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Anesth Analg 1999;88:1131-1136
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Digital Image Analysis of Erythema Development After Experimental Thermal Injury to Human Skin: Effect of Postburn Topical Local Anesthetics (EMLA®)

U. Mattsson, OD, PhD*, J. Cassuto, MD, PhD{dagger},{ddagger}, M. Jontell, OD, PhD*, A. Jönsson, MD, PhD{dagger}, R. Sinclair, MD, PhD{ddagger}, and P. Tarnow, MD, PhD§

Departments of *Endodontology/Oral Diagnosis and {dagger}Physiology and Pharmacology, Göteborg University, Göteborg; and Departments of {ddagger}Anesthesiology and §Plastic Surgery, Sahlgrenska University Hospital, Mölndal, Sweden

Address correspondence and reprint requests to Jean Cassuto, MD, PhD, Department of Anesthesiology, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Local anesthetics inhibit edema and improve circulation in experimental burns. We evaluated the effect of topical local anesthetics on human skin burns in volunteers using computerized color analysis that allowed repeated noninvasive quantitative measurements. A standardized partial-thickness burn (1 cm2) was induced in one forearm of 10 healthy volunteers and in the opposite forearm a week later. The burned areas were treated with lidocaine/prilocaine cream (EMLA®; Astra, Sweden) or a placebo cream for 1 h. The experimental skin area was photographed before and 1, 2, 4, and 12 h postburn. Digitized images were evaluated using normalized red-green-blue and Hue-Saturation-Intensity. Differences in erythema between skin treated with EMLA® and placebo were not significant during the first 4 h postburn. However, 12 h postburn, a pronounced decrease in the degree of erythema was observed in EMLA-treated skin compared with placebo-treated skin. We conclude that topical local anesthetics administered for 1 h postburn significantly reduces the duration of erythema after a mild thermal injury, which suggests a potential use in clinical practice in the treatment of minor skin burns.

Implications: Burn injury constitutes a serious type of tissue damage that activates inflammatory mechanisms, often causing pain, disfiguration, or malfunction. We treated burns using an anesthetic cream and demonstrated a reduction in burn-induced inflammation by using computer-based color image analysis.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
When evaluating clinically visible skin color changes by ocular inspection, there is a potential risk of inter-and intraexaminer variability. The use of computerized image analysis has therefore been introduced in several fields of medicine in which objective and quantitative measurements of visible changes are required. The objectives have varied from clinical follow-up of dermatological lesions (1) to diagnostic aids and clinical classifications of dermatological lesions (2–5). Image analysis aimed at biological interpretation of tissue changes within the field of burn research was described as early as 1977 (6) and has also been used for planimetric monitoring and analysis of wound healing (7,8). In two previous studies, we presented a noninvasive technique for the analysis of experimental burns in animals (9) and humans (10). The method is based on computerized digital analysis using two different systems for the evaluation of tissue color changes, i.e., normalized red-green-blue (n-rgb) and hue-saturation-intensity (HSI) (2,11).

Previous studies have shown that topical local anesthetics reduce edema (12,13) and progressive ischemia (14) in full-thickness experimental burns. In the present study, we used digital image analysis to evaluate the effect of a topically administered local anesthetic cream on human standardized partial-thickness experimental skin burns using a noninvasive, quantitative technique based on computer analysis of skin color changes.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
After institutional review board approval and informed consent, 10 healthy volunteers aged 25–35 yr (5 male and 5 female) were included. During the experiments, the subjects lay fully dressed on a couch in a room in which the temperature was maintained at 22°C.

A mild burn injury was produced on the flexor surface of both forearms by a modified technique previously described by Cassuto et al. (12) using an electrically heated aluminum rod with a bottom surface of 1 cm2 connected to a chart writer for temperature recording. The system was calibrated by setting the room temperature on the calibration curve against a thermometer. The bottom surface of the probe was subsequently immersed in water (5 mL) and heated by turning on the current until the water boiled. At this point, the calibration curve leveled off, and the level for 100°C was set, serving as the second fixed point on the calibration curve. The current was discontinued, and the hot plate was removed from the water, dried, and allowed to cool in the air. When the temperature reached 51°C, the probe was put on the skin of the subject's forearm until the temperature reached 45°C, then removed. This procedure allowed a constant amount of heat to be administered to each skin area independent of possible variations in skin temperature. Probe pressure was standardized to 1.2 N/cm2 by pushing down a cylindrical handle, which compressed a spring on the graded probe. Possible variations in burn injury based on differences in the skin and underlying adipose tissue were minimized by using each individual as his or her own control.

The two experimental burn areas were covered with lidocaine/prilocaine cream (25 mg of each in 1 g; EMLA®, Astra, Sweden) or an identical placebo cream (except for the local anesthetic) and covered with a plastic dressing. The creams were allowed to act for 1 h, then gently removed without rubbing the skin. The volunteers and the investigator responsible for the image analysis were blinded to the experimental protocol.

Methodological evaluation of image analysis has been previously described (10). Color photographs (magnification x1.5) of the skin were taken preburn and 1, 2, 4, and 12 h postburn. Before the burn injury, two sides of the burn area were marked with a water-proof marker pen to facilitate identification of the experimental area on the photographs. A standardized focus-object distance was used in accordance with the technique described by Eliasson and Heyden (15). The camera equipment consisted of a 35-mm single lens reflex camera. A 100-mm macro lens and a telephoto converter were used with a double electronic flash unit.

All color slides were digitized using an image scanner (Dixel 2000; Hasselblad Electronic Imaging AB, Göteborg, Sweden) with a resolution of 512 x 368 pixels. The digitization was performed in 24-bit mode with 8 bits per color separation (rgb); each separation value could thus range from 0 to 255. The digitized images were then transferred to a personal computer with an extended graphics card (ATVista; Truevison Inc, Indianapolis, USA) and stored on the hard disk of the computer.

Image features were extracted from the area exposed to thermal injury in each digitized image (Fig. 1). The color changes within the test area at the time intervals mentioned above were repetitively monitored. Mean ± SD values for the color features were registered and stored in a separate file. Two color systems, n-rgb and HSI, were used in the analysis, and the algorithms were modified based on the techniques of Dhawan (2) and Ledley et al. (11).



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  		Figure 1. Upper panel, Comparison of color image feature values from unburned skin (left) to burned skin (right).Lower right panel, The thermally injured area is shown by increased n-r and decreased n-g and n-b values when described using normalized red-green-blue (rgb) values. Lower left panel, The same color changes are characterized by a pronounced increase in saturation and decreased intensity, paralleled by a small decrease in the hue value, when expressed using hue-saturation-intensity (HSI) values.

 
The values of n-rgb (n-r, n-g, n-b) were calculated from the digitized rgb values and describe the relative amount of each color separation in each pixel. An increased n-r value paralleled by decreased n-g and n-b values describes an object becoming increasingly red (Fig. 1).

The HSI system is a three-dimensional color system composed of variables adapted to the nonlinear perception of the eye. Hue (H) refers to the attribute that permits the classification and description of a color as, for example, red or green. In the HSI system, all hues are arranged in a radial fashion with values of 0–360°, in which red colors are found around 180°, as described by Jönsson et al. (9). Saturation (S) describes the purity of the color or the extent to which the color is mixed with white. A highly saturated color contains very little white. Intensity (I) is a color-neutral variable that describes the "lightness" of the color (Fig. 1).

Tissue color changes were described as differences in mean values for image variables at different time intervals. A paired two-tailed t-test was used to measure statistical differences between EMLA®- and placebo-treated sites. P < 0.05 was regarded as statistically significant.


   Results
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 Abstract
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 Methods
 Results
Discussion
 References
 
The experimental skin area remained intact during the course of the experiments, and there was no blister formation in any of the test sites. The thermally injured area could be easily identified as a sharply demarcated red area where the thermal probe had been in contact with the skin (Fig. 2). Differences in color image variables outside and within the experimental burn area are shown in Figure 1. When using normalized rgb values, burn erythema was characterized by an increased n-r value and decreased n-g and n-b values compared with unburned skin (Fig. 3). The same burn erythema expressed with HSI variables showed decreased H and I and increased S (Fig. 4).



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  		Figure 2. Clinical appearance of the skin on the flexor side of the forearm in a volunteer exposed to a standardized thermal injury treated during the first hour postburn with placebo cream or local anesthetic cream (EMLA®; Astra, Sweden). The clinical appearance of the experimental skin area preburn and 2 and 12 h postburn is shown.

 


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  		Figure 3. Relative color changes (mean ± SEM) observed in normalized red-green-blue values in burned skin treated with local anesthetic cream (EMLA®; Astra, Sweden) or placebo cream at each time interval.

 


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  		Figure 4. Relative color changes (mean ± SEM) observed for Hue-Saturation-Intensity values in burned skin treated with local anesthetic cream (EMLA®; Astra, Sweden) or placebo cream at each time interval.

 
Color changes in the erythematous burn area were clearly visible at the placebo-treated control sites of all subjects after 12 h (Fig. 2). Rgb changes in both groups were characterized by increased n-r and decreased n-g and n-b values, reaching peak values 2 h after the thermal injury, then decreasing during the following hours (Fig. 3). The magnitude of color change in EMLA®-treated sites was suppressed throughout the observation period compared with control sites, although differences were not significant during the first 4 h postburn. At 12 h postburn, erythema was significantly less pronounced in EMLA®-treated skin, as demonstrated by higher n-r and lower n-g and n-b values in the control group (P < 0.05)(Fig. 3).

During the first 2 h postburn, as erythema increased toward a peak value, 19 of 20 test sites exhibited a significant decrease in H paralleled by increased S and decreased I (Fig. 4). The color changes that occurred during the first 4 h postburn were similar in pattern in both groups, but the magnitude was less pronounced in the EMLA®-treated burn sites (Figs. 2 and 4), although differences between the groups were not statistically significant. When comparing the observed differences in image features between 0 and 12 h postburn, 8 of 10 individuals had less pronounced residual erythema on the EMLA®-treated site 12 h postburn compared with the control site (P < 0.05).


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The degree of clinically visible erythema has been described with several noninvasive techniques, such as clinical scores and various forms of spectrophotometric techniques, including the use of chromameters (16–19). Clinical scores are based on discrete variables, which are subjective because they are performed using the naked eye and depend on the interpretation of the observer. Spectrophotometric methods offer an objective measurement of light reflected from the skin surface, but the time required for registration is relatively time-consuming, and the area available for measurements is limited by the diameter of the registration probe. The digital image analysis technique described in the present study is related to spectrophotometric methods. Light reflected from the skin surface is collected on photographic film, thereby registering the clinical appearance of the skin at each time point. Digitization transforms the information in the color slides into variables that can be extracted and measured, thereby enabling objective quantitative and noninvasive analysis of skin color changes during the course of the experiment (10).

Great care was taken in placing the thermoprobe in areas of similar pigmentation, and the flexor side of the forearm was used as a test area. A clinically visible erythema developed in all test sites after the thermal injury, which could be described by both color systems (n-rgb and HSI) used in the analysis. When using n-rgb-values, the development of erythema was associated with increased n-r values and decreased n-g and n-b values (Fig. 3). The variables of the HSI system describe separate attributes of color perception and can be analyzed independent of each other. The development of erythema was marked by decreased I and H values and increased S values (Fig. 4). Moiniche et al. (20) failed to detect any reduction in color scores after the topical application of EMLA® cream to volunteers exposed to an experimental burn injury. The results of their study are questionable from several points of view. They reported blister formation and ulceration in the burned skin, which reflects significantly more extensive tissue damage than that in the present study, in which neither of these signs were found. The formation of a fluid-containing blister would inevitably produce altered optical properties (21) and jeopardize adequate color analysis. Furthermore, blister formation does not allow the local anesthetic to remain in contact with the burned skin and forms a substantial barrier for further penetration of the EMLA® cream into the skin. In addition, the authors failed to use a proper placebo cream treatment, and tissue responses were evaluated by using a subjective and crude scoring with a mixture of visual and palpatory variables, which did not allow appropriate quantification of data.

In the present study, the thermal trauma to the skin did not induce blister formation in any of the test sites. Peak erythema was observed 1–2 h postburn, as shown by increased n-r values and S values (Figs. 3 and 4). Between 2 and 4 h postburn, most test sites demonstrated a decrease in erythema, as shown by decreased n-r values (Fig. 3) and decreased S values (Fig. 4), which suggests that the amount of blood in the thermally injured area had decreased as a result of reduced venular stasis. The maximal degree of erythema was more pronounced in placebo-treated burn sites (Figs. 3 and 4) and peaked later than that in EMLA®-treated sites. Differences in n-rgb and HSI variables between the groups were not statistically significant during the first 4 h postburn, although the suppressed erythema in the EMLA® group suggests that the cream may have interfered with the initial reflex-induced postburn hyperemia of the skin secondary to its known biphasic vascular effects (22,23). This is supported by a previous study in human volunteers using the present experimental burn technique, which reported a high linear correlation between the degree of erythema (measured by using the same digital technique) and increased skin perfusion (measured by laser Doppler) during the first 4 h postburn (10), which represents early physiological changes, rather than late pathological alterations.

Significant color differences between EMLA® and placebo were found 12 h postburn (Figures 2–4). Although the skin color changes represent the visible result of all pathophysiological processes in the tissue, it seems reasonable to assume that the late phase of skin erythema is largely attributed to postburn inflammation-induced processes and that topical treatment of the burned skin with local anesthetics induces a faster restitution of tissue changes, such as venular stasis and erythrocyte sludging. The eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA®) used in the present study has been used in several clinical situations in which dermal anesthesia is required (24) and has been shown to possess high skin penetration ability, which allows it to reach deep into the thermally injured tissues. There could be several mechanisms by which local anesthetics influence burn pathophysiology because the drugs interfere with tissue inflammation at various levels. They inhibit leukocyte migration and metabolism (25–27), leukocyte adherence (25) and phagocytosis (28), and release of lysosomal enzymes (29) and oxygen radicals (29,30). Local anesthetics also act as antagonists of the arachidonic acid cascade (30,31) and, at certain concentrations, inhibit the release of histamine from rat mast cells (32). Preliminary data based on treatment of small accidental burns with EMLA® show a marked improvement of the healing processing by subduing the exaggerated and detrimental inflammatory reaction. Impairment of the skin barrier after a partial-thickness thermal injury suggests that using formulations with extremely good skin penetrability, such as EMLA® (24), is not mandatory. When using topical local anesthetics on burns, however, covering small areas is not a problem from the point of systemic toxicity, but this risk must be considered when covering larger areas. Because of the enhanced absorption from the burned skin, it is advisable to use the total doses recommended for IV administration when administering a local anesthetic topically.

The digital image analysis technique was used to measure the degree of erythema in thermally injured areas by using objective variables. The results of the present study suggest that topical treatment of a partial-thickness thermal injury using local anesthetics significantly reduces the extent and duration of inflammatory erythema. These findings, in combination with results from animal studies using a similar experimental burn technique (12) and showing that topical local anesthetics markedly reduced albumin extravasation (12,13) and significantly improved burn perfusion (14), suggest that these anesthetics are capable of reducing tissue damage from a thermal injury in humans.


   Acknowledgments
 
Supported by Swedish Medical Research Council Grants B95-17X-11234-01A, B96-17X-11234-02B and K99-73X-11234-05A.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 1, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press