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PRELIMINARY COMMUNICATION
Plasma Epinephrine Levels and Cardiovascular Response to High Administered Doses of Epinephrine Contained in Local Anesthesia Emanuel S. Troullos, D.M.D., David S. Goldstein, M.D., Ph.D., Kenneth M. Hargreaves, D.D.S., Ph.D., Raymond A. Dionne, D.D.S., Ph.D. Pain Research Clinic, National Institute of Dental Research, Bethesda, Maryland
Summary The effects of administering an epinephrine-containing local anesthetic on plasma catecholamine levels and cardiovascular parameters were evaluated. Significant elevations were observed following administration of 8 dental cartridges of 2% lidocaine with epinephrine 1 :100,000 (144 ug) throughout the 20 minute observation period, while minimal changes were observed in the patients who received 6 cartridges of 3% mepivicaine. One minute after injection, the mean plasma epinephrine level in the group receiving epinephrine was 27.5 times higher than baseline. Concurrent elevations in systolic pressure (15%), heart rate (33%), and the rate-pressure product (52%) were also observed. These results indicate that significant amounts of epinephrine can be systemically absorbed following intraoral injection and the absorbed epinephrine can alter the cardiovascular status of the patient.
Epinephrine is widely used in dental anesthetic solutions to produce localized vasoconstriction. Concentrations ranging from 1:50,000 (20 ,ug/ml) to 1:200,000 (5 ,ug/ml) are found in commercially available dental cartridges. Until recently, it was generally accepted in the dental literature that the amount of epinephrine given as a vasoconstrictor in dentistry produces little systemic effect.1'2 A 1955 report by the New York Heart Association suggested that up to 200 Ag of epinephrine in conjunction with procaine could be administered to cardiac patients.3 The ADA currently advises 200 jig as the maximum dose for healthy patients.4 The amount of epinephrine absorbed following local dental anesthesia has been hypothesized to be less than the amount produced endogenously in response to pain due to inadequate anesthesia5 or due to anxiety associated with the procedure.6 Studies investigating the administration of 1.8 ml (one dental cartridge) of 2% lidocaine with epinephrine 1:100,000 (18 ug) reported elevated plasma epinephrine levels (94.5+13 pg/mI and 105+28 pg/ml) Received December 8, 1986; accepted January 23, 1987
Address correspondence to Emanuel S. Troullos, D.M.D., NIDR, 900 Rockville Pike, Bldg. 10, Room 65225, Bethesda, MD 20892.
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with minimal cardiovascular changes.7'8 The administration of 5.4 ml (3 cartridges) of 2% lidocaine with epinephrine 1 :100,000 (54 ug) resulted in still higher plasma epinephrine levels (302 +142 pg/ml) leading to increases in both cardiac output and heart rate.9 '0 The dichotomy between a minimally detectable cardiovascular response at approximately one-tenth of the maximum recommended dose and a significant response at one-fourth of the maximal dose, indicates that it is inappropriate to extrapolate the effects of lower doses to high doses without confirmation from experimental evidence. No studies, however, have directly assessed the effects of higher doses of epinephrine administered with dental local anesthesia."1 This study evaluated plasma epinephrine following administration of 8 cartridges of 2% lidocaine with epinephrine (144 ug) and resultant changes in blood pressure, heart rate, and plasma norepinephrine levels.
Methods The study was an open, parallel group design conducted in oral surgery outpatients. The subjects were 15 young (mean age 22.5 years), healthy (ASA class I) men (n=9) and women (n=6) who were free of allergy to any of the test medications. The surgical procedure consisted of the removal of four wisdom teeth. All patients were informed of the possible risks and signed an institutionally approved consent form. ANESTHESIA PROGRESS
An infusion of 0.9 normal saline was started in a vein of the left antecubital fossa. The patients rested quietly in a semisupine position for 20 minutes. Measurements of blood pressure and pulse were obtained, and a 10 ml blood sample collected. Local anesthesia was then administered in all four quadrants of the oral cavity with a dental aspirating syringe using standard technique. One group (n=10) received 8 cartridges of 2% lidocaine with epinephrine 1:100,000 (EPI). The other group (n=5) received 6 cartridges of 3% mepivicaine (NO EPI). Blood samples and circulatory measurements were obtained at 1, 4, 8, 12, and 20 minutes after completion of the administration of local anesthesia. The total dose of anesthetic in the EPI group was 288 mg lidocaine and 144 ,ug epinephrine. The NO EPI group received 324 mg mepivicaine. The skewed distribution of treatments was chosen based on previous studies9'10 showing little change in epinephrine levels following lidocaine administration alone and the preliminary nature of the investigation. Blood pressure and heart rate were measured by a cuff attached to the right arm and connected to an automatic blood pressure recorder (SENTRON ASD 400, Automated Screening Devices, Inc., Costa Mesa, CA) or by auscultation and palpation. The product of systolic pressure and heart rate was calculated as an index of myocardial oxygen consumption.12 This noninvasive method has been found to correlate well with direct measurement of myocardial oxygen consumption via catheterization of the coronary sinus. Blood samples were collected into chilled tubes containing EDTA, centrifuged under refrigeration within 30 minutes of collection, frozen in dry ice, and stored at -80°centigrade. The assaytechnique used high pressure liquid chromatography with electrochemical detection, the validity and reliability of which have been previously documented.13 Minimum detectable levels were about 5 pg/ml for both epinephrine and norepinephrine. Statistical analysis of catecholamine levels and physiologic variables was accomplished using analyses of variance for repeated measures. Analyses of covariance for repeated measures was performed on systolic blood pressure and norepinephrine levels because of the disparity in baseline values between the treatment groups. Duncan's multiple range test was used when appropriate to ascertain differences within and between groups. Pearson's correlation coefficient was calculated for the relationship between the change in plasma epinephrine and the change in heart rate at one minute after anesthetic injection.
Results Baseline levels of plasma epinephrine were similar in the two subject groups (Fig. 1 A). Levels were significantly higher after anesthesia in the EPI group JANUARY/FEBRUARY 1987
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1 min 4 min 8 min 12 min 20 min Time
Plasma epinephrine concentration (pg/ml, mean +SEM) before (baseline) and after (1, 4, 8, 12, and 20 min) administration of local anesthesia (A). Pulse rate (beats/min, mean +SEM) before and after administration of local anesthesia (B). Systolic pressure (mmHg, mean+±SEM) before and after administration of local anesthesia. (C). a = significant difference from baseline, p < .05; b = significant difference from baseline, p < .01; c = significant difference between groups, p < .05; d = significant difference between groups, p < .01 L], NO EPI; B, EPI.
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Catecholamine Levels and Cardiovascular Parameters Before and Afterthe Administration of Local AnesthesiaWith (EPI) or Without (no EPI) 144 ,ug Epinephrine
TABLE 1
Baseline
Norepinephrine (pg/ml±SEM) 211.4±28 EPI 267.4±39 NO EPI Diastolic Pressure (mmHg±SEM) 74.2±4 EPI 71.0±2 NO EPI Pressure-Rate Product (±SEM) 8278±476 EPI 7545±694 NO EPI
1 Minute
4 Minutes
8 Minutes
12 Minutes
20 Minutes
316.4±38bc
341 ±50b,c 326.4±60
366.0±77b
387.046b,c
386.757b,c 329.6±80
388.1 ±56b,C 317.6±72
73.1±6 76.8±6
70.8±4 80.4±7b,d
305.2±46 74.5±4 79.2±5a
72.8±4 76.0±6
12,592±732b,d
11,314±736b,d
11,165±7700bd
11,657±699bd
12,280+705b,d
8600±569
8494±376
9037±373
9051±517
9537±759a
aSignificant difference from baseline, p < .05. bSignificant difference from baseline, p < .01. CSignificant difference between groups, p < .05. dSignificant difference between groups, p < .01. than the NO EPI group at all time points (F=35.9, d.f. = 1,13, p < .001). The peak epinephrine level at one minute was 27.5 times higher than baseline in the EPI group. All posttreatment levels were significantly higher than baseline in the EPI group (p < .01). In the NO EPI group, only small and nonsignificant changes in plasma epinephrine were observed at all time points. Norepinephrine levels increased in both groups after administration of the local anesthesia (Table 1). Changes in plasma norepinephrine from baseline were significantly larger in the EPI group than in the NO EPI group at all postinjection time points (ANCOVA F=8.9, d.f.=1,12, p=
