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Skin testing after anaphylactoid reactions to dental local anesthetics
Skin testing after anaphylactoid dental local anesthetics
reactions to
A comparison with controls Tinlothy A. Hodgson, BDS,” Penelope J. Shirlcrw, BDS, FDS KG.’ Stephen J. Chullacombe, BDS, PhD, FRCPath,” London, Englund DtPARTMbNT Gl’\i’S
01:
OR&L
hl~D1CINt
;ZND
PATHOLOGY,
L,NITl:D
Mt-IllCAL
and
,-\ND
DtNTAl.
SCIIOOLS,
IIOSPll‘i\l.
Reactions to scratch and intradermal challenge with a variety of local anesthetics were examined In 90 patients and compared with 45 controls. The frequency of a positive scratch test was 13 of 90 in the patient group and 12 of 45 in the control group. Thus scratch testing did not appear to discriminate between test and control groups. Significantly greater numbers of patients (22 of 90) gave a positive intradermal response than controls (4 of 45) (chi-squared test p < 0.05). Nine patients showed reactions to more than one agent. The majority of reactions in both patients and controls were in atopic subjects (chi-squared test p < 0.05). In 87 of the 90 patients with suspected anaphylactoid reactions to local anesthetic agents, negative skin reactions to at least one of the agents allowed intrabuccal challenge and subsequent recommendation of an agent for future use. Skin testing, though not providing formal proof of allergy, provides a useful test to indicate local anesthetics that may be used for future procedures. (OR,%1 SliRG
ORAL
MEI>
OR\I.
P,\-~HOI
1993;75:706-1
T rue allergy to amide-type
I)
local anesthetic agents is extremely rare and may relate to the anesthetic agent itself or to its additives.‘-j The level of risk. however, may only be assessed in relation to the scale of use. The estimated number of dental local anesthetics administered annually in the United Kingdom is of the order of 70 million cartridges.” In comparison, the total number of adverse reactions reported after the administration of lidocaine and prilocaine containing preparations over the period July 1963 to January 1990 was 249 (nine of which were fatal).’ Of these, true allergy could be demonstrated in and accounted for less than I o/oof the total reactions to these agents.j. i-X It has been suggested that the majority 01 these reactions were of the delayed rather than the immediate type.” Most complications that arise from local anesthetic agents are the direct consequence of the pharmaco-
,‘Research bResearch
Rssiatant rn C)rnl Medicine. Fellows in Oral Medicine.
‘Professor ogy. C‘opyright
and Head
0030-42X/93/$1
706
1993
of Department bj
Mosby-Year
.OO +
IO
of Oral Hook,
7/13/45956
Medicine Inc
and Patho-
logic properties of the drug, the presence of a vasoconstrictor, concomitant drug therapy, or apprehension. Toxicity that results from the local anesthetic agent itself is usually the result of intravascular injection or rapid absorption of high doses of the drug. Among the published reports of allergy to lidocaine, few have confirmed any immunologic basis for the reaction or determined that, even if the reaction was allergic in nature, the reaction was to lidocaine rather than some other component of the anesthetic solution.7. 10 Intradermal skin testing has been found to be of value in assessing allergies to local anesthetic agents. “-” The aims of this study were to compare the frequent) of positive skin reactions with local anesthetic agents in control patients and in patients with a reported history of local anesthetic allergy. Also to determine whether negative reactions may indicate which proprietary agent could be used for intrabuccal challenge and therefore routine dental treatment. MATERIAL AND METHODS Study groups
Patient group. Ninety patients came to the Oral Medicine and Pathology Department. United Medi-
OKAI
SIJKGERY
OR,IL
Volume
75. Number
Table
I. Test
M~DICINL
ORAL
PATHOI
Hodgson, Shirlaw, and Challacombe
OGY
solutions I I 2
Proprietary
I
name
Saline Xylotox
Citanest + Octapressin 5 6 in United
Constituents Sodium chloride Lidocaine* hydrochloride 2% Adrenaline I:80000 (as Tartratej Sodium metabisulphite 0.5mg Sodium chloride BP 6.0mg Lidocaine hydrochloride 3’6 Sodium chloride Prilocaine hydrochloride .I“; Sodium chloride Felypressin Prilocaine hydrochloride Mepivacaine hydrochloride Sodium chloride
Lignostab
*I-ignocanx
707
6
Citanest plain Scandonest Kingdom.
cal and Dental Schools, Guy’s Hospital between the period October 1986 and December 1990, ranging in age from 10 to 65 years (mean age f standard deviation, 38.9 ? 8.9) for allergy testing, after reported adverse reactions to dental local analgesia. They were entered into the patient group. The main features of the reactions that had resulted in referral were swelling at the site of injection (27%), collapse (24%), rashes (19%), nausea (lo%), dyspnea (5%), ulceration at the site of injection (2%), and swelling at a site distant to that of injection (2%). Forty-two (47%) gave an atopic history (including asthma, hayfever, eczema, and drug allergy) and the ratio of female to male patients was 3:2 (54:36). Control group. A control group of 45 patients, ranging in age from 18 to 57 years (mean age f standard deviation, 35.8 i 8.1) with no previous history of adverse reaction to dental local analgesia, included 21 members with a history of atopy (46.4%). The female to male ratio was 3:2 (27: 18). Method (modified from Fisher 1984).15 A detailed history enabled the clinician to determine whether an immediate or delayed type hypersensitivity response was the likely cause of the adverse reaction. Any drug history that could modify (for example, antihistamines) or interfere with (for example, systemic steroid therapy) the subject’s response was also established. These subjects were excluded from the trial until therapy had been temporarily adjusted. Resuscitation facilities were available in the test room including oxygen, adrenaline 1: 1000, promethazine, aminophylline, and hydrocortisone. Intravenous access was only secured if the history warranted it. Pulse and blood pressure were noted at the beginning and during the procedure. After an explanation of the testing procedure, the flexor aspect of the forearm of the test subject was labeled with test areas
numbered one to six. The numbers corresponded to the test solutions (Table I). The skin was then lightly cleaned with isopropyl alcohol and left to dry. Test
methods
Scratch test. Fifty microliters of test solution was dispensed onto the skin and four superficial scratches made with a sterile needle. The response was recorded 10 minutes after the application of the test solution by measurement of the maximum diameter of both wheal and flare and compared with that to a saline solution control. Zntradermal test. Twenty-five microliters of test solution was injected intradermally by introducing a sterile needle into the skin at an angle of 10 degrees until the central hole was covered. The intradermal response was measured 15 minutes after injection. A positive response to either test was recorded when the wheal (papule and pseudopods) and flare (erythema) was 2mm or more than that of the saline control. For subjects with a history of delayed reactions the intradermal challenge was reread at 24 and 48 hours. Intrabuccal challenge. The criteria used to determine which test solution was to be used for the intrabuccal challenge was a negative response to both scratch and intradermal tests. An injection of 0.5 ml of the test solution was administered slowly into the upper buccal sulcus, and signs and symptoms noted for 45 minutes afterwards. A subject with a history of a delayed reaction was reviewed 24 and 48 hours after the buccal challenge. All patients were asked to contact the department if there were any further reactions. RESULTS
In the control group, 14 subjects (3 1.1%) with no history of allergy to local anesthetic agents produced
708
Hodgson, Shirlaw, and Challacomhe
Local Anesthetic Lidocaine + Adr
Lidocaine plain Prilocaine + Fely
Prilocaine plain
Mepivacaine 14 12 10 X 6 4 Percentpositive Fig.
Table
2
0
_1 4 6 8 10 12 14 Percent positive
1. Comparison of patients and controls using scratch testing.
II. Comparison of positive skin reactions in atopic and nonatopic persons
Agent which response
zo
positive occurred
Lidocaine + adrenaline Lidocaine plain Prilocaine + felypressin Prilocaine plain Mepivacaine Total number of positive skin reactions Total number of patients reacting
0 1 10
(23.87;)
12
(2X.6’;;)
(6.3%)
a positive skin response to scratch (26.6%) or intradermal (8.8%) testing. None of these subjects produced a delayed-type response. Two subjects from this group reacted positively to two agents during cutaneous testing. Twenty-seven of the 90 patients (30%) with a reported allergy to dental local anesthetic agents developed a positive skin response, a rate that was not significantly different from the controls. Thirteen (14.4%) of the patient sample reacted positively to scratch testing with one or more agent, which was not a significantly different response rate from the control group (26.6%). However, significantly greater numbers of the patient group gave positive intradermal
responses to one or more agent (24.6%) than controls (8.8%) (chi-squared testp < 0.05). There was no significant difference between the number of patients (7.9%) and controls (6.6%) who reacted to both intradermal and scratch testing. Nine patients in the study group (I 0%) responded to intradermal challenge with more than one agent. In only one case of the 90 referrals did a subject respond to all five test solutions. The most common agent to promote a positive skin reaction was lidocaine; 24 of 90 (26.7%) patients and 7 of 45 (15.5%) controls reacted to either scratch (Fig. I ) or intradermal challenge (Fig. 2). Although the proportions of patients and controls who responded to
ORAL
Volume
SURGERY
0~41.
75. Number
MFDICINF
ORAL
Hodgson, Shirlaw, and Challacombe
PATt~oLoGy
709
6
m
Local Anesthetic Lidocaine + Adr
Patients
7Lj
Controls
I
~
Lidocaine plain Prilocaine + Fely
~ ~
Prilocaine plain Mepivacaine 25 * = p
! ~--I-. .L-I 20 15 10 5 Percent positive
e0
5
-----i---i10 15 20 Percent positive
25
Fig. 2. Comparison of patients and controls using intradermal testing.
scratch tests with lidocaine was similar (7.7% and 13.3%) (Fig. l), significantly greater numbers of patients (22.2%) than controls (6.6%) (chi-squared test p < 0.02) showed a positive intradermal reaction (Fig. 2). Only five patients showed a positive intradermal reaction to prilocaine preparations (compared with one control), and only two showed a positive reaction to mepivacaine (none of the controls) (Figs. 1 and 2). These latter results were too small for reliable statistics. In the test group, the proportion of atopic patients who responded to scratch testing with local anesthetics, 10 of 42 (23.8%) was significantly greater compared with 3 of 48 (6.3%) nonatopic patients (Chisquared test p < 0.05). A similar result was obtained in the control group in which 9 of 21 (42.9%) atopic patients and 3 of 24 (12.5%) nonatopic patients produced positive reactions to scratch testing (chisquared test p < 0.05). In contrast, on intradermal challenge, no significant difference was found in both tests groups [ 12 of 42 (28.6%) atopic patients, 9 of 48 (18.8%) nonatopic patients] and control [3 of Z!l (14.3%) atopic patients, 1 of 24 (4.2%) nonatopic patients] (See Table II). The female patients in the test group responded positively to skin testing with similar frequency to the males (28% to 33%). In the control group, there was negligible difference in the frequency of positive responses between females and males (33% to 28%). In 87 cases (97%), a local anesthetic agent that did not produce a skin response was successfully used for intrabuccal challenge. In the remaining three cases,
two were challenged successfully intrabuccally with prilocaine and felypressin (Octapressin) after oral antihistamine preparations, and the cutaneous reactions of the third case were so marked to all agents with the scratch test that further testing was not carried out. In the patient sample, 25 subjects who reacted positively to one or more agent produced an immediate-type response. The two remaining subjects, who were female and atopic, produced a delayed-type response to intradermal but not to scratch testing with plain lidocaine. DISCUSSION The vast majority of adverse reactions to local anesthetic agents are not a result of a true allergy. The wide variety of types of reactions reported by the patients would support this. However, the patient group was a small proportion of the population who had received local anesthetic agents for routine dental treatment and who had been referred for the exclusion of a possible allergy to local anesthetics. In general intradermal skin testing has been found to be of value in the assessment of allergic reactions to local anesthetic agents. li-l4 In this study, 99% of patients reported to have had an allergic-type response to these agents were provided with an alternative that produced no unwanted side effects. Of these, 70% produced no reaction to cutaneous testing, which suggests that the clinical diagnosis of allergy to these agents was incorrect and that there was an alternative reason for the adverse reaction. Intradermal testing was found to discriminate the patient group from the control group better than
710
Hodgson,
Shit-law,
and C’hallaconzbr
scratch testing (Figs. 1 and 2). In the control group with no previous history of local anesthetic allergy. 14 of 45 (3 1.1%) of the total sample responded to skin testing. .4 large proportion of the reactions in the control group (I 2 of 45, 26.6%) were to scratch testing. This is surprising as the reported incidence of allergy to local anesthetics agents remains low. However. this apparently high number of positive reactions in the control group is consistent with other studies.‘” This emphasizes the importance of including controls to evaluate skin testing to local anesthetic agents. The fact that numbers of the control group (26%) who had no previous histor! of local anesthetic allergy produced a positive reaction to scratch testing indicates that scratch testing alone is an unreliable method to determine a suitable agent to be used for intrabuccal challenge. Indeed the majorit) of those control patients who produced an increased arca ol erythema in response to scratch testing produced no response to intradermal testing. It is recognized that interpretations of positive skin test are dificult. It has been suggested that result5 may vary depending on the cleaning of the skin. volume of allergen injected, time of day, temperature. depth of injection. and concommittent drug therapy. ‘I. ” False positive reactions may be attributed to the localized subcutaneous release of histamine as a result of needle-stick trauma, distension of the tissues. differences in osmolality, or additives in the solution. However, false positive responses to direct histamine release will usually arise rapidly and fade within twenty minutes. lx False negatives are ;I theoretical problem because many drugs have a molecular weight that is too low to elicit a positive response in patients with known allergy to that preparation. It is also accepted that cellular components of skin, particularly mast cells, may differ from that in mucosa and may account for positive reactions in skin with a negative response to intrabuccal challenge. Intradermal challenge with the plain lidocaine preparation used in this study produced the largest number of positive intradermal responses ( 17.0”1). However. this preparation contains only lidocaine and saline, and thus reactions cannot be accounted for by anesthetic solution additives. The reasons for the greater number of positive results with lidocainecompared with other preparations remains unclear. A significantly greater number of atopic persons in the patient group (23.8%) showed positive scratch reactions to local anesthetics when compared with nonatopic persons (6.3%). This is not unexpected because an atopic person is more susceptible to Type I hypersensitivity reactions as a result of mast cell degranulation. The mast cells in these subjects are
already activated to many agents that cause histamine release. The trauma incurred by the scratch test itsell may be sufficient in the atopic subject to promote histamine release. It should be noted that there is no signilicant difference when atopic and nonatopic subject\ in both stud] groups are challenged with the use ol intradermal testing. This would reinforce the use 01‘ the intradermal test as the primary consideration fol proceeding to intrabuccal challenge. Although positive cutaneous reactions to local anesthetic agents do not necessaril! indicate allerg),, this cannot be L’Yeluded. particularly in those patients who xho\f rcactions to more than one agent. The results 1,1‘cutaneous challenge with local anesthctic agent:, are nevertheless clinically of value.‘” In all but one case. the cutaneous tests were negative to at least one agent. This allowed intrabuccal challenge and administration 01‘ local anesthetic without adverse side ell‘ects in X9 of 90 patients referred with ‘allergy‘ to locnl anesthetic. This number included many whose rcstorati\.e treatment had hcen performed under general anesthetic or whose treatment had been abandoned. In on11 two cases did reactions to the challcngc neccssitatc antiallergic therapy in spite of manq’ patients who had been hospitalized after local anesthetic injections for routine treatment. Thus cutaneous challenge under controlled conditions can bc 3 useful test in elucidating appropriate local anesthetic agents for future use even though ;I definitive allerg) cannot be proven. Although there are criticisms against using scratch testing alone. \I hen it is used in combination with intradermal testing, cutaneousand subsequent intrabuccal challenge provides :I simple method of assessing the safest agent to use for dental local anesthesia. It should. however. be noted that in the sensitive person these procedures maq precipitate anaphylaxis and should bc undertaken with extreme caution and where resuscitation facilities arc easily accessible. REFERENCES BahaJe\L\ \\ I\,ln:\i L The rclationshlp het\vcecn III viva and in vitro ruct~\ its 01 patients history 01‘allerg! to local anaesIhetics Br Dent J 1982;152:385-7. \driani _I_ Zcpernick R. Allergic reaction\ to ioc:~I ;tnesthetic\ South Med .I lYXl:74:6Y3-9. Caason K 2. (‘urwn I. Whittington [>I{. .The h,r/,lrd\ of duLII IUC;I/ an;re\thelics. Br Dent .I 1983;154:253-8. Incaundo (i. Schatr M, Patterson R. Roscnherg M. L.Imamoto I-, I lamburger RN. Administration of local anesthrtic:, to putient\ with II history of a prior adverse rcaclion. J AIIcrgq (‘Iin Immunol 1978;hl:339-45. Lilley JD. Ruxl C. Walker RO. Waterhouse JAlf. Use and misuse 01’ equipment Ibr dental local analges~x .I Dent I ‘)7X:6 I3.%4(,. Honke\ 4.1. I.,iurencc DR. Lovel KLL. O’Neil R, Verrill PJ .\dverse rcactionC to local an3esthelic/vnsocon\trictor prepa rations. Hr Dent J 1972; 133: 137.40.
OKAL SURC;~RY ORRI M~DI(:IYF Volume 75, Number 6
ORAL
Hodgson, Shirlaw, and Challacomhe
PATHOI.OGY
7. Aldrete JA, Johnson DA. Evaluation of intracutaneous testing for the investigation of allergy to local anesthetic agents. Anesth Analg I970;49: 173-81; Comment by Adriani J, 182-3. 8. Verrill PJ. Adverse reactions to local anaesthetics and vasw constrictor drugs. Practitioner 1975;214:380-5. 9. Giovannitti JA, Bennett CR. Assessment of allergy to local anesthetics. J Am Dent Assoc 1979;98:701-6. IO. Seskin L. Anaphylaxis due to a local anaesthetic hypersensi-tivity: report of a case. J Am Dent Assoc 1978;96:841-3. Il. Braun DT. Beamish D. Wildsmith JAW. Allergic reaction to an amide type local anaesthetic. Br J Anaesth 1981;53:435-7. 12. Arora SK, Aldrete JA. Investigation of possible allergy to local anesthetic drugs, correlation of intradermal with intramuscular injections. Anaesth Rev 1976;3:13-6. 13. Fisher M. The diagnosis of acute anaphylactoid reactions to anaesthetic drugs. Anaesth Intensive Care 198 1;9:38 l-6. 14. SchatL M. Skin testing and incremental challenge in the evaluation of adverse reactions to local anaesthetics. J Allergy Clin lmmunol 1984:74:606-16.
15. Sage DR. Intradermal testing following anaphylactic reactions to anaesthetic drugs. Anaesth Intensive Care I98 1;9:38 l-6. 16. Aldrete JA. Johnson DA. Allergy to local anesthetics. JAMA 1969;207:356-7. 17. Campbell RL, Gregg JM, Levin KJ, Elliott RA. Vasovagal response during oral surgery. J Oral Surg 1976;34:698-701. 18. Fisher M. Intradermal testing after anaphylactoid reaction to anaesthetic drugs: practical aspects of performance and interpretation. Anaesth Intensive Care 1984;12: I 15-20. 19. Assem ESK, Punnia-Moorthy A. Allergy to local anaesthetics: an approach to definitive diagnosis. Br Dent J 1988: I64:44-7. Reprint requests: Timothy A. Hodgson, BDS Department of Oral Medicine UMDS Guy’s Hospital London, England SEI 9RT
and Pathology
What’s new in OOO? Look for a %ew look” in The July issue will have a tinue its 46 year tradition ence Citation Index). The
711
the July 1993 issue of ORAL. S~R~IZRY, ORAL MEDICINE, ORAL PATHOLO~~Y. new cover and new design with a more modern look, but “Triple 0” will conof providing you with the most frequently cited articles in the field (1991 SciEditors and Publishers welcome your comments.
reactions to
A comparison with controls Tinlothy A. Hodgson, BDS,” Penelope J. Shirlcrw, BDS, FDS KG.’ Stephen J. Chullacombe, BDS, PhD, FRCPath,” London, Englund DtPARTMbNT Gl’\i’S
01:
OR&L
hl~D1CINt
;ZND
PATHOLOGY,
L,NITl:D
Mt-IllCAL
and
,-\ND
DtNTAl.
SCIIOOLS,
IIOSPll‘i\l.
Reactions to scratch and intradermal challenge with a variety of local anesthetics were examined In 90 patients and compared with 45 controls. The frequency of a positive scratch test was 13 of 90 in the patient group and 12 of 45 in the control group. Thus scratch testing did not appear to discriminate between test and control groups. Significantly greater numbers of patients (22 of 90) gave a positive intradermal response than controls (4 of 45) (chi-squared test p < 0.05). Nine patients showed reactions to more than one agent. The majority of reactions in both patients and controls were in atopic subjects (chi-squared test p < 0.05). In 87 of the 90 patients with suspected anaphylactoid reactions to local anesthetic agents, negative skin reactions to at least one of the agents allowed intrabuccal challenge and subsequent recommendation of an agent for future use. Skin testing, though not providing formal proof of allergy, provides a useful test to indicate local anesthetics that may be used for future procedures. (OR,%1 SliRG
ORAL
MEI>
OR\I.
P,\-~HOI
1993;75:706-1
T rue allergy to amide-type
I)
local anesthetic agents is extremely rare and may relate to the anesthetic agent itself or to its additives.‘-j The level of risk. however, may only be assessed in relation to the scale of use. The estimated number of dental local anesthetics administered annually in the United Kingdom is of the order of 70 million cartridges.” In comparison, the total number of adverse reactions reported after the administration of lidocaine and prilocaine containing preparations over the period July 1963 to January 1990 was 249 (nine of which were fatal).’ Of these, true allergy could be demonstrated in and accounted for less than I o/oof the total reactions to these agents.j. i-X It has been suggested that the majority 01 these reactions were of the delayed rather than the immediate type.” Most complications that arise from local anesthetic agents are the direct consequence of the pharmaco-
,‘Research bResearch
Rssiatant rn C)rnl Medicine. Fellows in Oral Medicine.
‘Professor ogy. C‘opyright
and Head
0030-42X/93/$1
706
1993
of Department bj
Mosby-Year
.OO +
IO
of Oral Hook,
7/13/45956
Medicine Inc
and Patho-
logic properties of the drug, the presence of a vasoconstrictor, concomitant drug therapy, or apprehension. Toxicity that results from the local anesthetic agent itself is usually the result of intravascular injection or rapid absorption of high doses of the drug. Among the published reports of allergy to lidocaine, few have confirmed any immunologic basis for the reaction or determined that, even if the reaction was allergic in nature, the reaction was to lidocaine rather than some other component of the anesthetic solution.7. 10 Intradermal skin testing has been found to be of value in assessing allergies to local anesthetic agents. “-” The aims of this study were to compare the frequent) of positive skin reactions with local anesthetic agents in control patients and in patients with a reported history of local anesthetic allergy. Also to determine whether negative reactions may indicate which proprietary agent could be used for intrabuccal challenge and therefore routine dental treatment. MATERIAL AND METHODS Study groups
Patient group. Ninety patients came to the Oral Medicine and Pathology Department. United Medi-
OKAI
SIJKGERY
OR,IL
Volume
75. Number
Table
I. Test
M~DICINL
ORAL
PATHOI
Hodgson, Shirlaw, and Challacombe
OGY
solutions I I 2
Proprietary
I
name
Saline Xylotox
Citanest + Octapressin 5 6 in United
Constituents Sodium chloride Lidocaine* hydrochloride 2% Adrenaline I:80000 (as Tartratej Sodium metabisulphite 0.5mg Sodium chloride BP 6.0mg Lidocaine hydrochloride 3’6 Sodium chloride Prilocaine hydrochloride .I“; Sodium chloride Felypressin Prilocaine hydrochloride Mepivacaine hydrochloride Sodium chloride
Lignostab
*I-ignocanx
707
6
Citanest plain Scandonest Kingdom.
cal and Dental Schools, Guy’s Hospital between the period October 1986 and December 1990, ranging in age from 10 to 65 years (mean age f standard deviation, 38.9 ? 8.9) for allergy testing, after reported adverse reactions to dental local analgesia. They were entered into the patient group. The main features of the reactions that had resulted in referral were swelling at the site of injection (27%), collapse (24%), rashes (19%), nausea (lo%), dyspnea (5%), ulceration at the site of injection (2%), and swelling at a site distant to that of injection (2%). Forty-two (47%) gave an atopic history (including asthma, hayfever, eczema, and drug allergy) and the ratio of female to male patients was 3:2 (54:36). Control group. A control group of 45 patients, ranging in age from 18 to 57 years (mean age f standard deviation, 35.8 i 8.1) with no previous history of adverse reaction to dental local analgesia, included 21 members with a history of atopy (46.4%). The female to male ratio was 3:2 (27: 18). Method (modified from Fisher 1984).15 A detailed history enabled the clinician to determine whether an immediate or delayed type hypersensitivity response was the likely cause of the adverse reaction. Any drug history that could modify (for example, antihistamines) or interfere with (for example, systemic steroid therapy) the subject’s response was also established. These subjects were excluded from the trial until therapy had been temporarily adjusted. Resuscitation facilities were available in the test room including oxygen, adrenaline 1: 1000, promethazine, aminophylline, and hydrocortisone. Intravenous access was only secured if the history warranted it. Pulse and blood pressure were noted at the beginning and during the procedure. After an explanation of the testing procedure, the flexor aspect of the forearm of the test subject was labeled with test areas
numbered one to six. The numbers corresponded to the test solutions (Table I). The skin was then lightly cleaned with isopropyl alcohol and left to dry. Test
methods
Scratch test. Fifty microliters of test solution was dispensed onto the skin and four superficial scratches made with a sterile needle. The response was recorded 10 minutes after the application of the test solution by measurement of the maximum diameter of both wheal and flare and compared with that to a saline solution control. Zntradermal test. Twenty-five microliters of test solution was injected intradermally by introducing a sterile needle into the skin at an angle of 10 degrees until the central hole was covered. The intradermal response was measured 15 minutes after injection. A positive response to either test was recorded when the wheal (papule and pseudopods) and flare (erythema) was 2mm or more than that of the saline control. For subjects with a history of delayed reactions the intradermal challenge was reread at 24 and 48 hours. Intrabuccal challenge. The criteria used to determine which test solution was to be used for the intrabuccal challenge was a negative response to both scratch and intradermal tests. An injection of 0.5 ml of the test solution was administered slowly into the upper buccal sulcus, and signs and symptoms noted for 45 minutes afterwards. A subject with a history of a delayed reaction was reviewed 24 and 48 hours after the buccal challenge. All patients were asked to contact the department if there were any further reactions. RESULTS
In the control group, 14 subjects (3 1.1%) with no history of allergy to local anesthetic agents produced
708
Hodgson, Shirlaw, and Challacomhe
Local Anesthetic Lidocaine + Adr
Lidocaine plain Prilocaine + Fely
Prilocaine plain
Mepivacaine 14 12 10 X 6 4 Percentpositive Fig.
Table
2
0
_1 4 6 8 10 12 14 Percent positive
1. Comparison of patients and controls using scratch testing.
II. Comparison of positive skin reactions in atopic and nonatopic persons
Agent which response
zo
positive occurred
Lidocaine + adrenaline Lidocaine plain Prilocaine + felypressin Prilocaine plain Mepivacaine Total number of positive skin reactions Total number of patients reacting
0 1 10
(23.87;)
12
(2X.6’;;)
(6.3%)
a positive skin response to scratch (26.6%) or intradermal (8.8%) testing. None of these subjects produced a delayed-type response. Two subjects from this group reacted positively to two agents during cutaneous testing. Twenty-seven of the 90 patients (30%) with a reported allergy to dental local anesthetic agents developed a positive skin response, a rate that was not significantly different from the controls. Thirteen (14.4%) of the patient sample reacted positively to scratch testing with one or more agent, which was not a significantly different response rate from the control group (26.6%). However, significantly greater numbers of the patient group gave positive intradermal
responses to one or more agent (24.6%) than controls (8.8%) (chi-squared testp < 0.05). There was no significant difference between the number of patients (7.9%) and controls (6.6%) who reacted to both intradermal and scratch testing. Nine patients in the study group (I 0%) responded to intradermal challenge with more than one agent. In only one case of the 90 referrals did a subject respond to all five test solutions. The most common agent to promote a positive skin reaction was lidocaine; 24 of 90 (26.7%) patients and 7 of 45 (15.5%) controls reacted to either scratch (Fig. I ) or intradermal challenge (Fig. 2). Although the proportions of patients and controls who responded to
ORAL
Volume
SURGERY
0~41.
75. Number
MFDICINF
ORAL
Hodgson, Shirlaw, and Challacombe
PATt~oLoGy
709
6
m
Local Anesthetic Lidocaine + Adr
Patients
7Lj
Controls
I
~
Lidocaine plain Prilocaine + Fely
~ ~
Prilocaine plain Mepivacaine 25 * = p
! ~--I-. .L-I 20 15 10 5 Percent positive
e0
5
-----i---i10 15 20 Percent positive
25
Fig. 2. Comparison of patients and controls using intradermal testing.
scratch tests with lidocaine was similar (7.7% and 13.3%) (Fig. l), significantly greater numbers of patients (22.2%) than controls (6.6%) (chi-squared test p < 0.02) showed a positive intradermal reaction (Fig. 2). Only five patients showed a positive intradermal reaction to prilocaine preparations (compared with one control), and only two showed a positive reaction to mepivacaine (none of the controls) (Figs. 1 and 2). These latter results were too small for reliable statistics. In the test group, the proportion of atopic patients who responded to scratch testing with local anesthetics, 10 of 42 (23.8%) was significantly greater compared with 3 of 48 (6.3%) nonatopic patients (Chisquared test p < 0.05). A similar result was obtained in the control group in which 9 of 21 (42.9%) atopic patients and 3 of 24 (12.5%) nonatopic patients produced positive reactions to scratch testing (chisquared test p < 0.05). In contrast, on intradermal challenge, no significant difference was found in both tests groups [ 12 of 42 (28.6%) atopic patients, 9 of 48 (18.8%) nonatopic patients] and control [3 of Z!l (14.3%) atopic patients, 1 of 24 (4.2%) nonatopic patients] (See Table II). The female patients in the test group responded positively to skin testing with similar frequency to the males (28% to 33%). In the control group, there was negligible difference in the frequency of positive responses between females and males (33% to 28%). In 87 cases (97%), a local anesthetic agent that did not produce a skin response was successfully used for intrabuccal challenge. In the remaining three cases,
two were challenged successfully intrabuccally with prilocaine and felypressin (Octapressin) after oral antihistamine preparations, and the cutaneous reactions of the third case were so marked to all agents with the scratch test that further testing was not carried out. In the patient sample, 25 subjects who reacted positively to one or more agent produced an immediate-type response. The two remaining subjects, who were female and atopic, produced a delayed-type response to intradermal but not to scratch testing with plain lidocaine. DISCUSSION The vast majority of adverse reactions to local anesthetic agents are not a result of a true allergy. The wide variety of types of reactions reported by the patients would support this. However, the patient group was a small proportion of the population who had received local anesthetic agents for routine dental treatment and who had been referred for the exclusion of a possible allergy to local anesthetics. In general intradermal skin testing has been found to be of value in the assessment of allergic reactions to local anesthetic agents. li-l4 In this study, 99% of patients reported to have had an allergic-type response to these agents were provided with an alternative that produced no unwanted side effects. Of these, 70% produced no reaction to cutaneous testing, which suggests that the clinical diagnosis of allergy to these agents was incorrect and that there was an alternative reason for the adverse reaction. Intradermal testing was found to discriminate the patient group from the control group better than
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scratch testing (Figs. 1 and 2). In the control group with no previous history of local anesthetic allergy. 14 of 45 (3 1.1%) of the total sample responded to skin testing. .4 large proportion of the reactions in the control group (I 2 of 45, 26.6%) were to scratch testing. This is surprising as the reported incidence of allergy to local anesthetics agents remains low. However. this apparently high number of positive reactions in the control group is consistent with other studies.‘” This emphasizes the importance of including controls to evaluate skin testing to local anesthetic agents. The fact that numbers of the control group (26%) who had no previous histor! of local anesthetic allergy produced a positive reaction to scratch testing indicates that scratch testing alone is an unreliable method to determine a suitable agent to be used for intrabuccal challenge. Indeed the majorit) of those control patients who produced an increased arca ol erythema in response to scratch testing produced no response to intradermal testing. It is recognized that interpretations of positive skin test are dificult. It has been suggested that result5 may vary depending on the cleaning of the skin. volume of allergen injected, time of day, temperature. depth of injection. and concommittent drug therapy. ‘I. ” False positive reactions may be attributed to the localized subcutaneous release of histamine as a result of needle-stick trauma, distension of the tissues. differences in osmolality, or additives in the solution. However, false positive responses to direct histamine release will usually arise rapidly and fade within twenty minutes. lx False negatives are ;I theoretical problem because many drugs have a molecular weight that is too low to elicit a positive response in patients with known allergy to that preparation. It is also accepted that cellular components of skin, particularly mast cells, may differ from that in mucosa and may account for positive reactions in skin with a negative response to intrabuccal challenge. Intradermal challenge with the plain lidocaine preparation used in this study produced the largest number of positive intradermal responses ( 17.0”1). However. this preparation contains only lidocaine and saline, and thus reactions cannot be accounted for by anesthetic solution additives. The reasons for the greater number of positive results with lidocainecompared with other preparations remains unclear. A significantly greater number of atopic persons in the patient group (23.8%) showed positive scratch reactions to local anesthetics when compared with nonatopic persons (6.3%). This is not unexpected because an atopic person is more susceptible to Type I hypersensitivity reactions as a result of mast cell degranulation. The mast cells in these subjects are
already activated to many agents that cause histamine release. The trauma incurred by the scratch test itsell may be sufficient in the atopic subject to promote histamine release. It should be noted that there is no signilicant difference when atopic and nonatopic subject\ in both stud] groups are challenged with the use ol intradermal testing. This would reinforce the use 01‘ the intradermal test as the primary consideration fol proceeding to intrabuccal challenge. Although positive cutaneous reactions to local anesthetic agents do not necessaril! indicate allerg),, this cannot be L’Yeluded. particularly in those patients who xho\f rcactions to more than one agent. The results 1,1‘cutaneous challenge with local anesthctic agent:, are nevertheless clinically of value.‘” In all but one case. the cutaneous tests were negative to at least one agent. This allowed intrabuccal challenge and administration 01‘ local anesthetic without adverse side ell‘ects in X9 of 90 patients referred with ‘allergy‘ to locnl anesthetic. This number included many whose rcstorati\.e treatment had hcen performed under general anesthetic or whose treatment had been abandoned. In on11 two cases did reactions to the challcngc neccssitatc antiallergic therapy in spite of manq’ patients who had been hospitalized after local anesthetic injections for routine treatment. Thus cutaneous challenge under controlled conditions can bc 3 useful test in elucidating appropriate local anesthetic agents for future use even though ;I definitive allerg) cannot be proven. Although there are criticisms against using scratch testing alone. \I hen it is used in combination with intradermal testing, cutaneousand subsequent intrabuccal challenge provides :I simple method of assessing the safest agent to use for dental local anesthesia. It should. however. be noted that in the sensitive person these procedures maq precipitate anaphylaxis and should bc undertaken with extreme caution and where resuscitation facilities arc easily accessible. REFERENCES BahaJe\L\ \\ I\,ln:\i L The rclationshlp het\vcecn III viva and in vitro ruct~\ its 01 patients history 01‘allerg! to local anaesIhetics Br Dent J 1982;152:385-7. \driani _I_ Zcpernick R. Allergic reaction\ to ioc:~I ;tnesthetic\ South Med .I lYXl:74:6Y3-9. Caason K 2. (‘urwn I. Whittington [>I{. .The h,r/,lrd\ of duLII IUC;I/ an;re\thelics. Br Dent .I 1983;154:253-8. Incaundo (i. Schatr M, Patterson R. Roscnherg M. L.Imamoto I-, I lamburger RN. Administration of local anesthrtic:, to putient\ with II history of a prior adverse rcaclion. J AIIcrgq (‘Iin Immunol 1978;hl:339-45. Lilley JD. Ruxl C. Walker RO. Waterhouse JAlf. Use and misuse 01’ equipment Ibr dental local analges~x .I Dent I ‘)7X:6 I3.%4(,. Honke\ 4.1. I.,iurencc DR. Lovel KLL. O’Neil R, Verrill PJ .\dverse rcactionC to local an3esthelic/vnsocon\trictor prepa rations. Hr Dent J 1972; 133: 137.40.
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7. Aldrete JA, Johnson DA. Evaluation of intracutaneous testing for the investigation of allergy to local anesthetic agents. Anesth Analg I970;49: 173-81; Comment by Adriani J, 182-3. 8. Verrill PJ. Adverse reactions to local anaesthetics and vasw constrictor drugs. Practitioner 1975;214:380-5. 9. Giovannitti JA, Bennett CR. Assessment of allergy to local anesthetics. J Am Dent Assoc 1979;98:701-6. IO. Seskin L. Anaphylaxis due to a local anaesthetic hypersensi-tivity: report of a case. J Am Dent Assoc 1978;96:841-3. Il. Braun DT. Beamish D. Wildsmith JAW. Allergic reaction to an amide type local anaesthetic. Br J Anaesth 1981;53:435-7. 12. Arora SK, Aldrete JA. Investigation of possible allergy to local anesthetic drugs, correlation of intradermal with intramuscular injections. Anaesth Rev 1976;3:13-6. 13. Fisher M. The diagnosis of acute anaphylactoid reactions to anaesthetic drugs. Anaesth Intensive Care 198 1;9:38 l-6. 14. SchatL M. Skin testing and incremental challenge in the evaluation of adverse reactions to local anaesthetics. J Allergy Clin lmmunol 1984:74:606-16.
15. Sage DR. Intradermal testing following anaphylactic reactions to anaesthetic drugs. Anaesth Intensive Care I98 1;9:38 l-6. 16. Aldrete JA. Johnson DA. Allergy to local anesthetics. JAMA 1969;207:356-7. 17. Campbell RL, Gregg JM, Levin KJ, Elliott RA. Vasovagal response during oral surgery. J Oral Surg 1976;34:698-701. 18. Fisher M. Intradermal testing after anaphylactoid reaction to anaesthetic drugs: practical aspects of performance and interpretation. Anaesth Intensive Care 1984;12: I 15-20. 19. Assem ESK, Punnia-Moorthy A. Allergy to local anaesthetics: an approach to definitive diagnosis. Br Dent J 1988: I64:44-7. Reprint requests: Timothy A. Hodgson, BDS Department of Oral Medicine UMDS Guy’s Hospital London, England SEI 9RT
and Pathology
What’s new in OOO? Look for a %ew look” in The July issue will have a tinue its 46 year tradition ence Citation Index). The
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the July 1993 issue of ORAL. S~R~IZRY, ORAL MEDICINE, ORAL PATHOLO~~Y. new cover and new design with a more modern look, but “Triple 0” will conof providing you with the most frequently cited articles in the field (1991 SciEditors and Publishers welcome your comments.