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Benzyl alcohol with epinephrine as an alternative to lidocaine with epinephrine
The Journal of Emergency Medicine, Vol 21, No 4, pp 375–379, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/01 $–see front matter
PII S0736-4679(01)00404-8
Original Contributions
BENZYL ALCOHOL WITH EPINEPHRINE AS AN ALTERNATIVE TO LIDOCAINE WITH EPINEPHRINE Joel M. Bartfield,
MD,
Holly E. May-Wheeling,
MD,
Nancy Raccio-Robak,
RN, MPH,
and Shin-Yi Lai
Department of Emergency Medicine, Albany Medical College, Albany, New York Reprint Address: Joel M. Bartfield, MD, Department of Emergency Medicine, MC-139, Albany Medical College, 43 New Scotland Avenue, Albany, NY 12208
e Abstract—A randomized, prospective, double-blind study comparing benzyl alcohol with epinephrine, 1:100,000 (BA), and lidocaine with epinephrine, 1:100,000 (LID), as local anesthetics was carried out on adult patients with simple lacerations. The two study groups were compared for pain of infiltration (100 mm visual analog scale) and need for additional anesthesia. Pain scores were compared by a Mann Whitney Independent Rank Sum test and need for additional anesthesia by a Fishers Exact test. A total of 52 subjects (26 per group) were analyzed. The groups were similar in demographics and wound characteristics. The median pain score for BA, 7.5 mm, was less than for LID, 19.5 mm (p ⴝ 0.049). Although more patients receiving BA required additional anesthesia as compared to LID (8/26 versus 2/26), this difference did not reach statistical significance. BA is a reasonable alternative local anesthetic to LID for patients who are allergic to LID. © 2001 Elsevier Science Inc.
ber of patients requiring wound repair, the emergency physician will likely encounter a patient who reports an allergy to lidocaine or other local anesthetic. The incidence of true anaphylaxis to local anesthetics, especially amides, is unknown but believed to be rare (2–5). Skin testing has shown that the majority of patients do not have a true allergy, but more often an allergy to methylparaben, a bacteriostatic agent frequently found in multidose vials but not in single dose anesthetic or cardiac lidocaine (5,6). Using an ester anesthetic, a traditional alternative to amides, may not be appropriate because a degradation product of esters, para-amino benzoic acid (PABA), structurally resembles methylparaben and may induce the same allergic reaction (2,6). Skin testing in the ED is not a viable option as it is both time-consuming and potentially risky (6). Because the risk of an allergic reaction for a minor surgical procedure may not be warranted, there is a need for an effective alternative local anesthetic. Diphenhydramine has been shown to be a potential substitute for lidocaine for minor surgical procedures (6 –9). Although antihistamines are structurally related to local anesthetics, they differ enough that no allergic cross-reactivity has been reported (6). However, diphenhydramine is more painful to administer via local injection than lidocaine (1,6 –10). Diphenhydramine may also cause local skin irritation such as erythema and pruritis, and occasionally skin necrosis (6 – 8,11). It also has been noted to cause sedation (6,8).
e Keywords— benzyl alcohol; lidocaine; anesthesia; local; wounds; penetrating
INTRODUCTION Wound management is one of the most frequent problems encountered by emergency physicians, with an estimated 11 million wounds seen in emergency departments (EDs) in the U.S. each year (1). Proper cleaning and repair of wounds often requires administration of an effective local anesthetic. Lidocaine is the most frequently used local anesthetic (1,2). Given the large num-
RECEIVED: 6 December 2000; FINAL ACCEPTED: 23 April 2001
SUBMISSION RECEIVED:
10 April 2001; 375
376
J. M. Bartfield et al.
Benzyl alcohol also has been shown to be a potential alternative for anesthesia for minor surgical procedures (12). Benzyl alcohol is an aromatic alcohol that differs structurally from other local anesthetics as well as methylparaben (10). It causes little pain on intradermal injection, but its short duration of anesthesia (its effect starts to wear off in 2–3 min) has limited its clinical use (10). The addition of epinephrine to benzyl alcohol has been shown to prolong its duration of activity when tested in volunteer subjects (13,14). This study investigates benzyl alcohol with epinephrine versus lidocaine with epinephrine in a clinical setting. We compared the two agents as local anesthetics for laceration repair. Outcomes measured included the pain of infiltration and efficacy of anesthesia as measured by the need for additional anesthesia during repair. Our null hypothesis was that there would be no difference in either outcome.
MATERIALS AND METHODS This is a prospective, randomized, double-blind clinical trial comparing 0.9% benzyl alcohol with epinephrine, 1:100,000, to 1% lidocaine with epinephrine, 1:100,000, as local anesthetics for laceration repair. Emergency department patients, 18 years old or greater, with simple (no vascular, nerve, or tendon injury) lacerations ⬎ 1 cm in length were eligible for the study. Patients who had a contraindication to the use of epinephrine (such as a grossly contaminated wound or wound in an area supplied by end-arteriolar circulation) were excluded. Patients with a known allergy to one of the study solutions or an altered pain sensation such as intoxication or an injury to the sensory nerves supplying the laceration were also excluded. Subjects were enrolled as a convenience sample by one of the investigators or the provider taking care of the patient. The study was performed in an urban, university hospital emergency department with an annual census of 60,000 patients. Residents from emergency medicine, surgery, pediatrics, internal medicine, and obstetrics/gynecology and mid-level providers staff the department. Full-time emergency medicine attendings provide 24 h a day supervision. The institutional review board approved the study. Subjects received either 0.9% benzyl alcohol with epinephrine, 1:100,000, or 1% lidocaine with epinephrine, 1:100,000. Study solutions were supplied in number coded, single use, look alike, 20 cc vials that were prepared by the hospital pharmacy. Both study solutions were clear. The benzyl alcohol solution was prepared by making a 1:100 dilution of epinephrine 1:1000 with multidose normal saline that contained 0.9% benzyl al-
cohol. Bicarbonate was not added to any of the study solutions. Because the shelf life of benzyl alcohol with epinephrine is unknown, study solutions were stored in a refrigerator after preparation and discarded if not used within 1 month. Solutions were allowed to warm to room temperature for at least 1 hour prior to their use. Any solution that remained at room temperature for more than 24 h was discarded. Written informed consent was obtained. Subjects were assigned to a study solution according to a previously determined computer generated order. Neither the subject nor the individual giving the injection (investigator or practitioner) was aware of which solution was being given, thus establishing a double-blind protocol. A 0.5 mL intradermal (raising a wheal) injection of study solution was given through the inside edge in the middle of the laceration. This initial injection was given over 5 seconds (timed by either a wrist watch or clock) through a 3/4 inch 25 gauge needle using a 1 mL tuberculin syringe. Immediately after receiving this initial injection, subjects rated the pain of this injection on a previously validated 100 mm visual analog pain scale (15). Subjects were asked to evaluate the pain of infiltration only, not the pain of the needle stick. The remainder of the wound was then anesthetized using the same study solution and the time that this was completed was recorded. Wound management proceeded according to standard practice and was not dictated by the protocol. Per standard practice, wounds were anesthetized by local injection through the inside of the wound into the margins of the wound. As per standard protocol, wounds were assessed for adequacy of anesthesia by the provider prior to suturing. If the subject required additional anesthesia (as evidenced by any degree of pain during suturing), 1% lidocaine was used and the time that the additional anesthesia was administered was recorded. Subjects could either ask for more anesthesia if they experienced pain during the procedure, or the provider could ask the subject if more anesthesia was desired if incomplete anesthesia was suspected. The total time required for laceration repair (defined as the time from wound anesthesia with study solution to last suture placement) was also recorded. Wound characteristics (location and length), time for repair, time that additional anesthesia was given, and volume of anesthesia were recorded by the individual performing the repair. After all subjects were enrolled, pain scales were quantified by one of the investigators by making measurements to the nearest millimeter from the point of origin to the point marked by the patient (maximum ⫽ 100 mm). Pain scores failed normality testing and are reported as medians with interquartile ranges. The two study groups were compared for demographics, time needed for wound repair, and wound character-
Benzyl Alcohol with Epinephrine as an Alternative to Lidocaine with Epinephrine Table 1. Demographic and Wound Characteristics for the Two Study Groups
Mean Age ⫾ SD (years) Gender ⫽ Male (%) Race (%) Caucasian African American Other Wound location (%) Hand Arm Leg Face Scalp Trunk Mean wound length ⫾ SD (cm)
Lidocaine (N ⫽ 26)
Benzyl Alcohol (N ⫽ 26)
35.8 ⫾ 19.8 22 (85)
30.8 ⫾ 11.8 21 (81)
23 (88) 2 (8) 1 (4)
17 (65) 8 (31) 1 (4)
8 (31) 5 (19) 1 (4) 3 (12) 8 (31) 1 (4)
6 (23) 3 (12) 7 (27) 2 (8) 8 (31) 0 (0)
3.4 ⫾ 1.8
3.5 ⫾ 2.4
377
Table 2. Characteristics of Anesthesia Given for the Two Study Groups
P 0.28 ⬎0.9 0.11
Mean ml/cm* ⫾ SD Mean time for repair ⫾ SD (minutes)
Lidocaine (N ⫽ 26)
Benzyl Alcohol (N ⫽ 26)
P
1.4 ⫾ 1.2
1.7 ⫾ 0.8
0.28
19 ⫾ 21
21 ⫾ 18
0.60
* Volume of study solution given (in mL)/wound length (in cm) 0.26
0.86
istics using t tests for continuous data and 2 or Fishers Exact test for categorical data. Pain scores for the two study solutions were compared by a Mann-Whitney Independent Rank Sum test. The need for additional anesthesia during wound repair was compared with a Fishers Exact test. All tests were two-tailed with significance defined as p ⬍ 0.05. A sample size calculation was performed for pain of infiltration by assuming a parametric distribution of the data (using variance data from our previous study (14)), based upon a t test with ␣ ⫽ 0.05 and  ⫽ 0.20. We estimated that we would require a sample size of 50 subjects to detect a difference of at least 15 mm in pain scores. This difference was felt to be clinically significant based upon previous studies that conclude that 13 mm to 18 mm (out of 100 mm) visual analog pain score differences are of clinical significance (16,17).
RESULTS A total of 57 patients were enrolled in the study. Five were excluded for protocol violations (three complex wounds and two subjects in whom pain scales were not administered until after wound repair), leaving a total of 52 subjects for analysis. There were 26 subjects randomized to each group. There were no differences in demographics or wound characteristics between the two groups (Table 1). There was also no difference in the amount of anesthesia given per length of laceration (defined as ml/cm) or the time required to repair the lacerations (Table 2). All lacerations were repaired as single layer closures. No subject was enrolled more than once. Only one laceration was included in subjects who had
more than one laceration. No untoward effects were observed in any study patient. The median pain score for benzyl alcohol with epinephrine, 7.5 mm (IQR ⫽ 1 mm to 20.5 mm) was significantly less than the median pain score for lidocaine with epinephrine, 19.5 mm (IQR ⫽ 5 mm to 47 mm) (p ⫽ 0.049). Eight of the 26 patients (31%; 95% CI 13%, 49%) receiving benzyl alcohol with epinephrine required additional anesthesia compared to only two of the 26 (8%; 95% CI 0%, 18%) in the lidocaine with epinephrine group. This difference was not statistically significant (p ⫽ 0.075). The times that the additional anesthesia was given for these subjects are listed in Table 3.
DISCUSSION Though true anaphylactic reactions to local anesthetics are rare, it would be useful to have an alternative for those patients needing anesthesia for wound repair or other minor surgical procedures. When a patient claims to have an allergy to lidocaine, it is more often an allergy to the bacteriostatic agent methylparaben (found in multidose vials) (5,6). Giving an ester anesthetic may induce a similar allergic reaction in these patients, as a degradation product of esters, para-amino benzoic acid (PABA), is structurally similar to methylparaben (2). In the case of a known allergy to the methylparaben, single dose cardiac lidocaine (which contains no bacteriostatic agents) may be an option. However, most patients have not had skin testing performed and are unable to make
Table 3. Number of Minutes Prior to Additional Anesthesia Benzyl Alcohol (N ⫽ 8)
Lidocaine (N ⫽ 2)
5 7 10 16 20 20 20 50
25 85
378
this distinction. When confronted with a patient reporting a lidocaine allergy, alternative anesthetic agents must be sought. Diphenhydramine has been investigated as an alternative to traditional local anesthetics. Though 1% diphenhydramine provides comparable anesthesia to 1% lidocaine, its primary drawback is that it is more painful to inject (6,7,9). Buffering diphenhydramine does not reduce pain of infiltration (1). Furthermore, numerous side effects have been reported by study subjects including local erythema, vesicle formation, tissue necrosis, prolonged anesthesia, and sedation (1,6,8,9). Benzyl alcohol has a low systemic toxicity, low allergic potential, low cost, and ready availability, making it an appealing option as an alternative to traditional local anesthetics (18,19). The agent has been shown to be entirely safe at a dose of 1 mL/kg (0.9% benzyl alcohol in normal saline) in dogs and monkeys (19). Benzyl alcohol has been investigated as an alternative anesthetic in prior studies (10 –12). The primary obstacle to its use is its short duration of action (10). The addition of epinephrine to benzyl alcohol has been shown to increase its duration of action in volunteer subjects with uninjured skin (13,14). However, in both of these studies, the benzyl alcohol and epinephrine solution did not last as long as lidocaine solutions (13,14). In the current study of subjects with simple lacerations, we compared benzyl alcohol with epinephrine to lidocaine with epinephrine for pain of infiltration and efficacy of anesthesia. The results of this double-blind study revealed that the median pain score (maximum ⫽ 100 mm) for benzyl alcohol with epinephrine (7.5 mm) was significantly less than lidocaine with epinephrine (19.5 mm). However, prior studies have concluded that 13 mm to 18 mm (out of 100 mm) visual analog pain score differences are of clinical significance (16,17). Therefore, this statistically significant difference may not represent a clinically significant one. More patients receiving benzyl alcohol with epinephrine in the current study required additional anesthesia during laceration repair (8/26, 31%) compared to those receiving lidocaine with epinephrine (2/26, 8%), although this difference was not statistically significant (p ⫽ 0.075). The number of minutes prior to additional anesthesia ranged from 5 to 50 min for benzyl alcohol with epinephrine compared to 25 to 85 min for lidocaine with epinephrine. Three of eight patients requiring additional anesthesia in the benzyl alcohol group had ⬍ 15 min of adequate anesthesia for suture placement. Adequacy of anesthesia was assessed prior to beginning suturing. We therefore feel that the need for additional anesthesia represents anesthesia wearing off as opposed to inadequacy of initial anesthesia. However, if the physician managing the wound did an incomplete job of
J. M. Bartfield et al.
testing for adequacy, anesthesia would have been considered worn off as opposed to inadequate from the start. Although there is no reason to suspect that this would have occurred in one group more frequently than the other, this possibility does exist and introduces a confounder and limitation in the study. We assessed the quality of anesthesia by the need for additional anesthesia. We did not assess pain of suture repair per se and are therefore unable to comment on any potential differences between the two solutions regarding this parameter. This study has several other limitations including insufficient power to detect differences between benzyl alcohol and lidocaine in need for additional anesthesia. As previously stated, four times as many patients required additional anesthesia in the benzyl alcohol group compared to the lidocaine group. Although this difference did not reach statistical significance, we suspect that a clinical difference does exist between the two groups. The fact that three of the patients in the BA group required additional anesthesia in ⬍ 15 min once again suggests a real difference between the two anesthetics. It is possible that repair could have been completed in these patients by using more benzyl alcohol with epinephrine; however, this option was not possible due to the study protocol. Future studies may address this question. Patients in this study were enrolled as a convenience sample, thus introducing the possibility of selection bias. Although we have no reason to suspect that the study population differs from the patients who were not enrolled, this comparison was not made. It is possible that injections in some locations with thicker epidermis or more sensory innervation may have been more painful than others. The groups were similar with respect to location; however, this characteristic only partially controls for this potential confounder. The anesthetic properties of the benzyl alcohol with epinephrine solution used in this study have been ascribed to the benzyl alcohol. Although the study did not test this, it is possible that some of the anesthetic properties could have been due to either the normal saline itself or the epinephrine. A previous study suggested that plain normal saline has very little anesthetic properties (10). Nevertheless, it would be more proper to draw conclusions regarding the test solution containing 0.9% benzyl alcohol, normal saline, and epinephrine 1:100,000 rather than ascribing all of the anesthetic properties to benzyl alcohol per se. It might be useful for a future study to address this issue. A further limitation is that the number of subjects may be too small to detect side effects of drugs tested. In addition, although benzyl alcohol seemed to provide adequate anesthesia for most simple laceration repairs, this result is not applicable to more invasive surgical procedures. A large prospective trial using patients un-
Benzyl Alcohol with Epinephrine as an Alternative to Lidocaine with Epinephrine
dergoing more invasive surgical procedures may be indicated in the future to determine if these results are generalizable and to better study any potential side effects. We conclude that benzyl alcohol with epinephrine is a potential alternative anesthetic for patients with simple lacerations, suspected allergy to lidocaine, and no contraindication to the use of epinephrine. Practitioners should be aware of the possibility of a relatively short duration of activity when using this agent. Acknowledgment—We thank Terry L. Peters, MS, for help with data analysis.
REFERENCES 1. Singer AJ, Hollander JE. Infiltration pain and local anesthetic effects of buffered vs plain 1% diphenhydramine. Acad Emerg Med 1995;2:884 – 8. 2. Orlinsky M, Dean E. Local and topical anesthesia and nerve blocks of the thorax and extremities. In: Roberts JR, Hedges JR eds. Clinical Procedures in Emergency Medicine, ed 2. Philadelphia: WB Saunders; 1991:450 – 86. 3. Chandler MJ, Grammer LC, Patterson R. Provocative challenge with local anesthetics in patients with a prior history of reaction. J Allergy Clin Immunol 1987;79:883– 6. 4. Incaudo G, Schatz M, Patterson R, et al. Administration of local anesthetics to patients with a history of prior adverse reaction. J Allergy Clin Immunol 1978;61:339 – 45. 5. Adriani J, Zepernick R. Allergic reactions to local anesthetics. South Med J 1981;74:694 –9.
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6. Green S, Rothrock S, Gorchynski J. Validation of diphenhydramine as a local anesthetic. Ann Emerg Med 1994;23:1284 – 8. 7. Ernst AA, Marvez-Valls E, Mall G, et al. 1% lidocaine versus 0.5% diphenhydramine for local anesthesia in minor laceration repair. Ann Emerg Med 1994;23:1328 –32. 8. Dire DJ, Hogan DE. Double-blinded comparison of diphenhydramine versus lidocaine as a local anesthetic. Ann Emerg Med 1993;22:1419 –22. 9. Ernst A, Anand P, Nick T, et al. Lidocaine versus diphenhydramine for anesthesia in the repair of minor lacerations. J Trauma 1993;34:354 –7. 10. Wightman MA, Vaughan RW. Comparison of compounds used for intradermal anesthesia. Anesthesiology 1976;45:687–9. 11. Nuttall GA, Barnett MR, Smith RL, et al. Establishing intravenous access: a study of local anesthetic efficacy. Anesth Analg 1993; 77:950 –3. 12. Thomas DV. Saline with benzyl alcohol prevents pain of needle insertion. Anesth Analg 1984;63:882–3. 13. Martin S, Wilson L. Benzyl alcohol with epinephrine as an alternative local anesthetic. Ann Emerg Med 1999;33:495–9. 14. Bartfield JM, Weeks Jandreau S, Raccio-Roback N. A randomized trial of diphenhydramine versus benzyl alcohol with epinephrine as an alternative to lidocaine local anesthesia. Ann Emerg Med 1998; 32:650 – 4. 15. Scott J, Huskisson EC. Graphic representation of pain. Pain 1976; 2:175– 84. 16. Todd KH, Funk KG, Funk JP, et al. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996;27:485–9. 17. Funk JP, Todd K. The minimum clinically important difference in the physician-assigned visual analogue pain scores. Acad Emerg Med 1996;3:142– 6. 18. Novak E, Stubbs SS, Sanborn EC, Eustice RM. The tolerance and safety of intravenously administered benzyl alcohol methylprednisolone sodium succinate formulations in normal human subjects. Toxicol Appl Pharmacol 1972;23:54 – 61. 19. Kimura ET, Ebert DM, Dodge PW. Parenteral toxicity studies with benzyl alcohol. Toxicol Appl Pharmacol 1971;18:54 – 61.
PII S0736-4679(01)00404-8
Original Contributions
BENZYL ALCOHOL WITH EPINEPHRINE AS AN ALTERNATIVE TO LIDOCAINE WITH EPINEPHRINE Joel M. Bartfield,
MD,
Holly E. May-Wheeling,
MD,
Nancy Raccio-Robak,
RN, MPH,
and Shin-Yi Lai
Department of Emergency Medicine, Albany Medical College, Albany, New York Reprint Address: Joel M. Bartfield, MD, Department of Emergency Medicine, MC-139, Albany Medical College, 43 New Scotland Avenue, Albany, NY 12208
e Abstract—A randomized, prospective, double-blind study comparing benzyl alcohol with epinephrine, 1:100,000 (BA), and lidocaine with epinephrine, 1:100,000 (LID), as local anesthetics was carried out on adult patients with simple lacerations. The two study groups were compared for pain of infiltration (100 mm visual analog scale) and need for additional anesthesia. Pain scores were compared by a Mann Whitney Independent Rank Sum test and need for additional anesthesia by a Fishers Exact test. A total of 52 subjects (26 per group) were analyzed. The groups were similar in demographics and wound characteristics. The median pain score for BA, 7.5 mm, was less than for LID, 19.5 mm (p ⴝ 0.049). Although more patients receiving BA required additional anesthesia as compared to LID (8/26 versus 2/26), this difference did not reach statistical significance. BA is a reasonable alternative local anesthetic to LID for patients who are allergic to LID. © 2001 Elsevier Science Inc.
ber of patients requiring wound repair, the emergency physician will likely encounter a patient who reports an allergy to lidocaine or other local anesthetic. The incidence of true anaphylaxis to local anesthetics, especially amides, is unknown but believed to be rare (2–5). Skin testing has shown that the majority of patients do not have a true allergy, but more often an allergy to methylparaben, a bacteriostatic agent frequently found in multidose vials but not in single dose anesthetic or cardiac lidocaine (5,6). Using an ester anesthetic, a traditional alternative to amides, may not be appropriate because a degradation product of esters, para-amino benzoic acid (PABA), structurally resembles methylparaben and may induce the same allergic reaction (2,6). Skin testing in the ED is not a viable option as it is both time-consuming and potentially risky (6). Because the risk of an allergic reaction for a minor surgical procedure may not be warranted, there is a need for an effective alternative local anesthetic. Diphenhydramine has been shown to be a potential substitute for lidocaine for minor surgical procedures (6 –9). Although antihistamines are structurally related to local anesthetics, they differ enough that no allergic cross-reactivity has been reported (6). However, diphenhydramine is more painful to administer via local injection than lidocaine (1,6 –10). Diphenhydramine may also cause local skin irritation such as erythema and pruritis, and occasionally skin necrosis (6 – 8,11). It also has been noted to cause sedation (6,8).
e Keywords— benzyl alcohol; lidocaine; anesthesia; local; wounds; penetrating
INTRODUCTION Wound management is one of the most frequent problems encountered by emergency physicians, with an estimated 11 million wounds seen in emergency departments (EDs) in the U.S. each year (1). Proper cleaning and repair of wounds often requires administration of an effective local anesthetic. Lidocaine is the most frequently used local anesthetic (1,2). Given the large num-
RECEIVED: 6 December 2000; FINAL ACCEPTED: 23 April 2001
SUBMISSION RECEIVED:
10 April 2001; 375
376
J. M. Bartfield et al.
Benzyl alcohol also has been shown to be a potential alternative for anesthesia for minor surgical procedures (12). Benzyl alcohol is an aromatic alcohol that differs structurally from other local anesthetics as well as methylparaben (10). It causes little pain on intradermal injection, but its short duration of anesthesia (its effect starts to wear off in 2–3 min) has limited its clinical use (10). The addition of epinephrine to benzyl alcohol has been shown to prolong its duration of activity when tested in volunteer subjects (13,14). This study investigates benzyl alcohol with epinephrine versus lidocaine with epinephrine in a clinical setting. We compared the two agents as local anesthetics for laceration repair. Outcomes measured included the pain of infiltration and efficacy of anesthesia as measured by the need for additional anesthesia during repair. Our null hypothesis was that there would be no difference in either outcome.
MATERIALS AND METHODS This is a prospective, randomized, double-blind clinical trial comparing 0.9% benzyl alcohol with epinephrine, 1:100,000, to 1% lidocaine with epinephrine, 1:100,000, as local anesthetics for laceration repair. Emergency department patients, 18 years old or greater, with simple (no vascular, nerve, or tendon injury) lacerations ⬎ 1 cm in length were eligible for the study. Patients who had a contraindication to the use of epinephrine (such as a grossly contaminated wound or wound in an area supplied by end-arteriolar circulation) were excluded. Patients with a known allergy to one of the study solutions or an altered pain sensation such as intoxication or an injury to the sensory nerves supplying the laceration were also excluded. Subjects were enrolled as a convenience sample by one of the investigators or the provider taking care of the patient. The study was performed in an urban, university hospital emergency department with an annual census of 60,000 patients. Residents from emergency medicine, surgery, pediatrics, internal medicine, and obstetrics/gynecology and mid-level providers staff the department. Full-time emergency medicine attendings provide 24 h a day supervision. The institutional review board approved the study. Subjects received either 0.9% benzyl alcohol with epinephrine, 1:100,000, or 1% lidocaine with epinephrine, 1:100,000. Study solutions were supplied in number coded, single use, look alike, 20 cc vials that were prepared by the hospital pharmacy. Both study solutions were clear. The benzyl alcohol solution was prepared by making a 1:100 dilution of epinephrine 1:1000 with multidose normal saline that contained 0.9% benzyl al-
cohol. Bicarbonate was not added to any of the study solutions. Because the shelf life of benzyl alcohol with epinephrine is unknown, study solutions were stored in a refrigerator after preparation and discarded if not used within 1 month. Solutions were allowed to warm to room temperature for at least 1 hour prior to their use. Any solution that remained at room temperature for more than 24 h was discarded. Written informed consent was obtained. Subjects were assigned to a study solution according to a previously determined computer generated order. Neither the subject nor the individual giving the injection (investigator or practitioner) was aware of which solution was being given, thus establishing a double-blind protocol. A 0.5 mL intradermal (raising a wheal) injection of study solution was given through the inside edge in the middle of the laceration. This initial injection was given over 5 seconds (timed by either a wrist watch or clock) through a 3/4 inch 25 gauge needle using a 1 mL tuberculin syringe. Immediately after receiving this initial injection, subjects rated the pain of this injection on a previously validated 100 mm visual analog pain scale (15). Subjects were asked to evaluate the pain of infiltration only, not the pain of the needle stick. The remainder of the wound was then anesthetized using the same study solution and the time that this was completed was recorded. Wound management proceeded according to standard practice and was not dictated by the protocol. Per standard practice, wounds were anesthetized by local injection through the inside of the wound into the margins of the wound. As per standard protocol, wounds were assessed for adequacy of anesthesia by the provider prior to suturing. If the subject required additional anesthesia (as evidenced by any degree of pain during suturing), 1% lidocaine was used and the time that the additional anesthesia was administered was recorded. Subjects could either ask for more anesthesia if they experienced pain during the procedure, or the provider could ask the subject if more anesthesia was desired if incomplete anesthesia was suspected. The total time required for laceration repair (defined as the time from wound anesthesia with study solution to last suture placement) was also recorded. Wound characteristics (location and length), time for repair, time that additional anesthesia was given, and volume of anesthesia were recorded by the individual performing the repair. After all subjects were enrolled, pain scales were quantified by one of the investigators by making measurements to the nearest millimeter from the point of origin to the point marked by the patient (maximum ⫽ 100 mm). Pain scores failed normality testing and are reported as medians with interquartile ranges. The two study groups were compared for demographics, time needed for wound repair, and wound character-
Benzyl Alcohol with Epinephrine as an Alternative to Lidocaine with Epinephrine Table 1. Demographic and Wound Characteristics for the Two Study Groups
Mean Age ⫾ SD (years) Gender ⫽ Male (%) Race (%) Caucasian African American Other Wound location (%) Hand Arm Leg Face Scalp Trunk Mean wound length ⫾ SD (cm)
Lidocaine (N ⫽ 26)
Benzyl Alcohol (N ⫽ 26)
35.8 ⫾ 19.8 22 (85)
30.8 ⫾ 11.8 21 (81)
23 (88) 2 (8) 1 (4)
17 (65) 8 (31) 1 (4)
8 (31) 5 (19) 1 (4) 3 (12) 8 (31) 1 (4)
6 (23) 3 (12) 7 (27) 2 (8) 8 (31) 0 (0)
3.4 ⫾ 1.8
3.5 ⫾ 2.4
377
Table 2. Characteristics of Anesthesia Given for the Two Study Groups
P 0.28 ⬎0.9 0.11
Mean ml/cm* ⫾ SD Mean time for repair ⫾ SD (minutes)
Lidocaine (N ⫽ 26)
Benzyl Alcohol (N ⫽ 26)
P
1.4 ⫾ 1.2
1.7 ⫾ 0.8
0.28
19 ⫾ 21
21 ⫾ 18
0.60
* Volume of study solution given (in mL)/wound length (in cm) 0.26
0.86
istics using t tests for continuous data and 2 or Fishers Exact test for categorical data. Pain scores for the two study solutions were compared by a Mann-Whitney Independent Rank Sum test. The need for additional anesthesia during wound repair was compared with a Fishers Exact test. All tests were two-tailed with significance defined as p ⬍ 0.05. A sample size calculation was performed for pain of infiltration by assuming a parametric distribution of the data (using variance data from our previous study (14)), based upon a t test with ␣ ⫽ 0.05 and  ⫽ 0.20. We estimated that we would require a sample size of 50 subjects to detect a difference of at least 15 mm in pain scores. This difference was felt to be clinically significant based upon previous studies that conclude that 13 mm to 18 mm (out of 100 mm) visual analog pain score differences are of clinical significance (16,17).
RESULTS A total of 57 patients were enrolled in the study. Five were excluded for protocol violations (three complex wounds and two subjects in whom pain scales were not administered until after wound repair), leaving a total of 52 subjects for analysis. There were 26 subjects randomized to each group. There were no differences in demographics or wound characteristics between the two groups (Table 1). There was also no difference in the amount of anesthesia given per length of laceration (defined as ml/cm) or the time required to repair the lacerations (Table 2). All lacerations were repaired as single layer closures. No subject was enrolled more than once. Only one laceration was included in subjects who had
more than one laceration. No untoward effects were observed in any study patient. The median pain score for benzyl alcohol with epinephrine, 7.5 mm (IQR ⫽ 1 mm to 20.5 mm) was significantly less than the median pain score for lidocaine with epinephrine, 19.5 mm (IQR ⫽ 5 mm to 47 mm) (p ⫽ 0.049). Eight of the 26 patients (31%; 95% CI 13%, 49%) receiving benzyl alcohol with epinephrine required additional anesthesia compared to only two of the 26 (8%; 95% CI 0%, 18%) in the lidocaine with epinephrine group. This difference was not statistically significant (p ⫽ 0.075). The times that the additional anesthesia was given for these subjects are listed in Table 3.
DISCUSSION Though true anaphylactic reactions to local anesthetics are rare, it would be useful to have an alternative for those patients needing anesthesia for wound repair or other minor surgical procedures. When a patient claims to have an allergy to lidocaine, it is more often an allergy to the bacteriostatic agent methylparaben (found in multidose vials) (5,6). Giving an ester anesthetic may induce a similar allergic reaction in these patients, as a degradation product of esters, para-amino benzoic acid (PABA), is structurally similar to methylparaben (2). In the case of a known allergy to the methylparaben, single dose cardiac lidocaine (which contains no bacteriostatic agents) may be an option. However, most patients have not had skin testing performed and are unable to make
Table 3. Number of Minutes Prior to Additional Anesthesia Benzyl Alcohol (N ⫽ 8)
Lidocaine (N ⫽ 2)
5 7 10 16 20 20 20 50
25 85
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this distinction. When confronted with a patient reporting a lidocaine allergy, alternative anesthetic agents must be sought. Diphenhydramine has been investigated as an alternative to traditional local anesthetics. Though 1% diphenhydramine provides comparable anesthesia to 1% lidocaine, its primary drawback is that it is more painful to inject (6,7,9). Buffering diphenhydramine does not reduce pain of infiltration (1). Furthermore, numerous side effects have been reported by study subjects including local erythema, vesicle formation, tissue necrosis, prolonged anesthesia, and sedation (1,6,8,9). Benzyl alcohol has a low systemic toxicity, low allergic potential, low cost, and ready availability, making it an appealing option as an alternative to traditional local anesthetics (18,19). The agent has been shown to be entirely safe at a dose of 1 mL/kg (0.9% benzyl alcohol in normal saline) in dogs and monkeys (19). Benzyl alcohol has been investigated as an alternative anesthetic in prior studies (10 –12). The primary obstacle to its use is its short duration of action (10). The addition of epinephrine to benzyl alcohol has been shown to increase its duration of action in volunteer subjects with uninjured skin (13,14). However, in both of these studies, the benzyl alcohol and epinephrine solution did not last as long as lidocaine solutions (13,14). In the current study of subjects with simple lacerations, we compared benzyl alcohol with epinephrine to lidocaine with epinephrine for pain of infiltration and efficacy of anesthesia. The results of this double-blind study revealed that the median pain score (maximum ⫽ 100 mm) for benzyl alcohol with epinephrine (7.5 mm) was significantly less than lidocaine with epinephrine (19.5 mm). However, prior studies have concluded that 13 mm to 18 mm (out of 100 mm) visual analog pain score differences are of clinical significance (16,17). Therefore, this statistically significant difference may not represent a clinically significant one. More patients receiving benzyl alcohol with epinephrine in the current study required additional anesthesia during laceration repair (8/26, 31%) compared to those receiving lidocaine with epinephrine (2/26, 8%), although this difference was not statistically significant (p ⫽ 0.075). The number of minutes prior to additional anesthesia ranged from 5 to 50 min for benzyl alcohol with epinephrine compared to 25 to 85 min for lidocaine with epinephrine. Three of eight patients requiring additional anesthesia in the benzyl alcohol group had ⬍ 15 min of adequate anesthesia for suture placement. Adequacy of anesthesia was assessed prior to beginning suturing. We therefore feel that the need for additional anesthesia represents anesthesia wearing off as opposed to inadequacy of initial anesthesia. However, if the physician managing the wound did an incomplete job of
J. M. Bartfield et al.
testing for adequacy, anesthesia would have been considered worn off as opposed to inadequate from the start. Although there is no reason to suspect that this would have occurred in one group more frequently than the other, this possibility does exist and introduces a confounder and limitation in the study. We assessed the quality of anesthesia by the need for additional anesthesia. We did not assess pain of suture repair per se and are therefore unable to comment on any potential differences between the two solutions regarding this parameter. This study has several other limitations including insufficient power to detect differences between benzyl alcohol and lidocaine in need for additional anesthesia. As previously stated, four times as many patients required additional anesthesia in the benzyl alcohol group compared to the lidocaine group. Although this difference did not reach statistical significance, we suspect that a clinical difference does exist between the two groups. The fact that three of the patients in the BA group required additional anesthesia in ⬍ 15 min once again suggests a real difference between the two anesthetics. It is possible that repair could have been completed in these patients by using more benzyl alcohol with epinephrine; however, this option was not possible due to the study protocol. Future studies may address this question. Patients in this study were enrolled as a convenience sample, thus introducing the possibility of selection bias. Although we have no reason to suspect that the study population differs from the patients who were not enrolled, this comparison was not made. It is possible that injections in some locations with thicker epidermis or more sensory innervation may have been more painful than others. The groups were similar with respect to location; however, this characteristic only partially controls for this potential confounder. The anesthetic properties of the benzyl alcohol with epinephrine solution used in this study have been ascribed to the benzyl alcohol. Although the study did not test this, it is possible that some of the anesthetic properties could have been due to either the normal saline itself or the epinephrine. A previous study suggested that plain normal saline has very little anesthetic properties (10). Nevertheless, it would be more proper to draw conclusions regarding the test solution containing 0.9% benzyl alcohol, normal saline, and epinephrine 1:100,000 rather than ascribing all of the anesthetic properties to benzyl alcohol per se. It might be useful for a future study to address this issue. A further limitation is that the number of subjects may be too small to detect side effects of drugs tested. In addition, although benzyl alcohol seemed to provide adequate anesthesia for most simple laceration repairs, this result is not applicable to more invasive surgical procedures. A large prospective trial using patients un-
Benzyl Alcohol with Epinephrine as an Alternative to Lidocaine with Epinephrine
dergoing more invasive surgical procedures may be indicated in the future to determine if these results are generalizable and to better study any potential side effects. We conclude that benzyl alcohol with epinephrine is a potential alternative anesthetic for patients with simple lacerations, suspected allergy to lidocaine, and no contraindication to the use of epinephrine. Practitioners should be aware of the possibility of a relatively short duration of activity when using this agent. Acknowledgment—We thank Terry L. Peters, MS, for help with data analysis.
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