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Anesth Prog 39:187-193 1992
BRIEFREVIEWS
Vasoconstrictors in Local Anesthesia for Dentsty
Allen L. Sisk, DDS
Department of Oral and Maxillofacial Surgery,
Medical College of Georgia School of Dentistry,
Augusta, Georgia
Addition of a vasoconstrictor to a local anesthetic tion has several potentially beneficial effects. It may de-
may have several beneficial effects: a decrease in crease the peak plasma concentration of the local anes-
the peak plasma concentration of the local thetic agent,1'2 increase the duration of anesthesia and
anesthetic agent, increase in the duration and the improve its quality,3'4 decrease the minimum concentra-
quality of anesthesia, reduction of the minimum tion of local anesthetic agent needed for nerve block,5-7
concentration of anesthetic needed for nerve and reduce blood loss during surgical procedures.8'9 The
block, and decrease of blood loss during surgical only vasoconstrictors marketed in the US in combination
procedures. The addition of a vasoconstrictor to a with local anesthetics are epinephrine, levonordefrin, and
local anesthetic may also have detrimental effects. norepinephrine; all are sympathomimetic amines. The
A review of the literature indicates that following discussion will primarily concern epinephrine,
vasoconstrictor concentrations in local anesthetics the best studied and most widely used vasoconstrictor.
marketed for dental use in the United States are The other vasoconstrictors used in local anesthetics in the
not always optimal to achieve the purposes for US, namely levonordefrin and norepinephrine, have not
which they are added. In most cases, a reduced been examined extensively and will be only briefly men-
concentration of vasoconstrictor could achieve the tioned.
same goal as the marketed higher concentration, Epinephrine produces its vasoconstrictor effects by
with less side-effect liability. binding to and stimulating both a1-, and a2-adrenergic
receptors located in walls of arterioles. Epinephrine also
has /32-adrenergic activity and may cause vasodilation in
tissues, such as skeletal muscle, which have a predomi-
nance of /32-adrenergic receptors. In tissues that have
A 11 local anesthetics currently available for dental use approximately equal numbers of a and ,8 receptors, the
in the United States (US) have ,/ effects of epinephrine will normally predominate due
and increase blood flow in the tissuesvasodilating activity to greater sensitivity of the /3 receptors to epinephrine. At
injected. Increased blood flow at the into which they are the low systemic concentrations normally associated with
increased site of injection may dental anesthesia, epinephrine can increase heart rate
promote blood concentrations of the anesthetic (a 81-adrenergic effect), cardiac output, and peripheral
agent, with greater likelihood of overdose reactions. In- vasodilation. Local anesthetics with epinephrine marketed
creased blood flow may also result in a shorter duration for dental use in the US contain either 1: 50,000 (0.02
of anesthetic action; the degree to which the anesthetic mg/mL), 1: 100,000 (0.01 mg/mL), or 1:200,000
action is shortened clinically also depends upon other (0.005 mg/mL) concentrations of the vasoconstrictor.
specific factors, such as tissue binding of the drug. If the When epinephrine is administered intravenously, it has a
purpose of the local anesthetic injection is to allow a soft half-life of 1 to 3 min.
tissue or osseous surgical procedure to be performed, Levonordefrin and norepinephrine, like epinephrine,
increased local blood flow may resultin increased intraop- are direct-acting sympathomimetic amines; their actions
erative bleeding and complicate the performance of the are directly exerted on adrenergic receptors. Levonor-
surgical procedure. defrin and especially norepinephrine have qualitatively
Addition of a vasoconstrictor to a local anesthetic solu- less /32 activity than epinephrine. Levonordefrin is sup-
plied for dental use in the US only in a 1: 20,000
(0.05 mg/mL) concentration. The 1: 20,000 solution of
Received April 20, 1992; accepted for publication December 18, 1992. levonordefrin is believed to have about the same clinical
Address correspondence to Dr. Allen L. Sisk, Department ofOral and activity and cardiovascular side-effect liability as an equal
Maxillofacial Surgery, Medical College of Georgia School of Dentistry, volume of 1: 100,000 epinephrine10; however, data
Augusta, GA 30912-1270. from one animal study suggest that inadvertent intravas-
C 1992 by the American Dental Society of Anesthesiology ISSN 0003-3006/92/$6.00
187
188 Vasoconstrictors Review
Anesth Prog 39:187-193 1992
cular injection of 1: 20,000 levonordefrin might cause traoral injection of 1.8 mL of 2% lidocaine with
greater stress on the cardiovascular system than the 1: 100,000 epinephrine (18 ug of epinephrine), Tolas
standard concentration of epinephrine." Norepinephrine and coworkers'7 found plasma epinephrine concentra-
is supplied for dental use in a 1: 30,000 (0.033 mg/mL) tions to be 240 + 69 pg/mL (mean + SD) compared to a
strength. baseline level of 98 + 38 pg/mL. When lidocaine without
vasoconstrictor was injected, plasma epinephrine did not
POTENTIAL BENEFITS differ significantly from baseline. In the healthy subjects
in this study, heart rate, mean arterial pressure, and rate-
pressure product were not significantly different from
While it is generally accepted that addition of a vasocon- baseline after epinephrine injection. Cioffi et al,18 in a
strictor will retard local anesthetic absorption into the sys- study of hemodynamic and plasma catecholamine re-
temic circulation,12 not all studies have demonstrated de- sponses to amalgam restoration ofa single tooth with local
layed local anesthetic absorption. Goebel et al'3 studied anesthesia (also 1.8 mL of 2% lidocaine with 1: 100,000
peakplasmaconcentrations oflocalanesthetics aftermax- epinephrine), found plasma epinephrine to increase
illary supraperiosteal infiltration of 1.8 mL of 2% lidocaine from a baseline of 28 + 8 pg/mL to 105 + 28 pg/mL 5
with 1: 100,000 epinephrine or the same volume of 2% (mean + SE) min after injection. Heart rate increased in
lidocaine without vasoconstrictor. These investigators parallel with the plasma epinephrine concentration, but
found that addition of 1: 100,000 epinephrine did not mean arterial pressure was unaltered. Chernow et al'9
significantly alter the peak plasma concentration of lido- found a transient increase in heart rate for 2 min after
caine. Even if local anesthetic absorption is retarded, it is inferior alveolar nerve block with epinephrine-containing
not absolutely certain that this will provide an additional local anesthetic. Eight min afterinjection, plasma epineph-
margin of safety. The vasoconstrictor is also absorbed into rine levels were 3.5 times greater than preinjection control
the systemic circulation, and its presence could conceiv- without significant hemodynamic response.
ably lower the threshold of the central nervous system or Twostudiesinwhich54,gofepinephrinewasadminis-
cardiovascular system to the local anesthetic agent. tered demonstrated significant cardiovascular system
Although adding epinephrine or other vasoconstricting changes.20'21 In these studies, the use of 5.4 mL of 2%
agents to local anesthetics usually will increase the dura- lidocaine with 1: 100,000 epinephrine for unilateral max-
tion of anesthetic action, this is not true for all local anes- illary and mandibular third molar extractions resulted in
thetic drugs in all concentrations. Keesling and Hinds'4 plasma epinephrine titers 5 min after injection that were
studied the depth and duration of local anesthesia with approximately five times greater than baseline. Both heart
lidocaine combined with various strengths of epinephrine. rate and systolic blood pressure were significantly in-
Epinephrine concentrations of 1: 250,000 to 1: 300,000 creased. Plasma epinephrine, blood pressure, and heart
were as effective in prolonging the duration of lidocaine rate were not significantly increased when 2% lidocaine
as was 1: 50,000 epinephrine. Gangarosa and Halik3 also without vasoconstrictor was used for third molar extrac-
studied the effects of epinephrine concentration on lido- tions on the opposite sides. Knoll-Kohler et al,22 in a study
caine local anesthesia, and found 1: 300,000 epinephrine of cardiovascular and serum catecholamine responses to
to be as effective on depth and duration of anesthesia third molar removal with local anesthesia, found that an
and degree of hemostasis as 1: 100,000 epinephrine. increase in circulating epinephrine concentrations to more
Kennedyetal,15 in a report ofthe cardiorespiratory effects than six times the previously reported threshold for blood
of epinephrine in local anesthesia, stated that increasing pressure increase23 did not cause significant hemody-
the concentration of epinephrine above 1: 200,000 does namic changes. A tentative conclusion that may be
notincrease the duration ofa local anesthetic block. How- reached from these studies is that, in healthy patients,
ever, Cowan,16 using a minimum dosage technique, re- administration of the dose of epinephrine found in one
ported that the duration of anesthesia increased as epi- standard cartridge of 2% lidocaine with 1: 100,000 epi-
nephrine concentration was raised to 1: 100,000 from nephrine results very quickly in plasma epinephrine two
1: 200,000. times greater than baseline. This increase is not associated
with any biologically significant cardiovascular change.
SYSTEMIC UPTAKE AND CARDIOVASCULAR Administration of three standard cartridges of the same
EFFECTS local anesthetic/vasoconstrictor combination is associated
with a fivefold increase in plasma epinephrine; significant
Several studies have looked at the systemic responses to cardiovascular system changes may occur, but are not
administration of catecholamines in doses associated with consistently associated with this dose.
local anesthetic injections for dentistry. Five min after in- It is reported that the threshold plasma epinephrine
level for an increase in blood pressure is 50 to 100 pg/
Anesth Prog 39:187-193 1992 Sisk 189
mL, the threshold foran increase in systolic blood pressure volume and decreased afterload and mean arterial pres-
is 75 to 125 pg/mL, and the threshold for a decreased sure. These hemodynamic changes were more severe in
diastolic blood pressure is 150 to 200 pg/mL.23 However, older patients.
the study from which these threshold values were deter- Barkin and Middleton26 used electrocardiogram (ECG)
mined used only six healthy subjects. As mentioned pre- monitoringin 225 patients undergoing oralsurgical proce-
viously, the mean maximum circulating epinephrine con- dures with local anesthetic only (2% lidocaine with
centrations after administration of 18 ,ug of epinephrine 1: 100,000 epinephrine). Thirty-six patients (16%) were
were from 105 to 240 pg/mL, and the maximum plasma noted to have either preoperative or intraoperative dys-
epinephrine reported after 54 ,ug of epinephrine was rhythmias. No distinction was made between a dysrhyth-
302 + 142 pg/mL (mean + SD).21 The cardiovascular mia detected before local anesthetic/vasoconstrictor injec-
changes that should have occurred based upon threshold tion, and those occurring after injection, but the overall
values did not occur with 18 ,tg of epinephrine, but were incidence of dysrhythmia was sufficient that the authors
seen when 54 ,ug was administered. recommended routine precordial stethoscope or ECG
monitoring of all patients receiving local anesthetics.
Anargumentfrequently heard forthe inclusion ofvaso-
ADVERSE EFFECTS constrictors in local anesthetic solutions is that the amount
of endogenousepinephrine released in response to inade-
Unfortunately, the effects of vasoconstrictors are not al- quate anesthesia or stress is much greater than that which
ways beneficial. The cardiac excitatory action of epineph- reaches the circulation from a dental injection. Many re-
rine, which is desired in the management of medical emer- cent studies, using lidocaine with epinephrine as experi-
gencies such as anaphylaxis, may be detrimental to a mental treatment and lidocaine without epinephrine as
patient with reduced cardiovascular system reserve. An- control, have not supported this argument.18,20.21.27 These
gina or myocardial infarction could conceivably result if studies have used standard dental injections, usually su-
the patient's cardiovascular system is unable to respond praperiosteal infiltration, posterior superior alveolar nerve
to the demands caused by actions of the vasoconstrictor. block, and inferior alveolar nerve block. Studies of an
Epinephrine may indirectly cause central nervous system alternative injection technique, the periodontal ligament
excitation, as well have effects on metabolism and bron- injection, have also demonstrated significant effects on the
chial and gastrointestinal smooth muscle. Signs and symp- cardiovascular system despite its use of reduced volumes
toms of vasoconstrictor toxicity include hypertension, when compared to standard techniques.28 Since the peri-
tachycardia, tremors, headache, palpitations, and cardiac odontal ligament injection is essentially an intraosseous
dysrhythmias. injection,29 Smith and Pashley feel that the high pressures
While vasoconstrictors administered with local anes- developed duringthese injections may force solutions into
thetics may have minimal effects on healthy patients, they capillaries and venules so rapidly that the technique may
may cause significant changes in patients with hyperten- mimic an intravascular injection.30 Vasoconstrictors in-
sion, heart disease, hypokalemia, and other medical con- jected with the local anesthetic are rapidly absorbed into
ditions, and may interact with other drugs that a patient the circulation, regardless of the type of dental injection,
may be taking or receiving as part of the anesthetic man- and may cause significant cardiovascular system changes
agement. Most studies of the systemic effects of vasocon- within minutes of the time of injection.
strictors in local anesthetic solutions are carried out in
healthy patient populations. Abraham-Inpijn and others24
recorded changes in blood pressure, heart rate, and the DRUG INTERACTIONS
electrocardiogram during and after tooth extraction under
local anesthesia for both normotensive and hypertensive Significant drug interactions may occur between vasocon-
(preoperative systolic blood pressure -160 mm Hg, or strictors injected with local anesthetic agents and either
diastolic blood pressure - 95 mm Hg) patients. Thirty- tricyclic antidepressants or /3 blockers. Tricyclic antide-
eight of 40 patients received 2% lidocaine with 1: 80,000 pressants inhibit the neuronal uptake of catecholamines,
epinephrine. Both groups showed a statistically significant resulting in increased concentrations of catecholamines
increase in blood pressure, but the hypertensive patients at the sympathetic neuroeffector junction. Yagiela et al31
experienced greater increases. Also noted was a 7.5% found that the cardiopulmonary response to epinephrine
incidence of potentially dangerous cardiac dysrhythmias was not significantly affected in tricyclic antidepressant-
in the hypertensive group. In a study of catecholamine treated dogs if the dose of epinephrine was less than 0.67
effects on cardiovascular function Kiyomitsu et a125 found mg/kg. From these data a maximum limit of 0.05 mg of
thatthe addition of 1: 80,000 epinephrine to2% lidocaine exogenous epinephrine was proposed for the patient on
resulted in increased cardiac output, heart rate, and stroke tricyclic antidepressants. Yagiela et al reported that the
Review
190 Vasoconstrictors Anesth Prog 39:187-193 1992
action of epinephrine was increased in dogs concurrently tentiation of lidocaine toxicity by epinephrine could be
administered the tricyclic antidepressant desiprimine two due to either epinephrine-induced effects on the cardio-
to four times and that the potency of levonordefrin and vascular system, which alter the distribution of lidocaine,
norepinephrine was increased seven to eightfold in these or a lidocaine-epinephrine interaction that directly en-
experimental animals.31 hances central nervous system or cardiovascular system
Beta blockers inhibit the vasodilation of arterioles by toxicity.
sympathomimetic drugs. This a-receptor blockade will
allowthe vasoconstricting a-adrenergic effects ofepineph-
rine to predominate, since compensatory vasodilation HEMOSTASIS
cannotoccur. Administration ofepinephrine oreven levo-
nordefrin to a patient who is f8 blocked may result in a Vasoconstrictors are added to local anesthetic solutions
significant increase of blood pressure.32 The more cardio- to provide hemostasis at surgical sites. A 1: 50,000 con-
selective (,81) the blocker is the less chance there is for centration of epinephrine is sometimes used for this pur-
this interaction to occur.33 pose, although many studies have shown that this is not
It is unclear whether inclusion of a vasoconstrictor in the concentration of epinephrine that provides optimal
the local anesthetic solution alters the response to the vasoconstriction balanced with potential for cardiovascu-
local anesthetic agent if inadvertent intravascular injection lar system toxicity. For example, studies of epinephrine's
occurs. Since epinephrine is used in the treatment of local effects on cutaneous blood flow have indicated that no
anesthetic-induced cardiovascular collapse, it has been measurable difference exists between equal volumes of
suggested that epinephrine-containing local anesthetic so- 1: 50,000, 1: 100,000, and 1: 200,000 solutions.40 Har-
lutions are safer than the local anesthetic alone. Moore rington and Carpenter,41 in a study using a laser Doppler
andScurlock hypothesized that added epinephrine would device to follow dynamic changes in skin perfusion after
counteract local anesthetic cardiovascular toxicity.34 Ber- infiltration of 1% lidocaine with graded concentrations of
nards et al,35 in a study to determine whether 1: 200,000 epinephrine, found that the lidocaine alone caused an
epinephrine altered bupivacaine toxicity, administered increase in local blood flow of two to three times base-
bupivacaine with or without epinephrine intravenously to line. Five min after infiltration of 1% lidocaine plus
pigs until cardiovascular collapse occurred. Epinephrine epinephrine (1: 50,000, 1:100,000, 1:200,000
had no effect on the dose of bupivacaine that caused 1: 400,000), the vasodilating effect of lidocaine was effec-
cardiovascular collapse or the ability to resuscitate the tively counterbalanced by each of these concentrations.
animals. Epinephrine, however, decreased the dose of Concentrations of 1: 800,000 and 1: 1,600,000 were not
bupivacaine that produced cardiac dysrhythmias and sei- reliably effective at 5 and 10 min. Periodontal flap surgery
zures, although the plasma concentration of bupivacaine may be an exception, however, in that the 1: 50,000
was identical in the two groups at onset of seizures. The concentration might be superior to more dilute solutions
authors felt that epinephrine produced a peripheral vaso- of epinephrine. According to a study by Buckley et al,42
constriction that resulted in a reduced volume of distribu- blood loss with 2% lidocaine plus 1: 100,000 epinephrine
tion and led to exposure of the central nervous system injected locally for hemostasis is more than double that
to a higher concentration of bupivacaine. In this model when 2% lidocaine with 1: 50,000 epinephrine is used.
of local anesthetic toxicity, epinephrine did not increase
the margin of safety of the local anesthetic; it did not Ropivacaine
protect the animals against bupivacaine-induced cardio-
vascular collapse; nor did it make the animals any easier Ropivacaine, a new long-acting local anesthetic, has been
to resuscitate after collapse. Other animal studies have demonstratedto causevasoconstriction when used alone.
shown that epinephrine may potentiate the lethality of Kopacz et al43 evaluated both bupivacaine and ropiva-
the local anesthetic when both drugs are administered caine, with and without added epinephrine, for effects on
intravascularly. Measurements ofradioactive-labeled lido- local cutaneous blood flow after subcutaneous infiltration
caine have shown that epinephrine promotes entry of in pigs. Solutions of 0.25% and 0.75% ropivacaine re-
local anesthetics into brain tissues due to a greater propor- duced blood flow by 52% and 54%, respectively. Solu-
tion of cardiac output being directed to the brain.36'37 tions of 0.25% bupivacaine increased blood flow by 90%,
Kambam and associates,' in a survival study of rats after and 0.75% bupivacaine increased blood flow by 82%.
cardiotoxic doses of 0.5% bupivacaine with or without Ropivacaine may prove to be a useful agent in dentistry.
1: 200,000 epinephrine, found that the addition of epi- If its vasoconstricting effect decreases its vascular uptake
nephrine potentiated the cardiotoxic effects of bupiva- and prolongs its action, ropivacaine could be used alone,
caine. Yagiela,39 in a report conceming the influence of thereby eliminating potential side effects from systemic
epinephrine on lidocaine toxicity, postulated that the po- absorption of epinephrine.
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