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A comprehensive review of the autonomic nervous system (ANS) is outside the scope of this article. This discussion will focus on epinephrine and levonordefrin, the vasoconstrictors currently used in local dental anesthetics in the United States. These vasoconstrictors act on the adrenergic receptors of the sympathetic branch of the ANS. The major types of adrenergic receptors are α-1, α-2, β-1, and β-2 receptors. The alpha receptors are found on arterioles in the mucosa and skin; alpha receptor agonism results in vasoconstriction and increases systolic blood pressure.1,2 β-1 receptors are principally located in the heart where agonism results in an increase in heart rate, contractile force, and myocardial oxygen consumption.1,3 β-2 receptors are located in many tissues, but their principal hemodynamic effect is demonstrated in vascular tissues, dilating larger systemic arteries that supply skeletal muscle, hepatic arteries, and coronary vessels. The vasodilation that accompanies β-2 receptor activation will result in a decrease in diastolic blood pressure.1,3-5
The hemodynamic profile of epinephrine and levonordefrin varies, as do their relative affinities for different adrenergic receptors. Epinephrine has an approximately equal affinity for both alpha and beta adrenergic receptors.1,5 The overall effect of stimulating alpha and beta adrenergic receptors is to redistribute blood flow from the skin and mucosa to the skeletal muscles while increasing heart rate and contractility.5 The net hemodynamic effect is to increase heart rate (β-1 effect) and systolic blood pressure (α-1 effect) with a decrease in diastolic blood pressure (β-2 effect) and the mean arterial pressure remains the same.4 Levonordefrin has a different receptor affinity, with a 75% affinity for alpha receptors and 25% affinity for beta receptors. The main hemodynamic effect exhibited by levonordefrin is a vasoconstriction (α-1) effect, which can raise blood pressure.1
Vasoconstrictor Indications in Local Dental Anesthesia
The indications for the administration of a vasoconstrictor with local anesthetic are well established. Local anesthetics, with the exception of cocaine, have vasodilatory properties.1,2 By causing the constriction of blood vessels in the mucosa, medications such as epinephrine and levonordefrin prevent the systemic uptake of local anesthetic at the site of injection. Thus, vasoconstriction has several effects: prolonging the duration and augmenting the depth of local anesthesia, reducing the systemic absorption of local anesthesia, and improving hemostasis.1-4
Epinephrine is available at three concentrations in local anesthetic formulations: 1:50,000; 1:100,000; and 1:200,000. Levonordefrin is available in a 1:20,000 concentration in cartridges. Levonordefrin is less potent than epinephrine, so a 1:20,000 concentration of levonordefrin can be thought of as being equivalent to a 1:100,000 concentration of epinephrine.3 The 1:100,000 or 1:200,000 epinephrine concentration is sufficient to improve depth and duration of local anesthetic.1 For hemostasis, the 1:50,000 epinephrine concentration is more effective than the 1:100,000 or 1:200,000 concentrations when paired with 2% lidocaine.1,2 Different local anesthetics produce different degrees of vasodilation; the 1:200,000 epinephrine concentration provides sufficient hemostasis when paired with bupivacaine or prilocaine.1 There is also concern for rebound vasodilation, meaning that there is a vasodilation, potentially from the β-2 receptor activation, following the initial vasoconstriction when using a vasoconstrictor. There have been observations of delayed healing and an increase in postoperative bleeding from extraction sockets when 2% lidocaine with epinephrine is used as compared to 3% mepivacaine.1
There is a misconception that using a local anesthetic without a vasoconstrictor, such as mepivacaine 3% plain, will provide a shorter duration of soft-tissue anesthesia than a local anesthetic with a vasoconstrictor, such as 2% lidocaine with 1:100,000 epinephrine. Mepivacaine does offer shorter pulpal anesthesia (20 to 40 minutes) as compared to lidocaine with epinephrine (60 to 90 minutes), but soft-tissue anesthesia is similar between the two anesthetics: 120 to 180 minutes and 120 to 240 minutes for mepivacaine plain and lidocaine with epinephrine, respectively. Hersh et al found that “the onset of soft tissue numbness, peak numbness effects, and numbness duration were quite similar” when comparing 3% mepivacaine plain and 2% lidocaine with epinephrine.6-8
Using 3% mepivacaine plain instead of 2% lidocaine with epinephrine does not provide any benefit with respect to the prevention of postoperative lip/mouth trauma, but the higher concentration of local anesthetic in the 3% mepivacaine solution makes it easier to reach or exceed the MRD. This is especially alarming when treating small children, as local anesthetic toxicity is related to dose and the patient’s weight.6,7,9-12
Vasoconstrictor Contraindications and Dose-Reductions
There are several contraindications, absolute or relative, which warrant avoidance or dose reduction if a vasoconstrictor is used with a local anesthetic. These clinical situations include allergy, cardiac comorbidities, and potential drug interactions.
True allergic reactions to current amide local anesthetics are rare but patients may have an allergic reaction to other components of the local anesthetic formulation. Allergic reactions to ester local anesthetics are more common than with amides. Esters are all metabolized to para-aminobenzoic acid, which is the source of allergenicity. Potential for cross-allergenicity exists between methylparaben, sulfonamide antibiotics, and PABA, as they all contain a phenyl ring with an amine substation in the para position. Allergic reactions to amides are more rare. Articaine is classified as both an ester and an amide but it does not have a PABA metabolite and is not of concern if there is a reported ester allergy.4 Sulfite preservatives are added to local anesthetic preparations when a vasoconstrictor is present. One should avoid a local anesthetic that contains a vasoconstrictor if there is a history of sulfite allergy. Sulfite-sensitive asthmatics should also be treated with caution, avoiding vasoconstrictor as it contains sulfites.1 There is no cross-allergenicity between sulfites and sulfonamide antibiotics. While epinephrine itself is impossible, patients may have an allergic reaction to other components of a local anesthetic formulation. Epinephrine is an endogenous catecholamine and the treatment of choice for an allergic reaction.1,3,4
When injected properly, a vasoconstrictor will prevent systemic uptake of the local anesthetic and reduce systemic effects of local anesthetic toxicity. It is a false misconception that the vasoconstrictor is not absorbed. Vasoconstrictor is indeed absorbed and will have hemodynamic effects.4 If accidentally injected intravascularly, both the local anesthetic and vasoconstrictor are absorbed systemically. Another misconception is that the vasoconstrictor will always prevent local anesthetic systemic toxicity. In fact, when injected intravascularly, the vasoconstrictor can potentially worsen the situation. The cumulative effect of alpha and beta-receptor activation will cause increased cardiac output and blood flow to the brain. Therefore, the local anesthetic will have enhanced delivery to the brain and may worsen local anesthetic systemic toxicity.1
Yet another misconception is that the amount of vasoconstrictor is so small in the dental cartridge as compared to the surgical stress of the procedure. Studies demonstrate a lack of change in plasma levels of epinephrine, blood pressure, and heart rate when lidocaine without vasoconstrictor was injected.1 In fact, even one cartridge of 2% lidocaine with 1:100,000 epinephrine demonstrated a two- to four-fold increase of plasma epinephrine levels as compared to baseline.1,2 Increases in plasma epinephrine levels were detected regardless of whether the patient received procedural sedation when local anesthetic with vasoconstrictor was administered for impacted third molar extractions.1 Hemodynamic changes, including an elevation in heart rate, myocardial oxygen consumption, and systolic blood pressure persisted for 20 minutes following injection.1 These studies debunk the myth that the physiologic and/or psychological stresses of surgery result in a greater release of endogenous epinephrine than the epinephrine administered in a local dental anesthetic.
The use of vasoconstrictors in local anesthetic should be cautiously examined when treating patients with the following comorbidities: those with a history of uncontrolled hypertension (systolic over 200 mmHg or diastolic over 115 mmHg); uncontrolled or decompensated congestive heart failure; uncontrolled cardiac arrhythmias; unstable angina pectoris; uncontrolled hyperthyroidism; and/or myocardial infarction, cerebrovascular accident, or coronary artery bypass surgery within the past 6 months. These patients are less able to compensate for the cardiovascular changes of the vasoconstrictors, namely the increase in systolic blood pressure, increased heart rate, increased myocardial oxygen consumption, and decreased diastolic blood pressure.1,3 When the patient’s myocardial oxygen supply cannot meet their myocardial oxygen demand they are at heightened risk for cardiac arrhythmias, myocardial ischemia, and myocardial infarction.2 The literature describes a case report in which a 58-year-old man was administered five cartridges of 2% lidocaine with 1:50,000 epinephrine (0.180 mg of epinephrine) with symptomatic angina and a history of two myocardial infarctions suffered a fatality.1
Another common misconception is to assume that levonordefrin is a “safer” choice than epinephrine when treating patients with a significant history of one of the aforementioned comorbidities. Levonordefrin has a stronger affinity for alpha-receptors; its alpha-receptor affinity is 75% and its beta-receptor affinity, 25%. Epinephrine’s affinity for alpha and beta-receptors is more equal. β-1 receptor agonism produces increases in heart rate and contractility; this may feel like palpitations or a racing heartbeat. With epinephrine, there is alpha, β-1, and β-2 activation, so while patients may experience palpitations, they also have the compensatory vasodilation mediated by the β-2 receptors.2 Patients report less palpitations with levonordefrin, because there is more alpha-receptor activation. The alpha agonism increases vasoconstriction and peripheral vascular resistance. This increase in afterload may actually be more hazardous to the myocardium.1,2
One should avoid administering a vasoconstrictor and reschedule elective non-urgent dental treatment if cocaine has been ingested.1,4 Cocaine prevents dopamine and norepinephrine reuptake and sensitizes the effects of alpha and beta receptors to catecholamines. Together with a vasoconstrictor, this drug interaction can lead to hypertension, arrhythmia, and death.1,5
Dose reductions of vasoconstrictor are advisable in patients on certain antidepressants. Tricyclic antidepressants (TCAs) are of concern because they inhibit the reuptake of serotonin and catecholamines such as norepinephrine, epinephrine, and levonordefrin. Selective serotonin reuptake inhibitors (SSRIs) do not interfere with the reuptake of norepinephrine, epinephrine, and levonordefrin. Therefore, SSRIs do not warrant a dose reduction.1
Monoamine oxidase inhibitors (MAOIs) are another type of antidepressant but do not warrant a dose reduction when epinephrine or levonordefrin is the vasoconstrictor. MAOIs inhibit the metabolism of epinephrine, norepinephrine, serotonin, and dopamine. However, catecholamines such as epinephrine, levonordefrin, and norepinephrine are primarily metabolized by catechol-O-methyltransferase (COMT). The risk of a drug interaction with sympathomimetic drugs with a noncatecholamine structure, such as ephedrine, is a greater concern.1 Additionally, patients with Parkinson’s disease on COMT inhibitors may be at risk for accumulation of epinephrine or levonordefrin, so a dose reduction may be warranted.13
Beta blockers are often used to treat angina, cardiac arrhythmias, and hypertension.1,5 Nonspecific beta blockers are of concern because they block both β-1 and β-2 receptors, allowing for unopposed alpha stimulation.1,3,4 Alpha stimulation results in vasoconstriction and increased blood pressure and reflex bradycardia. The β-2 receptor is blocked, prohibiting dilation of larger systemic arteries that supply skeletal muscle, hepatic arteries, and coronary vessels and the reduction.1 Nonselective beta blockers include propranolol, nadolol, timolol, pindolol, sotalol, and oxprenolol.3 Selective beta blockers, which only block the β-1 receptor, do not have this drug interaction.
Digoxin is used in patients with congestive heart failure and chronic atrial fibrillation. Side effects include increased cardiac excitability. It is advisable to use vasoconstrictor cautiously as there is a risk of arrhythmias with this drug interaction.4,14
Misconceptions Regarding Vasoconstrictor in Local Dental Anesthetic
These myths, as described previously, are all false:
Misconception #1: “Mepivacaine plain is better to reduce the duration of anesthesia and risk of lip chewing, especially in pediatric patients.”
Misconception #2: “Local dental anesthetic is injected submucosally, so there is no hemodynamic or cardiovascular effect.”
Misconception #3: “The use of a vasoconstrictor will always prevent local anesthetic overdose.”
Misconception #4: “There is so little epinephrine in the cartridge, the body releases more during surgery and so no dose reduction is ever warranted.”
Misconception #5: “ Levonordefrin is safer in cardiac patients; they do not feel any palpitations so it must be safer than epinephrine.”
Vasoconstrictor Dosing Recommendations
While there are no absolute dosing regimens for patients with the previously mentioned comorbidities or potential drug–drug interactions, there are some well-recognized recommendations in the literature. The most common recommendation is to keep the total epinephrine dose under 0.04 mg, which is approximately one cartridge of 1:50,000, two cartridges of 1:100,000, or four cartridges of 1:200,000 (Table).1,3 As discussed previously, levonordefrin is more alpha-selective and may have more adverse cardiovascular effects than epinephrine, so this discussion will only discuss the dosing restrictions with epinephrine.
There are some important considerations for determining the appropriate dose for a patient. First, one should consider the patient’s health history. The health history should be reviewed and updated at every visit to the dental office and baseline vital signs, such as heart rate and blood pressure, should be obtained at every visit. It may be advisable to avoid vasoconstrictor if the patient has active cardiac conditions, such as unstable angina or decompensated congestive heart failure. These are patients with uncontrolled episodes of chest pain or those who cannot lay down fully supine without difficulty breathing or patients who report that they cannot walk two blocks or a single flight of stairs without difficulty. Patients with better controlled comorbidities, such as stable angina, controlled congestive heart failure, and those able to walk up a flight of stairs with no restrictions may tolerate the 0.04 mg of epinephrine.1,2
The timing of local anesthetic administration is also an important consideration. After injection, epinephrine reaches peak levels within 5 to 10 minutes and hemodynamic effects have dissipated within 10 to 15 minutes.4 One may cautiously inject the local anesthetic using the aspirating technique to avoid inadvertent intravascular injection, limiting epinephrine to 0.04 mg. It is also advisable to avoid intraosseous and periodontal ligament injection techniques as they will have more rapid systemic uptake of vasoconstrictor.2 Additionally, systemic effects such as an increase in blood pressure and heart rate have been studied with epinephrine impregnated retraction cord. It has also been demonstrated that epinephrine impregnated retraction cord is no more efficacious in gingival retraction than other types of retraction cord. Therefore, epinephrine impregnated cord should be avoided.15,16 It would be prudent to check vital signs, heart rate, and blood pressure every 5 minutes to monitor for any adverse hemodynamic responses to the epinephrine. There are many commercially available automated noninvasive blood pressure monitors that can measure blood pressure and heart rate with minimal interruption to the dental appointment. One can determine if the patient is tolerating epinephrine well based on acceptable vital signs and the lack of any clinical symptoms, such as palpitations. For lengthier appointments, it would be rational to wait until one quadrant is completed to then anesthetize the next quadrant. This may minimally disrupt workflow as it will take several minutes for the patient to become numb in the next quadrant, but delaying administration of local anesthetic will allow for some time to elapse for the first dose of local anesthetic and vasoconstrictor to be metabolized before injecting subsequent doses. If the patient can only tolerate smaller doses of epinephrine, one can break the treatment up into shorter appointments. Local measures to ensure hemostasis should be taken in such patients to avoid excessive administration of vasoconstrictor.
Vasoconstrictors such as epinephrine and levonordefrin have a very important role in dental local anesthetic. By mediating vasoconstriction at the site of injection, they allow for prolonged duration and enhanced depth of local anesthesia in addition to providing hemostasis. There are some circumstances, however, that warrant avoidance or reduction in vasoconstrictor dosing, such as cardiac comorbidities and certain drug–drug interactions. This article aims to debunk misconceptions associated with vasoconstrictor use in local anesthetics and to provide a rational framework for dose reduction.
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