Local Anesthesia with or without Vasoconstrictor in Hypertensive and Diabetic Patients

João Vitor da Silva Rodrigues; Luciane Dias de Oliveira, Ph.D.; Simone Lapena; Letícia de Miguel Nazario; Taís Maria Cardoso de Oliveira; Alessandra Buhler Borges, Ph.D.; Regina El Dib, Ph.D.

ABSTRACT

Hypertensive and diabetic patients present a public health issue. Vasoconstrictors have been added to local anesthetics to increase the length of the anesthetic effect during dental procedures. However, there is no consensus showing whether local anesthetic is safer with or without vasoconstrictors in this population. This paper is a systematic review of the literature, undertaken to investigate the systemic effects resulting from the use of any local anesthetic with either adrenergic or non-adrenergic vasoconstrictor versus local anesthetic without vasoconstrictor in hypertensive patients with controlled blood pressure and/ or controlled diabetes during dental extraction, and periodontal or routine dental treatments.

The number of people with diabetes and hypertension is increasing globally. Despite being preventable, diabetes mellitus (DM) and hypertension fall among the top 10 leading causes of death globally.[1] In 2017, around 425 million people had DM; and this number is expected to rise to 629 million by 2045.[2] This estimate includes people diagnosed with the disease and patients suspected of having DM.[2] The arterial hypertension affects about one billion people worldwide.[3] It is estimated that by 2025, up to 1.56 billion adults worldwide will be hypertensive.[4]

Usually, elevated blood pressure is the leading risk factor for mortality and morbidity, accounting for 7% of disability, adjusted life years, and 9.4 million deaths in 2010.[5] About 75% of DM patients will develop hypertension over time. The rate at which hypertension co-exists with diabetes is such that diabetics are 1.5- to 2-times more likely to be hypertensive than their non-diabetic counterparts.[6]

Some soft-tissue abnormalities associated with oral DM problems were reported. They included xerostomia, cavities and periodontal diseases that require dental care.[7] The oral manifestations reported by hypertensive patients were related to the adverse effects of the antihypertensive drugs, including xerostomia, gingival hyperplasia manifested by pain, gingival bleeding and difficulty chewing.[8] Special care should be given to both DM and hypertensive patients undergoing dental procedures regardless of the reason that led them to treatment.

Local anesthetics are the most commonly used drugs in dentistry, and the usual method for controlling pain in dental practice.[9]

Local anesthesia is induced when the propagation of action potentials is avoided, so that the impulse cannot be transmitted from the source of stimulation, such as the tooth or the periodontium, to the brain. Local anesthetics act by blocking the entry of sodium ions into their channels, thus preventing the transient increase in the permeability of the nerve membrane to sodium, which is necessary for an action to occur. Nevertheless, local anesthetics cause vasodilation, which diffuses away from the site of action and results in a very short duration of action intraorally when these drugs are used alone.[10] This diffusion can be reduced by the addition of a vasoconstrictor, usually epinephrine.

For this reason, vasoconstrictors are added in many formulations in order to delay the clearance of the local anesthetic and prolong the anesthesia. This is particularly important because the local anesthetics themselves vary in their capacity to produce vasodilation. For example, when used without vasoconstrictors, lidocaine shortens its duration dilating the local vasculature, while mepivacaine and bupivacaine do not.[11] However, some studies have shown potential side effects that may result in dentists’ uncertainty about the choice of anesthetics.[12-15]

A recent study indicated that the vasoconstrictor felypressin, combined with prilocaine, produced similar cardiac effects as epinephrine combined with lidocaine.[16]

We, therefore, conducted a systematic review that assessed the systemic effects of any local anesthetic (e.g., prilocaine, mepivacaine, bupivacaine) with either adrenergic (e.g., epinephrine) or non-adrenergic (e.g., felypressin) vasoconstrictor versus local anesthetic without vasoconstrictor among hypertensive patients with controlled blood pressure (BP) and/or controlled diabetes, presenting for dental extraction, periodontal or routine dental treatments, regardless of numbers of anesthetics cartridges or concentration, and type of patient with diabetes.

Methods

The Cochrane Handbook for Intervention Reviews[17] guided our choice of methods. Our systematic review results were conducted and reported in accordance with the PRISMA (Preferred Reposting Items for Systematic Reviews and Meta-analysis) statement.[18] This review was registered at PROSPERO, the International Prospective Register of Systematic Reviews (http:// www.crd.york.ac.uk/prospero/index.asp), under the number CRD42018095626.

Eligibility Criteria

All randomized (RCTs) and non-randomized clinical trials (nonRCTs) evaluating any local anesthetics (e.g., mepivacaine, bupivacaine, prilocaine) with adrenergic (e.g., epinephrine) or non-adrenergic (e.g., felypressin) vasoconstrictor versus local anesthetic without vasoconstrictor among hypertensive patients and/or patients with controlled diabetes presenting for dental extraction, periodontal or routine dental treatments were considered, regardless of numbers of anesthetics cartridges or concentration, and type of patients with diabetes. Patients under antihypertensive treatment and with controlled blood pressure (BP) (i.e., systolic and diastolic BP lower than 140/90 mmHg, respectively) were considered hypertensive patients. Controlled diabetic patients were considered as patients under diet control, on insulin injection, or oral hypoglycaemic medication. Pregnant women and pediatric patients (age 12 or under) were excluded.

Patient-important outcomes were as followed: a) complications, such as arrhythmias, unstable angina; b) hemodynamic parameters, such as systolic and diastolic blood pressure, heart rate, ejection fraction (%), and ventricular function; and c) any other outcome reported by the included studies.

Data Source and Searches

The search was performed in the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 1, 2018); PubMed (OvidSP, 1966 to 2018); EMBASE (Excerpta Medica database) (OvidSP, 1980 to 2018); LILACS (Literatura Latino-americana e do Caribe em Ciências da Saúde) (1982 to 2018); and the ISI Web of Science. The databases were searched for published studies from inception up to Feb. 21, 2018.

The search was conducted using multiple combinations of the following key words: “hypertension,” “diabetes,” “local anesthetics” and “vasoconstrictors” (Appendix Table 1). No restrictions were placed on language, year of publication or publication status. In addition, a manual search of the reference lists of potential primary studies was conducted, and major conferences for abstracts were hand-searched for additional eligible studies.

Selection of Studies

Using standardized screening forms, three teams of two reviewers independently screened all titles and abstracts identified by the literature search, obtained full-text articles of all potentially eligible studies and evaluated these studies for eligibility. Reviewers resolved disagreement through discussion, with third party adjudication if necessary.

Data Extraction and Risk of Bias Assessment

Two pairs of reviewers independently extracted the following data using a pre-piloted, standardized data extraction form: characteristics of the study design; participants; interventions; outcomes; and follow-up periods. Authors were contacted for clarification if eligible articles had missing data.

Reviewers independently assessed risk of bias using the riskof-bias approach for Cochrane reviews modified by Busse and Guyatt.[19] Risk of bias was assessed using five separate criteria: adequacy of sequence generation; allocation sequence concealment; blinding (investigators, patients, collectors, statistician, outcome assessors); incomplete outcome data; and selective outcome reporting. For incomplete outcome data, loss to follow-up of less than 10%, and a difference of 5% in missing data between intervention and control groups as low risk of bias were considered.

Certainty of Evidence

The reviewers used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty of evidence for each outcome as high, moderate, low or very low. Detailed GRADE guidance was used to assess overall risk of bias,[20] imprecision,[21] inconsistency,[22] indirectness[23] and publication bias,[24] and results were summarized in an evidence profile.

Data Synthesis and Statistical Analysis

We planned to perform meta-analysis; however, this was not possible due to the small number of included studies and lack of data. Risk ratios (RRs) were planned to be calculated for dichotomous outcomes (i.e., one that takes on one of only two possible values when observed or measured, e.g., have arrhythmia or not having it) while mean differences (MD) for continuous variables (i.e., measurement on a numerical scale, e.g., blood pressure mean values), with the associated 95% confidence interval (CI) using a random-effects model with the Mantel-Haenszel statistical method. The variability in results was planned to address across studies by using I2 statistic and the P value obtained from the Cochrane chi square test. Our primary analyses were on eligible patients who had reported outcomes for each study (complete case analysis).

Subgroup analyses were planned accordingly to: different local anesthetics (e.g., mepivacaine versus prilocaine); different vasoconstrictors (e.g. adrenergic versus non-adrenergic); different duration of local anesthetics (e.g., ≤ 2 hours vs > 2 hours); different dental procedures (e.g., dental extraction versus implant); different studied population (e.g., hypertensive versus diabetic patients).

Based on guidance from the Cochrane Handbook, we planned to assess publication bias using visual inspection of funnel plots for outcomes with 10 or more studies; however, we were not able to assess it because there was an insufficient number of included studies to allow for this assessment. Review Manager (RevMan) (version 5.3; Nordic Cochrane Centre, Cochrane) was used for all analyses.[25]

Results

Search Results

Figure 1 presents the process of identifying eligible studies, including citations identified through search in electronic databases. Based on title and abstract screening, 57 full texts were assessed. From these, we included four publications describing two RCTs involving 136 participants [26,27] and two non-RCTs with a total of 104 participants.[28,29]

Characteristics of Included Studies

Table 1 describes study characteristics related to study design, setting, number of participants, mean age, gender, inclusion and exclusion criteria, and follow-up. All included studies[26-29] were conducted largely in Brazil. Randomized trials sample size ranged from 6,526 to 7,127, and non-RCTs studies from 5,428 to 5,029.

Table 2 describes study characteristics related to oral procedure, intervention and control groups, and local anesthetic and vasoconstrictors. Two studies were conducted during a dental extraction,[28, 29] one[26] during a routine dental procedure, and the other[27] a periodontal treatment. Of the four studies, one compared prilocaine 3% associated with felypressin 0.03 IU/ml to lidocaine 2% without vasoconstrictor,[26] another to prilocaine 4% without vasoconstrictor to prilocaine 4% associated with felypressin 0.03 IU/ml,[27] and the third compared mepivacaine 2% associated with epinephrine 1:100.000 to mepivacaine 3% without vasoconstrictors.[28] The last compared prilocaine 3% associated with felypressin 0.03 IU/ml versus lidocaine 2% associated with epinephrine 1:100.000.[29]

Risk of Bias in Individual Studies

Figure 2 and Table 3 describe the risk-of-bias assessment for the included studies. The major issues regarding risk of bias were the extent of allocation concealment, and blinding of both investigators and outcome assessors in all included studies. Non-RCTs had additional problems of generation of allocation[28, 29] and blinding of participants.[28]

Effectiveness of Interventions

We found four eligible trials in which three[26, 27, 29] were eligible for representation of meta-analysis. The insufficient number of included studies, lack of data, and difference between dental procedure and local anesthetics used precluded potential meta-analysis.

Mepivacaine with Epinephrine and Mepivacaine Only Results from one non-RCT28 suggest a possible decrease in symptom periprocedural (pain at dental luxation) with mepivacaine plus epinephrine in comparison to mepivacaine only (RR 0.11, 95% CI 0.02, 0.82; p = 0.03; I2=not applicable) (Appendix tables 2,4). However, related to the outcomes ST-segment alteration indicating the occurrence of myocardial ischemia (depression > 1.0mm) and CKMB mass abnormal, there were no statistically significant differences between mepivacaine with epinephrine and mepivacaine only (RR 6.73, 95% CI 0.37 to 123.79; p = 0.20; I2=not applicable; and RR 5.00, 95% CI 0.25 to 99.51; p = 0.29; I2=not applicable; respectively) (Appendix tables 2, 4).

Prilocaine with Felypressin versus Lidocaine Only

Results from one RCT26 suggest a reduction in the ventricular function 30-50 with the use of prilocaine associated with felypressin versus lidocaine only in patients with coronariopathy (RR 0.22, 95% CI 0.05 to 0.93; p = 0.04; I2=not applicable) (Appendix tables 2,4). There was no statistically significant difference between prilocaine with felypressin versus lidocaine alone related to the other ventricular function’s variables (Appendix tables 2,4).

Lidocaine with Epinephrine versus Prilocaine with Felypressin

Results from one non-RCT29 suggest a reduction in both systolic and diastolic blood pressures (MD -9.20, 95% CI -17.24 to -1.16; p = 0.02; I2=not applicable; and MD -9.00, 95% CI -15.48 to -2.52; p = 0.006; I2=not applicable, respectively) with the use of lidocaine with epinephrine compared to prilocaine with felypressin (Appendix tables 3,4).

Discussion

Main Findings

The use of adrenergic vasoconstrictors in local anesthesia in patients with cardiovascular diseases and/or diabetes is highly questionable in dentistry, since the use of epinephrine over felypressin has benefits, such as hemostasis during surgical procedures, and considering the fact that epinephrine can also be associated with widely used anesthetics in dentistry, such as articaine, lidocaine and mepivacaine. On the other hand, there is the possibility of epinephrine (even in small amounts) altering the patient’s systemic condition, which may increase blood pressure and/or blood glucose levels. The indication for epinephrine has been based on the control of a patient’s systemic disease, blood glucose and blood pressure levels at the time of treatment and according to the dental clinical case (e.g., degree of anesthesia and hemostasis required).

There is very limited evidence regarding the impact of any local anesthetic (e.g., prilocaine, mepivacaine, bupivacaine) in combination with either adrenergic (e.g., epinephrine) or nonadrenergic (e.g., felypressin) vasoconstrictor among hypertensive patients with controlled blood pressure (BP) and/or controlled diabetes, presenting for dental procedures.

There is little evidence that the use of mepivacaine with epinephrine demonstrated a statistically significant difference in decreasing pain at dental luxation in coronary patients, compared to mepivacaine alone. Furthermore, prilocaine with felypressin proved to be more efficacious than lidocaine alone in reducing ventricular function in patients with Chagas disease or coronaropathy with complex ventricular arrhythmia. Related to the comparison, lidocaine with epinephrine is more effective than prilocaine with felypressin. There was a reduction in both systolic and diastolic blood pressures with the use of the former compared to the latter in hypertensive patients undergoing conventional exodontia. No statistically significant difference was found in chest pain, palpitation, diaphoresis, dyspnea, ST-segment alteration, CKMB activities and Troponin T.

Strengths and Limitations

Strengths of our review include a comprehensive search; assessment of eligibility, risk of bias and data abstraction independently and in duplicate; assessment of risk of bias; and use of the GRADE approach in rating the certainty of evidence for each outcome.

The primary limitation of our review is the low certainty consequent on study limitations. Only a very small number of RCTs and non-RCTs were identified, with a modest number of participants. We planned to perform meta-analysis; however, this was not possible due to the small number of included studies and lack of data. Moreover, we could not address our hypothesis on diabetic patients due to lack of evidence.

Another limitation of this review was the insufficient number of included studies to allow the priori analysis. We were not able to assess publication bias because there were fewer than 10 eligible studies addressing the same outcome in a metaanalysis. Subgroup analyses were also planned according to the characteristics of different local anesthetics (e.g., mepivacaine versus prilocaine); vasoconstrictors (e.g., adrenergic versus nonadrenergic); duration of local anesthetics (e.g., ≤ 2 hours vs > 2 hours); and dental procedures (e.g., dental extraction versus implant); different studied population (e.g., hypertensive versus diabetic patients).

However, we were not able to conduct these analyses because there was an insufficient number of studies reporting on these data.

Synopsis of Included Trials

Louro et al. (2001),[29] compared the effects of prilocaine 3% associated to felypressin 0.03 IU/mL with 2% lidocaine associated to 1:100,000 epinephrine on blood pressure in hypertensive patients undergoing conventional exodontia. The authors found that 1:100,000 epinephrine and 0.03 IU felypressin can be used safely in hypertensive patients, provided they adhere to their maximum doses. According to the authors, pain control, through adequate anesthesia, and reduction of anxiety, through emotional control of the patient, is very important to avoid cardiovascular complications in the dental office.

Furthermore, Conrado et al. (2007),[28] evaluated the occurrence of variables detecting ischemia during or after dental treatment under anesthesia with vasoconstrictor epinephrine and verified that dental extraction performed under anesthesia with 1:100,000 epinephrine does not imply additional ischemic risks, as long as it is performed with good anesthetic technique and maintenance of the pharmacological treatment prescribed by the cardiologist. These studies are of great importance for dentistry because the use of epinephrine has advantages in local anesthesia and if used in low doses with the correct anesthetic technique, may be recommended in patients with controlled cardiovascular diseases.

According to Malamed (1986)[30] and Bennett (1984),[31] the maximum dose of epinephrine that the patient with controlled cardiovascular disease can receive per treatment session is 0.04 mg, equivalent to 2 epinephrine tubes 1:100,000 or 4 epinephrine tubes 1:200,000. Therefore, according to our findings, epinephrine is not contraindicated in patients with cardiovascular diseases. But its use should be minimized and always associated with a good anesthetic technique, respecting the control of the pain.

Regarding the non-adrenergic vasoconstrictor, Cáceres et al. (2008),[26] evaluated the hemodynamic effects of the use of local anesthetics with a non-adrenergic vasoconstrictor in patients with ventricular arrhythmia, when compared to the use of anesthetic without vasoconstrictor. The results suggested that prilocaine 3% associated with a felypressin 0.03 IU/mL can be safely used in patients with Chagas disease or coronaropathy with complex ventricular arrhythmia. Although this study was wellconducted and with relevant contributions, the comparison was performed with lidocaine without vasoconstrictor, which offers a very short time of pulpal and periodontal anesthesia, not a choice in dental procedures. Thus, in cases where there is contraindication to the use of epinephrine, the choice of prilocaine 3% associated with a felypressin 0.03 IU / mL is the most recommended, since it offers a longer time of anesthesia in relation to lidocaine without associated vasoconstrictor.

In this context, Bronzo et al. (2011),[27] investigated the effect of felypressin on blood pressure in hypertensive patients with controlled blood pressure and verified that felypressin increased the diastolic blood pressure of hypertensive patients with controlled blood pressure. Patients with high trait anxiety exhibited increases in systolic blood pressure during some procedures, suggesting that an increase in blood pressure might also be related to fear or anxiety. Since many patients are afraid of dental procedures, especially of the needle used in the anesthesia, it is common in these anxious patients to experience high endogenous release of adrenaline, which can promote a significant increase of pressure levels, because during a moment of stress, secreted catecholamines reach serum levels much higher than the doses used in dentistry. Thus, control of the patient’s fear and anxiety may be more important than the choice of the vasoconstrictor, since changes in blood pressure or blood glucose are also directly related to emotion, and it is complex to define a specific treatment protocol.

In conducting this review, we have attempted to answer several clinical questions.

• Is mepivacaine with epinephrine more effective than mepivacaine alone? Does the combination of anesthetic alter the patient’s systemic condition?

• Very low- to low-quality evidence suggests that mepivacaine with epinephrine is more effective than mepivacaine alone in decreasing pain at dental luxation; however, there was no evidence to suggest a difference in chest pain, palpitation, diaphoresis, dyspnea, ST-segment alteration, CKMB activities and Troponin T.

• Is prilocaine with felypressin more effective than lidocaine alone? Does the combination of anesthetic alter the patient’s systemic condition?

• Very low- to low-quality evidence suggests that prilocaine with felypressin is more effective than lidocaine alone in reducing ventricular function.

• Is lidocaine with epinephrine more effective than prilocaine with felypressin? Does the combination of anesthetic alter the patient’s systemic condition?

• Low-quality evidence suggests that lidocaine with epinephrine is more effective than prilocaine with felypressin in reducing both systolic and diastolic blood pressures.

Conclusions

There is no robust evidence regarding the systemic effects of local anesthesia, with or without vasoconstrictor, in hypertensive and/ or diabetic patients during dental extraction, and periodontal or routine dental treatments. Therefore, in the face of lack of data, dentists should consider patient values and preferences related to the choice of anesthesia and their past experience and own preferences. This review underlines the need to conduct well-designed trials in this field considering diabetic patients.

The authors have no conflicts of interest. Regina El Dib received a Brazilian Research Council (CNPq) scholarship (CNPq 310953/2015-4). Queries about this article can be sent to Dr. El Dib at el.dib@unesp.br.

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30. Malamed SF. Handbook of local anesthesia. 2nd ed. St Louis: Mosby-Year Book; 1986.

31. Bennett CR. Monheim’s local anesthesia and pain control in dental practice. 7th ed. St Louis: Mosby-Year Book; 1984. João Vitor da Silva Rodrigues is an undergraduate student, Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University - Unesp, São Paulo, São José dos Campos, Brazil.

Luciane Dias de Oliveira, Ph.D., is associate professor, Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University - Unesp, São Paulo, São José dos Campos, Brazil.

Simone Lapena is a graduate student, Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University - Unesp, São Paulo, São José dos Campos, Brazil.

Letícia de Miguel Nazario is an undergraduate student, Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University - Unesp, São Paulo, São José dos Campos, Brazil.

Taís Maria Cardoso de Oliveira is an undergraduate student, Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University - Unesp, São Paulo, São José dos Campos, Brazil.

Alessandra Buhler Borges, Ph.D., is associate professor, Department of Restorative Dentistry, Institute of Science and Technology, São Paulo State University - Unesp, São Paulo, São José dos Campos, Brazil.

Regina El Dib, Ph.D., is assistant professor, Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University - Unesp, São Paulo, São José dos Campos, Brazil. Department of Community Health and Epidemiology, Dalhousie University, Faculty of Medicine, Halifax, Canada.