Epinephrine in Local Anesthetic Agents

The use of local anesthetic agents is standard practice in dentistry. Some of the LA formulations in delivery systems intended for use in oral healthcare settings (i.e., cartridges) include epinephrine or levonordefrin for vasoconstriction.18-20 These adjuvants decrease the rate of LAs’ systemic absorption; prolong LAs’ duration of action; reduce the risk of LAs’ systemic toxicity; and with infiltration anesthesia, they may reduce bleeding in the operative field.18-20

The 2016 change in labeling standards mandated by the FDA for all single-entity epinephrine formulations does not apply to multiple-entity formulations containing epinephrine. However, to minimize medication errors, it may be prudent to think of dosage strengths of epinephrine in LAs in mg/mL rather than ratio expressions (e.g., 1:100,000) as well.4 It is of note that mepivacaine and prilocaine have no intrinsic vasodilating effect and are available without a vasoconstrictor.18

LAs available with vasoconstrictors (Table 3) include 2% lidocaine w/epinephrine 1:100,000 (i.e., 0.01 mg/mL) and w/epinephrine 1:50,000 (i.e., 0.02 mg/mL); 4% prilocaine w/epinephrine 1:200,000 (i.e., 0.005 mg/mL); 4% articaine w/epinephrine 1:100,000 (i.e., 0.01 mg/mL) and w/epinephrine 1:200,000 (i.e., 0.005 mg/mL); 0.5% bupivacaine w/epinephrine 1:200,000 (i.e., 0.005 mg/mL), and 2% mepivacaine w/levonordefrin 1:20,000 (i.e., 0.05 mg/mL).3,18-20

Table 3. Dosage strengths of local anesthetic agents in mg/mL of LA and epinephrine in mg/mL in LA and maximum safe doses in mL of LA.3
LA FormulationsMRD of LA in mgLA in mg/mL500 mg of LA in mL of LAMRD of EPI in mgEPI in mg/mL0.2 mg of EPI in mL of LA
Lidocaine 2%w/ epinephrine 1:100,00050020250.20.0120*
w/epinephrine 1:50,00050020250.20.0210*
Mepivacaine 2%w/levonordefrin 1:20,0004002020*1.00.0520*
Prilocaine 4%w/epinephrine 1:200,0006004015*0.20.00540
Articaine 4%w/epinephrine 1:100,0005004012.5*0.20.0120
w/epinephrine 1:200,0005004012.5*0.20/00540
Bupivacaine 0.5%w/epinephrine 1:200,00090518*0.20.00540
*Maximum safe dose of LAs in mL per visit predicated on the MRD of LA or MRD of epinephrine (levonordefrine).

Levonordefrin is a derivative of norepinephrine.21 It activates peripheral α2-adrenoceptors in vascular smooth muscles and produces vasoconstriction. It also activates α2-adrenoceptors in the cardiovascular control center of the CNS, suppresses sympathetic output from the brain and lowers BP. Levonordefrin, 0.05 mg, is bioequivalent to epinephrine, 0.01 mg. Levonordefrin is less likely than epinephrine to cause cardiac arrhythmias but it may cause reflex bradycardia.

In general, the maximum recommended dose (MRD) of epinephrine in LA formulations for healthy adults is 0.2 mg per visit.18 Based on this recommendation, the maximum safe dose of 2% lidocaine w/epinephrine 1:100,000 (0.01 mg/mL) is 20 mL and w/epinephrine 1:50,000 (0.02 mg/mL) it is 10 mL. Consequently, with these LA formulations, the MRD of epinephrine (0.2 mg) is reached before the MRD of 2% lidocaine, which is 500 mg or 25 mL of LA (Table  3).3

Mepivacaine 2% is available w/levonordefrin 1:20,000 (0.05 mg/mL). Levonordefrin, 0.05 mg, is bioequivalent to epinephrine, 0.01 mg; consequently, the MRD of levonordefrin is 1 mg. Based on this recommendation, the maximum safe dose of 2% mepivacaine w/levonordefrin 1:20,000 (0.05 mg/mL) is 20 mL. With 2% mepivacaine formulation, the MRD of levonordefrin (1 mg) and the MRD of mepivacaine (400 mg) are both reached with 20mL of LA (Table 3).

Prilocaine 4% is available w/epinephrine 1:200,000. The MRD of epinephrine (0.2 gm) is reached with 40 mL of LA, but based on the MRD of prilocaine (600 mg), the safe dose of 4% prilocaine is 15 mL (Table 3). Articaine 4% is available w/epinephrine 1:100,000 and 1:200,000. The MRD of epinephrine is reached with 20 mL and 40 mL of LA, respectively; however, based on the MRD of articaine (500 mg), the safe dose of 4% articaine is 12.5 mL (Table 3).

Epinephrine has a relatively narrow therapeutic window. Common adverse effects may occur even with the administration of recommended therapeutic doses and include restlessness, agitation, anxiety, tremulousness, headache, dizziness, pallor, palpitation, and tachycardia.3,17-20 In patients with Parkinson’s disease it may increase tremor and rigidity. Since epinephrine does not cross the blood-brain barrier, these ADRs are the result of peripheral effects.

Particularly vulnerable populations to the effects of therapeutic doses of epinephrine include the young and the old; those with high BP, severe cardiovascular disease (i.e., unstable angina pectoris, recent myocardial infarction (MI), decompensated heart failure, severe valvular disease, supraventricular arrhythmias with uncontrolled ventricular rate, and symptomatic ventricular arrhythmias); patients with uncontrolled hyperthyroidism; and those taking certain drugs.3,17-20

Epinephrine should be used with caution in patients on other sympathomimetic agents because of additivity.4,17-22 Epinephrine should be used with caution in patients on nonselective β-adrenoceptor antagonists, which block β2-adrenoceptor-mediated vasodilation resulting in unopposed α-adrenoceptor-induced vasoconstriction and high BP.4,17-22 Epinephrine should be avoided in patients on cocaine, it inhibits the reuptake of epinephrine increasing HR and BP.22

Epinephrine should be used with caution in patients under the influence of general anesthetics (e.g., halothane and cyclopropane) that sensitize the myocardium to epinephrine causing ventricular arrhythmias (premature ventricular contractions, tachycardia, or fibrillation).4,19-22 Levonordefrin should be avoided in patients on tricyclic antidepressants (e.g., amitriptyline) that inhibit the reuptake of norepinephrine increasing HR.4,19-22

Epinephrine should be used with caution in patients with supraphysiological thyroid levels (i.e., thyroid overdose or hyperthyroidism) that upregulate β-adrenoceptors in vascular smooth muscles sensitizing the myocardium to β-adrenergic effects of epinephrine increasing HR and BP.4,22 Caution is also recommended when patients are on digoxin and diuretics, which may increase cardiosensitivity and potentiate the arrhythmogenic effects of epinephrine, respectively.4

In high-risk populations, the therapeutic benefits of epinephrine must outweigh possible risks and a lower maximum dose of 0.02 to 0.05 mg is recommended.18 Since the main physiologic stimulus to epinephrine secretion is exercise, to establish the safe dose of epinephrine determine the patient’s functional capacity.23 Functional capacity (FC) reflects a person’s functional reserve to meet physiological demand for oxygen and is expressed in metabolic equivalents (METs).

One MET is defined as the FC required of a 70-kg, 40-year-old man at rest, sitting quietly in a chair, to meet metabolic demand for oxygen. Work at 1 MET requires a capacity to deliver 3.5 mL of O2/kg/min.24 Work at 2 METs requires twice the resting capacity, the individual must meet metabolic demand for 7 mL of O2/kg/min, work at 3 METs requires three times the resting capacity, the individual must meet metabolic demand for 10.5 mL of O2/kg/min, etc.

FC is reflected in a person’s ability to participate in and complete common daily activities (Box 1).24-27 FC is poor if the patient cannot perform to completion activities requiring ≥2 METs. FC is moderate is the patient can perform to completion activities requiting ≥2 METs but <5 METs. FC is good if the patient can perform to completion activities requiting ≥5 METs but <7 METs. FC is excellent if the patient can perform to completion activities requiting >7 METs.

Box 1. Estimated Energy Requirement for a Spectrum of Common Daily Activities.24-27

<4 METs
  Can you…
  • Take care of yourself?
  • Eat, get dressed, or use the toilet?
  • Walk indoor around the house?
  • Walk 100 m on level ground at 3 to 5 km per hour
≥4 METs

>10 METs
  Can you…
  • Climb two flights of stairs or walk uphill, or run a short distance?
  • Do heavy work around the house like scrubbing floors or lifting or moving heavy furniture?
  • Participate in strenuous sports like swimming, singles tennis, football, basketball, or skiing?

A FC of <4 METs is indicative of increased perioperative and long-term cardiac risk.23 Other clues indicative of increased cardiac risk include the physical findings of tremor, anxiety, cyanosis, pallor, diaphoresis, dyspnea, tightness and/or pain in the chest with minimal activity, and peripheral edema.1 Critically, the HR (normal: 60 to 100 beats per minute - bpm) and BP (normal: <120/80 mm Hg) of the patient must also be determined as part of risk assessment.1

The hemodynamic effects (determined by echocardiography) of infiltration anesthesia with 0.045 mg of epinephrine (i.e., 4.5 mL of 2% lidocaine w/epinephrine 1:100,000) in normotensive and hypertensive patients was reported to be less than those produced by ergometric stress testing at 4 METs.28 Consequently, from a mean resting (supine) metabolic state, 0.045 mg of epinephrine produces an approximate 4-fold transient increase in mean plasma epinephrine concentration.

Based on other studies conducted in oral healthcare settings, investigators reported mean resting (supine) plasma epinephrine concentrations of 27±4 pg/mL (n=11, mean age 24±3 years) and 28±8 pg/mL (n=14, mean age 33±4 years).11,12 These mean resting (supine) plasma epinephrine concentrations compare favorably to 34±18 pg/mL (n=60) reported by other investigators, and overlap the lower half of the reported mean resting (supine) range of <10-70 pg/mL.29,30

In one study, a randomized double-blind crossover design, nerve block anesthesia was obtained either with 1.8 mL of 2% lidocaine without epinephrine or w/epinephrine 1:100,000 (0.018 mg) in normotensive patients.11 To determine patient-response to nerve blocks, heart rate (HR), mean arterial pressure (MAP), plasma epinephrine and norepinephrine concentrations were quantified at two baselines (-30 and -20 minutes) and at 1, 2, 4, 8, 16, 30, and 60 minutes post-injection.

Lidocaine alone did not alter plasma catecholamine levels, HR, or MAP over the study period. Lidocaine with 0.018 mg of epinephrine resulted in ≈3.5-fold transient elevation of mean plasma epinephrine values from 27±4 pg/mL (baseline) to peak plasma levels of 94±13 pg/mL at 8 minutes post-injection. HR increased by a few beats, but MAP and norepinephrine values were unaffected. Clearly, the transient rise in epinephrine levels was due to the epinephrine in the LA.

In the other study, nerve block anesthesia with 1.8 mL of 2% lidocaine w/epinephrine 1:100,000 (0.018 mg) was obtained in normotensive patients requiring class II amalgam restoration of posterior teeth.12 HR, MAP, and plasma epinephrine and norepinephrine concentrations were determined at 11 time-points, including two baselines (-30 and -20 minutes), 5 and 10 minutes post-injection, and 10 minutes post-treatment during procedures lasting 62±4 minutes.

Lidocaine with 0.018 mg of epinephrine resulted in a transient ≈3.5-fold elevation of mean plasma epinephrine concentration from 28±8 pg/mL (baseline) to peak plasma levels of 105±28 pg/mL at 10 minutes post-injection. HR increased by 3-4 bpm at 5 and 10 minutes post-injection. MAP and mean plasma norepinephrine concentrations were unaffected. Once again, the transient rise in epinephrine levels was due to the epinephrine in the LA and not procedure-related.

The hemodynamic effects of 5.4 mL of 2% lidocaine w/epinephrine 1:100:000 (i.e., 0.054 mg) were evaluated in 21 patients undergoing third molar extractions.13 Mean plasma epinephrine concentration (semi-supine) rose 5-fold from 60±41 pg/mL (pre-operative baseline) to peak plasma levels of 269±140 pg/mL 5 minutes post-injection with increases in HR (64±8 to 80±20 bpm), systolic BP (114±15 to 130±25 mm Hg), and cardiac output (6.0±1.6 to 8.2±2.2 L/min).

It is instructive to note that mean plasma epinephrine concentrations were also reported to increase from mean resting (supine) values of 34±18 pg/mL nearly 2-fold (≈50 pg/mL) during quite standing; nearly 3-fold during cigarette smoking (≈100 pg/mL); and from 2 to 13-fold during mild to heavy exercise (≈75 to 425 pg/mL); and nearly 7-fold to peak plasma levels of 230 pg/mL in response to a decrement in plasma glucose levels from 95 to 60 mg/mL.29,30

Note as well that threshold epinephrine values for hemodynamic and metabolic effects begin at or are slightly above normal values (range: (<10 to 70 pg/mL).29,30 Based on graded infusion studies, plasma epinephrine threshold for increments in HR is 50-100 pg/mL, i.e., chronotropic effects occur at only 2 to 3-fold basal levels; and plasma epinephrine threshold for increments in systolic BP is 75-125 pg/mL and for decrements in diastolic BP it is 150-200 pg/mL.29,30

Data from graded infusion studies also showed that as mean plasma epinephrine values rose from 24 to 1,020 pg/mL, baseline HR rose by nearly 30 bpm, systolic BP rose by slightly more than 20 mm Hg, and diastolic BP decreased by about 20 mm Hg. Transient mean plasma epinephrine concentration of 1,024 pg/mL would require administering ≈0.17 to 0.21 mg of epinephrine (MRD in healthy adults: 0.2 mg) or ≈17 to 21 mL of LA w/epinephrine 1:100,000.11-13

Note that, in general, ADRs with therapeutic doses of epinephrine subside rapidly with rest and recumbency. Not only does epinephrine have a short half-life (≈2 minutes), it accelerates its own metabolic clearance.29,30 The reported mean plasma metabolic clearance rate of epinephrine in young men at steady-state plasma concentrations between 24-74 pg/mL is 52±4 mL/kg/min; at steady-state values between 90-1020 pg/mL it is 89±6 mL/kg/min (a 79% increase in clearance).

Epinephrine appears to regulate its metabolic clearance through β-adrenergic mechanisms. In normal subject, propranolol, a β-adrenoceptor blocking agent, reduced the stimulated clearance rate of epinephrine by more than 75%, i.e., to more than 50% below the basal clearance rate.29,30 The reduction in epinephrine clearance appears to be due to vasoconstriction and decreased delivery of epinephrine to the liver and other tissues critical in epinephrine clearance.29,30

Rarely, overdosage with epinephrine in oral healthcare settings may result from intravascular injection; administration of supratherapeutic doses, especially to high-risk patients; concomitant therapy with other drugs, which may potentiate adverse sympathetic effects; and additivity of epinephrine administered with the LA and endogenous epinephrine released in response to surgical stress, i.e., procedure-related stress mediated by the sympathoadrenal system.

The magnitude of surgical stress depends on the extent of procedure-related tissue trauma, duration of the procedure, volume of blood loss, fluid shifts in the body, and changes in core body temperature.31 For example, the mean plasma epinephrine concentration rose nearly 7-fold from baseline during elective cholecystectomy to >200 pg/mL.29 Plasma epinephrine at these levels can precipitate tachycardia, hypertension, and increase myocardial oxygen demand.

Surgical stress can also cause alterations in the balance between prothrombotic and fibrinolytic factors, resulting in hypercoagulability and possible coronary thrombosis (elevation of fibrinogen and other coagulation factors, increased platelet activation and aggregation, and reduced fibrinolysis).31 The extent of these responses is also proportional to the degree and duration of procedure-related surgical stress and contribute to myocardial ischemia and heart failure.

Cardiac risk, defined as myocardial infarction or cardiac death within 30 days of non-cardiac procedures, has been assessed.32 It was concluded that non-cardiac procedures may be associated with high, intermediate, or low cardiac-risk. Breast surgery, eye surgery, and dental procedures under local anesthesia were identified as low cardiac-risk procedures, i.e., the risk of a cardiac event is negligible unless, as noted earlier, strong patient-specific risk factors are present.32

Data from clinical trials that define perioperative cardiac risk for various dental procedures is limited.11-13 However, based on evidence from a retrospective analysis of EMS data in Seattle and King Counties, WA, with a combined population 1.5 million, over a seven year period only six major cardiac events (i.e., nonfatal MI, heart failure, or sudden cardiac death) were confirmed in community-based dental practices (<0.002/practice/year).33

Low cardiac-risk with dental procedures is further supported by data from two independent prospective surveys.34 Over a 10-year period, 4,309 dentists documented 30,602 medical emergencies, i.e., 0.5 emergencies per practice (not dentist) per year. Cardiovascular events included postural hypotension (17.8%), angina pectoris (4.6%), MI (1.4%), and cardiac arrest (1.1%) at an annual rate of 0.08, 0.02, 0.007, and 0.005 per dental practice per year, respectively.

The minimum lethal dose of epinephrine, based on data for subcutaneous injection, is estimated to be 4 mg.35 Autopsy findings in patients who died of epinephrine overdosage include evidence of circulatory collapse and congestion of most organs with blood (e.g. pulmonary edema).19 The treatment of acute epinephrine toxicity is mainly supportive - Call 911. While waiting for EMS, prepare to begin CPR and automated external defibrillation.