An overview of the role of carboxytherapy in dermatology

Carboxytherapy is defined as intradermal and/or subcutaneous microinjections of sterile purified carbon dioxide into different parts of the body for therapeutic aims. The vasodilatation effect and intradermal collagen reorganization associated with carboxytherapy have advantages for aesthetic dermatology and cosmetology.

by Luigi Parassoni at the XVI national meeting of Italian Society of Esthetical Medicine. 2,3 For the first time, in 2004, hypodermic infiltration of CO 2 was introduced as an alternative effective modality in association with liposuction procedures in treating localized adiposity and skin irregularities. 6 Since then, carboxytherapy has frequently been applied in the treatment of different types of lipodystrophies, as well as in aesthetic medicine.

| MECHANIS M OF AC TION
The combination of carbon dioxide with water molecules in tissues results in the formation of carbonic acid 4 within 1-3 min. 3 Secondary to decreased pH and subsequent Bohr effect, the bond between hemoglobin and oxygen weakens, leading to increased release of oxygen. 3,4,7,8 Subsequently, the low pH results in some events summarized in Figure 1.

| Direction of application
Carboxytherapy can be performed in 2 methods including: • Continuous administration: In this method, a predefined amount of CO 2 is gradually injected into the dermis, subdermis, or deeper structure regarding the site of pathologic condition. Longer F I G U R E 1 Mechanisms of action of carboxytherapy. [2][3][4][5]7,8 Increased permeability of the capillary walls at pH ≤6.8 Activation of dermal fibroblasts resulting in the production of collagen and elastin in higher quantity and better quality Increased collagen remodeling Increased flexibility and decreased firmness of collagen fibres at pH ≤ 6.5

Reduction of divalent calcium ions
Decreased tonus of arteries and capillaries leading to vasodilatation, increased blood flow to the injected site, and decreased blood pressure

| INDIC ATIONS
The vasodilatation effect and intradermal collagen reorganization from carboxytherapy have advantages in aesthetic dermatology.
These impacts are seen in early phases, usually after two therapy sessions or over 7-14 days, in the form of improved tonus and aesthetic parameters of the skin in clinical views. 9 In the following, we have summarized some of the most important applications of carboxytherapy in dermatology.

| Skin aging
Skin aging, as a natural and inevitable process, reverses the biological characteristics of the skin and results in cell death ( Figure 2). 10 In a clinical trial by Nassar et al. on 60 patients with facial wrinkles, the efficacy of radiofrequency, intense pulsed light, and carboxytherapy was assessed and compared in facial rejuvenation.
Patients received four sessions of each of these treatments with 3-4-week intervals, and the subjects were followed up 3 months after the last treatment. This study revealed that intense pulsed light was the most effective in facial rejuvenation, followed by carboxytherapy and radiofrequency, respectively. The results were confirmed by immunohistochemical assessment of matrix metallo-

| Alopecia
The efficacy of carboxytherapy has been assessed in different types of hair loss or alopecia. We have summarized some of the most important types:

| Alopecia areata
Alopecia areata is a common nonscarring hair loss, 13 and one of the most prevalent autoimmune disorders. 14 It is characterized by a disfiguring inflammatory condition perturbing hair follicles and nail structure. 15  In a clinical trial on nine patients with androgenetic alopecia, the efficacy of combination of using high concentration of minoxidil and carboxytherapy were assessed by measuring hair density and diameter trichograms before and after therapy. In this study, the authors showed the effectiveness of this approach in increasing the rate of hair growth. 17

| Cellulite
Cellulite is defined as a multifactorial alteration of subcutaneous tissue resulting in the appearance of wavy and irregular skin, frequently involving the buttocks and thighs. It is a complicated condition consisting of changes affecting the microcirculation, lymphatic system, extracellular matrix, and adipocytes. 5 It is reported in about 80%-90% of women after puberty resulting in great dissatisfaction and a negative impact on life quality of affected persons 5,18 in terms of physical appearance, self-esteem, and social acceptance. 18 From an etiopathophysiological view, hyperactivity of fibroblasts due to the effect of estrogen promotes the synthesis of glycosaminoglycans and collagen increasing the interstitial osmotic pressure and water retention. A variety of treatments have been used for this condition including balanced diet, physical activity, massage, radiofrequency, therapeutic ultrasound, light-emitting diode therapy, and topical agents. 5 In a study by Lee, the efficacy of carboxytherapy in management of cellulite was assessed over a 4-year period by measuring weight and the circumference of treated site. In this study, 101 women and 10 men underwent abdominal therapy, and 57 women received thigh therapy. This study showed the statistically significant weight loss and reduction of abdominal and thigh circumference in women, while the results in men were not significant. 19 In a study by Pianez et al. on 10 females with cellulite, carboxytherapy was done for eight sessions and the severity of cellulite was assessed by standardized digital photographs and ultrasonography.
The authors showed statistically significant reduction of the cellulite from degree III to degree II, and improved organization of the fibrous lines and the disposal of adipose tissue lines. 5 In a clinical trial, Eldsouky and Ebrahim compared the efficacy of carboxytherapy and mesolipolysis using phosphatidylcholine in the management of cellulite in 48 females by evaluating a cellulite grading scale and thigh circumference measurements. The subjects were classified into two groups, which received carboxytherapy and mesolipolysis, respectively. Both treatments were done once a week for six sessions. The women were followed for 6 months. The findings showed significant effectiveness of both treatments with no significant difference between them. The authors concluded that carboxytherapy can be a promising alternative therapeutic approach for cellulite treatment. 20

| Localized fat deposits
Regarding localized fat deposits, liposuction has been a good proce-  The mechanisms of carboxytherapy in lipolysis are not wellknown. In a study by Brandi and colleagues, histological examination showed that fat loss was related to release of triglycerides in the intercellular spaces and adipocytes. 25 It seems that vascular dilation, increased blood flow, and oxygenation induce a lipolytic process and adipocyte size reduction, and subsequently, diminish the localized adipocytes. Upon molecular examination, it has been shown that vasculature in subcutaneous fat tissue and its related factors including VEGF-a and FGF1 play important roles in regulation of the adipose tissues' remodeling. 22

| Striae distensae
Striae distensae is a prevalent cutaneous condition with psychological impact and challenging treatment. 26

| Infraorbital hyperpigmentation
Infraorbital dark circles, also known as infraorbital hyperpigmentation, periocular hyperpigmentation, infraorbital darkening, and periorbital melanosis, are a significant cosmetic concern exaggerated by the aging process in both males and females. It causes a tired appearance in affected persons. 8 It is manifested by bilateral round or semicircular brown pigmentation involving the periorbital region and is classified into vascular, structural, pigmentary, and mixed types. 30 It has a multifactorial etiology and its accurate diagnosis is important for choosing optimal therapeutic approaches. 31

| Lymphedema
Lymphedema is a prevalent and progressive disorder leading to deterioration of the quality of life of affected patients. It is classified into primary and secondary lymphedema. Secondary lymphedema is often associated with a malignancy or its treatment modalities.
Accurate diagnosis and effective treatment are mainstay for relieving the signs and symptoms. 36 In carboxytherapy, microcirculation at the level of metarterioles, arterioles and precapillary sphincters are affected by the interaction between CO 2 gas and regulating factors of tissue perfusion, which results in increasing tissue flow velocity and consequently, improving lymphatic drainage.
Carboxytherapy is applicable for managing lymphatic stasis, which acts through the positive impact on the increasing lymphatic flow. The basic hemodynamic, histologic, and biochemical data have been analyzed for revealing the effectiveness of carboxytherapy on severe lymphedema through its impact on microcirculation bed and lymphatic drainage. 37

| Psoriasis
Psoriasis is a common, chronic inflammatory skin disorder affecting about 125 million people worldwide with global variation in the prevalence rate. 38 It appears that carboxytherapy is effective in the management of psoriasis through anti-inflammatory, antioxidant, antimicrobial, antihypertrophic, reparative, and analgesic properties, tissue detoxification, improvement of immunity status, improvement of tissue trophism, and elimination of venous-interstitial lymphatic stagnation. 39 In a pilot study by Kamel and Abdelghani assessing the efficacy of carboxytherapy in treating psoriasis, 30 patients with chronic localized plaque psoriasis were recruited. Treatment was performed once a week for eight sessions and the subjects were assessed 2 weeks after the last session based on clinical and histopathological criteria.
According to the results, the authors recommended carboxytherapy as a promising modality for treating plaque psoriasis. 38

| Morphea and en Coup de Saber
Morphea is defined as an inflammatory, sclerosing skin condition involving the underlying soft tissues. It has cosmetic and functional impacts on the affected patients. Early diagnosis and treatment would be optimal for minimizing damages such as restriction of range of motion. 40

| Vitiligo
Vitiligo is a prevalent pigmentary skin disorder, manifested by acquired, idiopathic, progressive, circumscribed depigmentation of the skin and hair, with reduction of melanocytes in histology. It is worldwide, with an incidence rate of 0.1%-2%. It has a major impact on the quality of life of the patient suffering from it. Because its pathogenesis has not yet been understood, there is a plethora of different treatments. 43 In a prospective, split-body double-blind comparative trial by

| C O N T R A I N D I C AT I O N S
In Table 1, contraindications of carboxytherapy have been listed.

| COMPLIC ATIONS OF C ARBOX Y THER APY
In clinical practice, the pain due to carboxytherapy is the main limiting factor for its application resulting in the lack of treatment compliance and discontinuation of therapy, which have negative effects on the acceptability of this procedure. To control pain, a low-frequencypulsed current like transcutaneous electrical nerve stimulation (TENS), and medium-frequency alternating currents such as interferential current (IFC) and Aussie current can be applied. In a study by Sadala and colleagues, the efficacy of these three methods was assessed in decreasing pain during carboxytherapy in 75 patients.
Their study showed that in comparison with TENS, IFC and Aussie current were more effective in relieving pain of carboxytherapy due to induction of greater sensory comfort. 18 Heat sensation, tingling, and burning sensation (mainly due to the impact of CO 2 on the depolarization of nerve membranes) are immediate complications after therapy reported by patients. These sensations often resolve very soon, although prolonged heat sensation can be secondary to vasodilatation and usually resolves within 10-20 min. In more sensitive persons, these sensations may persist up to 24 h after therapy. 9 Ecchymosis and hematoma formation are other complications of carboxytherapy, which are induced by accidental vessel injuries and have been reported by 5% of cases. Persistent edema lasting for more than 48 h is another complication of this therapy, which is particularly reported in the periorbital area. 9

| FREQUEN C Y, N UMB ER , AND COS T OF THER APY S E SS I ON S
For every person, the required frequency and number of treatment sessions should be individualized based on the treated site and the acquired therapeutic responses, but usually between 5 to 20 sessions are needed for most cases. 9 This procedure is considered as an effective treatment with low cost for several skin and cosmetic conditions. 5  Combination of carboxytherapy with other aesthetic approaches will result in better responses. Some of these include microdermabrasion, laser therapy, microneedling, chemical peels, injection lipolysis, mesotherapy, cryotherapy, and injections of fillers, botulinum toxin, and PRP. 9

| CON CLUS ION
Carboxytherapy is a safe minimally invasive therapeutic approach used for the rejuvenation, restoration, and reconditioning of the skin. 2 Due to its role in vasodilatation and intradermal collagen reorganization, it has value in aesthetic dermatology. 9

CO N FLI C T O F I NTE R E S T S TATE M E NT
We declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

E TH I C S S TATEM ENT
We got the consent from all the patients whose adominal figures have been used in this article for publishing their figures.

CO N S E NT
The consent has been gotten from the patient for using the figure of her abdomen in the current review article.