September 1998 JOURNAL OF THE CALIFORNIA DENTAL ASSOCIATION
Feature Story
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Vasoconstrictors and the Heart

Thomas J. Pallasch, DDS, MS
Copyright 1998 Journal of the California Dental Association

The use of vasoconstrictors in local anesthetics, as topical hemostatic agents, and in gingival retraction cord, remains controversial although data exists from which to formulate reasonable guidelines. The value of such vasoconstrictors to increase local anesthetic efficacy and reduce systemic uptake is unquestioned. Elevated blood levels of epinephrine can occur with their use but do not generally appear to be associated with any significant cardiovascular effects in healthy patients or those with mild to moderate heart disease. Reduced dosages or local anesthetics without vasoconstrictors are indicated for patients with more significant disease and epinephrine-impregnated retraction cord should be used cautiously or avoided in certain situations. Endogenous epinephrine released in dental treatment-associated stress may also reach significant blood levels and make it difficult to determine causation of cardiovascular adverse events. The safely record of dental local anesthetics and their vasoconstrictors has been impressive and will remain so with continued judicious use of these agents.

Anyone in dental practice long enough has probably heard the admonition from a physician: "Don't use adrenalin in this patient." Such advice is based upon certain misconceptions that:

  • The vasoconstrictor content (dosage) of dental local anesthetics is comparable to those used for anaphylactic, asthmatic, or cardiac emergencies;
  • The resulting loss of anesthetic efficacy is without clinical consequences (the adrenal release of catecholamines seen with inadequate anesthesia is without harm); and
  • No guidelines have been established for the safe use of vasoconstrictors in dental local anesthetic solutions in medically compromised patients.

Consequently, the dental health professional is placed in the difficult position of either following inappropriate advice or disregarding it and using the his or her best clinical judgment.

Vasoconstrictors in Local Anesthetics

It is generally accepted that the good achieved by the inclusion of vasoconstrictors in dental local anesthetics greatly outweighs any potential deleterious effects of these agents. Their ability to retard anesthetic absorption, thereby both decreasing local anesthetic systemic toxicity and prolonging and increasing its activity at the site of deposition, is the rationale for their use. Additionally, local control of bleeding can be very advantageous. That the vasoconstrictor can be absorbed into the systemic blood circulation and at times produce significant plasma levels is well-established, but there are conflicting opinions on the potential consequences. The use of racemic epinephrine gingival retraction cord is of concern and contention. The adrenal release of epinephrine and norepinephrine can also be a significant and sometimes overlooked factor in any adverse cardiovascular effects.

Local anesthetics and their vasoconstrictors are remarkably safe as employed in dentistry. From 1943 to 1952, local anesthetics were responsible for 0.43 percent of all anesthetic deaths in New York City,1 possibly three deaths in 700 million dental injections in Britain from 1970 to 1979 (70 million cartridges/year),2 and 1 death in 490,000 to 1.85 million injections in oral surgery and 1 in 36 million general practitioner-administered local anesthetics.3

Many efforts have been made to determine the potential or actual adverse effects associated with vasoconstrictors in such local anesthetics. Several studies have indicated that under certain conditions the blood levels of epinephrine may attain concentrations of four to 27 times their baseline (pre-injection) level,4-7 but the majority of studies indicate that these elevated levels of epinephrine associated with dental treatment usually result in only minor to moderate changes in cardiovascular parameters (heart rate, blood pressure, stroke volume).4-11

Electrocardiographic changes may also occur in both healthy and cardiovascularly impaired patients both during local anesthetic administration and the dental procedure itself.8,12,13 These may entail slight ST segment (myocardial ischemic) depression usually not considered clinically significant.8,12,13,14 Such electrocardiogram changes may occur with local anesthetics administered without vasoconstrictors15 and can be present more often before than after vasoconstrictor use.14 Forty patients having had a recent myocardial infarction (average 12 days previously) underwent dental anesthesia (one cartridge of 1:100,000 solution) with no significant changes in blood pressure, heart rate or the electrocardiogram.16 Levonordefrin appears to produce norepinephrine-like effects of increased peripheral resistance and mean pressure and reduced heart rate and cardiac output.3

Epinephrine -- through its combined alpha- and beta-adrenergic agonist effects -- usually increases heart rate, stroke volume, systolic blood pressure, myocardial oxygen consumption, and cardiac automaticity, but reduces diastolic blood pressure. There is a certain threshold of increased blood epinephrine necessary to induce these changes: heart rate (50-100 pg/ml), systolic blood pressure (75-150 pg/ml) and diastolic pressure (150-200 pg/ml)16 which translates to 1, 2, and 4 cartridges of lidocaine with 1:100,000 epinephrine respectively.3 This data has been derived from a study of only six healthy patients,17 a number that may be too small to account for the significant variation in response to epinephrine seen clinically particularly with higher doses.4-11 It is hypothesized that some patients may be "hypersensitive" to epinephrine, particularly those already highly anxious;3,18 but there is no data to support this contention. Normal dose-response variations should be expected as with any other drug.

The hemodynamic alterations seen with elevated plasma epinephrine are usually quite short in duration,3,6,19 probably because of the very short plasma half-life of epinephrine (usually less that one minute).20,21 Epinephrine is largely eliminated from the blood in 10 minutes20,21 or less2 due to its metabolism by catechol-O-methyl transferase in the blood, liver, lungs, and other tissues.22

Epinephrine in local anesthetics is often required to control local bleeding. Twice the blood loss in periodontal surgery occurs when concentrations of 1:100,000 are used as opposed to 1:50,000.23 Concentrations of 1:100,000 may usually prove to be adequate.24 Epinephrine-induced surgical vasoconstriction may lead to delayed wound healing and significant "rebound" postoperative bleeding.25,26

Three official statements have been formulated by various bodies regarding the use of vasoconstrictors in dental local anesthetics. In 1986 and again in 1991, the American Heart Association27 stated that "if vasoconstrictors are necessary, care should be taken to use the smallest effective dose. Vasoconstrictor agents should be used in local anesthetic solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection." In 1964, the American Heart Association and the American Dental Association28 made this joint statement: "The typical concentration of vasoconstrictors contained in local anesthetics are not contraindicated with cardiovascular disease so long as preliminary aspiration is practiced, the agent is injected slowly, and the smallest effective dose is administered." In 1955, the New York Heart Association29 provided the following: "Under these conditions and with these precautions, the use of epinephrine with procaine for dental surgery presents no special hazards in persons with heart disease. We would recommend for any one session that there be used no more than 10.0 cc of 1:50,000 epinephrine -- no more than 0.2 mgm of epinephrine in any form." The conditions of concern to the New York Heart Association were that the dentist should have information from the physician about the nature and severity of the heart disease in the patient and knowledge of medications the patient is receiving, particularly such medication as might increase the activity of epinephrine. These recommendations remain generally reasonable; and many dentists today are sophisticated enough to assess mild to moderate cardiovascular disease without physician consultation, although such may be indicated in more advanced forms of the disease.

Table 1.

American Society of Anesthesiologists Physical Status Classifications (as adapted from Malamed 24).
I:   Normal healthy individual

II:  Patient with mild to moderate systemic disease

III:  Patient with severe systemic disease that limits activity but is not incapacitating

IV:  Patient with severe systemic disease that limits activity and is a constant threat to life

V:  Moribund patient not expected to survive 24 hours or without an operation
There are no absolute contraindications (never used under any circumstances) to the use of vasoconstrictors in dental local anesthetics as epinephrine is an endogenous neurotransmitter. However, severely ill patients (ASA Class IV or V) may be at too great a risk for elective dental care or require hospitalization for treatment (Table 1).24 It appears reasonable if possible to restrict the amount of epinephrine to 0.04 mg/appointment (Table 2) in patients with unstable (preinfarction, Crescendo) angina, daily anginal episodes, recent (in the past three to six months) myocardial infarction or coronary bypass, hyperthyroidism (thyrotoxicosis), uncontrolled cardiac arrhythmias and/or severe essential hypertension and congestive heart failure.3,18,24 Also, the total dose should be restricted, if possible, to 0.04 to 0.05 mg in patients taking tricyclic antidepressants or nonselective beta-adrenergic blocking drugs.3,24 It has been suggested30,31 that the above conditions are absolute contraindications to the use of vasoconstrictors without any advice as to how then to manage such patients. Local anesthetics without vasoconstrictors may not provide adequate anesthesia resulting in significant adrenal release of endogenous epinephrine, are without hemostatic efficacy, and could necessitate hospitalization for dental treatment with all the attendant risks. Local anesthetics with vasoconstrictors are generally safe in the presence of cardiovascular disease24,32 and the optimal concentration of the vasoconstrictor will depend on the type of anesthetic agent, the duration required, the site of injection and vascularity, and the requirements for local hemostasis.33 Local anesthetics without epinephrine (3 percent mepivacaine and 4 percent prilocaine) can prove advantageous in patients with relative vasoconstrictor contraindications.32

Table 2.
Vasoconstrictor Concentrations and Maximum Dosages (as adapted from Malamed(24) and Felpel (31).
Epinephrine
Normal Healthy Adult
Concentration Micrograms/Cartridge(2) Maximum Dose Number of Cartridges
1:200,000 9 0.2 mg 22 (40 ml)3
1:100,000 18 0.2 mg 11 (20 ml)3
1:50,000 36 0.2 mg 5 (10 ml)
Significant Cardiovascular Disease (ASA III or IV)
1:200,000 9 0.04 mg 4 (8 ml)
1:100,000 18 0.04 mg 2 (4 ml)
1:50,000 36 0.04 mg 1 (2 ml)
1.   The dosage for levonordefrin is 90 micrograms/cartridge, 1.0 mg maximum dose or 11 cartridges maximum in the healthy patient, which exceeds the maximum allowable local anesthetic dose.
2.  Each cartridge contains 1.8 ml.
3.  Exceeds the maximum allowable local anesthetic dose.
4.  Measurement Conversions:

1 milligram (mg) =0.001 gram = 10(-3) gram

1 microgram (ug) = 0.000001 gram (0.001 milligram) = 10(-6)

1 nanogram (ng) = 0.000000001 gram (0.001 microgram) = 10(-9) gram

1 picogram (pg) = 0.000000000001 gram (0.001 nanogram) = 10(-12) gram

Three groups of drugs have been potentially implicated in drug interactions with local anesthetic vasoconstrictors: phenothiazine and other neuroleptic antipsychotics, antidepressants (tricyclics, monoamine oxidase inhibitors), and beta-adrenergic blocking drugs (Table 3). Two others (selective serotonin reuptake inhibitors, cocaine) also merit discussion.

Since the phenothiazines and related antipsychotics possess alpha-adrenergic blocking activity, the potential exists for a combined alpha and beta agonist like epinephrine to interact with the unopposed beta receptor resulting in hypotension and reflex tachycardia. It does not appear that such an interaction has ever occurred clinically in dentistry.34,35

The antidepressant monoamine oxidase inhibitors primarily affect monoamine oxidase A that regulates the norepinephrine available for neuronal release in the sympathetic nervous system. Epinephrine is only a substrate for monoamine oxidase A after it is metabolized by catechol-O-methyl transferase. It does not release norepinephrine (as do indirect and mixed-acting adrenergics) and monoamine oxidase inhibitor-induced adrenergic activity may result in down regulation of the postjunctional adrenergic receptor. For these reasons, epinephrine may be safely employed in patients taking the monoamine oxidase inhibitors.34,36

It may be prudent in patients taking the tricyclic antidepressants to restrict the epinephrine dose to 0.05 mg or 5.4 ml of a 1:100,000 solution,34 although such an interaction may only occur at large doses if at all.37 There may not be a recorded clinical case of such an interaction.38 Currently, there are no drug interactions between epinephrine and the selective serotonin reuptake inhibitors;39,40 and there is no data regarding the miscellaneous antidepressants in Table 3.

Table 3.
Antidepressants and Beta-Adrenergic Blocking Drugs

Antidepressants Beta-Adrenergic Blocking Drugs
Tricyclic Antidepressants

    amitriptyline (Elavil)
    amoxapine (Asendin)
    clomipramine (Norpramin)
    doxepin (Sinequan)
    imipramine (Tofranil)
    nortriptyline (Aventyl, Pamelor)
    protriptyline (Vivactil)
    trimipramine (Surmontil)
Cardioselective

    acetutolol (Sectral)
    atenolol (Tenormin)
    betaxolol (Kerlone)
    bisoprolol (Zebeta)
    esmolol (Brevibloc)
    metoprolol (Lopressor)
Miscellaneous Antidepressants

    buprion (Wellbutrin)
    maprotiline (Ludiomil)
    mirtazapine (Remeron)
    nefazodone (Serzone)
    trazodone (Desyrel)
    venlafaxine (Effexor)
Noncardioselective

    carteolol (Cartol)
    carvedilol (Coreg)
    labetolol (Normodyne, Trandate)
    nadolol (Corgard)
    penbutolol (Levatol)
    pindolol (Visken)
    propranolol (Inderal)
    sotalol (Betapace)
    timolol (Blocarden)
Monoamine Oxidase Inhibitors

    phenelzine (Nardil)
    tranylcypromine (Parnate)
Alpha/Beta Adrenergic Blocking

    carvedilol (Coreg)
    labetolol (Normodyne, Trandate)
Selective Serotonin Reuptake Inhibitors

    fluoxetine (Prozac)
    fluvoxamine (Luvox)
    paroxetine (Paxil)
    sertraline (Zoloft)

Nonselective beta-adrenergic blocking drugs inhibit both the beta1 (cardiac) and beta2 (peripheral) adrenergic receptors, while the cardioselective beta-blockers inhibit only the beta1 receptors. Epinephrine administered to a patient taking a nonselective beta-blocker may result in hypertension and reflex bradycardia due to epinephrine interaction with the unopposed alpha-adrenergic receptor.41-43 In such patients, epinephrine is relatively contraindicated (reduced dosage); no reports have appeared of any such drug interaction in patients taking the cardioselective beta-blockers.41 Hypertension has been seen with the combination of propranolol and levonordefrin.44 There is probably no significant epinephrine drug interaction with the alpha/beta adrenergic blockers.

Sudden cardiac death associated with cocaine is well-documented.45,46 Some of these deaths occurred six hours or longer after acute cocaine ingestion, and it is possible that cocaine metabolites persisting for 48 hours after ingestion may have been responsible.47 Cocaine affects the cardiovascular system primarily by blocking the neuronal reuptake of norepinephrine and dopamine, by neuronal release of catecholamines, direct vasoconstriction, and local anesthetic effects.47 The cardiovascular effects of cocaine are complex and conflicting: adrenergic stimulation, increased heart rate, increased or decreased cardiac contractility, and slowed cardiac impulse conduction.47 Other effects include arrhythmias, myocarditis, cardiomyopathy, cardiac contraction band necrosis, platelet agglutination, accelerated atherosclerosis, and sudden death due to myocardial infarction, arrhythmias or heart block.47 Acute electrocardiogram changes include prolonged PR, QRS and QT intervals along with a prolonged cardiac refractory period. Increased QRS voltage, ST elevation and ST-T changes may occur in up to 39 percent of chronic cocaine abusers.48

It has been suggested24 that any dental patient who has taken or is suspected of taking cocaine recently have dental treatment postponed for 24 hours. This would appear reasonable, and possibly 48 hours would be better considering cocaine metabolites. The detection of dental patients who are substance abusers may be very difficult.46 There are presently no studies or case reports regarding interactions between cocaine or its metabolites and local anesthetics or their vasoconstrictors, but it would appear that the potential exists.

Catecholamine Blood Levels in Stress

Current opinion3,18 appears to minimize the role of endogenous adrenal catecholamine (epinephrine and norepinephrine) secretion in stressful dental situations and maximize the potential for toxic blood levels of epinephrine concentrations in local anesthetics. Previous opinions2,19,49-51 held that conventional doses of epinephrine in local anesthetics were too small to significantly influence the cardiovascular system and that stress/fear-induced adrenal catecholamine secretion was responsible for "adrenaline" adverse reactions. It is probable that both scenarios can operate in any given situation with considerable overlap.

The resting rate of epinephrine secretion for the adrenal medulla is estimated to be 29 to 39 pg/ml for epinephrine,3,4,52 and for norepinephrine is 228 pg/ml.52 This "resting" epinephrine level can be higher (98 pg/ml) prior to dental treatment.10 In chronic stress (severe ICU illness) epinephrine blood levels may rise from 0.034 ng/ml to 0.14 ng/ml (four-fold increase) and in acute maximal stress (cardiac arrest) from 0.034 ng/ml to 0.36 to 35.9 ng/ml (10- to 1000-fold increase) with norepinephrine levels increased by a factor of two and 32 times respectively.52 This is not to equate dental treatment with such intense stress; but norepinephrine and epinephrine blood levels may increase 40 times under stress,19 and certainly dental treatment may be in this category. Merely placing a syringe in a patient's mouth without any tissue penetration may raise blood pressure and heart rate.53 In any given clinical situation, it may be impossible to determine the relative influences of exogenous vs. endogenous vasoconstrictors in the etiology of an adverse event.

Gingival Retraction Cord

The use of gingival retraction cord impregnated with manufacturer-labeled 8 percent racemic (dl) epinephrine is controversial because of conflicting clinical pharmacokinetics and toxicity studies. It has been estimated that each inch of such cord contains between 225.524,54 and 661 micrograms55 of dl-epinephrine (113-330 micrograms of the pharmacologically active l-form) equating with 3.13 to 9.16 cartridges of 1:100,000 anesthetic solution.
One study has demonstrated very significant increases in heart rate (6-120/minute) and blood pressure (0-140 mm/Hg systolic; 0-48 mm/Hg diastolic) in dogs from racemic cord,56 while others see either no or only slightly significant increases/changes in the measured parameters (electrocardiogram, blood pressure, heart rate).57-64 A reported rise in blood epinephrine from 15 pg/ml to 316 pg/ml in a single patient was associated with no hemodynamic changes.61 In another study approximately 64 percent to 94 percent (average 81 percent) of cord epinephrine was "lost" (about 71 micrograms/inch) allegedly due to vascular absorption, however no accounting was made for drug "lost" because of removal by gingival crevicular fluid, saliva or catechol-O-methyl transferase metabolism.54 Some studies61,63 demonstrate little effect of epinephrine placed in intact gingival sulcus (understandable since it is probably not absorbed through intact epithelium), while others indicate that the traumatized gingival sulcus can allow for much greater drug absorption.65 The presence or absence of gingivitis may also play a role, and the tissue manipulation itself may cause hemodynamic changes.64 Interestingly, some studies57,61 leave the cord in place for 30 to 120 minutes, the validity of which is obscure as it relates to clinical practice. Only one study applied 8 percent racemic epinephrine on a cotton pledget (at an unknown volume) in dogs, which resulted in greater elevations in heart rate and blood pressure compared to racemic cord but with some animals exhibiting little or no hemodynamic changes;56 while another employed 8 percent racemic solution to intact gingiva and a gingival laceration with no blood pressure changes, only a slight effect when applied to gingivectomy wounds and very significant blood pressure elevation when applied to an apicoectomy wound.55

It is apparent that the concentration of epinephrine in gingival retraction cord or solution has the potential to induce significant cardiovascular effects, but the consequences in any given patient can be highly variable depending upon the:

  • Actual epinephrine concentration in the cord or solution;

  • The length of time the cord (solution) is left in the sulcus;

  • The amount of tissue trauma/gingivitis present in the sulcus;

  • The number of teeth ligated (area of tissue exposed);

  • Dilution/removal by crevicular fluid/saliva;

  • Metabolism by catechol-O-methyl transferase;

  • Localized vasoconstriction by epinephrine to retard its own absorption;

  • Operator trauma to the area in placing the cord; and

  • Individual patient threshold to any elevated blood levels of vasoconstrictor.
It is probably best to refrain from epinephrine-impregnated cord in patients known to be at risk from epinephrine as listed above and to use the minimum amount whenever possible.

Conclusions

The record of dentistry in the safe and judicious use of local anesthetics and their associated vasoconstrictors is impeccable. Even though clinical and laboratory studies indicate a potential for significant deleterious effects on the cardiovascular system by exogenous (or endogenous) epinephrine, the lack of clinically significant documentation of these adverse effects in actual patients is noteworthy. Yet complacency could alter these impressive statistics if care is not taken to remember that the proper dose of a drug is "enough"66: the amount that produces a suitable therapeutic benefit with the least attendant toxicity.

Author

Thomas J. Pallasch, DDS, MS, is a professor of pharmacology and periodontics at the University of Southern California School of Dentistry

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