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ORIGINAL ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 5  |  Page : 504-511
Efficacy and safety of carboxytherapy versus combined microneedling with topical glutathione in the treatment of patients with periorbital hyperpigmentation: An evaluator-blind, split-face, controlled pilot clinical trial


Dermatology, Venereology and Andrology Department, Faculty of Medicine, Sohag University, Sohag, Egypt

Date of Web Publication29-Dec-2022

Correspondence Address:
Amr Abdelhamed
Lecturer of Dermatology, Venereology, and Andrology, Department of Dermatology, Venereology, and Andrology, Faculty of Medicine, Sohag University, Sohag - 82524
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_394_21

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   Abstract 


Background: Periorbital hyperpigmentation (POH) is a common skin condition that presents as infraorbital darkening. POH has a multifactorial etiology. Studies evaluating POH treatment are several with varying satisfaction results. Objectives: To compare carboxytherapy and microneedling (MN) combined with topical glutathione for POH treatment. Materials and Methods: A split-face pilot clinical trial was conducted on 31 female patients with POH. Carboxytherapy injection was done at the right periorbital area, and MN with topical glutathione (Left periorbital area), for 6 biweekly sessions. Visual analogue scale (VAS), dermoscopic evaluation, patient satisfaction, and patient dermatology life quality index questionnaire (DLQI), safety evaluation were done with 3 months follow up. The trial registry number is NCT04389788. Results: Carboxytherapy showed a higher significant improvement as regards VAS evaluation compared to MN with glutathione during the active treatment phase (P = 0.001) and during the follow-up phase (P = 0.006). Also, the dermoscopic evaluation showed a statistically significant improvement in the Carboxytherapy group. DLQI showed a statistically significant improvement (P <.001). As regards patient satisfaction, carboxytherapy showed in comparison to MN with glutathione (80.6% vs 25.8% in moderate satisfaction) and (3.2% vs 0% in marked satisfaction respectively) (P = .05). As regards the patients' safety, there was no significant difference between both eyes (P = .23). Conclusions: Carboxytherapy showed higher efficacy than MN with glutathione in POH patients. Carboxytherapy improved clinical, dermoscopic, patient satisfaction, and patient DLQI; with a good safety profile.


Keywords: Carboxytherapy, microneedling, periorbital hyperpigmentation, topical glutathione


How to cite this article:
Assaf HA, Ahmed D, Abdelhamed A. Efficacy and safety of carboxytherapy versus combined microneedling with topical glutathione in the treatment of patients with periorbital hyperpigmentation: An evaluator-blind, split-face, controlled pilot clinical trial. Indian J Dermatol 2022;67:504-11

How to cite this URL:
Assaf HA, Ahmed D, Abdelhamed A. Efficacy and safety of carboxytherapy versus combined microneedling with topical glutathione in the treatment of patients with periorbital hyperpigmentation: An evaluator-blind, split-face, controlled pilot clinical trial. Indian J Dermatol [serial online] 2022 [cited 2023 Feb 5];67:504-11. Available from: https://www.e-ijd.org/text.asp?2022/67/5/504/366128





   Introduction Top


Periorbital hyperpigmentation (POH) is a common skin condition that presents as an infraorbital darkening. It sometimes extends to involve the upper eyelid, eyebrows, and malar area.[1] The majority of POH cases occur in African and Asian countries with a prevalence of 78% of the general population. Most POH cases occur in females who are 16-45 years old.[2] It represents a cosmetic problem as it has a negative impact on the patient's quality of life.[3] POH has a multifactorial etiology.[4] It is classified as a primary (idiopathic) type and secondary type which could be related to local or systemic known causes.[5] Secondary POH could be caused by various intrinsic and extrinsic factors.[6]

Topical whitening agents are the most commonly used POH treatment. Other treatment options, such as chemical peeling, laser, filler, and autologous fat transplantation, have been tried with variable success rates. New modalities such as platelet-rich plasma (PRP) and carboxytherapy might be promising in esthetic dermatology in facial rejuvenation and POH treatment.[1]

Carboxytherapy is a therapeutic modality through subcutaneous carbon dioxide (CO2) injection. It increases blood flow with increased oxygen and nutrients supply to the skin, leading to skin improvement.[7]

It might represent an effective and tolerated treatment for POH.[8] Its efficacy in POH has been used in a few studies.[9],[10],[11]

Skin microneedling (MN) is a technique that involves the puncture of the skin with fine needles. This leads to increased dermal collagen and elastin. Moreover, it creates small channels that could increase the absorption of topical preparations.[12] One of these topical preparations is glutathione which is an antioxidant and inhibits melanogenesis through inhibition of the tyrosinase enzyme.[13] Topical whitening or peeling agents have been tried in POH treatment in a few studies.[14],[15] Combined MN with peeling has been conducted in one study.[16]

After reviewing the literature, the POH treatment studies have a variable improvement rate. Also, the ideal number of sessions and the intervals in between is still not settled. Therefore, we try to compare carboxytherapy and MN with topical glutathione in a split-face study for POH treatment.


   Material and Methods Top


A split-face pilot clinical trial was conducted on 31 patients with POH seeking medical advice at Dermatology outpatient clinics, the University Hospital, in the period from November 2019 to November 2020. The study design was approved by the ethical and scientific research committee. Informed written consent was obtained from all participants. The study included patients aged 18-65 years. The trial registry number is NCT04389788. The outcome assessors were blind to the type of treatment. CONSORT flow chart of the study is shown in [Figure 1].
Figure 1: A CONSORT flow chart of the study

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Female patients with POH with Fitzpatrick skin type II-IV were included in the study. Patients with the following conditions were excluded: pregnancy and lactation, allergy to the formulations to be used, the presence of other cutaneous or systemic diseases (advanced liver and renal diseases) and the patient who had taken any treatment on the periorbital area performed less than 6 months before the start of the study.


   Methods Top


Methods of treatment

Patients were treated using the carboxytherapy method at the Right (Rt) side of the face followed by MN using dermapen combined with topical glutathione at the Left (Lt) side of the face. Six biweekly sessions were done. None of the patients received any treatment during the study.

Carboxytherapy injection (Right periorbital area)

Carbon dioxide (CO2) gas was intra-dermally/subcutaneously injected at the lateral one-third of each eyelid (about 5 cc gas in each puff according to standardized flowmeter) using an insulin syringe. Each patient received 4-6 puffs/session. The used carboxytherapy device is manufactured by (Arab medical company, China).

Microneedling with topical Glutathione (Left periorbital area)

Topical anesthesia was used before Dermapen. Dermapen is an automatic and rechargeable device with a vibrating frequency 6500-10000 r/m, and vibration speed level 5. Its model is Ultima A6, which is manufactured by (Dr. Pen, medical cure company, Korea). Dermapen needle tips (needles number in each tip 36) were disposable. Dermapen needle depth was adjusted to 0.25-0.5 mm. Then, patients were subjected to topical application of glutathione (Medical Cure Company, Spain) with vial concentration: 600 mg/5 ml. About 0.25 ml/session of glutathione was used.

Initial evaluation: All patients were subjected to

Local dermatological evaluation

Clinical classification of POH was done into Constitutional, post-inflammatory, vascular, and shadow effect types. Eyelid stretch test shows decreased pigment intensity in constitutional and shadow effect, while increased pigment intensity or no change in vascular and post-inflammatory types respectively.[17]

Photos

Photos were taken using a smartphone (iPhone 7) before every session and during the follow-up visits.

Visual analogue scale (VAS)

Using a physician visual analog scoring system, an independent dermatologist rated the patient's clinical improvement based on a comparison of the clinical photos of the active treatment phase (by comparing the baseline, after 3rd session and after 6th session), then a comparison of the follow-up phase (by comparing after 6th session, 1 month and 3 months follow-up).[18]

Dermoscopic evaluation

The majority of POH patients had a multicomponent pattern with Dermoscopy, which included more than one pattern of pigmentation, vasculature, and skin changes.[17] The dermoscopic evaluation was done using 3 gen DermLite HUD (Bioptics Company, USA) with a connection to I phone7 (Apple, Hong Kong). It was done at baseline, after the 3rd and 6th sessions, and during follow-up. Evaluation of dermoscopic photos was done through an independent dermatologist (blinded to clinical data) that rated the vascular, pigment, and skin improvement in the active treatment phase and follow-up phase.[17]

Patients' satisfaction

The patients were asked to evaluate their level of satisfaction after they completed the study on a 1-3 scale: 1 = slightly satisfied, 2 = moderately satisfied, and 3 = well satisfied.

Dermatology life quality index questionnaire (DLQI)

The Dermatology Life Quality Index Questionnaire was used in patients' evaluations. It consists of 10 questions with a 0-3 score for each answer. The DLQI was calculated by summing the score of each question with a range of 0-30 of the total score. The higher the score, the more quality of life is impaired.[19]

Follow up evaluation

Patients were evaluated 1 and 3 months after the stoppage of therapy by; initial evaluation tools and safety evaluation to detect any side effects either reported by the patient or by the physician.

Statistical analysis

Data were analysed using the Statistical Package for Social Sciences (SPSS) software program (version 25). Data were described using mean and median as measures of central tendency, standard deviation, and range as measures of dispersion for quantitative variables. Frequencies and percentages were used to describe categorical variables. In the case of normally distributed quantitative variables, the Student t-test was used. In the case of not normally distributed quantitative variables, the following tests were used: Wilcoxon test that was used in case of repeated design two times; Friedman test that was used in case of repeated design more than two times. P value ≤0.05 was considered significant.


   Results Top


The study was conducted on 31 female patients with POH. The mean age of patients was (25.2 ± 6.6) years ranging from 18 to 45 years. The POH median duration was 7 years with its interquartile range (IQR) being 5. Other socio-demographic data were shown in [Table 1]. On examination, a large percent of the included patients was type III skin 18 (58.1%). Constitutional and vascular POH was the most common type (38.7%). On dermoscopic examination, the mixed type was the most common 15 (48.4%). More details are summarised in [Table 1].
Table 1: Socio-demographic and clinical characteristics of periorbital hyperpigmentation patients (n=31)

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Carboxytherapy showed a higher significant improvement as regards Visual analogue scale (VAS) evaluation and the dermoscopic vascular, skin, and pigmentation improvement compared to MN with glutathione during the active treatment phase as shown in [Table 2], and during the follow-up phase as shown in [Table 3].
Table 2: Comparison of treatment phase evaluation between Carboxytherapy (Right eye) Vs Microneedling with topical glutathione (Left eye) by the independent dermatologist as regards 3 photos (Baseline/3rd session/6th session)

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Table 3: Comparison of follow-up phase evaluation between Carboxytherapy (Right eye) Vs left eye by the independent dermatologist as regards 3 photos (6th session, 1 Month follow-up, 2 Months follow up)

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Comparison of DLQI showed a statistically significant difference between intervals by Friedman test (P < .001). Comparison of times sessions assessed by Wilcoxon test, there was only a statistically significant difference between (Baseline Vs 3 months follow up) and between (3rd session Vs 3 months follow up) (P = 0.05) as shown in [Table 4].
Table 4: Comparison of Dermatology Life Quality Index (DLQI) at (baseline, 3rd session, 6th session, 1 month follow-up and 3 months follow up)

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As regards patient satisfaction, carboxytherapy showed in comparison to MN with topical glutathione (80.6% vs 25.8% in moderate satisfaction) and (3.2% vs 0% in marked satisfaction, respectively) (P = 0.05) as shown in [Figure 2]. As regards the patients' safety, there was no significant difference between both eyes (P = 0.23). Only 12.9% (4/31) of patients with MN with topical glutathione developed ecchymosis, while no side effects were reported with carboxytherapy.
Figure 2: Comparison between the two eyes according to patient satisfaction

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Representative photos of patients had been summarised in [Figure 3] and [Figure 4], showing the clinical photos and dermoscopy of patients in the treatment phase (A, C), and in the follow-up phase (B, D).
Figure 3: (a and b) A 26-year female patient showed grade 4 VAS improvement in POH for Rt eye and grade 2 for Lt eye through treatment phase (baseline, 3rd session, and 6th session) and the follow-up phase (6th session, 1 month, and 3 months follow up); (c and d) Baseline dermoscopic (x10) evaluation showed mixed (vascular & pigmented) type POH. Rt eye showed vascular and pigmented components improvement 30, 40% respectively through the treatment phase. Lt eye showed 15% improvement for the vascular component but no improvement in the pigmented component. These changes were maintained during the follow-up phase

Click here to view
Figure 4: (a and b) A 27-year female patient showed grade 3 VAS improvement in POH for Rt eye and grade 2 for Lt eye through treatment phase and the follow-up phase; (c and d) Baseline dermoscopic (x10) evaluation showed mixed (vascular & pigmented) type POH. Rt eye showed vascular and pigmented components improvement 20, 30% respectively through the treatment phase. Lt eye showed 20% improvement for both vascular and pigmented components. These changes were maintained during the follow-up phase

Click here to view



   Discussion Top


Peri-orbital hyperpigmentation is of great cosmetic concern as it makes the patient appears as sad, tired, and even older.[4] Its etiology is multifactorial with some familial components with several environmental factors.[4] Because of the complexity of its pathogenesis, various treatments are available for POH, but neither of them is satisfactory for all patients.[17] However, topical depigmenting agents represent the most common therapeutic options in clinical care for POH patients.[19]

The current study compares the efficacy and safety of carboxytherapy and combined MN with glutathione in POH treatment in a split-face clinical trial. Carboxytherapy showed a statistically significant improvement in POH patients as assessed by clinical evaluation by VAS score, dermoscopic evaluation, and DLQI. Moreover, this improvement was maintained up to 3 months of follow-up. In the current study, Carboxytherapy showed a significantly higher patient satisfaction compared to MN with glutathione (80.6% vs 25.8% in moderate satisfaction) and (3.2% vs 0% in marked satisfaction), respectively, with total satisfaction about 84% with carboxytherapy. This result is consistent with a study that compared a gel formula continuing Trichlorecetic acid (TCA) and lactic acid as chemical peeling with carboxytherapy, with 4 weekly sessions. Although there was no significant difference between the two sides, carboxytherapy showed excellent and good improvement in 47%, 40%, respectively, with a total patient improvement of about 87%.[10] The POH improvement with carboxytherapy in the current study was higher than reported in another study that showed improvement in 50-60% after 7 weekly sessions.[9] This lower improvement rate in the latter study could be explained that the latter study focused on evaluating Carboxytherapy on POH and peri-orbital fine lines, while the current study focused on POH only. Also, another study used Carboxytherapy in POH patients for seven weekly sessions. It showed significant improvement with both Carboxytherapy and PRP with no significant difference between them. It reported good and excellent improvement in 33, 20%, respectively, with a total improvement of 53% with carboxytherapy.[11] The lower rate of improvement in the mentioned two studies[9],[11] in comparison to the current study could be the use of biweekly sessions in the current study instead of a weekly session in the mentioned studies.

The definite mechanism of carboxytherapy is not well known. It is postulated that CO2 injection is recognised as an oxygen deficit leading to increased blood flow which is associated with increased several growth factors. These growth factors include vascular endothelial growth factor which stimulates new blood vessel production leading to improvement of skin elasticity, collagen remodeling, and dermal regeneration.[8]

In the current study, MN with topical glutathione showed less improvement of POH in comparison to carboxytherapy. There are no previous studies that compared those modalities of treatment in the literature. One study evaluated the efficacy and safety of MN with topical application of TCA 10% solution as a peeling agent. Both physician and patient assessment showed improvement in 92%.[16] The difference in the results of MN could be due to the use of topical glutathione in the current study, while the other study used a peeling agent. Therefore, a future study using MN alone is needed to evaluate its role alone. MN technique alone or combined with other procedures could provide promising solutions for different dermatological conditions. Another study compared Carboxytherapy vs chemical peeling vs Mesotherapy with vitamin C through five weekly sessions in POH patients. No significant difference was observed between the three groups. However, Mesotherapy showed excellent improvement with better patient satisfaction.[7] The higher improvement of mesotherapy in this study could be that Mesotherapy was done through direct syringe injection of vitamin C, while in the current study topical glutathione was applied after MN.

Skin MN could act in the treatment of POH patients in two different ways. The first one is through increasing the dermal absorption of active substances. The second way is through the controlled inflammation that is associated with the micro-puncture of MN. Also, micro-puncture of dermal blood vessels can lead to platelet activation with the release of several growth factors. These micro-punctures stimulate wound healing cascade leading to the release of growth factors including platelet-derived growth factor, transforming growth factor-alpha, and beta (TGF-α and TGF-β), and fibroblast growth factor.[20]

The current study used dermoscopic evaluation as an objective tool. Dermoscopy of POH patients usually shows more than one component of pigmentation, vascular, and skin changes.[17] The current study showed a mixed pattern in 48% followed by the pigmented pattern in 32%. Carboxytherapy showed significant dermoscopic improvement of pigmentation and vascular changes in comparison to MN with glutathione (90 vs 67%), (93 vs 77%), respectively. Moreover, this dermoscopic improvement was maintained 3 months after sessions. The significant clinical improvement with carboxytherapy could be attributed partially due to the mixed dermoscopic pattern of the included POH patients in the study, which makes carboxytherapy might be a more appropriate treatment option than glutathione than target pigmentation only.

In the current study, DLQI showed a statistically significant improvement between baseline 2 (1 -3) vs 3 months follow-up 1 (1-2). POH has a small effect on the DLQI. Baseline DLQI in the current study 2 (1-3) was close to the finding of another study that reported 4.9 in POH patients with more significant worsening in women.[21] It must be considered that the total score of the DLQI range is 0-30, with a score of 2-5 being associated with a small effect on the quality of life.[22]

In the current study, there was no significant difference between carboxytherapy and MN with glutathione as regards to the patients' safety. In carboxytherapy, mild transient pain at the injection site was considered a normal consequence rather than an adverse event. The high safety profile of carboxytherapy in the current study was consistent with the results of other studies. It showed good tolerability and compliance.[9],[10],[11] In the current study, MN with glutathione was associated with ecchymosis in 12.9%. This forced some patients to discontinue the sessions. Transient edema and erythema have been reported in MN with TCA of 10%.[16]

The current study has several limitations. The sample size was small due to the low number of female patients that fulfilled the inclusion criteria and were willing to participate in the study over six biweekly sessions. The follow-up of patients was 3 months only. Also, it will be better to avoid the assessment bias if the side of the face could be randomized for the allocation of the two treatments. Therefore, a multi-center study with large sample size and a longer follow-up duration is recommended.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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