconstrictor (e.g., epinephrine) that is commonly present in these preparations. Several approaches to the patient who presents a history of local anesthetic sensitivity have been recommended.5.6 Skin testing with the local anesthetic in question has been used by several groups, although problems exist with this approach, including our lack of knowledge of the precise antigens involved in true anesthetic allergy and our lack of proved reliable skin test reagents. Skin tests have, however, been reported with local anesthetics, and subsequent clinical use of these drugs based on test results has been tolerated? One recommended approach to the patient who presents with suspected local anesthetic sensitivity is based on the chemical derivation of the anesthetic. Two structurally dissimilar groups are available: group 1 consists of synthetic para-amino benzoic esters (e.g., procaine, tetracaine [Pontocaine; Breon Laboratories, Inc., New York, N.Y.], and benzocaine) and group 2 that lacks the para-amino benzoic acid group (e.g., lidocaine and mepivacaine). It is believed that cross-reactivity does not exist between the two groups. If the history clearly indicated a reaction to an agent of one group, some authors have advocated the use of the agent in the other, structurally dissimilar group. Other approaches have used progressive skin testing, starting with prick testing when it is indicated with dilute solutions, and progressing to intradermal testing with increasing concentrations of the local anesthetic until full strength is reached. Provocative dose testing is then recommended by the subcutaneous route until full strength concentration is attained?. 6 Recently, several groups have reported on a variety of adverse reactions to sulfiting agents including anaphylaxis, gastrointestinal upset, urticaria, angioedema, hypotension, and respiratory distress. Major attention has been directed to the role of the sulfites in asthma. Reactions to the sulfites can follow both the inhalation and ingestion of foods and drugs containing sulfiting agents by sulfite-sensitive persons. 3. 7-9
Sulfiting agents are used as antioxidants in various pharmaceutical formulations and are to be found in many solutions containing sympathomimetic amines. Thus, bisulfite or metabisulfite is present in solutions of procaine, chloroprocaine, bupivacaine, lidocaine, mepivacaine, tetracaine, and etidocaine with vasopressors.l~ Concentrations of the sulfites may range up to 2.0 mg/ml. Parabens, which can be present in these local anesthetics, have been demonstrated on occasion to cause hypersensitivity reactions.It In our patient there was no indication of any paraben sensitivity. The alteration made in her anesthetic agent was the absence of vasopressors and sulfites in her second clinical exposure. It appears that vasoconstrictors have been used in solutions of local anesthetics in order to prolong the duration of anesthesia; sulfites stabilize the vasoconstrictors. J2 The mechanism of the reaction in our patient is unclear. Prenner and Stevens 7 have reported a case of anaphylaxis after ingestion of sodium bisulfite and were able to demonstrate type 1 immediate hypersensitivity. Stevenson and Simon 13 were unable to demonstrate reagin-mediated sensitivity in their study of metabisulfite-sensitive asthmatic patients and postulated either a nonreaginic anaphylactoid reaction, SO2 generation acting on irritant receptors, or sulfite metabolites combining with mast cells because of specific membrane defects. Recently, in a study of sulfitesensitive asthmatic patients, subcutaneous doses up to 10 mg were unable to elicit an asthmatic response, although both inhaled and ingested sulfite administration resulted in significant decreases in the FEVI. These doses were up to 10 times the amount in usual doses found in local anesthetics. ~4 In our patient the subsequent administration of the local anesthetic without sulfite was tolerated without incident. This patient may represent another group of sulfite-sensitive patients whose reaction is nonasthmatic and who are exquisitely sensitive to parenteral exposure. Our patient did not appear to suffer from an anxiety attack. The widespread use of sulfites inadvertently exposes large numbers of potentially sensitive persons. The authors suggest that reactions to these sulfites can explain many of the hitherto poorly understood reactions to local anesthetics. Further studies in these patients are in progress. Until more definitive data are available, patients who report a history of severe "allergy" to local anesthetic agents should be considered as potentially sulfite sensitive. A challenge test as has been described is the only method currently available to confirm this diagnosis. This should be used when the history indicates a serious hazard from read-
VOLUME 75 NUMBER 4
m i n i s t e r i n g the a g e n t s , a n d t h e s u r g e o n d e e m s the u s e of anesthetics with a vasoconstrictor (and hence cont a i n i n g sulfites) m a n d a t o r y . P r e t r e a t m e n t o f the p a t i e n t w i t h oral v i t a m i n B~2 m a y b e o f u s e in p r o p h y l a x i s o f r e a c t i o n s in s u l f i t e - s e n s i t i v e p e r s o n s . ~5 REFERENCES
1. DeSwarte, RD: Drug Allergy. In Patterson R, editor: Allergic diseases, diagnosis, and management. Philadelphia, 1980, JB Lippincott Co, p 557 2. Van Arsdel PP: Adverse drug reactions. In Middleton E, Reed CE, Ellis EF, editors: Allergy, principles and practice. St. Louis, 1978, The CV Mosby Co, p 1154 3. Schwartz HJ: Sensitivity to ingested metabisulfites: variations in clinical presentation. J ALLERGY CL[N IMMUNOL71:487, 1983 4. Verill PJ: Adverse reactions to local anesthetics and vasoconstrictive drugs. Practitioner 214:380, 1975 5. Incaudo G, Schatz M, Patterson R, Rosenberg M, Yamamoto F, Hamburger RN: Administration of local anesthetics to patients with a history of prior adverse reaction. J ALLERGYCLIN IMMUNOL61:339, 1978
Bisulfite s e n s i t i v i t y m a n i f e s t i n g as a l l e r g y
527
6. deShazo RD, Nelson HS: An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients. J ALLERGYCLm IMMUNOL63:387, 1979 7. Prenner BM, Stevens JJ: Anaphylaxis after ingestion of sodium bisulfite. Ann Allergy 37:180, 1976 8. Baker GJ, Collett P: Bronchospasm induced by metabisulfite containing foods and drugs. Med J Aust 2:614, 1981 9. Simon RA, Green L, Stevenson DD: The incidence of ingested metabisulfite sensitivity in an asthmatic population. J ALLERGY CLIN IMMUNOL69:118, 1982 10. Physicians desk reference. 1984 11. Nagel JE, Fuscaldo JT, Fireman P: Paraben allergy. JAMA 237:1594, 1977 12. Krantz JC Jr, Cart CR: The pharmacologic principles of medical practice, ed 2. Baltimore, 1951, Williams & Wilkins, p 347 13. Stevenson DD, Simon RA: Sensitivity to ingested metabisulrites in asthmatic subjects. J ALLERGYCLIN IMMUNOL68:26, 1981 14. Goldfarb G, Simon R: Provocation of sulfite-sensitive asthma. J Allergy Clin Immunol 73:135, 1984 15. Jacobsen DW, Simon RA, Singh M: Sulfite oxidase deficiency and cobalamin protection in sulfite-sensitive asthmatics (SSA). J ALLERGYCLIN IMMUNOL73:135, 1984