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1.  The incidence of complications associated with local anesthesia in dentistry. 
Anesthesia Progress  1997;44(4):132-141.
Local anesthetics are frequently administered in dentistry and thus can be expected to be a major source of drug-related complications in the dental office. Additionally, the dentist will more often be confronted with the treatment of risk patients; thus, the incidence of side effects can be expected to rise. In this study, 2731 patients receiving dental anesthesia were evaluated by questionnaire for risk factors, type and dosage of local anesthetic applied, type and duration of treatment, and complications associated with the administration of the local anesthetic. Of all patients, 45.9% had at least one risk factor in their medical histories, with cardiovascular diseases and allergies being the most frequent. The overall incidence of complications was 4.5%. It was significantly higher in risk patients (5.7%) than in nonrisk patients (3.5%). The most frequently observed complications (dizziness, tachycardia, agitation, nausea, tremor) were transient in nature and did not require treatment. Severe complications (seizure, bronchospasm) occurred in only two cases (0.07%). Articaine was found to be administered in over 90% of all dental anesthesias in Germany despite the great variety of local anesthetics available. Articaine 1:100,000 caused more sympathomimetic side effects than did articaine 1:200,000. Additionally, doses of local anesthetics proved not to be strictly determined according to body weight, especially for patients weighing less than 50 kg. In summary, it can be stated that dental local anesthesia can be considered safe. Nevertheless, the incidence of complications due to dental anesthesia can be expected to be further reduced if (a) patients are routinely evaluated for risk factors with an adequate medical history prior to dental treatment, (b) doses of local anesthetics are strictly determined according to body weight, (c) anesthetics with low concentrations of epinephrine are used, and (d) the concept of a differentiated dental anesthesia is applied.
PMCID: PMC2148940  PMID: 9481957
2.  Use of anesthetics associated to vasoconstrictors for dentistry in patients with cardiopathies. Review of the literature published in the last decade 
Objective: The use of local anesthetics associated to vasoconstrictor agents in dentistry is thoroughly justified and is widely extended, but we cannot ignore the fact that anesthetic infiltration poses risk of complications throughout the dental treatment period. The objective of the present review is to document the reported effects the use of the local anesthetics most widely employed in dentistry, with or without association to vasoconstrictor agents may have in patients with any sort of cardiopathy. Study Design: We have searched for randomized clinical trials on the assessment of the cardiovascular effects of local anesthetics used in dentistry, without limits as regards age or sex, conducted in patients with any type of cardiopathy which were published during the last decade and were index-linked in Cochrane, Embase and Medline. Results: We have found six randomized clinical trials index-linked in Medline and Cochrane in the past ten years. These trials compare different types of anesthetics: lidocaine 2%, mepivacaine 2%, prilocaine 2% , associated or not to different vasoconstrictor concentrations such as adrenaline or felypressin. The cardiopathies affecting the patients included in the different trials range from hypertension, ischemic heart disease, arrythmias, chronic coronary disease to heart transplantation. Conclusions: The use of anesthetics associated to vasoconstrictor agents is justified in the case of patients with cardiopathies (once we get over the period in which any type of dental manipulation is contraindicated) and in controlled hypertensive patients. In any case, we must be very careful with the choice and execution of the anesthetic technique, being it possible to use a dose between 1.8 and 3.6 ml, on a general basis. Further studies are necessary to establish the effects of these drugs on severe hypertensive patients or in patients with other more advanced cardiopathies.
Key words:Vasoconstrictor agents, epinephrine/adverse effects, local anesthetics, dental restoration, oral surgery, cardiovascular diseases, coronary arteriosclerosis, heart disease, hypertension, arrhythmias, coronariopathy.
doi:10.4317/jced.50590
PMCID: PMC3908793  PMID: 24558534
3.  Pharmacokinetics of Lidocaine With Epinephrine Following Local Anesthesia Reversal With Phentolamine Mesylate 
Anesthesia Progress  2008;55(2):40-48.
Phentolamine mesylate accelerates recovery from oral soft tissue anesthesia in patients who have received local anesthetic injections containing a vasoconstrictor. The proposed mechanism is that phentolamine, an alpha-adrenergic antagonist, blocks the vasoconstriction associated with the epinephrine used in dental anesthetic formulations, thus enhancing the systemic absorption of the local anesthetic from the injection site. Assessments of the pharmacokinetics of lidocaine and phentolamine, and the impact of phentolamine on the pharmacokinetics of lidocaine with epinephrine were performed to characterize this potentially valuable strategy. The blood levels of phentolamine were determined following its administration intraorally and intravenously. Additionally, the effects of phentolamine mesylate on the pharmacokinetics of intraoral injections of lidocaine with epinephrine were evaluated. Sixteen subjects were enrolled in this phase 1 trial, each receiving 4 drug treatments: 1 cartridge lidocaine/epinephrine followed after 30 minutes by 1 cartridge phentolamine (1L1P), 1 cartridge phentolamine administered intravenously (1Piv), 4 cartridges lidocaine/epinephrine followed after 30 minutes by 2 cartridges phentolamine (4L2P), and 4 cartridges lidocaine/epinephrine followed by no phentolamine (4L). Pharmacokinetic parameters estimated for phentolamine, lidocaine, and epinephrine included peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve from 0 to the last time point (AUClast) or from time 0 to infinity (AUCinf), elimination half-life (t1/2), clearance (CL), and volume of distribution (Vd). The phentolamine Tmax occurred earlier following the intravenous administration of 1Piv (7 minutes than following its submucosal administration in treatment 1L1P (15 minutes) or 4L2P (11 minutes). The phentolamine t1/2, CL, and Vd values were similar for 1L1P, 1Piv, and 4L2P. The Tmax for lidocaine occurred later and the Cmax for lidocaine was slightly higher when comparing the 4L2P treatment and the 4L treatment. The phentolamine-induced delay of the lidocaine Tmax likely represents phentolamine's ability to accelerate the systemic absorption of lidocaine from oral tissues into the systemic circulation.
doi:10.2344/0003-3006(2008)55[40:POLWEF]2.0.CO;2
PMCID: PMC2424015  PMID: 18547152
Pharmacokinetics; Dental local anesthesia; Lidocaine; Phentolamine; Epinephrine
4.  Stress-Mediated Increases in Systemic and Local Epinephrine Impair Skin Wound Healing: Potential New Indication for Beta Blockers 
PLoS Medicine  2009;6(1):e1000012.
Background
Stress, both acute and chronic, can impair cutaneous wound repair, which has previously been mechanistically ascribed to stress-induced elevations of cortisol. Here we aimed to examine an alternate explanation that the stress-induced hormone epinephrine directly impairs keratinocyte motility and wound re-epithelialization. Burn wounds are examined as a prototype of a high-stress, high-epinephrine, wound environment. Because keratinocytes express the β2-adrenergic receptor (β2AR), another study objective was to determine whether β2AR antagonists could block epinephrine effects on healing and improve wound repair.
Methods and Findings
Migratory rates of normal human keratinocytes exposed to physiologically relevant levels of epinephrine were measured. To determine the role of the receptor, keratinocytes derived from animals in which the β2AR had been genetically deleted were similarly examined. The rate of healing of burn wounds generated in excised human skin in high and low epinephrine environments was measured. We utilized an in vivo burn wound model in animals with implanted pumps to deliver β2AR active drugs to study how these alter healing in vivo. Immunocytochemistry and immunoblotting were used to examine the up-regulation of catecholamine synthetic enzymes in burned tissue, and immunoassay for epinephrine determined the levels of this catecholamine in affected tissue and in the circulation. When epinephrine levels in the culture medium are elevated to the range found in burn-stressed animals, the migratory rate of both cultured human and murine keratinocytes is impaired (reduced by 76%, 95% confidence interval [CI] 56%–95% in humans, p < 0.001, and by 36%, 95% CI 24%–49% in mice, p = 0.001), and wound re-epithelialization in explanted burned human skin is delayed (by 23%, 95% CI 10%–36%, p = 0.001), as compared to cells or tissues incubated in medium without added epinephrine. This impairment is reversed by β2AR antagonists, is absent in murine keratinocytes that are genetically depleted of the β2AR, and is reproduced by incubation of keratinocytes with other β2AR-specific agonists. Activation of the β2AR in cultured keratinocytes signals the down-regulation of the AKT pathway, accompanied by a stabilization of the actin cytoskeleton and an increase in focal adhesion formation, resulting in a nonmigratory phenotype. Burn wound injury in excised human skin also rapidly up-regulates the intra-epithelial expression of the epinephrine synthesizing enzyme phenylethanolamine-N-methyltransferase, and tissue levels of epinephrine rise dramatically (15-fold) in the burn wounded tissue (values of epinephrine expressed as pg/ug protein ± standard error of the mean: unburned control, 0.6 ± 0.36; immediately postburn, 9.6 ± 1.58; 2 h postburn, 3.1 ± 1.08; 24 h post-burn, 6.7 ± 0.94). Finally, using an animal burn wound model (20% body surface in mice), we found that systemic treatment with βAR antagonists results in a significant increase (44%, 95% CI 27%–61%, p < 0.00000001) in the rate of burn wound re-epithelialization.
Conclusions
This work demonstrates an alternate pathway by which stress can impair healing: by stress-induced elevation of epinephrine levels resulting in activation of the keratinocyte β2AR and the impairment of cell motility and wound re-epithelialization. Furthermore, since the burn wound locally generates epinephrine in response to wounding, epinephrine levels are locally, as well as systemically, elevated, and wound healing is impacted by these dual mechanisms. Treatment with beta adrenergic antagonists significantly improves the rate of burn wound re-epithelialization. This work suggests that specific β2AR antagonists may be apt, near-term translational therapeutic targets for enhancing burn wound healing, and may provide a novel, low-cost, safe approach to improving skin wound repair in the stressed individual.
Rivkah Isseroff and colleagues describe how stress-induced elevation of epinephrine levels can impair the healing of burns in mice and suggest that β2 adrenergic receptor antagonists may have a role in improving skin wound repair.
Editors' Summary
Background.
Skin—the largest organ in the human body—protects the rest of the body against infection by forming an impervious layer over the whole external body surface. Consequently, if this layer is damaged by rubbing, cutting, or burning, it must be quickly and efficiently repaired. Wound repair (healing) involves several different processes. First, the clotting cascade stops bleeding at the wound site and immune system cells attracted into the site remove any bacteria or debris in the wound. Various factors are released by the immune cells and the other cells in and near the damaged area that encourage the migration of several different sorts of cells into the wound. These cells proliferate and prepare the wound for “re-epithelialization.” In this process, keratinocytes (a type of epithelial cell that makes a tough, insoluble protein called keratin; epithelial cells cover all the surfaces of the body) migrate into the wound site and form a new, intact epithelial layer. If any of these processes fail, the result can be a chronic (long-lasting) nonhealing wound. In particular, if the wound does not re-epithelialize, it remains open and susceptible to infection and loss of body fluids.
Why Was This Study Done?
One factor that impairs the repair of skin wounds is stress. In stressful situations (including situations in which wounds are likely to occur), the human body releases several chemicals that prepare the body for “fight or flight,” including cortisol and epinephrine (also called adrenaline). Most scientists ascribe the effects of stress on wound healing to stress-induced increases in cortisol, but might stress-induced epinephrine also affect wound healing? In this study, the researchers test whether epinephrine impairs keratinocyte migration and re-epithelialization of burn wounds (keratinocytes have a receptor for epinephrine called the β2 adrenergic receptor [β2AR] on their cell surface that allows them to respond to epinephrine). They chose to study burn wounds for two reasons. First, major burns cause a massive release of stress chemicals into the bloodstream that raises blood levels (systemic levels) of cortisol and epinephrine for days or weeks after the initial trauma. Second, despite recent therapeutic advances, many people still die from major burns (4,000 every year in the USA alone) so there is a pressing need for better ways to treat this type of wound.
What Did the Researchers Do and Find?
The researchers investigated the effects of epinephrine on wound healing in three types of experiments. First, they looked at the effect of epinephrine on keratinocytes growing in dishes (in vitro experiments). Levels of epinephrine similar to those in the blood of stressed individuals greatly inhibited the motility and migration of human keratinocytes (isolated from the foreskin of newborn babies) and of mouse keratinocytes. It also inhibited the repair of scratch wounds made in monolayers of keratinocytes growing on dishes. Treatment of the cultures with a β2AR antagonist (a chemical that prevents epinephrine activating the β2AR) reversed the effects of epinephrine. In addition, the migration of mouse keratinocytes that had been genetically altered so that they did not express β2AR was not inhibited by epinephrine. Next, the researchers investigated the healing of burn wounds made in small pieces of human skin growing in dishes (ex vivo experiments). Burn injuries rapidly increased the amount of epinephrine in these tissue explants, they report, and treatment of the explants with a βAR antagonist (an inhibitor of all types of βARs) greatly increased wound re-epithelialization. Finally, the researchers report that the re-epithelialization of burn wounds in living mice was improved when the mice were treated with a β2AR antagonist.
What Do These Findings Mean?
These findings reveal a second pathway by which stress can impair wound healing. They show that stress-induced increases in systemic and local epinephrine activate β2ARs on keratinocytes and that this activation inhibits keratinocyte motility and wound re-epithelialization. Although results obtained in animals do not always reflect what happens in people, the finding that the treatment of mice with β2AR antagonists improves the rate of burn wound re-epithelialization, suggests that beta blockers—drugs that inhibit all βARs and that are widely used to treat high blood pressure and to prevent heart disease—or specific β2AR antagonists might provide a new therapeutic approach to the treatment of burns and, perhaps, chronic nonhealing wounds.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000012.
Wikipedia has pages on wound healing, burn injuries, and epinephrine (Note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The MedlinePlus Encyclopedia has a page on burns (in English and Spanish)
MedlinePlus provides links to other information on burns (in English and Spanish)
doi:10.1371/journal.pmed.1000012
PMCID: PMC2621262  PMID: 19143471
5.  Comparison of lidocaine with and without bupivacaine for local dental anesthesia. 
Anesthesia Progress  1997;44(3):83-86.
The purpose of this study was to investigate the effectiveness of a combination of bupivacaine and lidocaine and that of lidocaine alone for local dental anesthesia. First, on different days, healthy volunteers were given 2% lidocaine with 1/80,000 epinephrine or 2% lidocaine with 1/80,000 epinephrine + 0.5% bupivacaine, after which pain was produced with a pulp tester. No difference was found in the time until onset of anesthetic effect between the preparations. However, the duration of anesthetic effect was longer with both lidocaine and bupivacaine than with lidocaine alone. Next, patients undergoing dental surgery were given one of the anesthetic preparations, after which serum concentrations of the anesthetics and epinephrine were measured. The maximal serum concentration of lidocaine was higher and was reached sooner after injection in patients receiving lidocaine alone (1.74 microgram/ml after 5 min) than in patients receiving both anesthetics (0.85 microgram/ml after 3 min). The mean maximal serum concentration of lidocaine was higher in patients receiving lidocaine alone (1.77 +/- 0.03 microgram/ml) than in those receiving both anesthetics (0.99 +/- 0.45 microgram/ml). Furthermore, the mean plasma concentration of epinephrine 1 min after injection was significantly higher in patients receiving lidocaine alone (0.671 ng/ml) than in patients receiving both lidocaine and bupivacaine (0.323 ng/ml). The results of this study suggest that the combination of lidocaine with epinephrine and bupivacaine produces lower systemic levels of the anesthetic and epinephrine and a longer duration of activity than lidocaine with epinephrine alone for local dental anesthesia.
PMCID: PMC2148928  PMID: 9481966
6.  A Prospective, Randomized, Double-Blind Comparison of 2% Lidocaine With 1 : 100,000 Epinephrine, 4% Prilocaine With 1 : 200,000 Epinephrine, and 4% Prilocaine for Maxillary Infiltrations 
Anesthesia Progress  2010;57(2):45-51.
Abstract
The purpose of this prospective, randomized, double-blind crossover study was to evaluate the anesthetic efficacy of 2% lidocaine with 1 : 100,000 epinephrine, 4% prilocaine with 1 : 200,000 epinephrine, and 4% prilocaine in maxillary lateral incisors and first molars. Sixty subjects randomly received, in a double-blind manner, maxillary lateral incisor and first molar infiltrations of 1.8 mL of 2% lidocaine with 1 : 100,000 epinephrine, 1.8 mL of 4% prilocaine with 1 : 200,000 epinephrine, and 1.8 mL of 4% prilocaine, at 3 separate appointments spaced at least 1 week apart. The teeth were pulp-tested in 3-minute cycles for a total of 60 minutes. Anesthetic success (ie, obtaining 2 consecutive 80 readings with the electric pulp tester) and onset of pulpal anesthesia were not significantly different between 2% lidocaine with 1 : 100,000 epinephrine, 4% prilocaine with 1 : 200,000 epinephrine, and 4% prilocaine for the lateral incisor and first molar. For both lateral incisor and first molar, 4% prilocaine with 1 : 200,000 epinephrine and 2% lidocaine with 1 : 100,000 epinephrine were equivalent for incidence of pulpal anesthesia. However, neither anesthetic agent provided an hour of pulpal anesthesia. For both lateral incisor and first molar, 4% prilocaine provided a significantly shorter duration of pulpal anesthesia compared with 2% lidocaine with 1 : 100,000 epinephrine and 4% prilocaine with 1 : 200,000 epinephrine.
doi:10.2344/0003-3006-57.2.45
PMCID: PMC2886917  PMID: 20553134
Lidocaine; Epinephrine; Prilocaine; Infiltration; Maxillary
7.  Cardiovascular effect of dental anesthesia with articaine (40 mg with epinefrine 0,5 mg % and 40 mg with epinefrine 1 mg%) versus mepivacaine (30mg and 20 mg with epinefrine 1 mg%) in medically compromised cardiac patients: A cross-over, randomized, single blinded study 
Objectives: The aim of the present study is to compare cardiovascular safety profiles of two dental anesthetics: articaine versus two standard mepivacaine solutions used during etiological periodontal treatment in cardiovascular patients. Study Design: Using a cross-over study design, ten cardiovascular patients were randomly assigned to dental treatment with 1.8mL of a local anesthetic injected on each quadrant of the mouth: Articaine (40mg with Epinephrine 0.5mg % and 40mg with Epinephrine 1mg %) or Mepivacaine (30mg and 20mg with Epinephrine 1mg %). A computer programme enabled continuous longitudinal data collection: O2 saturation, blood pressure (BP) and heart rate (HR). Results: No severe clinical side effects were observed. During the treatment period, we observed statistically significant differences as regards HR between injections with and without adrenalin (p< 0.039) and as regards systolic (p< 0.046) and diastolic (p < 0.046) blood pressure during the stabilization period. In both cases, the parameters under study increase. Age, gender, jaw treated, treatment duration and the rest of cardiovascular variables did not affect the results. None of the patients underwent ischemic alterations or any other complication derived from the treatment or the anesthesia. Conclusions: According to the results of our study, dental anesthetics with standard concentrations of Epinephrine seem to alter HR and BP. Although no cardiac ischemic alterations or any other cardiovascular complications have been observed, we must be cautious with the administration of anesthetics containing vasoconstrictors in patients with cardiovascular diseases.
Key words:Dental anesthesia, cardiovascular diseases, chronic periodontitis, drug toxicity.
doi:10.4317/medoral.17892
PMCID: PMC3476031  PMID: 22322521
8.  Investigation of previously reported mucosal swellings after injection with Citanest Forte. 
Anesthesia Progress  2002;49(4):113-123.
The purpose of this study was to determine the reason for an apparent increase in the number of mucosal swellings after maxillary infiltration with Citanest Forte (prilocaine HCl 4% solution with epinephrine 1:200,000), 2 years after its introduction in 1971 by Astra Pharmaceutical Co (now AstraZeneca) in the United States. Approximately 70% of these reported reactions were from California, where less than 11% of all cartridges were sold. Comparison with New York State, with 27% of total sales but less than 1% of the reactions, suggested that possible differences in practice characteristics were responsible for the swellings. On the basis of the Bureau of Economic Research and Statistics Survey of Dental Practice, dentists in the Far West (eg, California) were found to schedule appointments with a median length of approximately twice that of their Mid-East colleagues, the implication being that more anesthetic solution was injected per office visit. Follow-up telephone interviews of dentists reporting such reactions at that time verified that they administered more than the recommended 1.8-mL dose. The most important epidemiologic information was that prilocaine HCl 4% solution with epinephrine 1:200,000 had been on sale in Canada 4 years before it was introduced in the US market, with little or no evidence of drug-related effects. Comparison of the US and Canadian prilocaine HCl with epinephrine 1:200,000 specifications revealed that NaCl was added to an already hypertonic prilocaine solution in the US but not in Canada. Comparison of the responses to intradermal injection of US and Canadian prilocaine solutions into the backs of rabbits with follow-up studies of dose-related NaCl injections demonstrated that the added NaCl was responsible for the onset and duration of irritation from the initially marketed US Citanest solutions.
PMCID: PMC2007412  PMID: 12779112
9.  Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia 
Marine Drugs  2011;9(12):2717-2728.
Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 µg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001) or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.
doi:10.3390/md9122717
PMCID: PMC3280572  PMID: 22363247
tetrodotoxin; bupivacaine; epinephrine; local anesthesia; sciatic blockade
10.  Comparison of Periodontal Intraligamental Anesthesia Using Etidocaine HCL and Lidocaine HCL 
Anesthesia Progress  1985;32(5):202-205.
A double-blind method was used to compare anesthesia duration following intraligamental administration of 1.5% etidocaine with 1:200,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine. Durations of anesthesia in pulpal and soft tissues were monitored following periodontal ligament injections adjacent to the maxillary canines of 20 individuals. Complete pulpal anesthesia was attained in 35% of the teeth injected with etidocaine and in 55% of those receiving lidocaine. Soft tissue anesthesia was consistently achieved. Both pulpal and soft tissue anesthesia were of longer duration following the use of lidocaine solution. These findings suggest that anesthetic duration following periodontal ligament injections is more related to the concentration of vasoconstrictor than to the anesthetic solution employed.
PMCID: PMC2175406  PMID: 3866503
11.  The influence of propranolol on the cardiovascular effects and plasma clearance of epinephrine. 
Anesthesia Progress  1991;38(6):217-220.
The purpose of the present study was to determine how propranolol modifies the circulatory effects of epinephrine infused to produce plasma concentrations achieved during dental local anesthesia and to evaluate the effects of propranolol on the plasma clearance of epinephrine. The study was performed on six healthy male volunteers ranging in age from 25 to 34 yr. Five measurement series were performed on each of these subjects at the following times: pretreatment control, 15 min after the beginning of the first epinephrine infusion (10 ng/kg/min), 15 min after the cessation of the first epinephrine infusion, 3 min after the intravenous injection of propranolol 40 micrograms/kg, and 15 min after the beginning of the second epinephrine infusion. Plasma epinephrine clearance decreased to 54.7 +/- 9.3% of the control value after propranolol was given. Epinephrine showed initially a predominantly beta-adrenergic action, but this action was inhibited by propranolol. A relative alpha-dominant state may then occur, even when a routine volume of dental local anesthetic is administered to a chronic user of a nonselective beta blocker, and it is postulated that myocardial ischemia may develop in such patients.
PMCID: PMC2148693  PMID: 1842159
12.  Comparison of anesthetic efficacy of 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:80,000 epinephrine for inferior alveolar nerve block in patients with irreversible pulpitis 
Objectives: This study was done to compare the anesthetic efficacy of 4% articaine with 1:100,000 epinephrine with that of 2% lidocaine with 1:80,000 epinephrine during pulpectomy in patients with irreversible pulpitis for inferior alveolar nerve block in mandibular posterior teeth. Material and Methods: Patients with irreversible pulpitis referred to the Department of Conservative Dentistry and Endodontics, K.D. Dental College, randomly received a conventional inferior alveolar nerve block containing 1.8 mL of either 4% articaine with 1:100,000 epinephrine or 2% lidocaine with 1:80,000 epinephrine. After the patient’s subjective assessment of lip anesthesia, the absence/presence of pulpal anesthesia through electric pulp stimulation was recorded and the absence/presence of pain was recorded through visual analogue scale. Results: The pulpal anesthesia success for articaine (76%) was slightly more than with lidocaine (58%) as measured with pulp tester as well as for the pain reported during the procedure the success rate of articaine (88%) was slightly more than that of lidocaine (82%) although the difference between the two solutions was not statistically significant. Conclusions: Both the local anesthetic solutions had similar effects on patients with irreversible pulpitis when used for inferior alveolar nerve block.
Key words:Anesthesia, articaine, lignocaine, pulpitis.
doi:10.4317/jced.51617
PMCID: PMC4312679
13.  A clinical trial of long-acting local anesthetics for periodontal surgery. 
Anesthesia Progress  1990;37(4):194-198.
The efficacy of long-acting local anesthetics for anesthesia during periodontal surgery and for analgesia during the immediate postoperative period was evaluated. The rationale for using long-acting local anesthetics such as etidocaine and bupivacaine is that they can provide surgical anesthesia and, because of their long duration, prevent discomfort that may occur for 4-6 hours postoperatively. Two clinical trials were performed. The first enrolled patients requiring bilateral periodontal surgery. Using a matched pair design and double-blind randomized study conditions, 2% lidocaine 1/100,000 epinephrine was compared with 1.5% etidocaine 1/200,000 epinephrine for periodontal surgery. The time until complete recovery and the time until pain onset were found to be longer for the etidocaine surgeries. Postoperative pain appeared more severe, and the need for oral analgesics was greater for the lidocaine surgeries. Surgeons' rating of surgical bleeding was significantly greater for the etidocaine procedures. When matched bilateral surgeries were not available, a second double-blind randomized parallel trial was performed that compared 1.5% etidocaine 1/200,000 epinephrine to 0.5% bupivacaine 1/200,000 epinephrine. No significant differences were seen in the quality of anesthesia, degree of bleeding, or postoperative pain between these two long-acting anesthetics.
PMCID: PMC2148673  PMID: 2096742
14.  Unexpected atrial fibrillation during tooth extraction in a sedated elderly patient. 
Anesthesia Progress  1994;41(3):77-80.
A case is reported of unexpected atrial fibrillation in response to tooth extraction under intravenous sedation in a 70-yr-old patient with thoracic aneurysm of the aorta. Atrial fibrillation developed after the additional injection of a 2% solution of lidocaine containing 1:200,000 epinephrine. After 20 min, the arrhythmia disappeared spontaneously. The arrhythmia was associated with insufficient analgesia for tooth extraction, epinephrine in the local anesthetic, decreased blood pressure, and the presence of cardiovascular disease. Even when a low concentration of epinephrine is employed, caution should be paid to development of unexpected cardiovascular reactions in elderly patients with severe cardiovascular disease. We conclude that an electrocardiogram, blood pressure device, and pulse oximeter should be used in high-risk patients in order to prevent and detect potentially dangerous cardiovascular emergencies, even if dental treatment is scheduled under local anesthesia.
PMCID: PMC2148821  PMID: 8934964
15.  Anesthetic activity of the lipospheres bupivacaine delivery system in the rat. 
Anesthesia Progress  1992;39(6):197-200.
The Lipospheres Bupivacaine Delivery System (bupivacaine-lipospheres) is a novel sustained-release local anesthetic preparation that has recently been made available for research purposes. This investigation compared the local anesthetic efficacy and safety of 2% bupivacaine-lipospheres, 0.5% bupivacaine plus 1:200,000 epinephrine, lipospheres plain, and physiologic saline following subcutaneous tail injection in the rat. A modified tail-flick paradigm was used to assess local anesthetic efficacy. Animals treated with 2% bupivacaine-lipospheres or 0.5% bupivacaine with epinephrine displayed significant antinociception (P < 0.05) compared to saline or lipospheres plain with 5 min of injection. Bupivacaine with epinephrine had an anesthetic duration of 30 min, whereas 2% bupivacaine-lipospheres had a duration of 3 hr. The local anesthetic blockade produced by both active solutions was completely reversible. All animals gained weight normally during the 1-wk course of the study, and there were no signs of local tissue toxicity at the injection sites. We conclude that 2% bupivacaine-lipospheres is a safe and efficacious local anesthetic preparation in this particular animal model. It possesses an onset of action that is a rapid as 0.5% bupivacaine with 1:200,000 epinephrine, and a duration that is six times longer.
PMCID: PMC2148614  PMID: 8250341
16.  Onset and duration of intradermal mixtures of bupivacaine and lidocaine with epinephrine 
BACKGROUND/OBJECTIVE:
Bupivacaine and lidocaine are often used concurrently, in theory, to combine the more rapid onset of lidocaine and the longer duration of bupivacaine. The purpose of this study was to evaluate this concept.
METHODS:
Twenty-five subjects were enrolled in a double-blinded, randomized block design study to evaluate the onset and duration of four different mixtures of lidocaine and bupivacaine with epinephrine. The study was designed to achieve 80% power to detect an effect size of 0.37 at 5% overall significance. The four mixtures tested were: 0.25% bupivacaine with epinephrine (1:200,000); 1% lidocaine with epinephrine (1:100,000); 0.125% bupivacaine and 0.5% lidocaine with epinephrine (1:150,000); and 0.25% bupivacaine and 1% lidocaine with epinephrine (1:150,000). Four intradermal injections were made in the volar forearms of each participant. Time to effect and duration were measured by sensation of a sharp skin prick.
RESULTS:
Mean time to onset ranged from 12 s to 29 s without statistical significance across all tested solutions (P=0.891). Mean duration of effect ranged from 6 h 38 min to 7 h 25 min with a statistically significant difference across the tested solutions (P=0.036).
CONCLUSIONS:
No statistical benefit was measured when comparing lidocaine with epinephrine, bupivacaine with epinephrine, and mixtures of these local anesthetics with regard to onset of action. While a statistical difference was observed in duration of effect, the clinical benefit measured was narrow.
PMCID: PMC3891109  PMID: 24431939
Bupivacaine; Duration; Lidocaine; Local anesthetic; Onset
17.  Use of Bulleyaconitine A as an Adjuvant for Prolonged Cutaneous Analgesia in the Rat 
Anesthesia and analgesia  2008;107(4):1397-1405.
BACKGROUND
Bulleyaconitine A (BLA) is an analgesic and antiinflammatory drug isolated from Aconitum plants. BLA has several potential targets, including voltage-gated Na+ channels. We tested whether BLA elicited long-lasting cutaneous analgesia, when co-injected with lidocaine and epinephrine, as a model for prolonged infiltration anesthesia.
METHODS
The local anesthetic properties of BLA were assessed by the patch-clamp technique in HEK293t cells expressing Nav1.7 and Nav1.8 neuronal Na+ channels, both crucial for nociception. Drug solutions (0.6 mL) were injected subcutaneously via rat shaved dorsal skin. Inhibition of the cutaneous trunci muscle reflex was evaluated by pinpricks. Skin cross-sections were stained with hematoxylin and eosin or with antibodies against PGP9.5.
RESULTS
BLA at 10 µM interacted minimally with resting or inactivated Nav1.7 and Nav1.8 Na+ channels when infrequently stimulated to +50 mV for 3 ms. However, when stimulated at 2 Hz for 1000 pulses, their peak Na+ currents were >90% reduced by BLA. This use-dependent inhibition was not significantly reversed after 15-min washing. Complete nociceptive blockade after injection of lidocaine (0.5%)/epinephrine (1:200,000) lasted for approximately 1 h in rats; full recovery occurred after approximately 6 h. Co-injection of 0.125 mM BLA with lidocaine/epinephrine increased the duration of complete nociceptive blockade to 24 h. Full recovery occurred after approximately 6 days. Skin histology including peripheral nerve fibers appeared unaffected by BLA.
CONCLUSIONS
BLA inhibits Nav1.7 and Nav1.8 Na+ currents in a use-dependent manner. Co-injection of BLA at ≤0.125 mM with lidocaine and epinephrine elicits complete cutaneous analgesia that lasts for up to 24 h without adverse effects.
doi:10.1213/ane.0b013e318182401b
PMCID: PMC2712758  PMID: 18806059
18.  Epinephrine-reduced articaine solution (1:400,000) in paediatric dentistry: a multicentre non-interventional clinical trial 
Aim
In paediatric dentistry, epinephrine may contribute to systemic and local side-effects. On the other hand it is necessary to provide good and safe local analgesia. Therefore, an articaine solution with reduced epinephrine concentration was tested in a clinical setting.
Methods
In a non-interventional clinical study, dental treatment was performed in children and adolescents (4–17 years). For local analgesia, articaine 4 % plus epinephrine 1:400,000 was used in the technique chosen by the dentist. Efficacy and tolerance as well as duration of soft tissue analgesia and side-effects were evaluated.
Results
999 patients (50.5 % male, 49.5 % female) with a mean age of 7.9 (SD 2.34) years were treated. Two hundred seventy six patients (27.6 %) received sedation prior to treatment. The mean treatment time was 15 min (SD 10). In 93.5 % of cases, initial local analgesia was sufficient to perform the planned treatment. In 99 % of cases (n = 989) the planned treatment could be completed. A second injection was necessary in 6.5 % of cases. A mean duration of soft tissue analgesia of 2.19 h (SD 1.01) was seen. Slight side-effects occurred in 3.1 % of subjects.
Conclusions
Due to high efficacy, tolerance and safety, the articaine 4 % solution with the reduced epinephrine concentration (1:400,000) was a safe and suitable drug for paediatric routine treatment.
doi:10.1007/s40368-013-0024-9
PMCID: PMC3629280  PMID: 23559104
Paediatric; Dental; Local analgesia; Multicentre; Articaine; Epinephrine
19.  Effect of long acting local anesthetic on postoperative pain in teeth with irreversible pulpitis: Randomized clinical trial 
Objective
The objective of this study was to compare the effect of long acting anesthetics on postoperative pain in teeth with irreversible pulpitis.
Methodology
Forty patients were randomly assigned into two groups of twenty patients each. Each patient who fit the inclusion criteria was administered local anesthesia before undergoing root canal treatment. The anesthetic solution was either 2% lidocaine with 1:80,000 epinephrine or 0.5% bupivacaine with 1:200,000 epinephrine. Patients were instructed to complete a VAS pain score at 6, 12, 24 h after single visit root canal treatment. Data were analyzed by Mann–Whitney, Cochrane Q analysis and t test to compare qualitative and quantitative data between the groups.
Results
The results showed the levels of pain of the patients who received lidocaine as the anesthetic agent and had significantly more postoperative pain after root canal treatment (P < 0.05) but had significantly decreased pain by 24 h compared to the bupivacaine group patients who had significantly lower postoperative pain levels at 6 and 12 h.
Conclusion
The use of long acting local anesthetic can significantly reduce the postoperative pain in teeth with irreversible pulpitis.
doi:10.1016/j.jsps.2013.01.004
PMCID: PMC3909752  PMID: 24493972
Local Anesthetic; Irreversible Pulpitis; Postoperative Pain; Lidocaine; Bupivacaine
20.  Comparative study on anesthetic potency depending on concentrations of lidocaine and epinephrine: assessment of dental local anesthetics using the jaw-opening reflex. 
Anesthesia Progress  2001;48(1):16-20.
Anesthetic potency of a local anesthetic on the dental pulp was investigated by increasing or decreasing the concentration of lidocaine and that of epinephrine. An electromyogram of the digastric muscle in Japan White male rabbits was recorded during the jaw-opening reflex induced by electrical stimulation of the dental pulp. Probit analysis was used for the determination of the 50% effective volume (ED50) values of the anesthetic. The anesthetics used were plain 2% lidocaine solution (2Lid-0 group), 2% lidocaine solution with 12.5 microgram/mL of epinephrine (2Lid-1/8 group), 2% lidocaine solution with 6.25 microgram/mL of epinephrine (2Lid-1/16 group), and 4% lidocaine solution with 5 microgram/mL of epinephrine (4Lid-1/20 group). No anesthetic effect was shown in the 2Lid-0 group. The 2Lid-1/8 group indicated adequate anesthetic potency with the smallest dosage at all observation periods. The potency in the 2Lid-1/16 group was 0.3-0.5 times, and that in the 4Lid-1/20 group was 0.3-0.4 times as much as the 2Lid-1/8 group. The decrease in epinephrine concentration produced the decrease in the anesthetic potency on the dental pulp independent of lidocaine concentration. These results suggest that the increase in lidocaine concentration may not compensate the decrease in epinephrine concentration.
PMCID: PMC2007327  PMID: 11495400
21.  Intraosseous injection as an adjunct to conventional local anesthetic techniques: A clinical study 
Background:
The achievement of successful local anesthesia is a continual challenge in dentistry. Adjunctive local anesthetic techniques and their armamentaria, such as intraosseous injection (the Stabident system and the X-tip system) have been proposed to be advantageous in cases where the conventional local anesthetic techniques have failed.
Aim:
A clinical study was undertaken using intraosseous injection system by name X-tip to evaluate its effectiveness in cases where inferior alveolar nerve block has failed to provide pulpal anesthesia.
Materials and Methods:
Sixty adult patients selected were to undergo endodontic treatment for a mandibular molar tooth. Inferior alveolar nerve block was given using 4% articaine with 1:100,000 epinephrine. Twenty-four patients (40%) had pain even after administration of IAN block; intraosseous injection was administered using 4% articaine containing 1:100,000 epinephrine, using the X-tip system. The success of X-tip intraosseous injection was defined as none or mild pain (Heft-Parker visual analog scale ratings ≤ 54 mm) on endodontic access or initial instrumentation.
Results:
Intraosseous injection technique was successful in 21 out of 24 patients (87.5%), except three patients who had pain even after supplemental X-tip injection.
Conclusion:
Within the limits of this study, we can conclude that supplemental intraosseous injection using 4% articaine with 1:100,000 epinephrine has a statistically significant influence in achieving pulpal anesthesia in patients with irreversible pulpitis.
doi:10.4103/0972-0707.139828
PMCID: PMC4174701  PMID: 25298642
Inferior alveolar nerve block; Heft-Parker “visual analogue scale” pain scale; intraosseous anesthesia; stabident; X-Tip
22.  Metabolic responses to oral surgery under local anesthesia and sedation with intravenous midazolam: the effects of two different local anesthetics. 
Anesthesia Progress  1992;39(1-2):9-12.
The effects of epinephrine-free and epinephrine-containing local anesthetic solutions on plasma potassium and blood glucose concentrations were investigated in 20 patients undergoing oral surgery with intravenous midazolam sedation. Ten patients were randomly assigned to receive 4.4 mL of 2% lidocaine with 1:80,000 epinephrine as a local anesthetic and 10 were given 4.4 mL of 3% prilocaine with 0.03 IU/mL felypressin. There were significant changes from baseline potassium and glucose concentrations both within and between treatments in the early postinjection period. The epinephrine-containing local anesthetic significantly reduced the plasma potassium concentration 10 min after injection, by 0.16 +/- 0.20 mmol/L (mean +/- SD), and increased the blood glucose concentration at 10, 20, and 30 min (by 0.46 +/- 0.37, 0.63 +/- 0.45, and 0.56 +/- 0.28 mmol/L, respectively). Conversely, plasma potassium increased and blood glucose decreased 10, 20, and 30 min following the administration of the epinephrine-free solution. At 30 min potassium was increased by 0.24 +/- 0.16 mmol/L, and glucose was decreased by 0.23 +/- 0.16 mmol/L. It is concluded that epinephrine-free and epinephrine-containing local anesthetics differ in their metabolic effects during oral surgery with midazolam sedation.
PMCID: PMC2148719  PMID: 8507025
23.  Vasoconstrictors in local anesthesia for dentistry. 
Anesthesia Progress  1992;39(6):187-193.
Addition of a vasoconstrictor to a local anesthetic may have several beneficial effects: a decrease in the peak plasma concentration of the local anesthetic agent, increase in the duration and the quality of anesthesia, reduction of the minimum concentration of anesthetic needed for nerve block, and decrease of blood loss during surgical procedures. The addition of a vasoconstrictor to a local anesthetic may also have detrimental effects. A review of the literature indicates that vasoconstrictor concentrations in local anesthetics marketed for dental use in the United States are not always optimal to achieve the purposes for which they are added. In most cases, a reduced concentration of vasoconstrictor could achieve the same goal as the marketed higher concentration, with less side-effect liability.
PMCID: PMC2148619  PMID: 8250339
24.  An echocardiographic study of interactions between pindolol and epinephrine contained in a local anesthetic solution. 
Anesthesia Progress  1995;42(2):29-35.
An increasing number of dental patients are taking beta-adrenergic blockers for the treatment of hypertension or angina pectoris. If epinephrine-containing local anesthetics are administered to such patients, interactions between epinephrine and the beta-blocking agent may induce cardiovascular complications. We assessed in volunteers the effects of intraoral injection with 2% lidocaine containing 1:80,000 epinephrine (L-E) on cardiac function after pretreatment with the beta-blocking agent pindolol. M-Mode echocardiography was used for the assessment. The injection of L-E after administration of pindolol did not alter cardiac preload, whereas it reduced the stroke volume, due to an increase in afterload and a decrease in myocardial contractility. Reductions in stroke volume and heart rate led to a decrease in cardiac output. Because total peripheral vascular resistance increased markedly, blood pressure was elevated despite the reduced cardiac output. These results suggest that cardiac function of dental patients on beta-blocker therapy can be adversely affected by epinephrine-containing local anesthetics. Therefore, when such an anesthetic solution has to be used in patients on beta-blocker therapy, careful systemic monitoring is needed.
PMCID: PMC2148851  PMID: 8934951
25.  Comparison of effectiveness of 4% articaine associated with 1: 100,000 or 1: 200,000 epinephrine in inferior alveolar nerve block. 
Anesthesia Progress  2003;50(4):164-168.
This comparative study using 20 healthy volunteers evaluated the anesthetic efficacy of 4% articaine in association with 2 different concentrations of epinephrine, 1:200,000 (G1) and 1:100,000 (G2). The first premolars were tested with a pulp tester to verify the anesthesia induced by the inferior alveolar nerve block. The following parameters were measured: period of latency (PL; interval between the end of anesthetic injection and absence of response to the maximum output--80 reading--of the pulp tester); complete pulpal anesthesia (CPA; period in which the subject had no response to maximal output of the pulp tester 80 reading); partial anesthesia (PA; interval between the first reading below 80 and the return to basal levels); and the anesthesia of the soft tissues (AST; period of time from onset of anesthesia until the return to normal sensation of the lip). The Wilcoxon test (alpha = 0.05) was used to analyze the data. No significant difference was found regarding PL (P = .47), CPA (P = .88), PA (P = .46), and AST (P = .85). The results indicated that both solutions presented the same clinical effectiveness in blocking the inferior alveolar nerve.
PMCID: PMC2007445  PMID: 14959904

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