Hemodynamic assessment of local anesthetic administration by laser Doppler flowmetry

Hemodynamic assessment of local anesthetic administration by laser Doppler flowmetry Elie M. Fernieini, MHS,a Jeffrey D. Bennett, DMD,b David G. Silverman, MD,c and Thomas M. Halaszynski, MD, DMD,d Farmington and New Haven, Conn UNIVERSITY OF CONNECTICUT AND YALE UNIVERSITY

Objective. The hemodynamic effects of local anesthetic administration with and without a vasoconstrictor were compared by using laser Doppler flowmetry.

Study design. Seventeen people participated in a single study session in which they were given 2 intraoral injections. The injections, which were administered in random order, consisted of 1.8 mL lidocaine (2%) with epinephrine (1:100,000) and mepivacaine (3%). Hemodynamic parameters consisting of blood pressure, heart rate, and laser Doppler flowmetry were reordered at regular intervals. Results. The laser Doppler flowmeter detected changes in the peripheral perfusion of the finger that were not detected by changes in blood pressure and heart rate. The greatest change was associated with anxiety and occurred just before the injection. The inclusion of epinephrine in the local anesthetic resulted in a persistence of these changes. Conclusion. This investigation has confirmed the sensitivity of laser Doppler flowmetry as an investigational tool for assessing hemodynamic changes associated with anxiety and the administration of local anesthesia.

(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:526-30)

Hemodynamic (blood pressure and peripheral vascular tone) and cardiac (heart rate, rhythm, and contraction) changes have been demonstrated after both stressinduced release of endogenous catecholamines and the administration of local anesthetic agents containing sympathomimetics.1 The significance of these cardiovascular fluctuations remains controversial in dentistry. The relevance of these alterations is significant in establishing scientific parameters and recommendations regarding stress reduction protocols and decisions for inclusionexclusion of sympathomimetic agents (epinephrine) combined with local anesthetic administration. Typical monitoring techniques for cardiac and hemodynamic changes within the dental office include measurements of blood pressure and heart rate and rhythm. It has been shown that the range of blood pressure and heart rate measurements may remain unchanged compared with other parameters assessing a patient’s cardiovascular status.2 Because of this, they may not prove reliable or sensitive enough to determine the true physiologic aDental Student, University of Connecticut, School of Dental Medicine. bAssociate Professor, Department of Oral and Maxillofacial Surgery, University of Connecticut School of Dental Medicine. cProfessor and Director of Clinical Research, Department of Anesthesiology, Yale University School of Medicine. dAssistant Professor, Department of Anesthesiology, Yale University School of Medicine. Received for publication Aug 8, 2000; returned for revision Oct 26, 2000; accepted for publication Jan 12, 2001. Copyright © 2001 by Mosby, Inc. 1079-2104/2001/$35.00 + 0 7/12/114382 doi:10.1067/moe.2001.114382

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response from endogenous release or exogenous administration of sympathomimetics. The myocardium may sustain regional ischemic injury despite evidence of a stable blood pressure and heart rate. Such ischemic myocardial injury is attributable to the selective vasoconstriction of atherosclerotic coronary vessels.3 The laser Doppler flowmetry measurement technique expresses perfusion in terms of red blood cell flux by measuring the phase shift of reflected laser light (632.8 nmol/L) induced by moving red cells in the vessels under study. The laser Doppler provides mea- surement in millivolt units, which are taken and recorded in real time. It is highly sensitive to changes in perfusion and has been used to document vasoconstriction in response to pharmacologic and physiologic sympathomimetic challenges.4-7 Laser Doppler flowmetry of finger blood flow has also been found to be sensitive enough to identify microcirculatory vessel responses to anxiety-induced stress.6 This investigation evaluated the usefulness of laser Doppler flowmetry for the assessment of microcirculatory changes caused by the anticipation of the procedure and by the administration of an intraoral injection with and without a sympathomimetic agent.

MATERIAL AND METHODS Seventeen healthy volunteers (ASA 1 and 2) were recruited with Human Investigation Committee (HIC) approval for a single study session to assess the hemodynamic response to local anesthetic administration with and without epinephrine. Exclusion criterion included preg-

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nancy, smoking, substance abuse, extreme dental anxiety (value of 15 or higher on a 4-20 scale),8 and any history or symptoms of cardiovascular or respiratory disease. Subjects assumed the supine position in an isolated lowlight study room with a temperature range of 22° to 24°C. The following monitors were attached: a continuous 5lead electrocardiograph, a noninvasive blood pressure cuff (normally cycling every 3 minutes), a pulse oximeter, and a laser Doppler flowmeter (Periflux Pf2B; Perimed Jarfalla, Sweden) to the palmar surface of the fourth finger on the hand opposite the blood pressure cuff. Laser Doppler outputs (millivolts) were recorded continuously through an analogue-to-digital converter (DAS-16F Data Acquisition Board; Keithley/Metrabyte Corporation, Cleveland, Ohio) attached to an interfaced computer equipped with acquisition software (Snapshot Storage Scope Software; HEM Data Corp, Southfield, Mich). Subjects were left undisturbed, while being continuously monitored for 15 minutes. Baseline measurements were obtained at the end of the 15-minute time interval. After this assessment, the subjects were informed of the pending injection. This was initiated 2 minutes before the anticipated injection and reinforced at 30-second intervals (120, 90, 60, 30, and 0) until the injection was administered. At 10 seconds before the injection, the subjects were shown an uncapped 24gauge needle attached to a syringe. The injection consisted of a long buccal nerve block. The long buccal nerve was chosen because (1) the technique required is easy and simple, (2) the technique is easily reproducible and there is some assurance of continuity among volunteers, (3) it is relatively atraumatic, (4) it is only “mildly” painful, (5) it avoided the prolonged sensation of labial anesthesia, and (6) overall it is similar to intraoral injections that are routinely performed for mandibular dental procedures. Subjects received 1 ampule (1.8 mL) of either mepivacaine (3%) or lidocaine (2%) with epinephrine 1:100,000. The order of drug administration was randomized in a double blind manner. The subsequent drug was administered in the second component of the investigation. The subjects continued to be monitored for 10 minutes subsequent to each injection. Heart rate, blood pressure, and finger blood flow measurements were obtained and recorded during (a) the baseline interval, (b) the anticipation period (0-2 minutes before injection), (c) the visualization of the needle (10 seconds before the injection), and (d) the postinjection period. The resulting measurements were tabulated, compared, and then analyzed by using paired t tests. (P < .05 was considered statistically significant.) Anxiety levels and pain scores were recorded on a 10-point scale before and after each injection (0, no influence; 10, their worst sensation for pain and anxiety).

The study was repeated after the effect of the anesthetic agent subsided and the parameters had returned to baseline.

RESULTS All subjects received a score on the dental anxiety scale (scale, 4-20) during the recruitment and interview process. All volunteers were identified as not possessing extreme dental-anxiety with no score greater than 12 and a mean score of 8.47 ± 1.8 (Table I). All participants indicated a reduction in the degree of their anxiety subsequent to the injections. On a scale of 0 to 10 (0, indicating no anxiety; and 10, intense anxiety), a mean score of 3.41 resulted when subjects were asked to rate their anxiety immediately before the intraoral injection. After each injection, the volunteers’ mean anxiety value was 1.25. On the same 0-to-10 scale (0, no pain; 10, worst imaginable pain), the participants indicated a mean pain score of 1.25 caused by the intraoral injections. The results of blood pressure, heart rate, and finger flowmetry changes were recorded during the investigation and compared with baseline measurements (Table II). Systolic and mean arterial blood pressure responses changed insignificantly with the anticipation of the needle injection of either local anesthetic (P = NS). Systolic blood pressure and mean arterial blood pressure remained unchanged compared with baseline measurements even during and after local anesthetic injection. The heart rate increased in the mepivacaine group (108% of baseline, P = .003), but only slightly and insignificantly in the lidocaine-epinephrine group (103% of baseline, P = NS) during the anticipation of the intraoral injection. A nonsignificant increase in heart rate persisted for a short period after the injection of mepivacaine (106% of baseline, P = NS) but was not statistically significant. The heart rate increased after the injection of lidocaine-epinephrine. The increase in heart rate became statistically significant at the 4.5- to 5-minute measurement and persisted to the 10-minute measurement period. Rate pressure product (RPP) and pressure rate quotient (PRQ) were calculated for each parameter for each patient. The volunteer subject with the most extreme calculated values appears in Table III. These calculations occurred during the most anxiety-provoking period of this investigation (visualization of an uncapped needle). Laser Doppler flowmetry detected increasing peripheral vasoconstriction during the period preceding the injection. The greatest decrease in peripheral perfusion was associated with the visualization of the needle 10 seconds before the injection. The vasoconstriction associated with the visualization of the needle was significantly different from both baseline and from all

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Table I. Baseline dental anxiety score

in anxiety, the endogenous release of chemical mediators may be lessened as shown by the hemodynamic variable of heart rate return to pre-anxiety levels. There was no uniform evidence or continuity of increasing heart rate values during the anxiety-provoking periods and no evidence of statistically significant heart rate increases immediately after each injection. The delayed increase in heart rate (106% of baseline, P < .05) observed in the lidocaine-epinephrine group with an onset at 4.5 minutes after the injection is being attributed to the epinephrine contained within the local anesthetic. Diffusion and uptake of the epinephrine from the injection site may be responsible for this observation. Similar delayed heart rate increases were not expressed in the subjects who received plain mepivacaine. Despite statistically significant changes in peripheral perfusion detected by the laser Doppler flowmetry, which may correspond to changes in myocardial perfusion, changes in heart rate and blood pressure were not of clinical significance. This disparity is of concern because, for most dental procedures, detection of potential adverse cardiovascular events is assessed by monitoring blood pressure and heart rate measurements. To demonstrate a relationship between changes in heart rate and blood pressure and the vasoconstrictive changes as detected by laser Doppler flowmetry, this investigation looked at RPP (RPP = systolic blood pressure × heart rate) and PRQ (PRQ = mean arterial pressure/heart rate). RPP and PRQ are values that have attempted to use blood pressure and heart rate to predict an increase in myocardial oxygen demand that may be reflective of ischemia. The literature and current opinion is that there is a lack of correlation between RPP and PRQ and myocardial ischemia.20-22 This investigation demonstrated an equivocal correlation between RPP and peripheral perfusion as measured by laser Doppler. Additionally, changes in blood pressure and heart rate in these healthy subjects were not of clinical significance and both RPP and PRQ calculations did not approach values suggestive of myocardial ischemia. Therefore, changes in heart rate and blood pressure measurements may be of less significant magnitude and not be as reflective of early cardiovascular compromise. Laser Doppler flowmetry is a technique proven to be very sensitive in detecting alterations in microcirculatory blood flow. Microcirculatory blood flow is affected by increasing levels of sympathetic activity. The stimuli in this investigation causing increasing sympathetic activity consisted of (1) anticipation of an intraoral injection, (2) exposure of a needle attached to a syringe, and (3) the injection of a local anesthetic agent either with or without a sympathomimetic agent. All 3 of these situations may potentially contribute to a sympa-

All subjects Mean Standard error SD

DAS 8.4706 0.4298 1.7719

(Range, 4-20).

other time periods recorded in the study. Finger vasoconstriction returned to baseline in the mepivacaine group within 1 to 2 minutes after the injection. There was evidence of persistent vasoconstriction in the lidocaine-epinephrine group for up to 5 minutes after the injection.

DISCUSSION Dental treatment modalities can be associated with significant physiologic stress. Sympathoadrenal stimulation can potentially result from stress and anxiety associated with the fear of an injection and from the use of a vasoconstrictor contained within the local anesthetic agent.9 Although controversial, numerous studies have clearly demonstrated that there is an elevation in the plasma concentration of epinephrine associated with the administration of a local anesthetic containing epinephrine.2,10-14 Moderate changes in cardiac output, stroke volume, and total peripheral resistance have been associated with the increase in plasma epinephrine concentration.15,16 The percent change from baseline for both blood pressure and heart rate values is minimally influenced by the increase in plasma epinephrine concentration up to a certain level. Changes in heart rate measurements appear to be more sensitive and more variable to increasing levels of plasma epinephrine than are changes in blood pressure.1,17,18 Therefore, the heart may sustain regional ischemic injury despite evidence of stable blood pressure and heart rate values. This has been attributed to vasoconstriction of distal coronary arteries.3,19 Mild and inconsistent heart rate increases occurred during the anticipation period and upon visualization of the needle-attached syringe (108% of baseline, P = .003 in the mepivacaine group). This is presumed evidence that anxiety can result in the endogenous release of chemicals. These chemicals can result in a catecholamine surge. If great enough, the surge may influence hemodynamic variables such as heart rate. As this study has identified, the heart rate increase subsided immediately after injection of the local anesthetic, with or without the epinephrine (106% of baseline in the mepivacaine group [P = NS] and back to baseline in the lidocaine-epinephrine group [P = NS]). The return to baseline heart rate values immediately after the injection may be further evidence of diminishing catecholamine concentrations. With a reduction

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Table II. Hemodynamic measurements* 1

Finger flux HR SBP DBP MAP

Mepi Lido/epi Mepi Lido/epi Mepi Lido/epi Mepi Lido/epi Mepi Lido/epi

⁄2 to 1 min after information

11⁄2 to 2 min after information

10 sec before injection

89.1 ± 5.0 81.5† ± 4.2 105.1 ± 1.7 102.7 ± 1.5 95.8 ± 5.7 101.5 ± 1.3 99.0 ± 2.0 100.1 ± 1.8 97.4 ± 1.7 101.7 ± 1.8

77.6† ± 5.8 76.1† ± 5.4 107.9† ± 1.9 102.8 ± 1.6 104.2 ± 2.2 102.5 ± 2.0 100.3 ± 1.7 114.1 ± 13.6 101.8 ± 1.3 104.4 ± 2.1

67.5† ± 6.8 67.0† ± 6.2 108.5† ± 2.1 103.4 ± 1.9 NA NA NA

1

⁄2 to 1 min after injection

11⁄2 to 2 min after injection

41⁄2 to 5 min after injection

91⁄2 to 10 min after injection

83.3† ± 4.9 82.4† ± 4.9 106.1 ± 3.26 100.1 ± 1.6 102.2 ± 1.6 102.2 ± 1.8 104.0 ± 4.2 97.4 ± 1.6 100.3 ± 1.9 103.0 ± 1.7

103.9 ± 6.7 81.2† ± 6.3 102.9 ± 2.1 102.0 ± 2.2 102.1 ± 1.3 99.9 ± 1.5 102.9 ± 4.2 98.0 ± 1.8 100.9 ± 1.9 100.3 ± 1.6

95.6 ± 4.9 80.3† ± 6.9 101.4 ± 2.1 106.3† ± 2.0 100.3 ± 1.37 102.3 ± 1.4 102.9 ± 4.1 102.8 ± 4.1 99.0 ± 2.1 99.0 ± 2.1

103.5 ± 13.6 96.7 ± 17.7 100.1 ± 2.7 108.4† ± 1.6 101.8 ± 1.6 101.8 ± 1.6 98.2 ± 1.75 98.3 ± 1.7 102.2 ± 1.9 102.2 ± 1.9

Mepi, Mepivacaine; Lido, lidocaine; epi, epinephrine; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure. *Percent of base. †P < .05.

thetic response with resulting increases in plasma catecholamine levels secondary to endogenous release and from exogenous administration of epinephrine containing local anesthetics. Sympathomimetic agents can stimulate both α and β adrenergic receptors to varying degrees depending on the plasma concentrations achieved. Sympathomimetic adrenergic influences differ because of the variation in chemical substitution on the amine group of the agonist, which influences the relative α and β effect.23 Two classes of each α and β receptors have been demonstrated: α 1 and α 2, β 1 and β 2. The activation of α 1 adrenergic receptors causes selective activation at many locations in the smooth muscles cells of both the peripheral vasculature and the coronary arteries (in addition to those found in skin, intestinal mucosa, and splanchnic beds). The response of α 1 receptors as postsynaptic activators in both resistance and capacitance vessels is vasoconstriction. The postjunctional α 1 adrenoreceptors in the mammalian heart show a positive inotropic effect on cardiac tissue.24 The postsynaptic α 2 receptors of the myocardium, coronary arteries, and peripheral vasculature respond similarly.25 Stimulation of central presynaptic α 2 receptors mediates the inhibition of endogenous catecholamines into the synaptic cleft, serving as a negative feedback mechanism. This central effect results in decreasing systemic vascular resistance, decreasing cardiac output, decreasing inotropic state, and decreasing heart rate. The peripheral presynaptic α 2 receptor effects are similar. β 1 receptors (postsynaptic sites) predominate in the myocardium, in the sinoatrial node, and in the ventricular conduction system with a mediation of the effects of catecholamines. Stimulation of these receptors results in increasing inotropism and chronotropism. β 2 receptors are located in the smooth muscles of blood vessels in the skin, muscle, myocardium, and mesentery in both pre-

Table III. Rate pressure product and pressure/rate quotient Lidocaine/epinephrine Mepivacaine

RPP

PRQ

9514 10956

1.18 1.05

synaptic and postsynaptic sites. Presynaptic β 2-receptor activation accelerates the endogenous release of catecholamines. Stimulation of postsynaptic β 2 receptors produces vascular smooth muscle relaxation. The finger blood vessels, which the probe of the laser Doppler is measuring, have a predominance of α adrenergic receptors and sympathetic stimulation results in a decreased microcirculatory blood flow. Atherosclerotic coronary blood vessels are also innervated with α-adrenergic receptors and are highly sensitive to α-adrenergic agonists, making them susceptible to a resultant decrease in perfusion to the involved sites.26-28 Therefore, the detection of vasoconstrictive changes in the digital blood vessels may suggest significant alterations in perfusion of the myocardium. The laser Doppler flowmeter detected moderate decreases in peripheral perfusion after the subjects had been exposed to the experimental stimuli. The greatest change in peripheral vasoconstriction was associated with the visualization of the needle immediately before the injection. The decreased peripheral perfusion resolved shortly after the anxiety-provoking stimuli were removed and the injection was completed. However, the inclusion of a sympathomimetic agent in the local anesthetic was observed to prolong the vasoconstrictive effects detected by the laser Doppler. Because more than 1 ampule of lidocaine with epinephrine (0.018 mg) is frequently administered in clinical practice, it is likely that exogenously administered epinephrine may result in a more profound effect than

530 Fernieini et al

that observed in this investigation. Dose response studies are needed to compare the effects of anxiety with exogenous epinephrine administration. It was expected that anxiety and mental stress would cause vascular change. Mental stress has been shown to play a significant role in the creation of peripheral vasoconstrictive changes. It may also influence coronary vascular blood flow, which can contribute to a decreased cardiac function.29 The severity of this decrease, attributable to mental stress and anxiety, might have been less if the subject was not shown the needle. Setting the needle is not usually shown to a patient. However, the immediacy of the pending injection may also have contributed to the severity of the vasoconstrictive changes.

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12. 13.

14.

15. 16.

17.

CONCLUSION This investigation has confirmed the sensitivity of laser Doppler flowmetry as an investigational tool for assessing hemodynamic changes associated with anxiety and the administration of local anesthesia. The impact on actual clinical situations may result in a more judicious use of epinephrine containing local anesthetics. Further investigations are needed to assess (1) hemodynamic changes of those patients with a compromised status, and (2) hemodynamic changes associated with an increasing dose response to epinephrine contained within a local anesthetic for intraoral injections.

18. 19. 20.

21.

22.

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Reprint requests: Jeffrey Bennett, DMD Department of Oral and Maxillofacial Surgery University of Connecticut School of Dental Medicine 263 Farmington Ave Farmington, CT 06030