Plasma catecholamine and hemodynamic responses to the placement of epinephrine-impregnated gingival retraction cord

oral medicine Editor:

JAMES W. LITTLE, D.M.D., M.S.D.

School of Dentistry University of Minnesota 515 S. E. Delaware St. Minneapolis, Minn. 55455

Plasma catecholamine and hemodynamic responses to the placement of epinephrine-impregnated gingival retraction cord Craig L. Hatch, D.M.D.,* Bart Chernow, M.D., F.A.C.P.,** Geza T. Terezhalmy, D.D.S., F.I.C.D.,*** Michael Van Ness, M.D..**** Kathryn Hall-Boyer, M.D.. **** and C. Raymond Luke, M.D., Ph.D.,***** Bethesda, Md. NAVAL

DENTAL

SCHOOL

AND

UNIFORMED

SERVICES

UNIVERSITY

OF THE HEALTH

SCIENCES

A double-blind randomized crossover study was conducted to measure the changes in heart rate, mean arterial blood pressure, pulse pressure product, and plasma catechofamine levels for 60 minutes after the placement of racemic (r) epinephrine- or alum-impregnated retraction cords in intact gtngival sulci of nine healthy volunteers. The r-epinephrine-impregnated cord produced stgnitkant (p < 0.01) increases in plasma epinephrine concentrations after 60 minutes, but there were no epinephrine-induced hemodynamic changes. According to these findings, r-epinephrine-impregnated gingival retraction cord placed in an intact, nonlacerated gingival sulcus in a healthy young adult should produce no significant hemodynamic response. It is not known how the placement of epinephrine-impregneted retraction cord would affect elderly or medically compromised patients or patients with lacerated or periodontally involved gingivae. (ORAL fkmc. 58540-544, 1984)

R

acemic epinephrine (r-epinephrine) is routinely added to gingival retraction cords in restorative dentistry to minimize bleeding at the time of impression making. In animal studies, epinephrine C,, was rapidly absorbed immediately after impregnated retraction cords were placed around teeth prepared

for full crowns.’ Such absorption increases when the gingival tissues are lacerated or abraded.2 It is possible that epinephrine absorption from the gingival sulcus increases plasma catecholamine concentrations. Earlier investigations of the hemodynamic

The opinions or assertions contained in this article are the private ones of the writers and are not to be construed as official or as reflecting the views of the Department of the Navy or the Department of Defense. The protocol for this investigation was approved by the Research Committee and the Committee for the Protection of Human Subjects, Naval Hospital, Naval Medical Command National Capital Region, Bethesda, Md. This work was supported in part by funds provided under Naval Medical Command, Department of the Navy, Washington, D.C., Clinical Investigation Proposal No. 83-06-1825. *Resident, Oral Diagnosis Department, Naval Dental School.

**Director of Research, Critical Care Medicine Department, Naval Hospital, and Associate Professor of Medicine, Uniformed Services University of the Health Sciences. ***Associate Professor, Department of Dental Diagnostic Science, School of Dentistry, and Associate Professor, Department of Pharmacology, School of Biomedical Sciences, University of Texas Health Science Center at San Antonio; formerly Chairman, Oral Diagnosis Department, Naval Dental School. ****Department of Internal Medicine, Naval Hospital. *****Professor of Psychiatry and Pharmacology, Uniformed Services University of the Health Sciences.

540

Volume 58 Number 5

Responses to placement of epinephrine-impregnated gingival retraction cord

responseto the placement of gingival retraction cord offer conflicting results.3*‘6In these studies, conclusions are based on changes in heart rate and blood pressure instead of actual measurements of circulating catecholamine concentrations. In addition, there is no consensuson whether the increasesin heart rate and blood pressure associated with the retraction cord are due to exogenous epinephrine absorption from the gingival sulcus, to an anxiety-induced endogenous release of catecholamines, to the stimulation of presynaptic beta receptors by absorbed epinephrine which causes norepinephrine release, or to a combination of these mechanisms. The purpose of this double-blind randomized crossover trial was to compare the effects of r-epinephrine- and alumimpregnated retraction cord on hemodynamic response and catecholamine concentrations in nine healthy adults. MATERIALS

q q

P E

f

541

ALUM CORD EPINEPHRINECORO

80

e= 70 g 60 5 ii

50 -10

0.)

-10

Of1

4

16

60

2 4 TIME (min)

16

60

12

AND METHODS

Nine normotensive healthy adults (mean age 28 & 2 years, four men, five women) signed written informed consent forms. Each subject was studied twice. Subjects fasted overnight and were instructed not to smoke or drink coffee on the morning of the test. All subjects were physicians, dentists, or dental technicians. Each subject was randomly assigned on the first day of testing to either a “retraction cord without r-epinephrine” group (alum gingival retraction cord)* or to a “retraction cord with r-epinephrine” group (8% r-epinephrine-impregnated gingival retraction cord).? Neither the subjects nor the data collectors knew which group any of the patients represented. The alternate retraction cord was used on the second day of testing. At least 3 days separated the two test days, and only the dentist placing the retraction cord was aware of the code. The subjects were supine throughout the test. At 8 AM an l&gauge intravenous catheter was inserted percutaneously into an antecubital vein. Heart rate (HR) was monitored by electrocardiogram, and arterial blood pressure was measured by auscultation with a sphygmomanometer. Pulse pressure product (PPP) was calculated as the heart rate multiplied by the systolic blood pressure. The mean arterial pressure (MAP) was calculated as the diastolic blood pressure plus one-third of the pulse pressure. At 8:20 AM and 8:30 AM baseline venous blood specimenswere collected and baseline hemodynamic data (HR, MAP, and PPP) were recorded. The *Surgident Alu-Pak gingival retraction cord No. 2, Lactona Corporation, Dist. Subsidiary, Warner-Lambert Company, Philadelphia, Pa. TGingi-Pak No. 2, Gingi-Pak Division, Belport Company, Inc., Camarillo, Calif.

Fig. 1. Heart rate (upper panel) and meanarterial blood pressure(lower panel) responsesbefore (-10 and 0 values) and after (arrow) placement of gingival retraction cord. The data are expressed as mean f SEM. No significant changes were observed in either variable.

20-minute delay between the insertion of the catheter and the collection of the baseline data allowed for stabilization of the sympathetic nervous system after intravenous catheterization.” HR and MAP were recorded. At 8:35 AM a retraction cord 1 inch long was placed in an untraumatized gingival sulcus of a mandibular second or third molar. Venous blood samples for catecholamine determinations were collected 1, 2,4, 16, and 60 minutes after the retraction cord was placed. Blood samples were immediately put into chilled heparinized test tubes, kept in wet ice, and centrifuged at 4” C within 15 minutes of collection. The plasma was put into glutathione-containing plastic test tubes and stored at -70” C until assayed. Plasma norepinephrine and epinephrine concentrations were measured by a radioenzymatic technique. This assayusesa partially purified enzyme, catecholo-methyl transferase, which catalyzes the transfer of a titrated (3H)-methyl group from commercially available 3H-S-adenosylmethionine to the metahydroxyl group of endogenous norepinephrine and

Hatch et al.

542

Oral November,

plasma epinephrine levels from a baseline of 15 ? 2 pg/ml to a maximum of 316 f: 45 pg/mll6 minutes after placement of the r-epinephrine cord. Despite the rise in this patient’s plasma epinephrine level, no hemodynamic changes were observed. Minimal gingival hemorrhage was observed as a result of placement of the gingival retraction cord. No signs or symptoms of a hyperadrenergic state were noted in any of the nine subjects during any phase of the study.

= E 25

q ALUMCORD q EPlHEPHRlNECORD

,p 120 ii z 100 z I h

60

2

40

60

-10

0 +l

o+i ’

2

2

4

4 TIME (min)

16

16

Sury. 1984

60

60

Fig. 2. Plasmaepinephrine (upper panel) and norepinephrine (lower panel) responsesbefore (-10 and 0 values)and after (arrow] placementof gingival retraction cord. The data are expressedas mean 2 SEM. The only significant changefrom preplacementvalueswas an epinephrine-cord-inducedincreasein the plasmaepinephrine level at 60 minutes(p < 0.01).

epinephrine, forming 3H-normetanephrine and 3Hmetanephrine, respectively. The resulting measurements are accurate from a value of 25 pg of norepinephrine or 15 pg of epinephrine concentration per milliliter of plasma.I8 All data were analyzed by two-tailed, paired Student’s t tests. RESULTS

Baseline values did not vary significantly between the two test periods for HR, MAP, PPP, or plasma catecholamine concentrations. The HR, MAP, PPP, and plasma norepinephrine concentrations were unchanged after the placement of either the epinephrine- or alum-containing retraction cords (Figs. 1 and 2). There was a significant (p < 0.01) increase in the plasma epinephrine level, but only at 60 minutes after the r-epinephrine-impregnated retraction cord was placed (Fig. 2). One subject had an increase in

DISCUSSION

AND CONCLUSIONS

In this study, plasma epinephrine concentration increased significantly only at 60 minutes after cord placement. It is possible that the r-epinephrine in the cord is not readily absorbed through the intact epithelial lining of the gingival sulcus. The r-epinephrine solution used to impregnate the cord has a pH of 2.5. When placed in the gingival sulcus with a pH of about 6.8, the r-epinephrine is ionized and therefore not lipid-soluble. If the cord were placed in an area of low pH, such as an inflamed gingival sulcus, increased absorption could result. The greatest plasma epinephrine increase was seenin a subject in whom the r-epinephrine cord was placed in an area of marginal gingivitis. No significant increases in HR or MAP occurred in our study, despite an increase in plasma epinephrine concentrations. This finding is in accord with two earlier studies.“, *OIn a study performed with graded infusions of epinephrine, specific hemodynamic effects were produced at particular plasma threshold concentrations.*’ Elevated HRs were noted when the plasma epinephrine concentration increased from a baseline of 27.4 pg/ml to between 50 and 100 pg/ml. Similar plasma epinephrine increases were noted by Chernow and associates” and Tolas and co11eagues2o after injection of a local dental anesthetic (1.8 ml of 2% lidocaine with l/ 100,000 epinephrine). Chernow and associates noted a slight increase in HR over a 2-minute period, whereas Tolas and his co-workers observed no significant increase. The data collected in the current study suggest that retraction-cord-induced increases in plasma epinephrine levels may not have exceeded the threshold plasma epinephrine concentrations necessary to produce measurable hemodynamic effects. Increased epinephrine degradation, possibly due to the alkaline pH of the gingival sulci, in contrast to intravenous infusion or gingival injection, may explain the delayed and relatively small rise in plasma epinephrine concentrations. Taggart and colleagues2*observed a decrease in HR in the face of intense emotional arousal associat-

Volume 58 Number 5

Responses to placement of epinephrine-impregnated gingival retraction cord

ed with increased plasma epinephrine concentrations. They postulated that this discordance may have been due to a parasympathetic dominance, despite greatly enhanced sympathetic activity. Animal studies support this concept, suggesting that the effect of vagal stimulation may be potentiated by sympathetic stimulation.23 In this study the retraction cord was placed in an intact gingival sulcus, whereas in clinical situations the tissues of the gingival sulcus are traumatized during routine crown preparation. Epinephrine absorption was increased during routine crown preparation. Epinephrine absorption was increased in animal studies in which the cord was applied to a lacerated capillary bed,’ and the greatest absorption occurred when the cord was applied directly to the cortical bone.5 No adrenergic effect was observed when the cord was applied to intact gingivae.2,5 The current study supports this experimental observation. Periodontal injections, which are intraosseous, contribute to increased absorption of solutions into the systemic circulation. 24It is possible that, in association with unusually deep crown preparations, a similar increase in r-epinephrine absorption from retraction cords may be observed. Racemic epinephrine is an optical isomer of I-epinephrine with 50% biologic activity.25 A solution of 8% r-epinephrine used to impregnate the retraction cord is 40 times the concentration of 1-epinephrine used in 1 ml of l/ 1,000 solution recommended in emergency situations. Each inch of retraction cord contains 0.44 to 0.61 mg of repinephrine (equivalent of 0.22 to 0.30 mg l-epinephrine), which is comparable to the epinephrine content of twelve cartridges of local dental anesthetic with l/100,000 epinephrine. When placed in an inflamed or traumatized gingival sulcus, such concentrations may place medically compromised patients at higher risk. The adrenergic effect of r-epinephrine retraction cord placed in a traumatized gingival sulcus after crown preparation is being studied in this laboratory. Some investigators conclude that the increase in a patient’s hemodynamic response after gingival retraction cords are placed results from the patient’s anxiety and fear of the dentist and dental procedures.“-‘6 All subjects in the study were physicians, dentists, or dental technicians who had no phobia or anticipatory anxiety. However, stress can play a role for the average dental patient. According to the findings of this study, epinephrine-impregnated retraction cord placed in an intact gingival sulcus increases plasma epinephrine concentrations after 60 minutes, but in healthy subjects

543

these increases have no significant hemodynamic consequences.It is not known how the placement of epinephrine-impregnated retraction cord would affect elderly or medically compromised patients or patients with lacerated or periodontally involved gingivae.

REFERENCES I. Forsyth RP, Stark MM, Nicholson RJ, Peng CT: Blood pressure responses to epinephrine-treated gingival retraction strings in the rhesus monkey. J Am Dent Assoc 78: 13151319, 1969. Woychesin FF: An evaluation of the drugs used for gingival retraction. J Prosthet Dent 14: 769-776, 1964. Harrison JD: Effect of retraction materials on the sulcus epithelium. J Prosthet Dent 11: 514-521, 1961. Thayer KE, Sawyer JD: Gingival retraction agents: retraction in dogs. Iowa Dent J 49: 382-385, 1963. Gogerty JH, Strand HA, Ogilvie AL, Dille JM: Vasopressor effect of topical epinephrine in certain dental procedures. ORAL SURG lo: 614-622, 1957. 6. Phatak NM, Lang RL: Systemic hemodynamic effects of r-epinephrine gingival retraction cord in patients. J Oral Ther Pharmacol 2: 393-398, 1966. 7. Nicholson RJ, Stark MM, Scott HE, Hill B: The detection of C,, labeled epinephrine in the bloodstream of a rhesus monkey following gingival retraction. IADR Program and Abstracts of Papers (Abstr. No. 3 17). J Dent Res 45: I 18, 1966. 8. Pogue WL, Harrison JD: Absorption of epinephrine during tissue retraction. J Prosthet Dent 18: 242-247, 1967. 9. Pogue WL: The absorption of epinephrine in the dental sulcus during tissue displacement prior to impression procedures. JADR Program and Abstracts of Papers (Abstr. No. 7). J Dent Res 46: 37, 1967. 10. Stark MM, Nicholson RJ, Steig R: The measurement of systemic effects in humans following the use of an epinephrine-containing gingival retraction agent. IADR Program and Abstracts of Papers (Abstr. No. 109). J Dent Res 42: 63, 1963. I I. Houston JB, Appleby RC, DeCounter L, Callaghan N, Funk DC: Effect of r-epinephrine-impregnated retraction cord on the cardiovascular system. J Prosthet Dent 24: 373-376, 1970. 12. Munoz RJ: The cardiovascular effects of anxiety and r-epinephrine retraction cord in routine fixed prosthetic procedures. J Calif Dent Assoc 46: 10-13, 1970. 13. Fritts KW, Thayer KE, Yoder JL: The use of epinephrineimpregnated retraction cords. Gen Dent 18: 17-19, 1970. 14. Timberlake DL: Epinephrine in tissue retraction. Ariz Dent J 17: 14-16, 1971. 15. Pelzner RB, Kempler D, Stark MM, Lum LB, Nicholson RJ, Soelberg KB: Human blood pressure and pulse rate response to racemic-epinephrine retraction cord. J Prosthet Dent 39: 297-292, 1978. 16. Buchanan WT, Thayer KE: Systemic effects of epinephrineimpregnated retraction cord in fixed partial denture prosthodontics. J Am Dent Assoc 104: 482-484, 1982. 17. Lake CR. Zieeler MG. Kooin . IJ: Use of olasma noreoineoh. . rine for eval&on of sympathetic neuronal function in man. Life Sci 18: 1315-1325, 1976. 18. Durett LR, Ziegler MG: A sensitive radioenzymatic assay for catechol drugs. J Neurosci Res 5: 587-598, 1980. 19. Chernow B, Balestrieri F, Ferguson CD, Terezhalmy GT, Fletcher JR, Lake CR: Local dental anesthesia with epinephrine: minimal effects on the sympathetic nervous system or on hemodynamic variables. Arch Intern Med 143: 2141-2143, 1983.

544 Hatch et al. 20. Tolas AG, Pflug AE, Halter JB: Arterial plasma epinephrine concentrations and hemodynamic responsesafter dental injection of local anesthetic with epinephrine. J Am Dent Assoc 104: 41-43, 1982. 21. Clutter WE, Bier DM, Shah SD, Cryer PE: Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest 66: 94-101, 1980. 22. Taggart P, Hedworth-Whitty R, Carruthers M, Gordon PD:

Observations on electrocardiogram and plasma catecholamines during dental procedures: the forgotten vagus. Br Med J t: 787-789, 1976. 23. Levy MN, Zieske H: Effect of enhanced contractility on the left ventricular responseto vagus nerve stimulation in dogs. Circ Res 24: 303-3I I, 1969.

Oral Surg. November, 1984 24. Smith GN, Pashley DH: Periodontal ligament injection: evaluation of systemic effects. ORAL SURG 56: 571-574. 1983. 25. Shaw DH,

Krejci RF: Epinephrine-containing gingival retraction cords-how safe are they? J Nebr Dent Assoc 52: 7-9, 1916.

Reprint requests to: Dr. G. T. Terezhalmy Department of Dental Diagnostic Science School of Dentistry UTHSC 7703 Floyd Curl Dr. San Antonio, TX 78284