Australian Dental Journal

Australian Dental Journal The official journal of the Australian Dental Association SCIENTIFIC ARTICLE Australian Dental Journal 2011; 56: 148 153 doi: 10.1111/j.1834-7819.2011.01316.x Severe adverse reactions to dental local anaesthetics: systemic reactions PJ Sambrook,* W Smith, J Elijah,à AN Goss* *Oral and Maxillofacial Surgery Unit, The University of Adelaide, South Australia. Department of Immunology and Allergy, The Royal Adelaide Hospital, South Australia. àoffice of Product Review, Therapeutic Goods Administration, Australian Capital Territory. ABSTRACT Background: Occasionally, patients suffer systemic adverse effects from injections of local anaesthetic solutions. This may range from minor transient vasovagal attacks to life-threatening collapse. Methods: The suspected adverse reactions reported to the Office of Product Review of the Therapeutic Goods Administration (TGA) were analysed in detail. Results: There was a high incidence (70%) of adverse reactions associated with prilocaine, which is much greater than its market share (less than 20%). There is a tendency to consider all systemic adverse reactions as being allergic reactions although this is rarely the case. Syncope, cardiovascular and central nervous system reactions are much more common. There is also a risk of methaemoglobinaemia to prilocaine and articaine. A small series of cases referred to one of the authors were also reported. Conclusions: Recommendations are made as to the prevention, acute care and subsequent investigation of adverse reactions. The most important conclusion is not to just label the response as allergic and to use an alternative agent. Detailed investigation and reporting should be made for all cases of suspected severe adverse reaction to local anaesthetic agents. Keywords: Local anaesthetics, adverse reactions, systemic reactions. Abbreviations and acronyms: ACEI = angiotensin converting enzyme inhibitor; LA = local anaesthetic; OMS = oral and maxillofacial surgeon; TGA = Therapeutic Goods Administration. (Accepted for publication 2 September 2010.) INTRODUCTION Local anaesthetics are the most commonly administered drug in dental practice. 1,2 It has been estimated that approximately 200 million cartridges of dental local anaesthetics are used per year in the United States of America, 3 70 million annually in the United Kingdom 4 and 11 million in Australia. 5 Generally, local anaesthetic (LA) injection is effective and uneventful but systemic adverse reactions, ranging from temporary light headedness to collapse, may occur. These systemic adverse reactions are commonly ascribed to the patient being allergic to anaesthetics. Allergic reactions of several different types may theoretically occur to the various constituents of a LA cartridge (Table 1). However, when severe adverse systemic reactions to dental local anaesthesia are investigated, true allergy is rare. 6,7 Toxic drug overdose, rapid absorption, intravascular injection, cardiovascular, central nervous system, psychogenic or idiosyncratic reactions are much more likely to occur. Indeed, it has been suggested that true allergic reactions to local anaesthetics do not occur or are a myth. 8 However, there are multiple single-case reports of individual cases in the literature. 9 13 It has been estimated that true immunologic adverse reactions occur in approximately 1% of all adverse systemic reactions. 6 This paper reviews serious adverse reactions to dental local anaesthetics which have been reported to the Office of Product Review of the Therapeutics Goods Administration (TGA). Recent case histories managed by the South Australian Oral and Maxillofacial Surgery Unit are also presented. Recommendations are made on the management of patients who present with a history of adverse systemic reactions to dental local anaesthetics or patients who experience an adverse reaction. 148 ª 2011 Australian Dental Association

Adverse systemic reactions to local anaesthetics Table 1. Contents of local anaesthetic solution and their allergic potential Drug Allergic potential Local anaesthetic All very low risk of allergy lignocaine (1% of all adverse reactions) prilocaine articane mepivacaine bupivacaine Vasoconstrictor Nil allergic potential adrenaline may result in cardiovascular felypressin responses Preservative metabisulfite Low but most likely allergen in LA methylparben Not in dental cartridges Latex plunger and Theoretical risk not clinically diaphragm significant MATERIALS AND METHODS The TGA adverse drug reaction database was interrogated for suspected dental LA adverse reactions reported from 1973 to 2008. The records were checked, edited and adverse peripheral nerve responses removed. The data were placed on a stand-alone database and analysed by agent, patient demographics, reaction and outcome. Case records of the South Australian Oral and Maxillofacial Surgery Unit and the private specialist practice of one of the authors (ANG), involving severe adverse systemic reactions to local anaesthetics over a 12-month period were reviewed. A case of true allergy to dental LA occurring in South Australia, investigated by one of the authors (WS) is described. 13 RESULTS A total of 227 suspected adverse reactions to dental local anaesthetics were reported to the TGA in the study period. Six were adverse peripheral nerve responses; four prolonged anaesthesia and two facial nerve palsies. These were removed as they are not the topic of this study. 5 The data for the 221 severe systemic reactions are presented in Table 2. The information is sorted primarily by the LA drug involved. The reactions are grouped into syncope, CNS reaction, cardiovascular reaction, methaemoglobinaemia, allergic response and other. These groupings are determined by the reporting practitioner and often the nature of the reaction is not confirmed by independent investigation. Approximately 16 000 patients per year are seen through the public oral and maxillofacial surgery unit in Adelaide. Minor transient adverse reactions to local anaesthesia, usually anxiety related, are an almost daily event in the undergraduate dental extraction clinic. Six referred cases with a history of severe adverse reactions are presented in Table 3. DISCUSSION This study shows that severe adverse reactions to dental local anaesthetics are rare and multifactorial in origin. The key unusual finding is the large number of Table 2. Severe systemic adverse reactions reported to the Office of Medical Safety, TGA, Canberra Single agent Combinations Totals Lignocaine Prilocaine Articaine Bupivacaine Prilocaine plus lignocaine Prilocaine plus other Number 50 (23%) 131 (59%) 5 (2%) 9 (4%) 10 (5%) 13 (6%) 221 Age 1 29 35.5 67 42.5 34 38.5 41.0 4 72 0 79 47 85 32 70 11 69 11 67 0 85 Gender 1 Male 23 (10%) 47 (21%) 1 (0.5%) 3 (1%) 4 (2%) 5 (2%) 84 (38%) Female 27 (12%) 78 (35%) 4 (2%) 6 (3%) 6 (3%) 8 (4%) 132 (60%) Reaction Syncope 7 25 0 0 3 23 59 (27%) CNS 10 21 1 1 1 2 36 (16%) CVS 7 8 0 3 0 1 19 (9%) Allergy 16 44 4 4 3 5 76 (34%) Methaemoglobinaemia 0 6 0 0 0 0 6 (3%) Others 10 27 0 1 3 2 44 (20%) Outcome 3 Recovered 42 114 5 5 8 11 186 (92%) Not Recovered 5 7 0 1 0 0 13 (6%) Death 1 1 0 0 0 1 3 (1%) Unknowns: 1 Age. Unknown 17. 2 Gender. Unknown 11. 3 Outcome. Unknown 18. ª 2011 Australian Dental Association 149

PJ Sambrook et al. Table 3. Oral and maxillofacial surgery unit referrals for cases of severe adverse reactions to local anaesthetics Case Age History Medical history Investigation Diagnosis 1 46 M History collapse after LA at dentist 2 73 M History marked swelling after LA Consistent with angioedema Presented with a large tongue ulcer Fit and well. No allergies Fit and well 3 29 F Collapse following LA at dentist Multiple allergies Penicillin Sulfur Erythromycin Narcotics Some foods Reactions vary from rash to anaphylaxis 4 65 F History swelling after extraction LA LA biopsy then swelling in 2 hours 5 54 F Weak history of allergy to lignocaine. So usually had prilocaine, new dentist gave lignocaine fi ill for 3 days 6 30 F Collapsed following LA dental procedure fi ICU Hypertension Hyperthyroidism Allergy to Codeine Collapsed on placement of IV line Negative patch test Declined investigation Insisted on extraction and biopsy without LA Investigated Patch tests -ve Admitted for airway obstruction. Returned for investigation Severe vasovagal Angioedema Tolerated procedure without LA well Biopsy proven SCC Had surgery, radiotherapy for SCC and later osteoradionecrosis. Died of widespread cancer Severe vasovagal No allergy to LA but a patient fearful of allergic reactions Angioedema Fit and well Referral for investigation Not allergy idiosyncratic reaction Fit and well Investigation showed hereditary CI inhibitor deficiency Level 0.05 g l Normal 0.15 Admitted and given 2 units CI inhibitor pre op. Bupivacaine with no problems suspected adverse reactions to prilocaine reported to the TGA. Seventy per cent of all reports involved prilocaine, either alone or in combination. This is greater than prilocaine s market share, which is less than 20%. 5 The possibility that a bias in reporting rates is responsible for the apparent preponderance of adverse reactions to prilocaine could not be ruled out. It is noted that for many years prilocaine with felypressin has been promoted as the safe LA to use primarily for patients with cardiovascular and other systemic diseases. Reporting of adverse drug reactions to the TGA is voluntary (not mandatory) by healthcare professionals. It has been estimated that in the United Kingdom only 10% to 15% of serious adverse drug reactions are reported. 4 The percentage reported in Australia is probably similar. Generally, for medications used in general medical practice, Australia has a high level of reporting. 14,15 The level of reporting specifically for dental LA agents is not known. In general, only reactions requiring medical intervention, including hospital emergency department care, would be reported. Simple transient events managed in the dental clinic are unlikely to be reported. Overall, the TGA figures are a small but important sample of all of the serious adverse reactions. The most common type of adverse reactions was syncope, which is a transient self-limited loss of consciousness. The most common type of syncope is vasovagal, which is usually a vascular reaction to anxiety and fear, either prior to or during the injection. This has a rapid onset and usually if the patient is laid flat there is a prompt and spontaneous recovery. However, it is important to understand that syncope may also be the presentation of an adverse drug reaction, cardiac dysrhythmia, ischaemic heart disease or cerebrovascular disease. If the patient is slow to recover from syncope or has other signs and symptoms, medical assistance is required. 16,17 The second major groupings were central nervous system (CNS) responses with persistent depression, agitation or tremor. These variously represent an uncovering of the patient s preexisting psychological state or a direct effect of the drug on the CNS or a combination response. A smaller group of patients demonstrated cardiovascular problems including angina or myocardial infarction. It is unlikely this is solely the effect of the LA, including the vasoconstrictor, on a previously healthy patient. It is more likely an uncovering of either known or unknown underlying cardiovascular disease. This was reported to the TGA as occurring with both lignocaine and prilocaine. Methaemoglobinaemia is where haemoglobin is oxidized to methaemoglobin by prilocaine and articaine. 18 This results in sedation and cyanosis, with the bluish tinge being first noticed in the lips and fingers but it may be more generalized. This is a dose-related effect and occurs at above 8 mg kg in susceptible patients. Of the six patients, all with prilocaine, two 150 ª 2011 Australian Dental Association

Adverse systemic reactions to local anaesthetics were infants aged less than 1 year and 3 years; one was aged 27 years; and three were an unknown age. A range of allergic-type reactions is summarized in Table 1. The potential allergens are the LA drug itself and the preservative metabisulfite. Metabisulfite is found in all LA solutions which contain adrenaline. Methylparaben is used only as a preservative in multivial solutions, thus is not found in usual dental cartridges. It has also been suggested that there is a risk of latex allergy, as latex may be found in the bung and diaphragm of dental LA cartridges. A detailed review found that although there was some evidence that latex allergens could be released into the solutions contained in the cartridge, there were no recorded cases of clinical reaction to latex from the injected LA. 19 Latex allergy clearly does occur in dental practice from direct contact with latex gloves and rubber dam. 20,21 Type I immunoglobulin E mediated allergic reactions to local anaesthetics are rare. True anaphylaxis is a significant medical emergency with swelling of the airway, respiratory distress and cardiovascular collapse. There were 16 cases of anaphylaxis reported to the TGA over the 35 years of keeping records of adverse events. Assuming all cases of anaphylaxis were reported, and assuming on average 10 million cartridges were used per year, then this represents an incidence of 1 in 22 million LA injections. Hence, anaphylaxis is very rare. One of the authors (WS) has been involved in the investigation and management of only one case of true allergic reaction to dental local anaesthetics in 25 years as a consultant immunologist to a major state hospital. 13 As this case was reported in an international clinical immunology and allergy journal, unlikely to be accessed by general dental practitioners, the key elements are described. A 31-year-old female with no history of allergy received two cartridges (each cartridge, 66 mg in 2.2 ml) of mepivacaine (Scandonest) 3% prior to and during a dental procedure. Within a few minutes she experienced intense pruritus of the hands and feet accompanied by nausea and a need to go to the toilet. She rested for about 10 minutes but then attempted to walk to the toilet, vomited, and had a brief loss of consciousness. Erythema and swelling of the hands was noticed. She was transferred to a hospital by ambulance for further treatment and recovered. She was then referred to a clinical immunology and allergy specialist for further investigation. A blood test for specific IgE to latex was negative. Intradermal tests were carried out with mepivacaine and other LA; the test was positive for mepivacaine, bupivacaine and lignocaine but negative to prilocaine. She tolerated a challenge with prilocaine 0.5% up to 2 ml and has since undergone dental procedures with prilocaine without any reaction. Subsequently, an experimental test was developed (Phadia AB, Uppsala, Sweden) which confirmed the presence of specific IgE to mepivacaine. This is the first reported case of the detection of LA-specific IgE with proof by cross-inhibition studies. Fortunately, one of the OMS authors (ANG) has not had a patient suffer an allergic reaction to local anaesthetics in over 40 years of practice. However, he had been referred many alleged cases of dental LA allergy for investigation. The other author (PJS) has had one case. The patient was having a day stay general anaesthetic. At the end of the procedure, bupivacaine was injected for pain control and the patient suffered an immediate anaphylaxis. This response was controlled as the patient was still intubated and being monitored by an anaesthetist. Following a period in intensive care, the patient made a full recovery. This case was reported to the TGA. It is very important to try to distinguish true allergic anaphylactic reactions from other causes of cardiovascular collapse. Distinctive clinical features of anaphylaxis include pruritis and flat skin erythema, sometimes localized to the hands or feet or axillae or groin; hives (urticaria) which are itchy welts; and angioedema, usually a painless non-pruritic swelling occurring distant from the site of injection. However, importantly, some cases of true anaphylaxis can show only hypotension without any of these signs. Therefore, the absence of these features does not rule out a true systemic allergic reaction. Recently, the serum mast-cell tryptase test has become more widely available. A positive test confirms that the reaction was anaphylactic in nature although, of course, the result of the test will not become available until later. Blood should be drawn within 15 minutes to 6 hours after the onset of the reaction. The sensitivity of this test is not absolute so a normal value does not rule out anaphylaxis. A patient who has had a suspicious reaction should always be investigated, preferably by a specialist clinical immunologist allergist. The mechanism of true allergic reactions to LA is likely to be through IgE (Type 1 hypersensitivity). Blood tests for specific IgE to LA (formerly called RAST tests) are not routinely available but have been developed experimentally. 13 True allergy to LA can also be identified by skin tests (skin prick tests, intradermal tests). These tests need to be carried out by an allergy specialist. Most hospital immunology and allergy departments will have protocols in place for skin testing and challenge testing with LA. The challenge test is useful when the nature of the reaction is unclear. The patient is admitted to hospital for a day procedure and held in an intensive observation area with access to resuscitation equipment. Initially, skin testing is carried out and if the result is positive, challenge testing would not be carried out with that particular LA. Where skin tests are negative or equivocal, the patient is challenged by subcutaneous injection with the LA in graded doses, working ª 2011 Australian Dental Association 151

PJ Sambrook et al. towards the full therapeutic dose. Challenge testing can be done either with the LA that the patient is thought to have reacted to in the past (if there is some doubt as to whether there is a genuine problem) or with a different LA to find a suitable substitute. At the Royal Adelaide Hospital, in the majority of cases, the challenge test is negative. If a reaction does occur then its nature can be observed. The majority of positive challenges are considered to be idiosyncratic neurological reactions. Subsequent challenges with a different LA may find one that is better tolerated. On the other hand, if a reaction occurs but can be shown not to be dangerous (no cardiovascular or respiratory changes), then it might be possible to use that LA in the future with the expectation that the patient may experience some symptoms but is not at risk. Type IV reactions involve a delayed hypersensitivity and are usually localized. There may be a rash or they present as a localized soft tissue swelling or angioedema. The hereditary type of angioedema is due to an inherited deficiency of complement 1-esterase inhibitor. There is also an idiopathic type of angioedema which is associated with angiotensin converting enzyme inhibitors (ACEI), a class of drugs used in the management of hypertension. The swelling of angioedema commonly occurs after trauma to the area and is usually not strictly a reaction to the LA. In the cases reported to the TGA, there were 33 cases consistent with angioedematype reactions. In the OMS group of patients there were three cases, one of which had been identified prior to dental surgery and two cases identified after they had a reaction. There was quite a large other group which was difficult to classify. Most were minor, such as nausea or chills. However, two patients were reported as suffering blindness, one following a prilocaine injection and another from bupivacaine. These probably represent intra-arterial injection with the direct effect of vasoconstriction of the Circle of Willis in the brain. One of the authors (ANG) vividly remembers several decades ago performing a mandibular block with lignocaine and adrenaline with a negative aspirate where the patient immediately lost consciousness and had a profound blanching of the ipsilateral forehead. They were unconscious for less than five minutes and on recovery of consciousness, initially were blind in the ipsilateral eye. They were carefully monitored in a postoperative recovery facility and fully recovered without sequealae. The different LA agents used had different patterns of reaction. A large number of suspected adverse reactions reported to the TGA related to prilocaine used either alone or in combination with other local anaesthetics. Most were minor and self-limiting but some were severe including blindness, major cardiovascular events or anaphylaxis. Methaemoglobinaemia is specific to prilocaine and articaine. Lignocaine similarly covered the range of adverse events but were much less common, particularly when the predominant usage of lignocaine in dentistry is taken into account. Articaine, only recently introduced for general dental usage, has had a number of adverse systemic reactions. Four of the five were described as being allergic, although they were not fully investigated. Of the six cases of prolonged anaesthesia reported to the TGA, two were to articaine. These were removed from the data set as they were not systemic adverse reactions. The probable increase in prolonged anaesthesia from 4% articaine is discussed in another paper. 5 The number of adverse reactions to bupivacaine used in dental practice was low at nine, although they tended to be severe. Bupivacaine is not commonly used in general dental practice but is commonly used by OMS for pain management and extensive dental alveolar surgical cases, i.e. mainly the removal of wisdom teeth. However, bupivacaine is widely used in medical practice and a total of 162 cases were reported to the TGA. One-third of these related to either spinal anaesthesia or for pain control for general anaesthetic procedures. The remaining two-thirds were procedures performed with LA alone. The severe adverse reactions were mainly cardiovascular (15%) and suspected allergic reactions (23%). Thus, bupivacaine should only be used with caution in general dental practice. There were three cases of death reported to the TGA; one with prilocaine with felypressin and myocardial infarction in a 64-year-old male; one with lignocaine and myocardial infarction in a 48-year-old female and one with prilocaine and adrenaline and brain oedema in a 19-year-old female. In all three cases it is not possible to directly and solely implicate the LA agent (as patients were on concomitant medicines) but it may be a possible factor in a complex situation. All the Adelaide OMS cases reported relate to lignocaine. It should be noted that lignocaine is used solely in the OMS clinic which has a high percentage of morbidly ill patients who can be immunocompromised, have cardiovascular and neoplastic problems and other diseases. The management of adverse systemic reactions include both active prevention and if collapse occurs, immediate treatment. Subsequently, further investigation needs to be organized. With all new patients, adverse reactions to local anaesthetics need to be included in the medical and dental history. If the patient tells you they are allergic to a particular LA, don t just agree and try another type of local. Carefully check their history for signs of allergies, swelling, rash or breathing difficulty. If their history is positive for these, then refer the patient for workup by an appropriate specialist. Treat all patients carefully with reassurance to relieve fear and anxiety. It is best giving local anaesthetics in 152 ª 2011 Australian Dental Association

Adverse systemic reactions to local anaesthetics the supine position. Use an aspirating syringe and inject slowly. Do not give excessive doses, particularly prilocaine or articaine for children. Monitor any adverse reactions. Most will respond to reassurance and a supine position. If a patient with a reaction does not respond rapidly, consider whether it is toxic, psychological, idiosyncratic or an allergic reaction and be ready to initiate appropriate treatment. 17 If the condition persists, get appropriate paramedical assistance and transfer the patient to hospital. Once the emergency is over, it would be appropriate to refer and investigate the case and report the event to the TGA. It is the authors experience that some general medical practitioners would either undercall an adverse reaction or too swiftly label them as allergic reactions. Appropriate specialist referral includes the OMS, with an interest in adverse reactions, a specialist clinical immunologist or an anaesthetist who investigates adverse drug reactions. Do not tell the patient they are allergic as the odds are only 1% of all adverse reactions are correctly diagnosed. Always pay close attention to the issue and if in doubt, appropriately refer. ACKNOWLEDGEMENTS The authors acknowledge with thanks the permission of the Director of the Office of Product Review of the Therapeutic Goods Administration, the Commonwealth of Australia to analyse and present data held by the Office. REFERENCES 1. Bennett CR. Monheim s local anaesthesia and pain control in dental practice. 7th edn. St. Louis: Mosby, 1984:225 237. 2. Malamed SF. Handbook of local anaesthesia. 3rd edn. Chicago: Mosby, 1990. 3. Pogrel MA, Bryan J, Regezi J. Nerve damage associated with inferior alveolar nerve blocks. J Am Dent Assoc 1995;126:1150 1155. 4. Ball IA. Allergic reactions to lignocaine. Br Dent J 1999;186:224 226. 5. Sambrook PJ, Goss AN. Severe adverse reactions to dental local anaesthetics: prolonged mandibular and lingual nerve anaesthesia. Aust Dent J 2011;56:154 159. 6. Rood JP. Adverse reactions to dental local anaesthetic injection allergy is not the cause. Br Dent J 2000;189:380 384. 7. Chen AH. Toxicity and allergy to local anaesthesia. J Calif Dent Assoc 1998;26:683 692. 8. Baluga JC. Allergy to local anesthetics in dentistry. Myth or reality? Rev Alerg Mex 2003;50:176 181. 9. Seskin L. Anaphylaxis due to local anesthetic hypersensitivity: report of case. J Am Dent Assoc 1978;96:841 843. 10. Ogunsalu CO. Anaphylactic reaction following administration of lignocaine hydrochloride infiltration. Case report. Aust Dent J 1998;43:170 171. 11. Johnson WT, De Stigter T. Hypersensitivity to procaine, tetracaine, mepivacaine and methylparaben. Report of a case. J Am Dent Assoc 1983;105:53 56. 12. Malanin K, Kalimo K. Hypersensitivity to local anesthetic: articaine hydrochloride. Anaesth Prog 1995;42:144 145. 13. Venemalm L, Degerbeck F, Smith W. IgE-mediated reaction to mepivacaine. J Allergy Clin Immunol 2008;121:1058 1159. 14. Joelson S, Joelson IB, Wallander MA. Geographical variation in adverse event reporting rates in clinical trials. Pharmacoepidemiol Drug Saf 1997;6 Suppl 3:S31 S35. 15. Miller GC, Britt HC, Valenti L. Adverse drug events in general practice patients in Australia. Med J Aust 2006;184:321 324. 16. Giovannitti JA, Bennett CR. Assessment of allergy to local anesthetics. J Am Dent Assoc 1979;98:701 706. 17. Oral and Dental Expert Group. Therapeutic Guidelines: Oral and Dental. Version I. Melbourne: Therapeutics Guidelines Limited, 2007. 18. Wilburn-Goo D, Lloyd LM. When patients become cyanotic: acquired methemoglobinemia. J Am Dent Assoc 1999;130:826 828. 19. Shojaei AR, Haas DA. Local anesthetic cartridges and latex allergy: a literature review. J Can Dent Assoc 2002;68:622 626. 20. Task Force on Allergic Reactions to Latex. American Academy of Allergy and Immunology. Committee Report. J Allergy Clin Immunol 1993;92:16 18. 21. Ching M, Webster G, Goss AN. Allergy to gloves. Aust Dent J 1994;39:212 213. Address for correspondence: Professor Alastair Goss Oral and Maxillofacial Surgery Unit Faculty of Health Sciences The University of Adelaide Adelaide SA 5005 Email: alastair.goss@adelaide.edu.au Web: http://www.dentistry.adelaide.edu.au/ o&mfs/0&mfs_index.html ª 2011 Australian Dental Association 153