Post-inflammatory hyperpigmentation after carbon dioxide laser: review of prevention and risk factors (2024)

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Dermatol Reports
v.15(4); 2023 Dec 1
PMC10777097

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Dermatol Reports. 2023 Dec 1; 15(4): 9703.

Published online 2023 May 19. doi:10.4081/dr.2023.9703

PMCID: PMC10777097

PMID: 38205425

Alhanouf Bin Dakhil,¹ Asem Shadid,² and Saad Altalhab¹

Author information Article notes Copyright and License information PMC Disclaimer

Abstract

The CO₂ laser has been widely utilized in dermatology; its expanding clinical applications include the management of neoplastic lesions, benign growths, cosmetic conditions, and reactive disorders. The laser’s popularity is mainly due to the high precision and short recovery time this technology provides. However, postinflammatory hyperpigmentation (PIH) has been one of the challenging adverse effects of the CO₂ laser. Therefore, several modalities have been studied for the prevention of PIH following CO₂ laser treatment. This review aims to analyze the incidence of PIH after CO₂ laser therapy, identify its risk factors, and assess the efficacy of the examined treatment modalities in preventing PIH. Pubmed and Embase databases were searched for this study, and relative clinical trials were included in the review. Descriptive findings – including age, gender, skin type, types of intervention, and incidence of PIH – were reported. When appropriate, the incidence of PIH was compared across each possible individual factor, such as skin type, gender, and type of intervention. A total of 211 articles were identified, and 14 relevant articles were included in this review. Seventy percent of the subjects were females (n=219), and 30% were males (n=94), with a mean age of 30 years (SD=7.8). The most common skin types were type IV (59%) followed by type III (25%). In total, eight studies investigated the prevention of PIH. The incidence of PIH after CO₂ laser significantly varies between studies and differs based on the type of intervention. The studies indicate that the use of Clobetasol propionate 0.05% and fusidic acid cream appeared to effectively reduce PIH, recording an incidence rate of 39% and 53.3%, respectively. The Fitzpatrick-skinphenotype did not appear to influence the risk of PIH. There is a lack of high-powered clinical studies analyzing the incidence of PIH after CO₂ laser treatment and the associated risk factors. PIH occurrence may be related to inflammation resulting from thermal damage by the CO₂ laser. Consequently, the use of postoperative topical medications with anti-inflammatory properties might reduce its incidence. The use of ultra-potent topical corticosteroids and topical fusidic acid appeared to reduce PIH, possibly reducing postoperative inflammation effectively. Similarly, platelet-containing plasma may be beneficial in reducing CO₂ side effects, including PIH. However, more studies are needed to further establish the influence of skin type on PIH and investigate modalities to reduce PIH occurrence after CO₂ laser use.

Key words: CO₂ laser, postinflammatory hyperpigmentation, clobetasol propionate, fusidic acid, review

Introduction

With recent advancements in the field of dermatology, lasers have become an important and indispensable treatment modality with common application.¹ One of the first lasers developed was the carbon dioxide (CO₂) laser, which was created in 1964. Initially, the use of this particular type of laser was delineated to surgical procedures because of its high absorption by water.² However, over the years, the CO₂ laser’s usage has significantly expanded to include the treatment of both benign and malignant conditions, as well as cosmetic treatments and aesthetic imperfections. ^1,2 This is primarily due to the high precision that the CO₂ laser provides, in addition to the reduced presence of side effects like inflammation and slow healing.¹

CO₂ lasers are divided into two types: fractionated and unfractionated. Fractionated lasers are further separated into two subtypes: ablative and nonablative. Fractionated lasers, both ablative and nonablative, are considered safer than their nonfractionated counterparts due to their smaller columns’ microthermal zones. Nevertheless, both types can potentially lead to adverse effects, such as erythema and edema. Postinflammatory hyperpigmentation (PIH) is another side effect that is seen with the use of several different lasers, including CO₂.¹ This condition occurs due to hypermelanosis, which results from dermal inflammation. It is known to be the most common side effect of lasers in individuals with darker skin.³ Therefore, its occurrence in some geographic areas, such as the Middle East, is thought to be more common and severe.³ Although most cases resolve spontaneously, the duration of PIH varies depending on the patient, and the therapeutic options to accelerate its healing are very limited.¹ Similarly, little is known about preventing PIH after laser treatment, especially CO₂. To our knowledge, this is the first review to investigate the occurrence of PIH after CO₂ laser therapy, as well as the efficacy of the available modalities in preventing this adverse effect.

Materials and Methods

A literature search on the PubMed and Embase databases was conducted from the first available date until 30/9/2021. Pre-identified search terms included “carbon dioxide”, “laser”, “resurfaces” “fractional”, “ablation”, “pigmentation”, “hyperpigmentation”, and “postinflammatory”. Inclusion criteria is comprised of prospective studies investigating carbon dioxide (CO₂) lasers and addressing PIH. Case reports, case series, letters, comments, reviews, and non-English articles – or those that did not discuss carbon dioxide (CO₂) laser or address PIH – were excluded.

Study characteristics were extracted, including authors’ names, year of publication, and study design; participants’ age, gender, and skin type; types of interventions to reduce CO₂ side effects; and study outcomes. First, descriptive findings, including age, gender, skin type, types of intervention, and incidence of PIH were reported. When appropriate, the incidence of PIH was compared across possible influencing factors, such as skin type and method of intervention used to reduce PIH.

Results

Our search revealed a total of 211 records (Appendix 1). After removing duplicates, title and abstract screening were performed and led to the exclusion of 118 records. Full-text screening of the remaining 24 studies was thus completed. Ten records were further excluded for the following reasons: one study did not address PIH;⁴ another study did not involve CO₂ laser;⁵ others were a case report,⁶ and a review article;⁷ and six studies were retrospective analyses (Figure 1).^8-13 After these exclusions, fourteen studies met the inclusion criteria. The characteristics of the included studies are shown in (Table 1). The studies included 313 participants, with a ratio of 70% females (n=219) and 30% (n=94) males. The age was recorded in 273 subjects, with a reported mean age of 30 years (SD=8.1). Fitzpatrick skin phototypes were reported individually in 259 participants. The most common skin type was type IV (n=164, 59%) followed by type III (n=70, 25%) (Table 2). The overall incidence of PIH after CO₂ laser treatment significantly varies between the studies, ranging from 0% to 100%. The incidence of PIH differs based on whether a medical intervention was used to decrease side effects of CO₂; it is also dependent upon the type of the intervention. Eight studies including 258 participants examined the efficacy of medical interventions in the prevention of PIH.^3,11,14-19 These include the topical use of Fusidic acid compared to topical erythromycin (n=60);¹⁴ clobetasol propionate 0.05% compared to petroleum jelly (n=40);³ an experimental moisturizer containing 5% panthenol, madecassoside, and copperzinc- manganese (PMCZ) compared to triamcinolone acetonide 0.02% (n=20);¹⁶ MAS063DP (Atopiclair) cream compared to triamcinolone acetonide 0.02% (n=16);¹⁹ platelet-poor plasma gel compared to saline (n=36),¹¹ platelet-rich plasma (PRP) (n=30);¹⁷ epidermal growth factor compared to petroleum jelly (n=19);¹⁵ and multi-growth factor (MGF)-containing cream compared to placebo (n=20).¹⁸ Six studies did not use any adjunctive or postoperative interventions.^20-25

Topical corticosteroids were used by three studies.^3,16,19 This involved an ultra-potent corticosteroid (clobetasol propionate 0.05%), and a mid-strength treatment (triamcinolone acetonide 0.02%), either as an experimental intervention or as a control. When topical clobetasol propionate 0.05% was used, the incidence of PIH was 39%.³ However, the PIH incidence was with triamcinolone acetonide 0.02% was 55% and 43.7%.^16,19 Topical antimicrobials, fusidic acid cream erythromycin ointment, were examined by one study.¹⁴ The incidence of PIH with fusidic acid cream was 53.3%, while it was 91.1% with the use of erythromycin ointment. What’s more, PIH incidence was 52.6% with topical epidermal growth factor, and 60% with the use of PMCZ.²⁶ With MAS063DP, the incidence of PIH was recorded in 50% of the participants.¹⁹ Two studies examined concurrent injection of platelet-containing plasma.^11,17 With PRP, the incidence of PIH was only 16%, while it was 36% with platelet-poor plasma injection. The incidence of PIH based on gender and Fitzpatrick skin phototypes (FSP) were reported in 101 subjects. Ultimately, the difference in PIH incidence based on skin type was not significant in any study.

Figure 1.

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Diagram of the included studies.

Table 1.

Characteristics of the included studies

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PIH, postinflammatory hyper pigmentation; PMCZ, 5% panthenol, madecassoside, and copper-zinc-manganese; PRP, platelet-rich plasma; NR, not reported; NA, not applicable.

Table 2.

Fitzpatrick skin phototypes.

Type	N (%)
Not reported	18 (6.5)
Type I	3 (1.1)
Type II	6 (2.2)
Type III	70 (25.3)
Type IV	164 (59.2)
Type V	16 (5.8)

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Discussion

The development of PIH after CO₂ laser treatment has been postulated as a melanocyte response to inflammation, resulting from the thermal damage caused by irradiation.³ During the inflammatory phase, prostanoids, cytokines, chemokines, and other inflammatory mediators lead to the overproduction of melanin by melanocytes. This melanin is then transferred to the surrounding keratinocytes, thus leading to irregular dispersion of pigment.^3,27 Nonetheless, the fundamental processes in the development and variability of PIH in individuals are not fully understood – particularly the risk factors for the occurrence and severity of PIH. Some theorists propose that PIH incidence is somewhat related to the functionality and ability of an individual’s melanocytes to respond to inflammation with hyperpigmentation. In this assessment, they refer to the patient’s melanocytes as “weak” or “strong”.^3,28 In this review, the incidence of PIH after CO₂ laser therapy significantly varies in the included studies, between 0% to 100% occurrence.

It has been proposed that PIH is mostly observed in people with darker skin, hastily linking this occurrence to Fitzpatrick skin phototypes.¹ However, it must be noted that none of the included studies found a significant difference in PIH incidence among the participants based on FSP. The incidence was reported to be 0% in the Tan et al. study, in which all participants (n=7) had either FSP IV or V.²² In fact, the authors suggested that FSP IV and V carry a lower risk of the development of PIH after CO₂ laser treatment. On the other hand, all of the participants (n=40) in Cheyasak et al.’s study had FSP IV, and the PIH incidence was as high as 75%.³ The highest reported incidence of PIH (100%) was reported by Alster et al.; in this case, all the participants (n=7) had either FSP I or II.²⁰ Conducted by Wei et al., the study with the largest sample (n=60) reported FSP types ranging from III to IV, with a total incidence of PIH being up to 90%.¹⁴ Lastly, Lueangarun et al. reported that in their study, the incidence of PIH in FSP III and IV was identical (50%).¹⁹ These findings indicate that FSP might not be an independent risk factor for the development of PIH following CO₂ laser therapy. However, it should be noted that the inconsistency of these findings has three possible roots: the variation sample size, different PIH evaluation modalities, and the lack of individual PIH reporting based on FSP by all studies. Further studies are necessary to determine the relationship between skin phototype and PIH. The treatment of PIH is broadly challenging and requires patience and compliance. Some treatments – such as topical hydroquinone, tretinoin, glycolic acid, and vitamin C – have been used to remedy this skin reaction. But when PIH occurs, it may last for several months regardless of the use of treatment.^3,29,30

Therefore, the use of perioperative and postoperative therapies to prevent PIH in dermatologic procedures is viewed as a possible way to overcome this common complication. However, the evidence is still developing. Eight of the included studies examined the efficacy of off-label or investigational use of several treatments in the prevention of PIH after CO₂ laser use.^{3,11,14-19,22,24} Among these treatments are topical corticosteroids, antimicrobials, topical growth-factors, and experimental therapies.

Topical corticosteroids

TC reduce inflammation by inhibiting phospholipase A2 and delaying the release of arachidonic acid from the cell membrane. Because of PIH’s inflammatory nature, the use of TC after CO₂ lasers has been proposed as a potential preventative modality to decrease the risk of PIH. Takiwaki et al. have previously demonstrated that topical clobetasol propionate and hydrocortisone butyrate decrease the incidence of UVB-induced hyperpigmentation. ³¹ Topical corticosteroids (TC) after CO₂ laser therapy was described in two of the included studies.^3,16 Cheyasak et el. compared clobetasol propionate 0.05% ointment to petroleum jelly. In this comparison, they found that the use of clobetasol propionate 0.05% significantly decreased PIH incidence to 39%, compared to 75% with petroleum jelly (p<0.001). This finding supports the theory that controlling inflammation at earlier phases may reduce potential consequences like PIH. On the other hand, Lueangarun et al.¹⁶ investigated the effect of PMCZ cream on the incidence of CO₂ laser-related side effects. As a comparative tool, they also used triamcinolone acetonide 0.02% cream. The study reported that PIH was recorded in 55% of triamcinolone acetonide 0.02% group participants, compared to 60% with PNCZ cream. In another study by Lueangarun et al.,¹⁹ PIH with the use of triamcinolone acetonide 0.02% was recorded at 43.7%. Upon studying these results, it is possible that PIH incidence with triamcinolone acetonide (55% and 47.3%),^16,19 compared to clobetasol propionate (39%)³ could be related to the corticosteroids potency. Clobetasol propionate 0.05% is an ultra-potent TC; meanwhile, triamcinolone acetonide 0.02% is regarded as a mid-strength TC.³² Thus, it might be reasonable to postulate that the incidence of PIH with clobetasol propionate 0.05% was lower because of its more potent effect in reducing inflammation. Lueangarun et al.¹⁶ reported that PMCZ cream was not superior to triamcinolone acetonide 0.02% in reducing CO₂ laser postoperative downtime; however, both regimens reduced redness and swelling. Nevertheless, PMCZ is still a novel experimental moisturizer, and its anti-inflammatory properties have not yet been adequately studied.

Topical non-steroidal anti-inflammatory drugs

MAS063DP lotion is a non-steroidal anti-inflammatory moisturizer typically used to treat different forms of dermatitis. Lueangarun et al.¹⁹ used MAS063DP lotion (Atopiclair® brand lotion) after CO₂ ablation, in an effort to assess its ability to prevent PIH. The study found that MAS063DP was not superior to triamcinolone acetonide 0.02% in reducing the incidence of PIH after CO₂ ablation (50% vs. 47.3, respectively). The results of this study may endorse the theory that the preventative agent’s antiinflammatory potency is an important factor in controlling PIH. This is supported by the fact that clobetasol propionate 0.05% appeared to successfully reduce PIH, in contrast to triamcinolone acetonide 0.02% and MAS063DP.

Antimicrobials

The use of topical antimicrobials after laser therapy treatment has been described in the past; however, its effect on PIH development has not been completely established.³³ This rule was examined by Wei et al.,¹⁴ and included the use of fusidic acid cream or erythromycin ointment. The authors reported a statistically significant difference in the incidence and severity of PIH with the use of fusidic acid cream compared to erythromycin ointment (p<0.05).¹⁴ Fusidic acid cream (53.3%) appeared to effectively reduce PIH after CO₂ laser therapy more than erythromycin ointment (93.1%). Fusidic acid is the only approved topical antibiotic from the fusidane family.²⁶ The product has some anti-inflammatory properties, such as inhibiting proinflammatory cytokines of TNF-α, IL-1β, and COX-2.²⁶ The findings by Wei et al.¹⁴ might be due to the fact that fusidic acid reduces postoperative inflammation, and therefore decreased PIH. Nevertheless, more studies are needed to determine the influence of fusidic acid on PIH.

Platelet-containing plasma

Platelet-containing plasma either PRP or platelet-poor plasma – has been used in conjunction with CO₂ laser therapy. Two studies have demonstrated this treatment’s efficacy in reducing CO₂ laser side effects. Gad et al.¹¹ reported that PIH after CO₂ laser therapy significantly decreased with the use of platelet-poor plasma (p=0.021). Furthermore, the incidence of PIH after CO₂ laser treatment was only 16.6% with the use of PRP. The decrease of PIH with platelet-containing plasma could be attributed to its stimulation effect, which impacts the extracellular signal-regulated kinase and the suppressive effect of TGF-β1 on melanin synthesis.^11,34 This is in addition to the basem*nt membrane repair effect by platelet degranulation, and the release of laminin, collagen IV, and tenascin.^11,34

Epidermal growth factor

Epidermal growth factor (EGF) plays a crucial role in the wound healing process; yet its external use in the clinical setting has not been well established. Nevertheless, some studies examined the effect of topical EGF on prompting wound healing in acute tissue injuries – such as radiation-induced mucositis – and received positive results.³⁵ Techapichetvanich et al.¹⁵ evaluated the effect of topical EGF on PIH prevention after CO₂ laser therapy. However, the study did not find a statistically significant difference in PIH occurrence with the topical application of EGF. The authors proposed that the positive effect of EGF application on reepithelialization might be more observed in cases of chronic wounds, rather than post-laser wounds.¹⁵ These findings are in agreement with those reported by Shin et al.¹⁸ who did not find significant differences in the incidence of PIH with the multigrowth factor-containing cream compared to the placebo cream.

Bleomycin solution

In their study, Suh et al.²⁴ used bleomycin solution after CO₂ laser therapy while treating periungual warts. The objective was to evaluate the efficacy and safety of bleomycin solution for treating periungual warts; however, the authors noted that PIH occurred only in one patient with this treatment (5.8%). No other studies examined the effect of bleomycin solution in reducing PIH or inflammation after CO₂ laser therapy. Bleomycin is an antitumor agent with antibacterial and antiviral properties. It has been widely used as primary or adjunctive therapy for various cutaneous conditions.³⁶ This agent’s effect on inflammation have yet to be established, and one of its common side effects is inflammation at the application site. Currently, there is not sufficient evidence to support the use of bleomycin solution to reduce PIH after CO₂ laser therapy.

Hormonal changes

The effect of hormonal changes on the occurrence of PIH is an under-studied idea. Although most PIH occurs in women, it is likely related to the fact that females undergo laser therapy more often than men. Almohizea investigated the effect of the menstrual cycle on CO₂ laser-induced PIH.²¹ The author found that PIH was more severe when CO₂ laser therapy was performed during the patient’s menstrual cycle. Despite the limited sample size (n=7), the study’s findings are highly interesting. Pigmentary conditions, such as melasma, correspond with hormonal changes – those associated with pregnancy and the use of contraceptive medications. It is unclear if PIH severity in Almohizea’s study was related to the inflammatory response being affected by menstrual cycle, or if the melanocytes reaction is “strong”, as described by Ruiz-Maldonado, during this phase.²⁸ Puder et al.³⁷ reported that menstrual cycles are associated with changes in plasma inflammatory markers, suggesting that menstruation is linked to low-grade inflammation. The relation between inflammatory response after CO₂ laser therapy and the menstrual cycle begs further elaboration.

Limitations

Data was reported in a cumulative pattern by many studies, rather than for each participant individually. As a result, evaluating each possible risk factor of PIH using multivariable regression analysis was not viable. Therefore, it was not possible to determine if each factor – such as skin type and type of intervention – were independent of the other factors, such as gender and age. Additionally, the incidence of PIH might also depend on other medical and technical factors, such as the dermatological condition being treated, energy and density of the laser therapy, and sun exposure before and after treatment. This may have led to the variable incidence of PIH reported in the literature. Robust clinical trials with extensive, detailed documentation are needed to properly assess the risk of PIH after CO₂ laser therapy and determine the efficacy of preventative modalities.

Conclusions

CO₂ laser therapy is widely used in the field of dermatology due to its high precision and short postoperative downtime. However, PIH remains a challenging adverse effect that is frequently observed with this technology. The notion behind PIH occurrence is related to inflammation resulting from thermal damage by the CO₂ laser. Over time, each agent used to decrease the incidence of PIH has received variable results. From this data, the use of ultra-potent TC appeared to reduce PIH, possibly by reducing postoperative inflammation. Antimicrobial therapies with antiinflammatory properties, such as topical fusidic acid, may also be beneficial in preventing PIH. Similarly, platelet-containing plasma appeared to reduce CO₂ side effects, including PIH, when used in conjunction with CO₂ laser treatment. The patient’s FSP did not appear to play a major role in the occurrence of PIH, as per the reporting studies. Further research is required to establish a clearer relation between skin type and PIH, and to examine preventative modalities to reduce PIH after CO₂ laser treatment appropriately.

Funding Statement

Funding: none.

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