Clin Oral Invest DOI 10.1007/s00784-013-1010-7

ORIGINAL ARTICLE

Comparative clinical evaluation of different epinephrine concentrations in 4 % articaine for dental local infiltration anesthesia P. W. Kämmerer & J. Seeling & A. Alshihri & M. Daubländer

Received: 4 February 2013 / Accepted: 24 May 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Objectives The aims of this study were to compare and evaluate the clinical anesthetic efficacy of five 4 % articaine solutions with and without epinephrine in pulpal anesthesia after infiltration. Materials and methods In a randomized, double-blinded, crossover study, ten volunteers received local anesthesia infiltration in the maxillary right central incisor with five different solutions (4 % articaine+epinephrine 1:100,000, + epinephrine 1:200,000, + epinephrine 1:300,000, + epinephrine 1:400,000, without epinephrine). Electronic pulp tester was used to calculate the onset, utilization time, time to recede, and the surface integral under the time–effect curve. Additionally, cardiovascular parameters and postexperimental soft tissue anesthesia were examined. Results Onset as well as time to recede was not influenced by the epinephrine concentration. When using the epinephrine-free agent, time to recede was significantly P. W. Kämmerer (*) Department of Oral, Maxillofacial and Plastic Surgery, University Medical Centre Mainz, Augustusplatz 2, 55131 Mainz, Germany e-mail: [email protected] P. W. Kämmerer Harvard Medical School, Boston, USA J. Seeling Private Praxis, Rheingoldstraße 16, 68199 Mannheim, Germany A. Alshihri Department of Restorative and Biomaterial Sciences, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA M. Daubländer Dental Surgery Outpatient Clinic, University Medical Centre Mainz, Augustusplatz 2, 55131 Mainz, Germany

shorter. Upon decreasing epinephrine concentration, duration of pulpal anesthesia and total anesthetic efficacy declined. The shortest time of anesthesia and lowest anesthetic efficacy were seen for the solution without epinephrine. No association was found between the local anesthetic drug and cardiovascular parameters. Soft tissue anesthesia was significantly shorter without epinephrine. Conclusions This study shows the substantial benefits of vasoconstrictors in dental infiltration anesthesia. These findings were reflected by means of prolonged and deeper therapeutic effect in a dose-dependent manner. Clinical relevance Even when utilizing agents with reduced amount of epinephrine, a safe anesthesia is possible. The epinephrine-free solutions resulted in a distinct limitation of utilization time and efficacy. Keywords Dental local anesthesia . Infiltration . Articaine . Epinephrine . Reduction . Vasoconstrictor

Introduction Local anesthesia has been routinely efficient in eliminating dental pain. Several anesthetic solutions with various chemical adjuncts are commercially available. Among them is articaine, which is a common local anesthetic agent with low allergic and toxic potential [1]. It is a distinctive agent due to its thiophene ring with an ester linkage. The thiophene ring enhances lipid solubility and the ester side chains allow rapid hydrolytic metabolization by plasma esterase, rendering the molecule inactive after a short half-life of 20 min [2, 3]. The end product is the pharmacological inactive substance articanic acid. Like other local anesthetics, articaine has vasodilatative properties and is commonly used together with epinephrine as vasoconstrictive adjunct to provide local hemostasis and to concentrate the deposits at the injection site, therefore increasing anesthetic depth and duration. Epinephrine, on the other hand, may cause

Clin Oral Invest

relevant adverse reactions. Santos et al. reported that when using articaine, side effects mainly occur due to the vasoconstrictor [1]. The epinephrine adjunct may lead to general feelings of being unwell (headaches, paleness, sweating) together with cardiovascular disturbances like tachycardia and hypertension [4–6], tremor, mydriasis, and flu-like symptoms and to a potentiation of adverse drug reactions [7, 8]. Moreover, the increasing demand for the care of elderly patients with concomitant diseases and medications makes an anesthetic agent preferable, one that is effective enough to provide sufficient anesthetic effect with least side effects possible. Therefore, the balance between minimal epinephrine concentration and maximal anesthetic effect has to be investigated [9–11]. For mandibular inferior alveolar nerve block for tooth extraction, we demonstrated that the addition of epinephrine might not be needed. In the epinephrine-free group, anesthesia had a significant later onset and a significant shorter duration of action but yet enough for all treatments with the same low level of pain as in the group with epinephrine [10]. Furthermore, a 4 % articaine with 1:400,000 epinephrine formulation is also shown to be a safe and effective agent in dental short-time procedures [9]. Due to the radial dispersion at the injection site, local infiltration anesthesia depends to a high degree on concentration and dose of the local anesthetic agent. For infiltration, several clinical studies concerning changes in epinephrine concentrations are published [9, 12–16]. Nonetheless, no systematic evaluation has been conducted to address the optimal epinephrine concentration ranging from epinephrinefree to epinephrine 1:100,000 when using 4 % articaine. Therefore, the aim of this study was to evaluate the efficiency (onset, duration of pulpal anesthesia, time to recede) of anesthesia using 4 % articaine with different concentrations of epinephrine adjuncts in a clinical randomized, double-blinded, crossover trial. As secondary criteria, the impact of each solution on heart rate, blood pressure, and oxygen saturation as well as the quality and length of soft tissue anesthesia in healthy volunteers was measured.

Materials and methods Anesthetic agents Five anesthetic agents containing 4 % articaine with different epinephrine concentrations were tested (test group (TG) 1: without epinephrine, TG 2: epinephrine 1:100,000, TG 3: epinephrine 1:200,000, TG 4: epinephrine 1:300,000, TG 5: epinephrine 1:400,000). All solutions were supplied by 3M ESPE (Seefeld, Germany) and delivered in similar coded glass carpules containing 1.7 ml colorless fluid. Solutions for TG 2 (Ubistesin™ forte) and TG 3 (Ubistesin™) are commercially available agents. At the time of the experiments, solutions for TGs 1, 4, and 5 were made exclusively for the study.

Patients Ten volunteers participated in the study after a positive appraisal of the ethical committee of Rhineland-Palate, Germany. Inclusion criteria were as follows: signed informed consent, male gender, 18–35 years of age, body weight >50 kg, no concomitant diseases, anamnestic and vital maxillary central incisors without pathological findings, and without caries and/or prior filling therapy. The periodontium of each tooth had to be free from pathological signs as well. Exclusion criteria were as follows: ASA III–IV, contraindications for the use of articaine and/or epinephrine, allergy to sodium bisulfite, use of nicotine, and alcohol and/or drug abuse. At the time of the examinations, no volunteer was allowed to use painkillers and/or tranquilizer. Infiltration of the anesthetic solution In each volunteer, the five different solutions were injected via infiltration technique in a randomized crossover design. The right maxillary central incisor was anesthetized as the tooth of study in all patients. Between each single injection, which the same examiner performed at all times, a minimal waiting interval of 3 days was adhered. Each injection was given at the same time of the day under similar test conditions. Accordingly, each volunteer received all of the five local anesthetic agents for the same purpose under the same settings. In order to obtain a double-blinded design, the code on the carpule was noted for each injection and unblinded after the whole study was completed. Measurement of anesthesia Avacuum-forming guide for the anterior right maxillary incisor was fabricated for each patient. In the area of the tooth under examination, on the incisal third of the labial side of the guide, a hole was drilled in order to have a reproducible testing point for the electronic pulp tester (EPT; L. Goof Co., Hørsholm, Denmark) [17–19]. EPT device works with electrical current in defined stages; the intensity varies from 0 to 15 (15=200 μA). The respective tooth and both adjacent teeth were dried with cotton rolls and air and were then isolated with a small cofferdam [20]. For monopolar measurements, an indifferent electrode was inserted in the corner of the mouth of the patient. The stimulating electrode was coated with a contact gel (Elmex Gelee®, Wybert, Lörrach, Germany) and placed on the dry labial surface of the examined tooth. The volunteers were instructed to elevate a hand in case of any sensations. Prior to each injection, the individual detection threshold of the tooth was evaluated in triplicates and mean values were noted. Afterwards, 1.7 ml of the anesthetic agents was infiltrated in the supraperiosteal mucosa from the vestibular side in the area of the root apex of the tooth under examination. Each infiltration

Clin Oral Invest

Additionally, the length of soft tissue anesthesia, in minutes, was recorded as well.

was set at 100 s. Straight after injection, the first electronic measurement took place. The electronic threshold was measured continuously every minute until the maximal intensity (15=200 μA) was reached without volunteers’ response. Once maximal intensity was noted for three times in a row, subsequent measurements took place every 5 min. If a decent of the threshold was detected, measurements were conducted again for every minute. The experiment was considered complete if the threshold recorded was similar to the ones recorded prior to infiltration in three consecutive measurements.

Data proceeding and statistics All obtained data were recorded separately. After completing the clinical part of the study, an independent examiner revealed the blinded parameters and tabulated the collected data for statistical analysis. After descriptive evaluation, differences between the groups were tested via nonparametric Wilcoxon test for unrelated samples. A p value of ≤0.05 was termed significant. However, all reported significances are only seen descriptively. The used software was dBase IV (dBase, Oxford, NY, USA) and SPSS 4.0 (IBM, Armonk, NY, USA).

Data interpretation With the obtained data, the following parameters were calculated: & & & &

Onset (= time (in minutes) measured from injection until achievement of a threshold ≥200 μA) Time of pulpal anesthesia (= length (in minutes) of the maximal threshold of ≥200 μA)=therapeutic utilization time Time to recede (= time (in minutes) beginning from decreasing from the point of the maximal threshold until reaching the individual detection threshold of the tooth) Area under the curve (= surface integral under the time– effect curve)

Results The ten volunteers had a mean age of 30 years (24–34) with a mean body weight of 78 kg (62–85) and a mean height of 183 cm (176–194). Injections and repeated measurements of the electronic threshold neither resulted in local nor systemic complications. The individual detection threshold prior injection had a mean of 2.5 (≈10 μA; min 1, max 5). These thresholds were reached after each test series and were identical for each volunteer on each of the 5 days. With the four solutions containing epinephrine (solutions 2– 5), in all cases, the threshold of maximal intensity (15= 200 μA) was reached. After infiltration of solution 1 (without epinephrine), the maximal value was seen only in 4/10 volunteers. For the other six volunteers, the maximal threshold was 6–10 (≈32–80 μA). In accordance, for the epinephrine-free agent, the onset time was additionally calculated as the time to achieve the maximal degree of electronic stimulation (for n=6). For statistics, only the four patients with the full threshold were included.

Cardiovascular parameters In order to assess possible systemic effects of dental local anesthesia, measurements of heart rate frequency, systolic and diastolic blood pressures, as well as oxygen saturation were recorded with a NPB 4000 Monitor (Nellcor Puritan Bennett, Pleasanton, CA, USA). Five measurements were recorded: at the beginning of the experiment, during and at the end of injection, 15 min after injection, as well as after completing the experiment.

Onset Soft tissue anesthesia For all solutions, the mean onset was 5.1 min (±2.4). In Table 1, mean values with standard deviations of the different agents are shown. The differences between the groups were not statistically significant (p>0.1). However,

After completing the study, the volunteers had to estimate the present soft tissue anesthesia via a visual analog scale (0–10; 0=no anesthesia, 10=full anesthesia). Table 1 Onset of the different local anesthetic agents (test groups 1–5)

Mean value (min) SD (min)

TG 1 (4 % articaine without epinephrine)

TG 2 (4 % articaine+ epinephrine 1:100,000)

6.5 (n=4); 9.5 (n=6) 1.5 (n=4); 3.4 (n=6)

5 3.2

TG 3 (4 % articaine+ epinephrine 1:200,000)

TG 4 (4 % articaine+ epinephrine 1:300,000)

TG 5 (4 % articaine+ epinephrine 1:400,000)

4.7 2.6

4.2 1.9

5.3 2.3

Mean values (min) as well as standard deviations (SD) are shown. There was no statistical significant difference between the test groups (all have p>0.1)

Clin Oral Invest Table 2 Time to recede of the different local anesthetic agents (test groups 1–5) TG 1 (4 % articaine without epinephrine) Mean value (min) 23.5 (n=4); 41.3 (n=6) SD (min) 5.7 (n=4); 12.3 (n=6)

TG 2 (4 % articaine+ TG 3 (4 % articaine+ TG 4 (4 % articaine+ TG 5 (4 % articaine+ epinephrine 1:100,000) epinephrine 1:200,000) epinephrine 1:300,000) epinephrine 1:400,000) 58.8 26.4

61.2 20.2

62 27.6

55.2 24

Mean values (min) as well as standard deviations (SD) are given. There was a statistical significant difference between test group 1 and the others (all have p≤0.01)

the epinephrine-free solutions showed a prolonged onset when compared to the other groups. Time of pulpal anesthesia The longest utilization time was observed in TG 2 (mean 77.6 min (±30.1)). With reduced amount of epinephrine, the utilization time decreased as well (TG 3: mean 54.8 min (±17.5), TG 4: mean 43.3 min (±17.2), TG 5: mean 35.9 min (±15.1)). Therefore, the shortest utilization time was seen in TG 1 with a mean of 14.75 min (±5.8, n=4). In the other six volunteers of the epinephrine-free group, the required depth of anesthesia could not be reached. In this subgroup, the utilization time dropped to a mean of 5 min (±6, n=6). The differences were statistically significant between groups 2 and 5 (p=0.0017), between groups 3 and 5 (p=0.0172), and between groups 1 and 2, 3, 4, and 5 (all have p≤0.001). Time to recede Except for the agent without epinephrine, the epinephrine concentration did not show a significant influence on the defined time to recede. The mean values are shown in Table 2. There was a statistically significant difference between TG 1 and the other groups (all have p≤0.01). Area under the curve The surface integral under the time–effect curve is used to measure the total anesthetic efficacy of an anesthetic agent. The calculation is independent from the reached total threshold. Therefore, all data could be taken into consideration. In brief, a

clear dependent relationship between efficacy and amount of epinephrine could be seen. Values are given in Table 3. There was a statistically significant difference between TGs 2 and 3 (p=0.019), between TGs 2 and 4 (p=0.0007), between TGs 3 and 5 (p=0.049), and between TG 1 and the other groups (all have p≤0.0001). Cardiovascular parameter No systemic side effects or complications could be detected in all groups. The infiltration anesthesia did not affect heart rate frequency, blood pressure, or oxygen saturation. Soft tissue anesthesia For the solutions with epinephrine, comparable levels of soft tissue anesthesia were found. Statistically significant differences for the parameters intensity and time were only seen when comparing TG 1 with the other groups (all have p≤0.001, Tables 4 and 5).

Discussion Lidocaine is the most widely used local anesthetic worldwide. However, it was reported that articaine is a comparable local anesthetic agent, if not better, when considering its efficacy and safety range [21–23]. Reduction of vasoconstrictors such as epinephrine in articaine solutions may minimize potential side effects [11]. However, the general use of vasoconstrictorfree local anesthetic agents is considered to be controversial.

Table 3 Area under the curve of the different local anesthetic agents (test groups 1–5) TG 1 (4 % articaine without epinephrine)

TG 2 (4 % articaine+ epinephrine 1:100,000)

TG 3 (4 % articaine+ epinephrine 1:200,000)

TG 4 (4 % articaine+ epinephrine 1:300,000)

TG 5 (4 % articaine+ epinephrine 1:400,000)

Mean value (AU)

315.5

1,642.2

1,263.2

1,085.5

960.2

SD (AU)

138.3

404.6

227.2

225.9

273.3

Mean values (arbitrary units (AU)) as well as standard deviations (SD) are given. It can be clearly seen that the anesthetic efficacy decreases with decreased epinephrine concentrations. The differences were statistically significant between TGs 2 and 3 (p=0.019), between TGs 2 and 4 (p= 0.0007), between TGs 3 and 5 (p=0.049), and between TG 1 and the other groups (all have p≤0.0001)

Clin Oral Invest Table 4 Estimation of post-experimental soft tissue anesthesia of the different local anesthetic agents (VAS 0–10) TG 1 (4 % articaine without epinephrine) VAS (1–10) SD (VAS)

1.4 0.9

TG 2 (4 % articaine+ epinephrine 1:100,000)

TG 3 (4 % articaine+ epinephrine 1:200,000)

6.2 3

6.4 1.9

TG 4 (4 % articaine+ epinephrine 1:300,000)

TG 5 (4 % articaine+ epinephrine 1:400,000)

5.2 2

6.8 2

Mean values as well as standard deviations (SD) are given. Compared with the other groups, in the group without epinephrine, significantly lower VAS values were reported (all have p≤0.01)

Although the solution without vasoconstrictor seems to be useful in inferior block anesthesia [10], the effect in cases of infiltration is questionable [13, 24]. Therefore, a systemic evaluation of articaine solutions with different descending epinephrine concentrations for a reproducible injection technique with as less confounders as possible was conducted. The anterior maxilla was chosen in this model because the thin labial cortical bone facilitates the local diffusion of the anesthetic agent. Male volunteers were chosen to eliminate possible sex-specific confounders. Similarly, injections were executed at the same time of the study days. Additionally, influencing factors including analgesics, tranquilizer, alcohol, and nicotine were excluded as well. Comparative evaluations of electric thresholds for analysis of local anesthetic efficacy are well established [16, 25, 26]. The device used in this study possesses a stimulation current of 4–200 μA and can therefore perform a sufficient range of analysis. With a maximal stimulation of 200 μA that is equitable to complete pulpal anesthesia [27], a selective excitation of the dental pulp, without damaging and without accessory excitation of periodontal fibers, is possible [28, 29]. When comparing the onset of the different solutions, the mean onset time ranged between 4.2 and 6.5 min. No significant influence of the different epinephrine concentrations was seen. This is in accordance with the literature [16, 30–33]. A shorter onset when using 4 % articaine with epinephrine 1:100,000 compared to 1:200,000, as described by Szabo and Divinyi, could not be found [15]. For dental practice, the high inter- and intraindividual differences of articaine in the time of onset should be emphasized. Due to the high standard deviations, a full impact of anesthesia after up to 13 min of infiltration is not uncommon.

Additionally, it has to be kept in mind that the solution without epinephrine reached the maximal threshold in 4/10 of cases only. This is in accordance with Petrikas et al. who described articaine without vasoconstrictor to lack pulpal anesthesia [12]. The time to recede was also not influenced by the epinephrine concentration except for the epinephrinefree solution where a significant time shortening was seen. This is in accordance with other reports as well [13, 27, 31]. In contrast, the utilization time and the calculated area under the time–effect curve were affected significantly by the respective epinephrine concentration in a dose-dependent manner. The mean time of 55 min for the 1:200,000 agent is similar to the data reported by others [16, 30, 31]. It was also shown that when compared to the solution with the lowest epinephrine concentration (1:400,000), the 1:100,000 solution has more than double therapeutic utilization time (mean 36 vs. 78 min). These results confirm the already known additional effect of the vasoconstrictor [32, 34–37]. Nevertheless, the extent of this effect has been discussed controversially. Gangarosa and Halik reported no difference in anesthetic utilization time between 2 % lidocaine with epinephrine 1:100,000 and that with 1:300,000 [33]. Also for lidocaine, Keesling and Hinds demonstrated a significant difference in length of anesthesia when comparing epinephrine 1:750,000 and 1:250,000. However, they reported no differences between epinephrine 1:250,000 and 1:50,000 and concluded that such high concentrations do not lead to further prolongation of anesthesia [38]. Our results are comparable to those of Rahn and Mohr; however, they did not show a difference between 4 % articaine with epinephrine 1:200,000 and that with 1:400,000 [13]. Moreover, the time of pulpal anesthesia should be long enough for most dental treatments even when using 4 % articaine with epinephrine 1:400,000. On

Table 5 Time of post-experimental soft tissue anesthesia of the different local anesthetic agents (min)

Time (min) SD (min)

TG 1 (4 % articaine without epinephrine)

TG 2 (4 % articaine+ epinephrine 1:100,000)

TG 3 (4 % articaine+ epinephrine 1:200,000)

TG 4 (4 % articaine+ epinephrine 1:300,000)

60.3 24.2

151.7 27.6

129.3 19.2

117.2 22.7

TG 5 (4 % articaine+ epinephrine 1:400,000) 104 22.5

Mean values as well as standard deviations (SD) are given. Compared with the other groups, in the group without epinephrine, a significantly shorter soft tissue anesthesia was documented (all have p≤0.01)

Clin Oral Invest

the other hand, the removal of the vasoconstrictor diminishes the anesthetic success. Accordingly, the clinical effect of the epinephrine-free solution is critical. The maximal threshold for pulpal anesthesia was not reached in most of cases, and a mean utilization time of 15 min is comparably short. Consequently, it cannot be recommended for infiltration anesthesia especially for painful lengthy procedures. Schüle showed that painful treatments need a minimal electric threshold of 70 μA [14]. Therefore, even for patients with contraindications for epinephrine, rather mepivacaine with its known anesthetic profile [16, 34] should be taken into consideration. Several groups have shown that the injected epinephrine leads to an increase of epinephrine in the plasma [11, 39, 40]. Nevertheless, in the young and healthy volunteers of this study, this did not seem to influence cardiovascular parameters as what has been previously reported [39–41]. A higher adjunct of epinephrine (1:80,000) may lead to increased heart rate [42]. Therefore, for older and medically compromised patients, special care when using higher concentrations of epinephrine is recommended [39, 40, 43]. The subjective reports of soft tissue anesthesia confirm the prolongation of the anesthetic effect when using a vasoconstrictor [9, 10]. A mean anesthesia of 36 min, as seen for the epinephrine 1:400,000 solution, would be preferable especially in young patients to avoid unwanted self-induced lesions of the soft tissues such as biting of the tongue, lips, and cheeks [44, 45].

Conclusion In this study, the benefits of vasoconstrictor in dental infiltration anesthesia with articaine 4 % were shown in terms of prolongation and profoundness. Even when using agents with reduced amount of epinephrine, a safely produced anesthetic effect is achievable. The solution without epinephrine achieved a distinct limitation of pulpal anesthesia. Therefore, for local infiltration anesthesia, the combination of epinephrine and articaine is clinically recommended whenever needed for routine dental practice. Conflict of interest Professor Monika Daubländer is a member of the scientific advisory board of 3M ESPE. Monika Daubländer and the other authors have no conflicts of interest in regard of this publication.

References 1. Santos CF, Modena KC, Giglio FP, Sakai VT, Calvo AM, Colombini BL, Sipert CR, Dionísio TJ, Faria FA, Trindade ASJ, Lauris JR (2007) Epinephrine concentration (1:100,000 or 1:200,000) does not affect the clinical efficacy of 4% articaine for lower third molar removal: a double-blind, randomized, crossover study. J Oral Maxillofac Surg 65:445–452

2. Vree TB, Gielen MJ (2005) Clinical pharmacology and the use of articaine for local and regional anaesthesia. Best Pract Res Clin Anaesthesiol 19:293–308 3. Becker DE, Reed KL (2006) Essentials of local anesthetic pharmacology. Anesth Prog 53:98–108, Quiz: 109–110 4. Cheraskin E, Prasertsuntarasai T (1959) Use of epinephrine with local anesthesia in hypertensive patients. IV. Effect of tooth extraction on blood pressure and pulse rate. J Am Dent Assoc 58:61–68 5. Mochizuki M, Yokota S, Murata Y, Watanabe H, Nishibori M, Suzuki N, Nishibori M, Kubota Y (1989) Changes in heart rate and blood pressure during dental procedures with local anesthesia. Anesth Prog 36:234–235 6. Hasse AL, Heng MK, Garrett NR (1986) Blood pressure and electro-cardiographic response to dental treatment with use of local anesthesia. J Am Dent Assoc 113:639–642 7. Petitpain N, Goffinet L, Cosserat F, Trechot P, Cuny JF (2008) Recurrent fever, chills, and arthralgia with local anesthetics containing epinephrine-metabisulfite. J Clin Anesth 20:154 8. Goulet JP, Perusse R, Turcotte JY (1992) Contraindications to vasoconstrictors in dentistry: part III. Pharmacologic interactions. Oral Surg Oral Med Oral Pathol 74:692–697 9. Daubländer M, Kämmerer PW, Willershausen B, Leckel M, Lauer HC, Buff S, Rösl B (2012) Clinical use of an epinephrine-reduced (1/400 000) articaine solution in short-time dental routine treatments—a multicenter study. Clin Oral Investig 16:1289–1295 10. Kämmerer PW, Palarie V, Daubländer M, Bicer C, Shabazfar N, Brüllmann D, Al-Nawas B (2012) Comparison of 4% articaine with epinephrine (1:100.000) and without epinephrine in inferior alveolar block for tooth extraction—double blind, randomized clinical trial of anesthetic efficacy. Oral Surg Oral Med Oral Pathol Oral Radiol 113:495–499 11. Lipp M, Dick W, Daubländer M, Fuder H, Stanton-Hicks M (1993) Exogenous and endogenous plasma levels of epinephrine during dental treatment under local anesthesia. Reg Anesth 18:6–12 12. Petrikas A, Egorova VA, Ermilova KV (2009) [Articaine and adrenaline combinations efficacy for dental anesthesia]. Stomatol (Mosk) 88:24–26 13. Rahn R, Mohr A (1997) [Efficacy and length of anesthesia of a 4% articaine solution with different concentrations of epinephrine]. Dtsch Zahnärztl Z 52:335–337 14. Schüle H (1952) [Clinical experimental comparative examination of the anesthetic efficacy of some new local anesthetics]. Dtsch Zahnärztl Z 7:1376–1383 15. Szabo G, Divinyi T (1987) [Comparative examination of Ultracain ® D-S and Ultracain ® D-S forte]. Stomatol DDR 37:301–304 16. Winther JE, Nathalang B (1972) Effectivity of a new local analgesic Hoe 40 045. Scand J Dent Res 80:272–278 17. Bender IB, Landau MA, Fonsecca S, Trowbridge HO (1989) The optimum placement-site of the electrode in electric pulp testing of the 12 anterior teeth. J Am Dent Assoc 118:305–310 18. Chambers IG (1982) The role and methods of pulp testing in oral diagnosis: a review. Int Endod J 15:1–15 19. Pajic M, Vujaskovic M, Ivanovic V (1990) [Experimental study of accuracy of electro-odontometric device in establishment of apical constriction of a root canal]. Stomatol Glas Srb 37:55–62 20. Cooley RL, Stilley J, Lubow RM (1984) Evaluation of a digital pulp tester. Oral Surg Oral Med Oral Pathol 58:437–442 21. Pogrel MA (2012) Permanent nerve damage from inferior alveolar nerve blocks: a current update. J Calif Dent Assoc 40:795–797 22. Leith R, Lynch K, O'Connell AC (2012) Articaine use in children: a review. Eur Arch Paediatr Dent 13:293–296 23. Powell V (2012) Articaine is superior to lidocaine in providing pulpal anesthesia. J Am Dent Assoc 143:897–898 24. Moore PA, Boynes SG, Hersh EV, DeRossi SS, Sollecito TP, Goodson JM, Leonel JS, Floros C, Peterson C, Hutcheson M (2006)

Clin Oral Invest

25.

26.

27. 28.

29. 30.

31.

32. 33.

34.

The anesthetic efficacy of 4 percent articaine 1:200,000 epinephrine: two controlled clinical trials. J Am Dent Assoc 137:1572–1581 Schultze-Mosgau S, Schmelzeisen J, Strauch T (1994) [Comparative evaluation of the effectiveness of articaine 4% and 2%]. Dtsch Zahnärztl Z 49:388–391 Kämmerer PW, Palarie V, Schiegnitz E, Ziebart T, Al-Nawas B, Daubländer M (2012) Clinical and histological comparison of pulp anesthesia and local diffusion after periodontal ligament injection and intrapapillary infiltration anaesthesia. J Pain Relief (1):5. doi:10.4172/2167-0846.1000108 Raab WHM, Reithmayer K, Müller HF (1990) [A technique to test local anesthetic agents]. Dtsch Zahnärztl Z 45:629–632 Raab WHM (1985) [Pain-correlated cortical potential of humans after electric stimulation of the dental pulp]. Dtsch Zahnärztl Z 40:312–314 McDaniel KF, Rowe NH, Charbeneau GT (1973) Tissue response to an electric pulp tester. J Prosthet Dent 29:84–87 Ruprecht S, Knoll-Köhler E (1991) [Comparative examination of equimolar lidocaine and articaine solutions for local anesthesia]. Schweiz Monatsschr Zahnmed 101:1286–1290 Raab WHM, Müller R, Müller HF (1990) [Comparative evaluation of the anesthetic efficacy of articaine 2% and 4%]. Quintessenz 7:1207–1216 Cowan A (1977) Clinical assessment of a new local anesthetic agent-carticaine. Oral Surg Oral Med Oral Pathol 43:174–180 Gangarosa LP, Halik FJ (1967) A clinical evaluation of local anaesthetic solutions containing graded epinephrine concentrations. Arch Oral Biol 12:611–621 Aberg G, Sydnes G (1978) Studies on the duration of local anesthesia. Effects of volume and concentration of a local anesthetic solution on the duration of dental infiltration anesthesia. Int J Oral Surg 7:141–147

35. Jage J (1993) Circulatory effects of vasoconstrictors combined with local anesthetics. Anesth Pain Control Dent 2:81–86 36. Jastak JT, Yagiela JA (1983) Vasoconstrictors and local anesthesia: a review and rationale for use. J Am Dent Assoc 107:623–630 37. MacKenzie TA, Young ER (1993) Local anesthetic update. Anesth Prog 40:29–34 38. Keesling GR, Hinds EC (1963) Optimal concentration of epinephrine in lidocaine solutions. J Am Dent Assoc 66:337–340 39. Sack U, Kleemann PP (1992) Intraoral conduction anesthesia with epinephrine-containing local anesthetics and arterial epinephrine plasma concentration. Anesth Pain Control Dent 1:77–80 40. Tolas AG, Pflug AE, Halter JB (1982) Arterial plasma epinephrine concentrations and hemodynamic responses after dental injection of local anesthetic with epinephrine. J Am Dent Assoc 104:41–43 41. Chernow B, Balestrieri F, Ferguson CD, Terezhalmy GT, Fletcher JR, Lake CR (1983) Local dental anesthesia with epinephrine. Minimal effects on the sympathetic nervous system or on hemodynamic variables. Arch Intern Med 143:2141–2143 42. Salonen M, Forssell H, Scheinin M (1988) Local dental anaesthesia with lidocaine and adrenaline. Effects on plasma catecholamines, heart rate and blood pressure. Int J Oral Maxillofac Surg 17:392–394 43. Clutter WE, Bier DM, Shah SD, Cryer PE (1980) Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest 66:94– 101. doi:10.1172/JCI109840 44. Adewumi A, Hall M, Guelmann M, Riley J (2008) The incidence of adverse reactions following 4% septocaine (articaine) in children. Pediatr Dent 30:424–428 45. Ram D, Amir E (2006) Comparison of articaine 4% and lidocaine 2% in paediatric dental patients. Int J Paediatr Dent 16:252–256. doi:10.1111/j.1365-263X.2006.00745.x