J Oral Max~llotac 49.957-962.
Surg
1991
Cardiohemodynamic and Serum Catecholamine Response to Surgical Removal of Impacted Mandibular Third Molars Under Local Anesthesia: A Randomized
E. KNOLL-KCjHLER,
Double-Blind Parallel Crossover Study
MD,* M. KNaLLER,t
K. BRANDT,$
Group
and
AND J. BECKER,
DMD$
The aim of this study was to differentiate between the extent to which surgical stress and the epinephrine in local anesthetic solutions influence serum catecholamine, CAMP, and potassium levels, and contribute to changes in cardiohemodynamic parameters. One hundred sixty mg of articaine hydrochloride (4.0 mL of a 4% articaine hydrochloride solution) with two different epinephrine doses was injected into outpatients prior to removal of an impacted mandibular third molar in a randomized, double-blind parallel group and crossover design. The results showed that the amount of epinephrine absorbed from the intraoral injection site predominantly determined the serum epinephrine concentration. The anestheticinduced increase in the serum epinephrine level did not correlate with changes in the cardiohemodynamic parameters under study at any time during the operative procedure. The serum CAMP changes correlated with those of epinephrine, whereas the serum potassium levels remained unchanged. The procedure of tooth extraction was a stressful event when the 1:200,000 epinephrine-containing anesthetic solution was used, showing that the risk of inducing a cardiovascular incident during oral surgery seems to be higher the greater the extent of operation and the lower the epinephrine dose in the anesthetic solution.
the increase in the systemic EPI concentrations is controversial. Tolas et al4 reported no significant cardiovascular changes following injection of a single cartridge of an anesthetic containing 18 p,g EPI despite a twofold increase in plasma EPI. Following administration of lidocaine with 54 pg EPI, Dionne et al* observed threefold elevations in circulating EPI levels among unsedated patients and eightfold elevations among sedated patients. The heart rate increased by 11 to 13 beats per minute (bpm) in both groups. Troullos et al5 observed a 27.5times-higher plasma EPI level following the administration of eight dental cartridges of 2% lidocaine with EPI l:lOO,OOO.These authors found a significant correlation between the change in plasma EPI and heart rate. To clarify whether these differences in the results
Increases in plasma epinephrine (EPI) during dental anesthesia with EPI-containing local anesthetic solutions are well documented.“5 However, whether there is a cardiohemodynamic response to Received from the Freie Universitat Berlin, Germany. * Professor of Pharmacology and Toxicology, Institut fur Pharmakologie. t Assistant Physician, Poliklinik fiir Zahn-, Mund- und Kieferkrankheiten, Zahnklinik Nord. $ Medical Technical Assistant, Institut fiir Pharmakologie. 0 Surgeon for Oral Dentistry, Poliklinik fur Zahn-, Mund- und Kieferkrankheiten, Zahnklinik Nord. Address correspondence and reprint requests to Dr KnollKGhler: lnstitut fur Pharmakologie. Freie Universitat Berlin, Thielallee 69172, D-1000 Bedin 33, Germany. 0 1991 American geons
Association
of Oral and Maxillofacial
Sur-
0278-2391191/4909-0006$3.00/O
957
ARTICAINE AS LOCAL ANESTHETIC IN ORAL SURGERY
958
are caused by differences in study design, the present study was initiated to differentiate between the extent to which the dental procedure and exogenous EPI in the local anesthetic solutions contribute to heart rate and arterial blood pressure variations . Material and Methods The study employed a randomized, double-blind parallel group design and a randomized doubleblind crossover design. It was conducted on 33 normotensive male nonsmokers (mean age, 25 -+ 0.5 years; mean body weight, 71 + 1.6 kg). At the initial appointment, a comprehensive medical history was obtained, a physical examination was performed, and a written consent signed. The patients were not taking any pharmaceutical drugs and none was suffering from any acute or chronic illness or had allergies to any of the test substances. PROTOCOL After overnight fasting, the subjects were placed in a supine position on an operating table in an operating room that was closed to persons not taking part in the study. An 18-gauge intravenous catheter was inserted into the right antecubical vein, electrocardiographic leads were placed, and an automatic blood pressure cuff was applied. Twenty minutes later, baseline venous blood specimens were collected and heart rate and blood pressure were recorded automatically (78352-A Hewlett Packard, San Diego, CA). This time delay allowed for stabilization of the sympathetic nervous system in response to the intravenous catheter insertion. The heart rate pressure product (HRPP), considered to be a reliable index of myocardial oxygen consumption6 was calculated by multiplying the heart rate by the systolic blood pressure.’ According to a randomization schedule, the patients received in a double-blind design 4.0 mL of a 4% articaine hydrochloride solution containing either 1:200,000 (Ultracain D-S, Hoechst Co, Frankfurt, Germany) or
Table 1.
l:lOO,OOO EPI (Ultracain D-S forte, Hoechst Co) over a 60-second period, after aspiration. Patients undergoing two separate operations for removal of an impacted mandibular third molar were given the solutions in a randomized double-blind crossover design. One mL of this solution was injected to anesthetize the inferior alveolar nerve, 1.0 mL to anesthetize the inferior lingual nerve, and 2.0 mL to anesthetize the long buccal nerve. Those subjects who took part in the study twice were given appointments at the same time of day to exclude any influence of circadian rhythm. The solutions were coded with numbers and always injected by the same oral surgeon. All 33 patients reported profound local anesthesia within 4 minutes of injection. No supplemental injections were required at any time during the study. Further cardiovascular parameters were measured, and blood specimens were taken 3 minutes after injection of the anesthetic solution and at defined times during the operation, as shown in Table 1. The surgery was always performed by the same oral surgeon. The duration of the individual steps of operation, determined by a pilot study, was kept constant .
BLOOD SAMPLING Blood specimens were collected in chilled test tubes containing ethyleneglycol-bis-2-aminoethylether-N,N’-tetra-acetic acid (EGTA) and glutathione in amounts of 5.25 mmol/L and 0.1 mmol/L, respectively. EPI and nor-EPI were measured by a radioenzymatic technique according to the method of Peuler and Johnson,* modified by Thiede and Kehr,’ and recently described in detail by Knoll-Kohler et a1.3 To minimize patient discomfort and for sampling convenience, venous rather than arterial catecholamine concentrations were measured. Despite the perfusion rate-dependent arteriovenous difference, the venous EPI concentrations correlate with the arterial concentration after a certain lag phase when obtained from subjects in
Times of Data Collection During Extraction of an Impacted Mandibular Third Molar
Procedure
Duration (min)
Time After Injection (min)
Time in the Operating Room (min)
IV catheter insertion End of relaxation phase (basal value) After injection End of mucoperiosteal flap preparation Start of extraction Suturing End of the operation recovery phase
20.0 4.0 3.6 4.2 10.6 20.0
3.0 6.6 10.8 21.4 41.4
25.0 29.0 32.6 36.8 47.4 67.4
KNOLL-KOHLER
959
ET AL
recumbent position.109” All samples were assayed examiner-blind by the same technician. CAMP known to be closely correlated with the EPI serum level” was assayed with the CAMP (3H) radioassay kit (Amersham Int, England). Serum potassium was measured using the Autocalculation Flame Photometer 743 (Instrumentation Laboratory, Padermo, Italy). DATA ANALYSIS
Values were calculated as means 2 SEM. Data were statistically analyzed by a two-way analysis of variance with subsequent pairwise comparisons of means by the LSD test (least significant difference) using the computer program CSS, part Quick Anova (Statsoft lnc, Tulsa. AZ). Results
The data of the global analysis of variance showed significant differences in the serum catecholamine levels between the l:lOO,OOO and the
articaine hydrochloride 1:200,000 EPI-containing solutions (effect of LA, Table 2). All the other parameters under study showed no changes in relation to the EPI content of the anesthetic solution. Independent of the study design, dose-dependent differences (P 4 .Ol) in the EPI serum concentrations were evident during the first 3 minutes after injection (Tables 3 and 4). The nor-EPI serum level was only elevated significantly (P < .05) in the crossover design study after anesthesia with the 1:200,000 EPI-containing solution during the phase of tooth luxation when compared with the !: IOO,OOO EPI-containing value. Study design and time-dependent differences were observed in the serum catecholamine and CAMP levels as well as in the cardiovascular response pattern when compared with the basal value. In the parallel group design (Table 3), 3 minutes after injection of the anesthetic solution, the heart rate, HRPP, as well as the serum EPI and CAMP levels, increased significantly. The arterial systolic and diastolic pressure rose at the beginning of the preparation procedure. In both groups, the
2. Analysis of Variance of the Effect of Intraoral Injection of 4.0 mL 4% Articaine Hydrochloride Solution Containing 1:2W,ooO or 1:loO,ooO Epinephrine in Oral Outpatients Using a Randomized Double-Blind Parallel Group or Crossover Design
Table
Parallel Parameter HR
PS
PD
PM
HRPP
EPI
Nor-EPI
CAMP
Potassium
Effects Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA
Crossover
F Value
P Value
F Value
P Value
17.374 0.130 0.159 7.773 2.162 0.069 5.407 0.654 0.556 4.823 1.319 0.547 14.819 0.065 0.145 21.724 17.703 2.051 1.474 3.996 0.125 7.305 0.059 0.388 1.177 0.304 0.414
Surg
1991
Cardiohemodynamic and Serum Catecholamine Response to Surgical Removal of Impacted Mandibular Third Molars Under Local Anesthesia: A Randomized
E. KNOLL-KCjHLER,
Double-Blind Parallel Crossover Study
MD,* M. KNaLLER,t
K. BRANDT,$
Group
and
AND J. BECKER,
DMD$
The aim of this study was to differentiate between the extent to which surgical stress and the epinephrine in local anesthetic solutions influence serum catecholamine, CAMP, and potassium levels, and contribute to changes in cardiohemodynamic parameters. One hundred sixty mg of articaine hydrochloride (4.0 mL of a 4% articaine hydrochloride solution) with two different epinephrine doses was injected into outpatients prior to removal of an impacted mandibular third molar in a randomized, double-blind parallel group and crossover design. The results showed that the amount of epinephrine absorbed from the intraoral injection site predominantly determined the serum epinephrine concentration. The anestheticinduced increase in the serum epinephrine level did not correlate with changes in the cardiohemodynamic parameters under study at any time during the operative procedure. The serum CAMP changes correlated with those of epinephrine, whereas the serum potassium levels remained unchanged. The procedure of tooth extraction was a stressful event when the 1:200,000 epinephrine-containing anesthetic solution was used, showing that the risk of inducing a cardiovascular incident during oral surgery seems to be higher the greater the extent of operation and the lower the epinephrine dose in the anesthetic solution.
the increase in the systemic EPI concentrations is controversial. Tolas et al4 reported no significant cardiovascular changes following injection of a single cartridge of an anesthetic containing 18 p,g EPI despite a twofold increase in plasma EPI. Following administration of lidocaine with 54 pg EPI, Dionne et al* observed threefold elevations in circulating EPI levels among unsedated patients and eightfold elevations among sedated patients. The heart rate increased by 11 to 13 beats per minute (bpm) in both groups. Troullos et al5 observed a 27.5times-higher plasma EPI level following the administration of eight dental cartridges of 2% lidocaine with EPI l:lOO,OOO.These authors found a significant correlation between the change in plasma EPI and heart rate. To clarify whether these differences in the results
Increases in plasma epinephrine (EPI) during dental anesthesia with EPI-containing local anesthetic solutions are well documented.“5 However, whether there is a cardiohemodynamic response to Received from the Freie Universitat Berlin, Germany. * Professor of Pharmacology and Toxicology, Institut fur Pharmakologie. t Assistant Physician, Poliklinik fiir Zahn-, Mund- und Kieferkrankheiten, Zahnklinik Nord. $ Medical Technical Assistant, Institut fiir Pharmakologie. 0 Surgeon for Oral Dentistry, Poliklinik fur Zahn-, Mund- und Kieferkrankheiten, Zahnklinik Nord. Address correspondence and reprint requests to Dr KnollKGhler: lnstitut fur Pharmakologie. Freie Universitat Berlin, Thielallee 69172, D-1000 Bedin 33, Germany. 0 1991 American geons
Association
of Oral and Maxillofacial
Sur-
0278-2391191/4909-0006$3.00/O
957
ARTICAINE AS LOCAL ANESTHETIC IN ORAL SURGERY
958
are caused by differences in study design, the present study was initiated to differentiate between the extent to which the dental procedure and exogenous EPI in the local anesthetic solutions contribute to heart rate and arterial blood pressure variations . Material and Methods The study employed a randomized, double-blind parallel group design and a randomized doubleblind crossover design. It was conducted on 33 normotensive male nonsmokers (mean age, 25 -+ 0.5 years; mean body weight, 71 + 1.6 kg). At the initial appointment, a comprehensive medical history was obtained, a physical examination was performed, and a written consent signed. The patients were not taking any pharmaceutical drugs and none was suffering from any acute or chronic illness or had allergies to any of the test substances. PROTOCOL After overnight fasting, the subjects were placed in a supine position on an operating table in an operating room that was closed to persons not taking part in the study. An 18-gauge intravenous catheter was inserted into the right antecubical vein, electrocardiographic leads were placed, and an automatic blood pressure cuff was applied. Twenty minutes later, baseline venous blood specimens were collected and heart rate and blood pressure were recorded automatically (78352-A Hewlett Packard, San Diego, CA). This time delay allowed for stabilization of the sympathetic nervous system in response to the intravenous catheter insertion. The heart rate pressure product (HRPP), considered to be a reliable index of myocardial oxygen consumption6 was calculated by multiplying the heart rate by the systolic blood pressure.’ According to a randomization schedule, the patients received in a double-blind design 4.0 mL of a 4% articaine hydrochloride solution containing either 1:200,000 (Ultracain D-S, Hoechst Co, Frankfurt, Germany) or
Table 1.
l:lOO,OOO EPI (Ultracain D-S forte, Hoechst Co) over a 60-second period, after aspiration. Patients undergoing two separate operations for removal of an impacted mandibular third molar were given the solutions in a randomized double-blind crossover design. One mL of this solution was injected to anesthetize the inferior alveolar nerve, 1.0 mL to anesthetize the inferior lingual nerve, and 2.0 mL to anesthetize the long buccal nerve. Those subjects who took part in the study twice were given appointments at the same time of day to exclude any influence of circadian rhythm. The solutions were coded with numbers and always injected by the same oral surgeon. All 33 patients reported profound local anesthesia within 4 minutes of injection. No supplemental injections were required at any time during the study. Further cardiovascular parameters were measured, and blood specimens were taken 3 minutes after injection of the anesthetic solution and at defined times during the operation, as shown in Table 1. The surgery was always performed by the same oral surgeon. The duration of the individual steps of operation, determined by a pilot study, was kept constant .
BLOOD SAMPLING Blood specimens were collected in chilled test tubes containing ethyleneglycol-bis-2-aminoethylether-N,N’-tetra-acetic acid (EGTA) and glutathione in amounts of 5.25 mmol/L and 0.1 mmol/L, respectively. EPI and nor-EPI were measured by a radioenzymatic technique according to the method of Peuler and Johnson,* modified by Thiede and Kehr,’ and recently described in detail by Knoll-Kohler et a1.3 To minimize patient discomfort and for sampling convenience, venous rather than arterial catecholamine concentrations were measured. Despite the perfusion rate-dependent arteriovenous difference, the venous EPI concentrations correlate with the arterial concentration after a certain lag phase when obtained from subjects in
Times of Data Collection During Extraction of an Impacted Mandibular Third Molar
Procedure
Duration (min)
Time After Injection (min)
Time in the Operating Room (min)
IV catheter insertion End of relaxation phase (basal value) After injection End of mucoperiosteal flap preparation Start of extraction Suturing End of the operation recovery phase
20.0 4.0 3.6 4.2 10.6 20.0
3.0 6.6 10.8 21.4 41.4
25.0 29.0 32.6 36.8 47.4 67.4
KNOLL-KOHLER
959
ET AL
recumbent position.109” All samples were assayed examiner-blind by the same technician. CAMP known to be closely correlated with the EPI serum level” was assayed with the CAMP (3H) radioassay kit (Amersham Int, England). Serum potassium was measured using the Autocalculation Flame Photometer 743 (Instrumentation Laboratory, Padermo, Italy). DATA ANALYSIS
Values were calculated as means 2 SEM. Data were statistically analyzed by a two-way analysis of variance with subsequent pairwise comparisons of means by the LSD test (least significant difference) using the computer program CSS, part Quick Anova (Statsoft lnc, Tulsa. AZ). Results
The data of the global analysis of variance showed significant differences in the serum catecholamine levels between the l:lOO,OOO and the
articaine hydrochloride 1:200,000 EPI-containing solutions (effect of LA, Table 2). All the other parameters under study showed no changes in relation to the EPI content of the anesthetic solution. Independent of the study design, dose-dependent differences (P 4 .Ol) in the EPI serum concentrations were evident during the first 3 minutes after injection (Tables 3 and 4). The nor-EPI serum level was only elevated significantly (P < .05) in the crossover design study after anesthesia with the 1:200,000 EPI-containing solution during the phase of tooth luxation when compared with the !: IOO,OOO EPI-containing value. Study design and time-dependent differences were observed in the serum catecholamine and CAMP levels as well as in the cardiovascular response pattern when compared with the basal value. In the parallel group design (Table 3), 3 minutes after injection of the anesthetic solution, the heart rate, HRPP, as well as the serum EPI and CAMP levels, increased significantly. The arterial systolic and diastolic pressure rose at the beginning of the preparation procedure. In both groups, the
2. Analysis of Variance of the Effect of Intraoral Injection of 4.0 mL 4% Articaine Hydrochloride Solution Containing 1:2W,ooO or 1:loO,ooO Epinephrine in Oral Outpatients Using a Randomized Double-Blind Parallel Group or Crossover Design
Table
Parallel Parameter HR
PS
PD
PM
HRPP
EPI
Nor-EPI
CAMP
Potassium
Effects Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA Time LA Time x LA
Crossover
F Value
P Value
F Value
P Value
17.374 0.130 0.159 7.773 2.162 0.069 5.407 0.654 0.556 4.823 1.319 0.547 14.819 0.065 0.145 21.724 17.703 2.051 1.474 3.996 0.125 7.305 0.059 0.388 1.177 0.304 0.414
