A clinical evaluation of local anaesthetic solutions containing graded epinephrine concentrations

Archs oral Bid.

Vol.12, pp.611-621,

1967.

Pergamon Press Ltd.Printed in Gt.

Britain.

A CLINTCAL EVALUATION OF LOCAL ANAESTHETIC SOLUTIONS CONTAINING GRADED EPINEPHRINE CONCENTRATIONS* L. P. GANGAROSA and

Department

F. J. HALIK

of Dentistry and Dental Research, University of Rochester, School of Medicine and Dentistry, Rochester, N.Y., U.S.A.

Summary-A double-blind study using five local anaesthetic solutions and 542 patients was conducted by a group of dentists. The following properties of the anaesthetic solutions were evaluated: (1) speed of onset of anaesthesia, (2) efficacy of anaesthesia, (3) duration of soft tissue anaesthesia, (4) degree of haemostasis, (5) toxic symptoms. In comparing the anaesthetic solutions tested, it was found that solutionswith l/300,000 epinephrine were as satisfactory as solutions with 1/100,000 epinephrine, whether the local anaesthetic was lidocaine or propitocaine. Propitocaine without epinephrine compared favourably with any of the solutions with epinephrine when used in mandibular blocks, and in operative dentistry. A less favourable anaesthetic efficacy was obtained for propitocaine without epinephrine when used in infiltration anaesthesia and in surgery. The experiments support the idea that solutions with lower epinephrine concentrations can be used for effective dental anaesthesia, thus reducing the danger of epinephrine toxicity due to intravascular injection.

INTRODUCTION

AT A RECENTconference on the Management of Dental Problems in Patients with Cardiovascular Disease (1964), jointly sponsored by the American Heart and Dental Associations the “use of minimal concentrations of vasoconstrictors” in local anaesthetic solutions was recommended for dental patients with cardiovascular disease. Epinephrine concentrations of 1/50,000 to l/250,000 were considered safe when administered carefully and with preliminary aspiration. Direct intravascular injection was considered to be a major cause of serious complications. BRAUN (1924) first introduced the use of the vasoconstrictor adjuvant because procaine was found to be inadequate without epinephrine due to rapid removal and metabolism. Addition of minute amounts of epinephrine (l/100,000-l/200,000) resulted in satisfactory anaesthetic properties. The discovery of lidocaine by LOFGREN (1946) offered a local anaesthetic with distinct advantages compared to procaine, e.g. a longer duration of action, and good analgesia without added epinephrine (WIEDLING, 1959). BJ~RN and HULDT (1947) using an efficiency rating scale found an increased efficiency with increased epinephrine *A preliminary report of this paper was given at TADR meeting, 1965. Journal of Dental Research (preprinted abstract, Paper # 131). 611

612

L. P. GANGAROSA

AND F.J.

HALIK

to 25 /*g/ml, l/40,000) for 1y0 lidocaine. Holler (1951) demonstrated, however, that the vascular effects of lidocaine-vasoconstrictor combinations were achieved with l/3 to l/8 less epinephrine when compared to procaine-vasoconstrictor combinations. Recently, KEESLINGand HINDS (1963) reported little difference in duratron of analgesia (demonstrated by tooth pulp electrical stimulation) between 2% lidocaine solutions containing 1/50,000 or l/250,000 epinephrine. Furthermore, evidence is accumulating that certain newer local anaesthetic agents, e.g. mepivicaine (WEIL er al., 1961) or propitocaine (BERLINGand BJGRN, 1963), allow reduction of vasoconstrictors to a greater degree than lidocaine. The present experiments were designed to test the possibility that lidocaine and propitocaine could be used in local dental anaesthesia with less epinephrine than the l/50-l/100,000 concentrations presently employed.

(up

METHODS Seventeen practicing dentists evaluated anaesthetic solutions administered to 542 patients in a double-blind experiment. The patients were selected by the dentist from hospital-clinical practice or private practice when time to perform the evaluation was available. Both mandibular block and infiltration anaesthesia were evaluated. The unknown anaesthetics were used in the dentist’s normal clinical routine. Five anaesthetic solutions were used (Table 1). Each cartridge of anaesthetic was TABLE1. ANAESTHETIC SOLUTIONS EVALUATED

Solutions*

2% Lidocaine (l/lOO,OOOE) 2% 3% 3% 4%

Lidocaine (1/3OO,OOOE) Propitocaine (1/1OO,OOOE) Propitocaine (1/3OO,OOOE) Propitocaine s E

No. of times used 112 79 113 153 57

Abbreviationst (to be used in Tables and text) 20X+ JOE 20X + 3*3E 30P + 1OE 30P + 3.3E 4OP+O E

*The anaesthetics were kindly supplied in blinded cartridges by Astra Pharmaceuticals, Inc, lidocaine as Xylocaine HCl and propitocaine as Citanest. tX = lidocaine (Xylocaine), P = propitocaine, E = epinephrine; 20X + IOE means a solution containing 20 mg lidocaine and 1Org epinephrine per ml. Note: L was not used for lidocaine because propitocaine had been referred to as L67 at an early stage of its development.

supplied in a randomly numbered coin-envelope. The number of cartridges of each solution were unequal when distributed, which accounts for the unequal use of the solutions. The dentist completed an evaluation form for each patient which contained data concerning: (a) the patient (age, sex, colour, medical and dental history), (b) the procedure (diagnosis, type and duration), (c) the anaesthetic solution used (cartridge number, time of and type of injection, amount of solution used) and (d) results (speed of onset, amount of bleeding, depth of anaesthesia and untoward reactions). Duration

EVALUATION

OF EPINEPHRINE

613

IN LOCAL ANAESTHETICS

of soft tissue anaesthesia was calculated as the difference between the times of injection and of disappearance of numbness or tingling as reported by the patient on a post card. If no signs of anaesthesia were noted by the patient, he was not asked to return a post card and the duration was considered not ascertained. The data were transferred to IBM cards for processing. The definitions employed in the evaluations of the anaesthetic trials by the dentists follow. 1. Speed of onset a. Rapid, the dentist was able to start his procedure within 2 min after completing the injection. b. Medium, required to wait 5 min before starting procedure. C. Slow, required to wait 10 min. d. Reinjection needed. 2. Anaesthetic efficacy. the dentist’s overall evaluation (in terms of past experience) of analgesic properties of the solution which allowed him to perform the procedure with patient comfort. Only two categories were allowed-satisfactory or unsatisfactory. 3. Amount of bleeding (surgical cases only) a. None, curettage necessary to produce bleeding sufficient to form a clot. b. Slight, sufficient normal bleeding for clot formation. C. Moderate, extra time and procedures (e.g. gauze packing) required to arrest bleeding. d. Severe, haemostatic aids (e.g. gel foam pack, suturing, clotting agents, etc.) needed to obtain a clot. During the initial planning stage of this study it was decided not to include data obtained by dentists performing less than ten trials each. Twelve dentists, who performed ten or more cases each, were engaged in the types of practice shown in Table 2. TABLE 2. TYPESOFPRACTICEANDNUMBERSOFPATIENTSTESTEDBYTHEDENTISTS No.

dentists

No. patients

General Dentistry Private Practice Hospital Interns

4 3

131 124

Oral Surgeons Private Practice Hospital Residents

2 2

111 95

Periodontist

1

43

Total 255

206

43 504

614

L. P. GANGAROSA

AND F. J. HALIK

This latter group of dentists showed a much higher percentage of satisfactory anaesthesia compared to the five dentists who performed less than ten trials (Table 3). The initial plan was adhered to; that is, only the data obtained by the dentists performing more than ten trials was used for the evaluation of anaesthetic efficacy. However, it was TABLET. COMPARISONOFANAESTHETICEFFICACYBETWEENDENTISTSREPORTING MORETHANOR LESSTHANTENCASES No. of cases

tested

No. of dentists

-z 10 cases > 10 cases

5

12

Satisfactory

Unsatisfactory

23 436 459

8 49

Total

57 N.A.

*516 26 542

*N.A. equals not ascertained

found that the use of the data of all seventeen dentists for the analysis of anaesthetic efficacy would not have substantially altered the results reported or the conclusions reached. RESULTS

1. Speed of onset The speed of onset was not significantly different when the five agents were compared in infiltration anaesthesia. A statistical difference was found when mandibular block anaesthesia was compared (Table 4). More dentists were able to start in 2 min when TABLE

4. SPEED OF ONSET IN MANDIBULAR (Percentageofcases)

Solution

Rapid

20X+ IOE 20X + 3*3E 30P + 10E 30P + 3*3E 4OP+OE *A statistically significant 20X + 10E or 30P + IOE.

38 35 39 58* 50 increase

BLOCK

ANAESTHESIA

5 min or more 62 65 61 42 50

(P-C 0.05) compared

to

using propitocaine with 1/300,000 E @ < 0.05 when compared to 20 x + 10E). There appears a similar trend with4OP + OE, but the difference was not statistically significant. It should be pointed out that slow injection time was emphasized in discussions with the participating dentists, but no further attempt to control this factor was employed.

EVALUATION

OF EPINEPHRINE

IN LOCAL

615

ANAESTHETICS

2. Anaesthetic eficacy

The anaesthetic efficacy (percentage of satisfactory cases reported) is presented for lidocaine in Fig. 1 and for propitocaine in Fig. 2. 2% LIDOCAINE m m

= 3.3~~4E/ml = lO~~pE/ml

100 G

90

i=

80

2

to

be

60

FIG. 1. Anaesthetic efficacy (percentage of satisfactory anaesthesia) ent conditions of dental use. Lidocaine Notes (on figure) 1. Grouped by type of injection. 2. Grouped by type of procedure,

under differ-

PROPITOCAINE

* SIGNIFICANTLY DIFFERENT (pcO5) COMPARED TO 7.0% + IOE

n=oE m = 3.3po Ehl m - IO yo E/ml

FIG. 2. Anaesthetic efficacy (percentage satisfactory anaesthesia). Propitocaine Notes (on figure) 1. Grouped by type of injection. 2. Grouped by type of procedure.

For lidocaine, increasing the concentration of epinephrine does not appear to be advantageous. Propitocaine solutions containing the two concentrations of epinephrine were also relatively similar in all the categories of use studied. Propitocaine solutions with epinephrine compared favourably with lidocaine solutions with epinephrine. Propitocaine without epinepluine was as effective as 20X + 10E for operative procedures and mandibular blocks, but less effective for surgery and when used in infiltrations (p < O-05 by x 2 test). However, when all cases were considered, 40P + 0 E and 20X + 10E were not significantly different statistically in effectiveness.

616

L. P. GANGAROSA

AND

F. J. HALIK

3. Duration of soft tissue anaesthesia For the first 346 cases of this study (GANGAROSAand HALIK, 1965) the hourly intervals reported for loss of soft tissue anaesthesia were plotted against the cumulative percentage of patients reporting loss of anaesthesia before or at the hourly interval. The time opposite the 50 per cent point on the ordinate of such a frequency distribution (DIXON and MASSEY,1957) was referred to as the 50 per cent anaesthetic time (AT,,). A typical plot for 20X+ 10E is presented in Fig. 2. The graphically determined

u FIG. 3.

60

120 180 240 TIME(MIN.)

300

Duration of anaesthesia and derivation of the median anaesthetic time

(AT,,). ATS0 can be defined as the time at which 50 per cent of the patients reported loss of anaesthesia. In order to determine the relationship between the ATbo(a median anaesthetic duration) and the mean duration time, both values were computed for the last 196 cases of this study (Table 5). Note that the ATbOis slightly larger in all cases, a TABLE 5. C~MPARIXINOF

Solution tested 20X+ 10E 20X+ 3.3E 30P+ 10E 30P+ 3*3E 4OP+OE

AT6~swrm MEANDURATIONTIMES(LAST ATho 175 159 188 149 153

196CASES)

Mean duration 169 149 177 146 144

result which might be expected since the median value of a skewed distribution is larger than the mean when the skew is to the right (ORKIN and COLTON,1942). Plots of anaesthetic duration show a skew to the right since very few cases report early loss of anaesthesia. When normal distribution plots were constructed for each anaesthetic agent (not shown here) obvious or hidden bimodal normal distributions corresponding to infiltration (early hump) or mandibular blocks (late hump) were obtained. Thus, in constructing plots to determine the AT,,% each injection route was treated separately.

EVALUATIONOFEPINEPHRINEIN

617

LOCAL ANAESTHETICS

The AT,,‘s for lidocaine were obtained as indicated in Fig. 3. Similar plots (not shown here) were obtained for all of the solutions tested. The bimodal nature of the normal distribution may be noted since mandibular blocks were always to the right of infiltrations. The ATso’s so obtained for all solutions are summarized in Table 6. TABLE 6. ANAESTHETK

TIME 50's (AT,,) (FOR THE ENTIRE STUDY)

Infiltration ATso

Solution tested

Mandibular block AT,,

160 138 150 138 90

10E 20X+ 3.3E 30P+ 10E 30P+ 3.3E 4OP+O E 20X +

203 180 210 210 216

The AT50)s obtained in this study compare favourably with mean duration times obtained in other studies using similar methods of evaluation (Astra Data, 1963 ; EPSTEIN,1965) with the exception of 40P + 0 E when used in mandibular blocks. The latter was longer in the present studies (AT, about 216 min). The former authors reported a mean duration of soft tissue anaesthesia of 165 minutes in a study of a larger patient sample (134 cases). Using either figure, the drug exhibits a prolonged duration of anaesthesia when employed in nerve blocks. 4. Amount of bleeding In 205 cases of oral or periodontal surgery, severe bleeding was not reported. No statistically significant differences could be found between any of the five agents when the number of moderate bleeders was compared to the number of patients with no and slight bleeding. 5. Untoward reactions

Out of 534 patients, fourteen (Table 7). The Astra data on quency of 1a6per cent for three All of the solutions appear TABLET.

(2.6 per cent) were reported to show untoward reactions propitocaine (1963) indicated an adverse reaction freof the solutions tested here. to be relatively free from toxic manifestations.

NUMBERANDTYPESOFUNTOWARDREACTIONS

of patients with reactions/ total times used Syncopy*

No.

Solution 20X + 10E 20X + 3.3E 30P + 10E 30P + 3.3E 4OP+O E

5/1187 l/84 2/111 5/150: l/56

1 1

Anxiety* 3 I 3

2 -

-

Tremors

Local pallor

Allergy

Other

-

-

-

-

-

I

11;;: -

General pallor

-

1

1

*These reactions may not be dependent upon drug toxicity, but no attempt was made to determine the exact cause. tone patient was reported to have two reactions. $One patient was reported to have four reactions.

618

L. P. GANGAROSA

AND F.J. HALIK

DISCUSSION

is therapeutically sound to reduce the concentration of vasoconstrictor in local anaesthetic solutions when this reduction does not result in loss of good local anaesthetic properties such as (1) a rapid speed of onset, (2) good anaesthetic efficacy, (3) long duration of action, (4) some reduction of blood flow, (5) low toxicity. Speed of onset and anaesthetic efficacy are usually considered to be properties of the local anaesthetic agent itself. However, these properties might be altered by changing vasoconstrictor concentrations (e.g. BJ~~RN and HULDT, 1947). For 2% lidocaine solutions, the speed of onset was found to be the same for either 1/100,000 or 1/300,000 epinephrine concentration. Anaesthetic efficacy was also found to be excellent for both solutions. The 3% propitocaine solutions showed a more rapid onset for mandibular block anaesthesia with the lower concentration of epinephrine, while 30P + 10E was about equal to 20X + 10E when speed of onset was compared. Also, propitocaine solutions (4%) showed a trend toward a more rapid speed of onset of mandibular block anaesthesia, but statistical significance was not obtained when compared to 20X + 10E. The anaesthetic efficacy of both 3% propitocaine solutions was excellent and about equal to the lidocaine solutions tested. Four per cent propitocaine without epinephrine also was excellent in anaesthetic efficacy in mandibular block anaesthesia and/or for operative procedures, but less efficient in infiltrations and/or for surgical procedures. The studies reported by Astra (1963) and by EPSTEIN(1965) showed that propitoCaine with 1/300,000 or without epinephrine is about equal to lidocaine in anaesthetic efficacy when the procedure is of short duration, but when used in mandibular block a more satisfactory anaesthesia might be obtained with propitocaine. In the present study, the dentists were not limited as to duration of procedure; rather they were asked to use the unknown agents in their normal clinical routine. The difference in duration of procedures in the present study and in those reported by others could account for any difference in anaesthetic efficacy reported. Thus it may be that the greater percentage of unsatisfactory anaesthesia for 40P + 0 E in infiltrations and surgery was due to long procedures. With respect to speed on onset and anestheticefficacy, the studies reported here show no advantage for the higher concentration of epinephrine. On this basis, the lower concentration of epinephrine should be favoured. Vasoconstrictors are reputed to be responsible for the remaining three properties of the anaesthetic solutions: prolongation of anaesthesia, reduction of blood flow (aiding in haemostasis during surgery), and diminution of toxicity of the local anaesthetic. Prolongation of the duration of action of the local anaesthetic is the most important reason for adding vasoconstrictor. To accomplish this purpose BRAUN(1924) used concentrations of l/100,000 or l/200,000 epinephrine in procaine solutions. Braun consistently warned against using higher concentrations because of the dangers of toxicity. However, the use of 1/50,000 epinephrine in procaine solutions in dentistry appears to be based upon two factors. (1) BRAUN’S formula for preparing the anaesthetic solutions used tablets containing a fixed ratio of procaine/epinephrine (1000/l) which It

EVALUATION

OF EPINEPHRINE

IN LOCAL

ANAESTHETICS

619

resulted in increasing epinephrine concentrations as the procaine concentration increased. According to ALLEN (1920) this was used mainly as a stock solution to be diluted. (2) In certain types of peripheral nerve blocks and in surgery of vascular areas (such as the oral cavity) the more concentrated procaine solutions (therefore, increased epinephrine concentration) were recommended. In the present experiments, duration of anaesthesia was to be found to be only slightly reduced when the lower concentration of epinephrine (l/300,000) was employed. Remarkably, propitocaine without epinephrine gave a prolonged duration of soft tissue anaesthesia when used in mandibular block anaesthesia. However, in infiltration anaesthesia 40P + 0 E was shorter in duration than solutions containing epinephrine in agreement with other studies (Astra Data, 1963; EPSTEIN,1965). Thus, when used without epinephrine in infiltrations, propitocaine should be used for short procedures. Considering that good duration of anaesthesia is not sacrificed by lowering the concentration of epinephrine, it would again seem best to choose the solution with the lesser vasoconstrictor concentration. The use of epinephrine in the local anaesthetic solutions may fail to control haemorrhage since injection may not be into areas which affect the rate of blood flow in the surgical field. Even if haemorrhage were temporarily delayed when the effect of the vasoconstrictor dissipates, a reactive hyperaemia may ensue, or small bleeders which were inhibited may later create difficulty. With the availability of more efficient methods to locally control bleeding, it seems questionable whether the temporary ischaemic effect of the vasoconstrictor in the local anaesthetic soluton is desirable. In the present experiments no differences in amount of surgical bleeding appear evident between the lower and higher concentrations of epinephrine with either anaesthetic agent, which again supports the use of the solution with lower vasoconstrictor concentration. Systemic toxicity of the anaesthetics administered subcutaneously can be reduced by delaying their absorption. However, the rationale of adding epinephrine to reduce subcutaneous local anaesthetic tocixity may be questioned since the major cause of complication is intravascular injection. Epinephrine can have severe toxic effects when injected intravascularly. If a cartridge of local anaesthetic containing 1/50,000 epinephrine (- 40 pg) was injected in 5 set, the rate of epinephrine administration would be 480 pg/min which would be excessive especially in a sensitive patient (e.g. in heart disease or hyperthyroidism). The maximum safe subcutaneous dose was believed to be 500 pg by BRAUN(1924), since at this dose some systemic toxicity was manifested. Furthermore, HOLLER(1952) presented evidence that intravenous toxicity of local anaesthetics was increased in the presence of epinephrine 4-5 fold for procaine and 2-3 fold for lidocaine. TAINTER,THRONDSON and MOOSE(1938) reported a rise in toxic symptoms among patients injected with l/25,000 epinephrine solutions compared to those treated with l/50,000 concentrations. The chance of accidental intravenous administration argues for a reduction of epinephrine concentration to avoid the toxicity of the vasoconstrictor and its possible synergism with local anaesthetic toxicity. The present experiments and others indicate about equal toxicity of solutions containing

620

L. P. GANGAROSA

AND F. J. HALIK

I/lOO,OOOor l/300,000 epinephrine. In the long run, the lower concentration should give less toxic effects. In summary, the present experiments support the idea recently advanced by KEESLING and HNNDS(1963) and by TULLARand ROBERTS(1961) that less epinephrine can be used for dental local anaesthesia. Since no clinical advantage seems to be obtained for 1/100,000 epinephrine as compared to l/300,000 in lidocaine solutions, it would seem reasonable to accept the lower concentration of vasoconstrictor. Similarly, it appears possible to use propitocaine for effective anaesthesia with little epinephrine or, under certain conditions, without vasoconstrictor. Acknowledgemenr-The authors gratefully acknowledge support for this study through a grant in aid from the Astra Pharmaceutical Co., Worcester, Mass. and USPHS Training Grant, RI DE 3. Dr. ARTHURDUTTONand Mr. JAMESPIFERwere helpful in discussions of statistics and data processing. The technical assistance of Cyrus., HETSKO and MRS. J. SINKO are also acknowledged. R&sum&Une etude doublement aveugle, portant sur cinq anesthesiques locaux et 542 patients, a ete entreprise par un groupe de dentistes. Les proprietbs suivantes des solutions anesthCsiques sont appr&%es: (1) vitesse de d&but de l’anesthesie, (2) &cache de I’anesthCsie, (3) duree de l’anesthesie des tissus mous, (4) degre de I’h6mostase et (5) symptbmes toxiques. En comparant les differentes solutions, il apparait que les solutions a l/300.000 d’epinephrine sont aussi efficaces que les memes solutions & 1/100.000, que I’anesthesique local ait ete la lidocaine ou la propitocaine. La propitocaine, sans Cpinephrine, est aussi efficace que les solutions avec Bpinephrine en anesthesie tronculaire mandibulaire et aux tours d’actes de dentisterie opbatoire. Une action anesthesique moms favorabie est obtenue pour la propitocaine sans 6piniphrine, en anesthesie par infiltration et en chirurgie. 11ressort de cette etude que les solutions avec des concentrations faibles en epinephrine sont satisfaisantes pur obtenir de bonnes anesthesies dentaires, diminuant ainsi le danger de la toxicite de l’epinephrine en cas d’injection intravasculaire. Zusammenfaasung-Von einer Gruppe Zahnlrzte wurde ein Doppelblindversuch durchgeftihrt, bei dem 5 Lokalanaesthetika-LGsungen und 542 Patienten eingesetzt waren. Folgende Eigenschaften der Anaesthetika-Losungen wurden beobachtet: (1) Schnelligkeit des Anaesthesiebeginns, (2) Wirksamkeit der Anaesthesie, (3) Dauer der Anaesthesie im Weichgewebe, (4) Grad der Haemostase, (5) Toxische Symptome. Beim Vergleich der gepriiften Anaesthetika-Losungen wurde gefunden, daB Lijsungen mit 1:300,000 Epinephrin genauso zufriedenstellend waren wie Liisungen mit 1: 100,000 Epinephrin, gleich ob das Lokalanaesthetikum Lidocain oder Propitocain war. Propitocain ohne Epinephrin erwies sich im Vergleich zu irgend einer der Losungen mit Epinepbrin als vorteilhaft, wenn es zur Mandibularanaesthesie und in der konservierenden Zahnheilkunde verwendet wurde. Weniger vorteilhaft erwies sich die anaesthetische Wirksamkeit fur Propitocain ohne Epinephrin bei der Infiltrationsanaesthesie und in der Chirurgie. Die Untersuchungen unterstiitzen die Vorstellung, daR Losungen mit geringeren Epinephrinkonzentrationen fur eine wirksame zahn&rztiiche Anaesthesie benutzt werden konnen und so die Gefahr der Epinephrin-Toxizitlt bei intravaskulgrer Injektion vertnindem. REFERENCES ALLEN, D. 1920. Local and Regional Anuesfkesiu (2nd ed.). Saunders, Philadelphia. ASTRA DATA. 1963. Clinical evaluation of Citanest 4 % and Citanest 3 % with epinephrine

in dentistry, Supplement 2, on file at Astra Pharmaceutical

Products, Inc.

1:300,000

EVALUATION OF EPINEPHRINE IN LOCALANAESTHETICS

621

and BJGRN, H. 1963. L 67-A new local anaesthetic of anilide type. Experimental detcrmination of its efficacy in dental plexus anaesthesia in man. Translation from Sver. Tundliik Forb. Tidn. 51 l-522, 1960. BJ~RN, H. and HULDT, S. 1947. The efficiency of xylocaine as a dental terminal anaestheticcompared to that of procaine. Svensk Tundllik Tidskr. 40, 831-851. BRAUN,H. 1924. Local Anaesthesiu (2nd Am. ed.) (6th Germ. rev.). Lea and Febiger, New York. DIXON, W. and MASSEY,F. 1957. Introduction to Statistical Analysis. McGraw Hill, New York. EPSTEIN, S. 1965. Clinical comparison of a new local anaesthetic propitocaine with lidocaine. /. oral Ther. & Pharmacol. 2, 161-170. GANGAROSA,L. P. and HALIK, F. J. 1965. A clinical evaluation of local anaesthetics. I.A.D.R. Preprinted Abstracts, No. 131. HOLLER, W. 1952. Die Toxizitat einiger Localanlsthetika und ihre Beeinflussung durch Vasokonstringentien. Dr. Zahniirztl. Z. 7, 1198-1199. KEESLING,G. R. and HINDS, E. C. 1963. Optimal concentration of epinephrine in lidocaine solution. J. Am. dent. Ass. 66, 337-340. LOFGREN,N. 1946. Studien iiber Localanasthetica. Ark. Kemi Miner. Geol. 22A, No. 18. Management of Dental Problems in Patients with Cardiovascular Disease. 1964. Report of a Working Conference Jointly Sponsored by the American Dental Association and American Heart Association. J. Am. dent. Ass. 68, 333-342. ORKIN, H. and COLTON,R. 1942. An Outline of Statistical Methods (4th ed.). Barnes and Noble, New York. TAINTER, M. L., THRONDSON,A. and MOOSE,S. 1938. Vasconstrictors on the clinical effectiveness and toxicity of procaine anaesthetic solutions. J. Am. dent. Ass. 25, 1321-1334. TULLAR, P. E. and ROBERTS,E. W. 1961. Effectiveness of L-67 and lidocaine as block anaesthetics (abstract). J. dent. Res. 40,678. WEIDLING,S. 1959. Xy/ocaine. Almquist and Wikselle Boktrycheri AB, Uppsala. WEIL, E., SANTAANGELO, C., WEIMAN,F. S. and YACHEL,R. F. 1961. Clinical evaluation of mepivicaine hydrochloride by a new method. J. Am. dent. Ass. 63, 26-32. BERLING, C.