Damage to tissue defenses by a topical anesthetic agent

ORIGINAL CONTRIBUTION anesthetics, topical; TEC; tetracaine

Damage to Tissue Defenses by a Topical Anesthetic Agent The purpose of this study was to determine the effect of a topical application of a solution containing 0.5% tetracaine, 1:2,000 epinephrine, and 11.9% cocaine on the wound's ability to resist infection. In this experimental study, this solution potentiated the development of wound infection. This effect can be explained by its vasoconstrictive action limiting access of the cellular defenses to the bacteria on the wound surface. [Barker W, Rodeheaver GT, Edgerton MT,, Edlich RF: Damage to tissue defenses by a topical anesthetic agent. Ann Emerg Med 11:307-310, June 1982.]

William Barker, MD George T. Rodeheaver, PhD Milton T. Edgerton, MD Richard E Edlich, MD, PhD Charlottesville, Virginia From the Emergency Medical Service, University of Virginia Medical Center, Charlottesville, Virginia.

INTRODUCTION Clinical use of topical anesthetic agents has been limited to mucosal surfaces. Until recently, local anesthesia for skin lacerations has been accomplished by either local infiltration anesthesia or regional nerve blocks. A recent clinical study reported by Pryor, Kilpatrick, and Opp 1 indicated that skin lacerations could be anesthetized by topical application of a solution containing 0.5% tetracame, 1:2,000 epinephrine, and 11.8% cocaine (TEC). In a randomized prospective study of 138 patients, 1 TEC offered distinct advantages over infiltration anesthesia with 1% lidocame. The most important advantage was that it resulted in anesthesia without the discomfort associated with injection of infiltration anesthesia. The pain encountered during infiltration anesthesia is related to the needle puncture wound as well as to dissemination of the local anesthetic agent through the tissue. In addition, the injected anesthetic agent resulted in considerable swelling and distortion of the wound edges, making meticulous structural reapproximation of the wound edges more difficult. Anesthesia with TEC did not involve this assault, but was accomplished by applying a 4 x 4 inch gauze pad saturated with a solution of TEC. This painless induction of local anesthesia was associated with a reduction in the length of time required for suture closure of lacerations in children from 1 to 5 years of age and 11 to 17 years of age as compared to that when infiltration anesthesia was used m patients of similar age groups. An additional benefit of TEC was its intense vasoconstrictive effect, which resulted in a bloodless wound. This vasoconstrictive effect was so profound that investigators did not employ this topical anesthetic solution in lacerations involving the ear, penis, or digits to avoid compromising their limited vascularity. This hemostatic effect of TEC may, however, limit access of the body's defenses to the wound and decrease the wound's resistance to infection. The increased potential for infection of TEC-treated wounds was not evident in the small clinical study reported by Pryor, Kilpatrick, and Opp. t Their inability to identify i1-npaired host defenses in TEC-treated wounds may be due to the design of their clinical study and/or the level of bacterial contamination in the wounds. Most lacerations treated in the emergency department are clean wounds contaminated with a subinfective dose of bacteria {<10 s bacteria/gram of tissue} and have a very low risk for infection (1% to 2%).2 With this extremely low rate of infection, clinical trials involving patients with lacerations must include a larger patient population (> 500 patients} to show treatment effects. A simpler and less time-consuming approach to determine the potential toxicity of wound treatments has been to initiate well-designed experimental 11:6 June 1982

Annals of Emergency Medicine

Presented at the University Association for Emergency Medicine Annual Meeting in San Antonio, Texas, April 1981. Address for reprints: Richard E Edlich, MD, PhD, Emergency Medical Service, University of Virginia Medical Center, Charlottesville, Virginia 22908.

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TOPICAL ANESTHETIC Barker et al

Fig. 1. Topical application of TEC potentiated the development of refection and resulted in tissue necrosis. TEC also encouraged proliferation of bacteria in wounds.

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studies. We report the results of such an experimental study that was designed to detect the potential toxicity of TEC.

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Drugs The topical anesthetic agent employed a solution containing epinephrine (1:2,0001, tetracaine (0.5% I, and cocaine {11.8%). Solutions were prepared immediately before each experiment to prevent oxidation of epinephrine.

Experimental Design Male Hartley guinea pigs were used in the first series of experiments. Using a standardized experimental model, two incisions were made in the p a r a v e r t e b r a l s k i n and e x t e n d e d through the panniculus carnosus. 7 The wounds were contaminated with 104 Staphylococcus aureus (ATCC No. 2801) contained in 0.05 ml of 0.9% sodium chloride. Five minutes later, one wound in each animal received 1 ml TEC soaked in a 2 x 2 inch gauze sponge, while the contralateral wound received 1.0 ml of 0.9% sodium chloride serving as a control. Five minutes after t r e a t m e n t , the edges of the wounds were approximated with microporous tape (Reinforced SteriStrips, 3M Center, St Paul, MN). Four days later, the inflammatory responses of the wotmds were measured. Using aseptic technique, the wounds were opened and inspected for evidence of purulent discharge and/or necrosis of the wound edge. An estimate of the n u m b e r of viable b a c t e r i a in the wound was determined by swabbing the length of the wound with a sterile, cotton-tipped applicator and then determining the bacterial count of the applicator using standard bacteriologic techniques. 7 The second series of experiments examined the influence of the components of TEC on the tissue's ability to resist infection. Male, albino rabbits, weighing 2 kg to 3 kg, were anesthetized with sodium pentobarbital {33 mg/kg) administered intravenously. Each animal's back was shaved, depilated, and washed with a 70% ethyl 38/388

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CONTROL alcohol solution. Inoculation sites in the animal's paravertebral skin were separated by a distance of 5 cm. An intradermal injection of 0.1 ml of a designated solution was delivered to each inoculation site through a 25gauge needle. The test solutions contamed a known number of S aureus suspended in TEC, cocaine (10%) and tetracaine (0.5%), cocaine (10%), tetracaine (0.5%), or saline (0.5%). Four days later, the inflammatory responses of the inoculation sites were recorded. The presence of necrosis of the skin edges was also noted. An incision was made through each inoculation site with a sterile NO. 15 surgical blade. Gross infection was judged to be present when purulent discharge was evident. The inoculation sites were excised with a 2- to 4,ram margin of uninflamed skin. The tissues were homogenized separately and the n u m b e r of viable b a c t e r i a in the Annals of Emergency Medicine

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TEC h o m o g e n a t e w a s d e t e r m i n e d by routine serial dilution techniques. 7

RESULTS T h e topical a p p l i c a t i o n of TEC damaged the host defenses and invited the development, of infection. The infection rate of TEC-treated wounds was significantly higher than that of the controls (P < 0.05} {Figure 1). An even more alarming finding was the tissue necrosis at the edges of infected TEC-treated wounds. The bacterial counts of the wounds were proportional to the incidence of infection. The TEC-treated wounds displayed a significantly higher bacterial count than did the saline-treated wounds (P < 0.001)(Figure 1). ' The infection-potentiating effects of TEC appeared to be due, in part, to the cocaine (Figures 2A and 2B). The infection rate of tissues treated with cocaine alone or cocaine with tetra11:6 June 1982

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Fig. 2. A. Infection rate and incidence of necrosis of contaminated tissues subjected to TEC, cocaine, and a m i x t u r e of tetracaine and cocaine were greater than that of control tissues. B. Bacterial counts of tissue subjected to these anesthetic agents were higher than those of controls.

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DISCUSSION The use of topical anesthesia dates back to the oldest writing of Greek medicine in 900 BC. 8 Until recently, topical anesthetic agents have been reserved for local anesthesia of mucous m e m b r a n e s . In a study of over 40 drugs by Adriani and Zepernick, 3 tetra11:6 June 1982

caine, cocaine, dibucaine, lidocaine, dyclonine, and hexylcaine proved to be the most effective topical anesthetic agents for use on mucous membranes. Vasoconstrictors, detergents, or demulcents did not enhance or prolong the effects of local anesthetic agents. Pryor, Kilpatrick, and Opp 1 reported that a mixture of tetracaine, epinephrine, and cocaine w a s an effective topical anesthetic agent for wounds. An additional benefit of this mixture was its hemostatic effect, which was attributed to the v a s o c o n s t r i c t i v e activity of the topical agents. The use of this topical agent did not signifiAnnals of Emergency Medicine

c a n t l y i n c r e a s e the i n c i d e n c e of wound complications. Epinephrine is an aromatic amine that acts at adrenergic receptors, resulting in vasoconstriction. When added to s o l u t i o n s of a n e s t h e t i c agents, it prolongs the duration of anesthesia when injected perineurally, peridurally, intrathecally, or into tissue (infiltration anesthesia), but has no significant effect on the duration of topical anesthesia? Cocaine, a benzoic acid ester, is the only local anesthetic agent that consistently produces vasoconstriction; its mechanism is inhibition of uptake of catecholamines into tissue degradation sites. 4 This inhibitory effect on catecholamine breakdown, particularly norepinephrine, is ultimately responsible for the prolonged state of vasoconstriction after administration of cocaine. Topical s o l u t i o n s of cocaine have been c o m m o n l y employed for intranasal surgery. This agent produces vasoconstriction of the mucosal vessels, reducing operative blood loss. Delilkan 5 reported that a c o m b i n a t i o n of e p i n e p h r i n e and cocaine offered no advantage over 5% cocaine. Tetracaine (2-dimethylaminoethyl 4-butylaminobenzoate) is the most potent of the aminoesters in clinical use and is usually employed by itself as an i n j e c t a b l e and topical a n e s t h e t i c agent. It remains the most commonly used drug for spinal anesthesia. Blood flow studies have shown that tetracaine causes vasodilation. 6 Our e x p e r i m e n t a l study demonstrated that TEC damaged the local wound defenses and encouraged the development of infection. The infect i o n - p o t e n t i a t i n g effect of TEC is probably related to its vasoconstrictive action which can be readily identified by the intravenous injection of a fluorescein dye. This vasoconstrictive effect can be blocked by the addition of phentolamine to the solution. As a result of its effects, TEC may cause hypoxic conditions that limit white blood cell function. 3(}9/39

TOPICAL ANESTHETIC Barker et al

Fig. 3. T e t r a c a m e did n o t d a m a g e h o s t defenses a n d i n v i t e infection. Bacterial counts of tissues s u b j e c t e d to tetracaine did n o t differ significantly from those of controls.

NECROSIS GROSS INFECTION

In vitro studies by Hohn et aP and Mandell 1° have d e m o n s t r a t e d t h a t hypoxia retards killing of S aureus by leukocytes. This increased infectabilivy of TEC-treated wounds m a y result from impaired killing of S aureus by wound leukocytes at low oxygen tensions. T h e potential danger of the v a s o c o n s t r i c t i v e a c t i o n of TEC is consistent with the toxicity of other vasoconstrictors studied in our laboratory. H In those investigations, epinephrine potentiated the development of i n f e c t i o n in e x p e r i m e n t a l contaminated wounds. When the vasoconstrictive effect of epinephrine was blocked by phentolamine, its deleterious effects on w o u n d defenses were eliminated. While our recent studies s h o u l d serve as a warning about using TEC in the emergency department, research to identify a safe, n o n t o x i c topical anesthetic agent for use in wounds should n o t be deterred. Tetracaine may not damage tissue defenses, but its efficacy as a topical anesthetic agent in skin wounds has not been documented. Moreover, its systemic side effects after topical use m u s t also be considered. Before initiating h u m a n clinical trials, we m u s t be assured that this agent is not absorbed from the wound in toxic amounts. Until a topical anesthetic agent has been proven safe and effective for clinical use, infiltration anesthesia with lidocaine remains the safest and most effective local anesthesia for use in the emergency department. 11 We reco m m e n d that lidocaine be delivered either as a regional block or through the intact skin around the cut edges of the wound. While this infiltration anesthesia is associated with considerable pain, the magnitude of this discomfort can be reduced by employing a 27- or 29-gange needle.

SUMMARY A topical anesthetic solution (TECI containing 0.5% tetracaine, 1:2,000 epinephrine, and 11.8% cocaine has been recommended for use in patients w i t h s k i n l a c e r a t i o n s . In our experimental study, exposure of wounds to TEC damaged host defenses and increased susceptibility to infection. T h e infection-potentiating effect of 40/810

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T E C w a s due to t h e p r e s e n c e of cocaine and epinephrine, and probably can be explained by their vasoconstrictive action. Tetracaine by itself had no deleterious effects on host defenses.

REFERENCES 1. Pryor G, Kflpatrick WR, Opp DR: Local anesthesia in minor lacerations: Topical TEC versus lidocaine infiltration. Ann Emerg Med 9:568-571, 1980. 2. Marshall KA, Edgerton NIT, Rodeheaver GT, et al: Quantitative microbiology: Its application to hand injuries. A m J Surg 131:730-733, 1976. 3. Adriani l, Zepernick R: Clinical effectiveness of drugs used for topical anesthesia. lAMA 181:711-716, 1964. 4. Muscholl E: Effect of cocaine and related drugs on the uptake of noradrenaline by heart and spleen. Br J Pharmacol 16: 352-359, 1961. 5. Delilkan AE: Topical cocaine/adrenalin combination in intranasal s u r g e r y - is it Annals of Emergency Medicine

necessary.~ Anaesth Intensive Care 6:328332, 1978. 6. Covino BG, Vassallo HG: Local Anesthetics. Mechanisms of Action and Clinical Use. New York, Gmne & Stratton, 1976, p 106. 7. Edlich RF, Tstmg M-S, Rogers W, et al: Studies in the management of the contaminated wound. I. Technique of closure of such wounds together with a note on a reproducible experimental model. J Surg Res 8:585-592, 1968. 8. Majno G: The Healing Hand, Man and Wound in the Ancient World. Cambridge, Harvard University Press, 1977, p 144. 9. Holm DC, MacKay RD, Halliday B, et al: Effect of 02 tension on microbicidal function of leukocytes in wounds and in vitro. Surg Forum 27:18, 1976. 10. Mandell GL: Bactericidal activity of aerobic and anaerobic polymorphonuclear neutrophils. Infect Immun 9:337, 1974. 11. Stevenson TR, Rodeheaver GT, Golden GT, et al: Damage to tissue defenses by vasoconstrictors. JACEP 4:532-535, 1975. 11:6 June 1982