Conventional ablative carbon dioxide (CO 2 ) and

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1 Lower-Fluence, Higher-Density versus Higher-Fluence, Lower-Density Treatment with a 10,600-nm Carbon Dioxide Fractional Laser System: A Split-Face, Evaluator-Blinded Study JIN YOUNG JUNG, MD, JU HEE LEE, MD, PHD, DONG JIN RYU, MD, SANG JU LEE, MD, PHD, y DONGSIK BANG, MD, PHD, AND SUNG BIN CHO, MD BACKGROUND Adequate laser settings in the treatment of scars using a carbon dioxide fractional laser system (CO 2 FS) have not been established. OBJECTIVE To compare the efficacy and safety of low-fluence, high-density with high-fluence, lowdensity treatment with CO 2 FS on acne scars and enlarged pores. METHODS Ten patients with mild to severe atrophic acne scars and enlarged pores were enrolled. Half of each subject s face was treated with a single session of CO 2 FS with a fluence of 70 mj and a density of 150 spots/cm 2 ; the other half was treated with a fluence of 30 mj and a density of 250 spots/cm 2. RESULTS Follow-up results 3 months after a single low-fluence, high-density treatment with CO 2 FS showed that four of 10 participants had clinical improvement of 51% to 75% from baseline. After the high-fluence, low-density CO 2 FS treatment, five of 10 patients demonstrated marked clinical improvements of more than 76%. CONCLUSION Higher-energy, lower-density laser settings seem to be more effective than lowerenergy, higher-density settings for acne scars and enlarged pores, although our results do not constitute a conclusive comparison of the two different modes of CO 2 FS. The authors have indicated no significant interest with commercial supporters. Conventional ablative carbon dioxide (CO 2 ) and erbium-doped yttrium aluminum garnet lasers have shown promising clinical outcomes for acne scarring, 1,2 but their usage is frequently limited in Asian patients because of the risk of adverse events, including relatively long recovery time, edema, prolonged erythema, scarring, and post-therapy dyschromia. 3,4 An ablative 10,600-nm carbon dioxide fractional laser system (CO 2 FS) is a device adopting fractional laser technology, which enables the increase of treatment area and use of higher pulse energy with minimal recovery time by leaving an intact epidermal architecture surrounding each coagulated treatment area. 3 7 Chapas and colleagues 2 reported that all 15 patients with acne scars had at least 26% to 50% improvement of their scars after three treatment sessions, and only two patients showed trace or mild post-therapy hyperpigmentation. Another study in which laser treatment was performed using two different modes (Deep FX and Active FX modes) of a CO 2 FS (Ultrapulse Encore, Lumenis, Inc., Santa Clara, CA) postulated that the combination of these two different modes of CO 2 FS could improve the therapeutic effect by providing a broader treatment zone with Active FX mode and selective coagulation of deeply located tissues with Deep FX mode, 8 but the clinical efficacy of CO 2 FS with different laser energies and densities has not been reported. In this report, we compared the efficacy and safety of low-fluence, high-density CO 2 FS treatment with that of high-fluence, low-density treatment on acne scars and enlarged Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; y Yonsei Star Skin and Laser Clinic, Seoul, Korea & 2010 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: Dermatol Surg 2010;36:1 8 DOI: /j x 1

2 TREATMENT PARAMETERS OF CO 2 FS pores in a controlled, split-face, evaluator-blinded study. Methods This was a prospective, split-face, evaluator-blinded study with low-fluence, high-density and high-fluence, low-density CO 2 FS treatments for acne scars and enlarged pores. The study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in approval by the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine, Seoul, Korea ( ). All participants provided written informed consent. Patients Ten male patients (mean age 22.2, range 19 25; Fitzpatrick skin type IV) with mild to severe acne scars and enlarged facial pores were enrolled in this study. Patient characteristics are summarized in Table 1. Patients with concomitant treatments such as skin resurfacing procedures, chemical reconstruction of skin scars using trichloroacetic acid, collagen induction therapy using a microneedle therapy system, or treatment with a nonablative 1,550-nm erbium-doped fractional photothermolysis system or CO 2 FS within the preceding 6 months were excluded. Patients with a propensity for keloids or who were pregnant, immunosuppressed, or using isotretinoin were also excluded. Laser Treatment Patients were treated in a single session of CO 2 FS using a 10,600-nm Mosaic eco2 laser (Lutronic Corporation, Goyang, Korea). The Food and Drug Administration has approved this laser, which is commercially available, for use in dermatologic procedures. For local anesthesia, the face was cleansed with a mild soap and 70% alcohol, and a topical eutectic mixture of 2.5% lidocaine hydrochloric acid and 2.5% prilocaine (AstraZeneca AB, Södertälje, Sweden) was applied to the entire face under occlusion 1 hour before laser therapy. Patients with a history of herpes virus infection were prophylactically prescribed oral valacyclovir hydrochloride (Valtrex, GlaxoSmithKline, Research Triangle Park, NC) for 3 days. On one side of the face, laser fluences were initially delivered with a pulse energy of 30 mj, a density of 150 spots/cm 2 in a single pass and in static operating mode (7.7% coverage). Additional treatment with settings of a pulse energy of 30 mj, a density of 100 spots/cm 2 in a single pass and in static operating mode (5.1% coverage) followed on the same side of TABLE 1. Improvement Grade and Patients Satisfaction Rate after a Single Session of Carbon Dioxide Fractional Laser System Treatment Improvement Grade Patient Satisfaction Grade Patient Number Sex/ Age 70 mj, 30 mj, 70 mj, 30 mj, 150 spot/cm spot/cm spot/cm spot/cm 2 1 M/ Slightly satisfied Slightly satisfied 2 M/ Satisfied Satisfied 3 M/ Satisfied Satisfied 4 M/ Satisfied Satisfied 5 M/ Satisfied Slightly satisfied 6 M/ Very satisfied Satisfied 7 M/ Very satisfied Very satisfied 8 M/ Slightly satisfied Unsatisfied 9 M/ Slightly satisfied Slightly satisfied 10 M/ Satisfied Slightly satisfied 2 DERMATOLOGIC SURGERY

3 JUNG ET AL the face, resulting in total treatment density with a pulse energy of 30 mj on one side of the face of 250 spots/cm 2 (12.8% coverage). The other half of the face was treated with a fluence of 70 mj, a density of 150 spots/cm 2 in a single pass and in static operating mode (12.3% coverage). The manufacturer provided calculated percentage coverage at each setting. To prevent an inflammatory reaction and reduce facial edema, patients were prescribed 10 mg of oral prednisolone for 3 days. Patients were instructed to use a moisturizer (Physiogel Cream, Stiefel Laboratories, Sligo, Ireland) several times daily for the first few days after treatment to promote wound healing and prevent dryness and to avoid overexposure to sunlight and use a broad-spectrum sunscreen after treatment. Patients were instructed to avoid the use of any bleaching or antiwrinkle agents during the course of treatment. Objective and Subjective Evaluations Photographs were obtained using identical camera settings, lighting, and patient positioning at baseline and 3 months after the treatment. Objective clinical assessments consisted of two blinded dermatologists comparing before and after photos separately on each side of the face in nonchronological order. The two evaluators were not informed as to the study design. We used a quartile grading scale on the evaluations (grade 1, o25% = minimal to no improvement; grade 2, 26 50% = moderate improvement; grade 3, 51 75% = marked improvement; and grade 4, 475% = near total improvement). 9 The patients were asked 3 months after the treatment about their overall rates of satisfaction (very satisfied, satisfied, slightly satisfied, unsatisfied) separately for each side of the face. Patients also reported on the side effects of the treatment, especially bleeding, oozing, post-therapy dyschromias, scaling or crusting, erythema, and aggravation of inflammatory acne lesions, also separately on each side of the face. Difference in relative pain intensity depending on the laser settings were evaluated within 1 hour after laser therapy. Histologic Evaluation To compare the histologic effects of the laser depending on the settings, we took biopsy specimens immediately after one treatment with the laser on the cheek at settings of 30 mj and 250 spots/cm 2 and 70 mj and 150 spots/cm 2, respectively, as described above from one of the healthy volunteers after obtaining informed consent, but because it is impossible to histologically compare the identical pore and scar before and after treatment, the followup biopsy was not performed. Mean diameter and depth of CO 2 FS-induced necrotic columns were calculated by measuring 10 necrotic columns on serial sections of the biopsy specimens. Statistical Analysis We compared clinical assessment scores, overall patient satisfaction levels, and the characteristics of adverse events associated with low-fluence, high-density and high-fluence, low-density treatment using the nonparametric Mann-Whitney U test with SPSS version 13.0 (SPSS, Inc., Chicago, IL). Differences were considered statistically significant at po.05. Results Follow-up results 3 months after a single low-fluence, high-density treatment with CO 2 FS, pulse energy of 30 mj and density of 250 spots/cm 2, indicated that six of 10 participants demonstrated clinical improvements of 26% to 50% from baseline (Table 1, Figures 1 and 2). Four of the patients showed moderate improvement of 51% to 75% (Figure 3). After the high-fluence and low-density CO 2 FS treatment, a pulse energy of 70 mj and density of 150 spots/cm 2, five of 10 participants demonstrated marked clinical improvements of more than 76% from baseline (Figure 3). Three patients showed moderate improvement of 51% to 75% (Figures 1 and 2), and two had clinical 36:**:2010 3

4 TREATMENT PARAMETERS OF CO 2 FS Figure 1. Atrophic acne scars and facial pores in patient 1 before (A) and 3 months after (B) treatment with 70 mj and 150 spots/cm 2 and before (C) and 3 months after (D) treatment with 30 mj and 250 spots/cm 2. improvements of 26% to 50%. The mean grade of clinical improvement based on clinical assessment was for low-fluence, high-density CO 2 FS and for high-fluence, low-density CO 2 FS (p =.02, Figure 4). After low-fluence, high-density CO 2 FS treatment, surveys evaluating overall patient satisfaction revealed that one of the 10 patients (10%) was very satisfied, five (50%) were satisfied, three (30%) were slightly satisfied, and one (10%) was unsatisfied (Table 1 and Figure 5). After highfluence, low-density CO 2 FS treatment, two of the 10 patients (20%) were very satisfied, four (40%) were satisfied, and four (40%) were slightly satisfied. The overall satisfaction levels of Figure 2. Atrophic acne scars and facial pores in patient 2 before (A) and 3 months after (B) treatment with 70 mj and 150 spots/cm 2 and before (C) and 3 months after (D) treatment with 30 mj and 250 spots/cm 2. 4 DERMATOLOGIC SURGERY

5 JUNG ET AL Figure 3. Atrophic acne scars and facial pores in patient 5 before (A) and 3 months after (B) treatment with 70 mj and 150 spots/cm 2 and before (C) and 3 months after (D) treatment with 30 mj and 250 spots/cm 2. high fluence, low-density CO 2 FS and low-fluence, high-density CO 2 FS were not significantly different (p =.29). Side effects included pain during treatment, posttreatment crusting or scaling, edema, post-therapy hyperpigmentation, bleeding and oozing from the treated sites, and aggravation of inflammatory acne lesions. All of the 10 participants replied that posttherapy crusting and scaling were resolved within a week, and no noticeable difference between the sides of the face was reported. The half of the face treated with higher fluence and lower density had a longer duration of postoperative erythema than the half with lower fluence and higher density in six of 10 patients (60%, cases 2, 4, 6, 7, 8, and 9). The difference in relative pain intensity revealed that seven of 10 patients (70%) could not feel a difference between the sides of the face, two (20%) had more pain on the side of the face treated with 70 mj and 150 spots/cm 2, and one (10%) had more pain on the side treated with 30 mj and 250 spots/cm 2. One Figure 4. Mean grade of clinical improvement according to laser settings; low-fluence, high-density (70 mj and 150 spots/cm 2 ) versus high-fluence, low-density (30 mj and 250 spots/cm 2 ). p =.02. Figure 5. Patient satisfaction levels according to treatment settings. 36:**:2010 5

6 TREATMENT PARAMETERS OF CO 2 FS patient experienced post-therapy hyperpigmentation (case 5) on both sides of the face that spontaneously resolved within 2 months. Other possible adverse events, including post-therapy blister formation, scarring, hypopigmentation, secondary bacterial infection, and viral infection, were not encountered on either side of the face. The specimens obtained from the cheek immediately after treatment showed formation of necrotic columns on the epidermis and upper dermis. The biopsy specimen from the side of the face treated with 30 mj and 250 spots/cm 2 showed two necrotic columns (original magnification 100) and the mean diameter and depth 7 standard deviation of the necrotic columns were and mm, respectively (Figure 6A). The specimen from the other side of the face treated with 70 mj and 150 spots/cm 2 presented one necrotic column at the same magnification, and the mean diameter and depth 7 standard deviation were and mm, respectively (Figure 6B). Discussion Numerous reports on nonablative and ablative FS have demonstrated its effectiveness in the treatment of a wide variety of dermatologic diseases, although there have been only a few reports comparing the therapeutic efficacy and safety of FS depending on the laser parameters. According to a recent study done in six subjects with photodamaged skin, higherdensity, lower-energy nonablative FS treatment has been found to be more effective for the treatment of pigmentary disorders. 10 Also, higher-energy, lowerdensity laser settings have been found to be better at textural improvement by producing deeper injury columns. 10 Hu and colleagues 11 reported the effectiveness of FS using a nonablative 1,550-nm erbium-doped fiber laser in treatment of atrophic acne scars. The authors divided the participants into two groups treated with different laser parameters; patients in the first group were treated with a nonablative FS at a Figure 6. Biopsy specimens obtained from cheek immediately after treatment with an ablative 10,600-nm carbon dioxide fractional laser system at settings of 30 mj and 250 spots/cm 2 (A) and 70 mj and 150 spots/cm 2 (B) (hematoxylin and eosin staining, original magnification 100; scale bars, 200 mm). setting of 15 to 20 mj/microthermal treatment zone (MTZ) and a density of 1,000 to 2,000 MTZ/cm 2. The other group of patients was treated with the same laser at a setting of 30 to 40 mj/mtz and a density of 392 to 520 MTZ/cm 2. There was no significant difference in therapeutic efficacy between the two groups. 11 In the present study, we performed CO 2 FS treatment using two different laser settings for acne scars and enlarged facial pores. Parameters of fluence and density were determined by referring to the values of percentage coverage, which a manufacturer provided. The concept of percentage coverage can reflect only two-dimensional effects of the laser 6 DERMATOLOGIC SURGERY

7 JUNG ET AL treatment. Moreover, our results demonstrating the mean diameter and depth of the necrotic columns immediately after treatment cannot exactly reflect the therapeutic effect of CO 2 FS because immediate tissue contracture with CO 2 FS treatment and selection of reviewed tissue section may significantly influence the data, 12 and therapeutic effects are correlated not only with the necrotic columns, but also with the surrounding thermal coagulated areas. However, our results may be used as reference data because most of the manufacturers provide percentage coverage values and penetration depth depending on the parameters of their CO 2 FS products. Our results showed that higher-energy, lower-density CO 2 FS treatment resulted in more pronounced clinical outcomes than with the higher-density, lower-energy setting. The results of our study were compatible with those of previous reports indicating therapeutic effects of nonablative FS on textural improvement and skin rejuvenation. 10,13 Kono and colleagues 13 reported that pain, erythema, and swelling were more pronounced or lasted longer in patients treated with higher densities and fluencies of a nonablative FS. In the present study, although the difference in the duration of post-therapy crusting and scaling depending on laser settings was not remarkable, post-therapy erythema was more pronounced and lasted longer with the setting of 70 mj and 150 spots/cm 2. Our study group previously demonstrated the therapeutic effect of a 1,550-nm erbium glass fractional laser on acne scars and enlarged pores. 14 We postulated that collagen reproduction in the dermis could result in textural changes and shrinkage of pores, mostly due to perifollicular collagen formation, as well as a direct effect on the follicular epithelium of the pore, 13 but multiple sessions of nonablative fractional laser therapy are generally required to achieve satisfactory clinical improvement. 2,15 In the present study, we observed clinical improvements in acne scars and enlarged pores with a single CO 2 FS treatment. Direct effect on the follicular epithelium of the pore was histologically shown with higher-density, lower-energy treatment, although considering our results, textural changes mostly due to perifollicular collagen formation might have mainly contributed to the pronounced clinical outcomes. In conclusion, we demonstrated the efficacy and safety of single-session treatment of acne scars and enlarged facial pores using CO 2 FS depending on different laser settings in East Asian patients in a randomized, split-face, evaluator-blinded study design. A higher-energy and lower-density laser setting seems to be more effective than one with lower energy and greater density for acne scars and enlarged pores. We believe our study could be used as an essential reference when choosing laser modalities for treatment of scars and enlarged pores. Our results do not constitute a conclusive comparison of the two different modes of CO 2 FS because of the small study sample, which also consisted of only male patients. References 1. Tay YK, Kwok C. Minimally ablative erbium:yag laser resurfacing of facial atrophic acne scars in Asian skin: a pilot study. Dermatol Surg 2008;34: Chapas AM, Brightman L, Sukal S, et al. Successful treatment of acneiform scarring with CO 2 ablative fractional resurfacing. Lasers Surg Med 2008;40: Hasegawa T, Matsukura T, Mizuno Y, et al. Clinical trial of a laser device called fractional photothermolysis system for acne scars. J Dermatol 2006;33: Lee HS, Lee JH, Ahn GY, et al. Fractional photothermolysis for the treatment of acne scars: a report of 27 Korean patients. J Dermatol Treat 2008;19: Manstein D, Herron GS, Sink RK, et al. Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Laser Surg Med 2004;34: Laubach HJ, Tannous Z, Anderson RR, Manstein D. Skin responses to fractional photothermolysis. Lasers Surg Med 2006;38: Geronemus RG. Fractional photothermolysis: current and future applications. Lasers Surg Med 2006;38: Cho SB, Lee SJ, Kang JM, et al. The efficacy and safety of 10,600-nm carbon dioxide fractional laser for acne scars in Asian patients. Dermatol Surg 2009;35: :**:2010 7

8 TREATMENT PARAMETERS OF CO 2 FS 9. Tanzi EL, Alster TS. Comparison of a 1450-nm diode laser and a 1320-nm Nd:YAG laser in the treatment of atrophic facial scars: a prospective clinical and histologic study. Dermatol Surg 2004;30: Walgrave S, Zelickson B, Childs J, et al. Pilot investigation of the correlation between histological and clinical effects of infrared fractional resurfacing lasers. Dermatol Surg 2008;34: Hu S, Chen M, Lee M, et al. Fractional resurfacing for the treatment of atrophic facial acne scars in Asian skin. Dermatol Surg 2009;35: Berlin AL, Hussain M, Phelps R, et al. A prospective study of fractional scanned nonsequential carbon dioxide laser resurfacing: a clinical and histopathologic evaluation. Dermatol Surg 2009;35: Kono T, Chan HH, Groff WF, et al. Prospective direct comparison study of fractional resurfacing using different fluencies and densities for skin rejuvenation in Asians. Lasers Surg Med 2007;39: Cho SB, Lee JH, Choi MJ, et al. Efficacy of the fractional photothermolysis system with dynamic operating mode on acne scars and enlarged facial pores. Dermatol Surg 2009;3: Rinaldi F. Laser: a review. Clin Dermatol 2008;26: Address correspondence and reprint requests to: Sung Bin Cho, MD, Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemoon-gu, Seoul , Korea, or sbcho@yuhs.ac 8 DERMATOLOGIC SURGERY