Letter to the Editor
Skin Necrosis Following Adipocitolitic Solution Injections
Aesthetic Surgery Journal 2016, Vol 36(2) NP74–NP76 © 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: [email protected] DOI: 10.1093/asj/sjv183 www.aestheticsurgeryjournal.com
Giuseppe Di Toro, MD; and Raffaele Rauso, MD, PhD Accepted for publication August 5, 2015; online publish-ahead-of-print October 26, 2015.
CLINICAL EXPERIENCE Rauso and Salti8 described their 4-year experience with Aqualyx injection alone. Ultrasonography (step 2) was not performed. Four trained physicians treated a total of 186 patients, and no patient experienced skin necrosis. All patients had mild to moderate swelling and reddening of the skin, which resolved 3 to 5 days after injection. Rates of transient events were as follows: hematoma, 1.61%; paresthesia, 1.07%; and ecchymosis, 6.45%. Pruritus was reported by 21.5% of patients, which began 3 to 7 days following injection.8 Subcutaneous nodules were noted in 1.61% and resolved within 4 months of injection. A transitory “strange feeling” was reported by 12.9% of patients, which lasted up to 2 months after final injection. Aesthetic outcomes were considered “very good” (score: 8/10) for 60.2% of the patients.8 Pinto et al7 of Spain retrospectively analyzed 331 sessions of Aqualyx injections performed in a total of 145 patients. There were no reports of skin necrosis, and the most common side effects were mild to moderate swelling and reddening of the skin, which were transitory.7 The next most common complication was subcutaneous nodule (61 cases among 145 patients). The authors surmised that the nodule occurrence likely related to limited physician experience: of the 61 sessions that resulted in a nodule(s), 53 of them (19 patients) were performed in a medical center where the physician had little or no previous experience with intralipotherapy.7 (Per the manufacturer’s information, this is the only injection technique to be used for Aqualyx.5,7) Dr Di Toro is a private practitioner in Milazzo, Italy. Dr Rauso is an Assistant Professor, Department of Dentistry, University of Foggia, Foggia, Italy. Corresponding Author: Dr Raffaele Rauso, c/o Centro Polispecialistico Santa Apollonia, Via Martiri del Dissenso 47, 81055 S. Maria C.V. (CE), Italy. E-mail: [email protected]
Downloaded from http://asj.oxfordjournals.org/ by guest on March 1, 2016
Injectable fat-reduction techniques emerged in the world literature in 2001, when Patricia Rittes, a dermatologist in São Paulo, Brazil, reported reduction of infraorbital fat after direct, transcutaneous injection of phosphatidylcholine (PC) combined with sodium deoxycholate (DC) solution.1 Despite lack of approval by any regulatory body, PC/DC combinations have been used off-label by healthcare practitioners to reduce subcutaneous fat in selected patients.2,3 In Europe, the only drug with CE marking (approval) for the reduction of localized fat is Aqualyx (Marllor International; San Giovanni in Marignano, Italy).4 Currently, it is approved in approximately 50 countries. Aqualyx is a DC-based solution with a lactose-based delivery system, formulated to control and enhance the action of external ultrasound waves for the microcavitation of adipose tissue.5 It does not contain PC. Aqualyx was designed for the medical treatment (reduction) of localized adipose tissue5 and is sold exclusively to physicians trained in intralipotherapy, the injection technique for its insertion.6 The product has been in clinical use since 2009 for the nonsurgical reduction of localized adiposity, lipohypertrophy, subcutaneous lipohyperplasia, and “buffalo hump”.6-8 Aqualyx is an aqueous microgelatinous solution comprised of the following: polymer of 3:6-anhydro-L-galactose and D-galactose; buffer systems; 3-alpha-12alpha-dihydroxy-5-beta24-oico cholanic acid sodium salt; and saline solution.7,8 The solution appears similar in composition to DC, but it is considered a medical device—not a drug. A claim regarding this matter has been submitted to the Italian Ministry of the Health.8 Aqualyx is marketed as a 2-step product: immediately following injection (step 1), it is recommended that external ultrasonography be performed (step 2).5 However, various physicians have demonstrated that Aqualyx solution is safe and effective without the application of external ultrasonography.9-12
Di Toro and Rauso
NP75
INTRALIPOTHERAPY TECHNIQUE Although intralipotherapy differs completely from liposuction, a similar instrument is utilized. Intralipotherapy is performed with a long (10 cm) 24-G needle supplied by the manufacturer of Aqualyx. This needle releases the solution into the subcutaneous fat only in retrograde fashion and in a continuous “streaming” manner, not in a “string-of-pearls” interrupted depot manner.7 Thus, the distribution of the product is as homogeneous as possible.8 The entire length of the needle must be inserted into the subcutaneous adipose tissue, parallel to the skin surface, but the injections must not be too superficial (in the skin) or too deep (into the muscles) (Figure 1).8 Multi-depth injections are required to achieve optimal results.8 The ray-type distribution pattern is similar to that of liposuction, and the multi-level effect helps to address thick layers of adipose tissue. The technique requires many inward and outward movements. Each time the needle is moved outward, 0.5 mL of the solution must be released in a retrograde fashion. This outward motion is similar to that performed with liposuction cannulae.8 Intralipotherapy also differs from mesotherapy, which is the most common injection technique for lipolysis. Duncan et al11 investigated various aspects of lipolysis, including how modifications of the formula and technique change the outcome; the role of each constituent of various formulas; and the degree of fat reduction and skin retraction attainable with these treatments. In addition, they evaluated the influence of injection depth, the distance between injection points, volume injection, and ratios of formula constituents, and provided update recommendations for the
clinical practice of injection lipolysis. The intralipotherapy technique was not considered in their study.11 When performing intralipotherapy technique, the released solution must be spread throughout the subcutaneous adipose tissue requiring reduction, in width as well as depth, and therefore numerous passes are necessary.7 Local anesthesia is not required because the needle is very sharp and the solution must be premixed with lidocaine (as noted by the manufacturer). Before injection, we add 0.2 mL of lidocaine 2% to each 8 mL vial of Aqualyx.8
CASE PRESENTATION This case is believed to be the first published report of skin necrosis following injection of Aqualyx. In September 2013, a 46-year-old Caucasian woman was referred to a private physician in Milazzo (Sicily, Italy) for noninvasive treatment of localized adiposity of the anterior thighs. The pinch-test result for each leg was 2.5 cm. One vial (8 mL) of Aqualyx was injected into each anterior thigh with the intralipotherapy technique. External ultrasonography was not applied after injection. Immediately after completion of the injections, reddening and swelling of the area appeared. During the initial posttreatment days, the clinical condition of treated areas worsened. A prolonged localized inflammatory phenomenon occurred. Palpation of the treated areas revealed hardened tissues, and the patient experienced pain during palpation. Approximately 3 weeks after the Aqualyx injections, an area of skin necrosis developed on each thigh. (Figure 2 shows the appearance of the thighs 40 days after Aqualyx treatment.) The necrotic
Downloaded from http://asj.oxfordjournals.org/ by guest on March 1, 2016
Figure 1. (A, B) Intralipotherapy is performed with the long (10 cm) 24-G needle supplied by the manufacturer. The entire length of the needle must be inserted into the subcutaneous adipose tissue, parallel to the skin surface.
Aesthetic Surgery Journal 36(2)
NP76
Figure 2. Anterior thighs of a 46-year-old Caucasian woman who experienced skin necrosis shortly after Aqualyx injections. This photograph was obtained 40 days after the injections.
Figure 3. Fourteen months after surgical revision, during which the scar tissue was removed. Wound closure was achieved with local flaps. (A) Right thigh. (B) Left thigh.
areas were treated with surgical curettage and antibiotics ointment medications. The skin healed in 3 months, with depressed scar tissue. Six months later, the scar tissue was surgically removed and the wounds were closed, undermining the surrounding tissues, with local flaps (Figure 3).
REFERENCES
This case corroborates the notion that not all DC-based solutions are fat-tissue selective, as evidenced elsewhere.2,3,12 Therefore, injecting such products (eg, Aqualyx) to reduce localized adiposity can result in adverse events such as skin necrosis, which was demonstrated recently by a multiplex assay performed by Duncan.4 As emphasized previously by Rauso et al,8 because the safety of DC itself is still under investigation, it is surprising that this DC-based solution could have gained approval as a medical device. Even though this instance of post-Aqualyx skin necrosis appears to be the only documented case worldwide, it strongly suggests that more investigations on the merchantability of this product are warranted.
Disclosures Dr Rauso received grants from Healthxchange (Manchester, UK) and Marllor (S. Giovanni in M., Cattolica, Italy), the company that distributes the drug solution in the United Kingdom and the drug’s manufacturer, respectively. Dr Di Toro has no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Funding The authors received no financial support for the research, authorship, and publication of this article.
Rittes PG. The use of phosphatidylcholine for correction of lower lid bulging due to prominent fat pads. Dermatol Surg. 2001;27:391-392. 2. Duncan D, Rotunda A. Injectable therapies for localized fat loss: state of the art. Clin Plast Surg. 2011;38:489-501. 3. Rotunda A. Injectable treatments for adipose tissue: terminology, mechanism, and tissue interaction. Lasers Surg Med. 2009;41:714-720. 4. Duncan D. Response to “Injection lipolysis with phosphatidylcholine and deoxycholate”. Aesthet Surg J. 2013;33 (7):1073-1075. 5. Aqualyx package leaflet. Motolese’s solution. CE 0373. LELX0010 Rev.00. 6. Salti G, Rauso R. Comments on “Injection lipolysis with phosphatidylcholine and deoxycholate”. Aesthet Surg J. 2014;34(4):639-640. 7. Pinto H, Hernandez C, Turra C, Manzano M, Salvador L, Tejero P. Evaluation of a new adipocitolitic solution: adverse effects and their relationship with the number of vials injected. J Drugs Dermatol. 2014;13(12):1451-1455. 8. Rauso R, Salti G. A CE marked drug used for localized adiposity reduction: a 4-year experience. Aesthet Surg J. 2015;35(7):850-857. 9. Rauso R. Non surgical reduction of buffalo hump deformity. Case report and literature review. Eur J Aesthet Med Dermatol. 2011;1(1):29-34. 10. Rauso R, Rusciani A, Curinga G. An adipocitolitic aqueous micro-gelatinous solution for buffalo hump deformity reduction. J Drugs Dermatol. 2014;13(10):1282-1284. 11. Duncan D, Rubin JP, Golitz L, et al. Refinement of technique in injection lipolysis based on scientific studies and clinical evaluation. Clin Plast Surg. 2009;36(2):195-209, v-vi; discussion 211-213. 12. Rotunda AM, Suzuki H, Moy RL, et al. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution. Dermatol Surg. 2004;30:1001-1008.
Downloaded from http://asj.oxfordjournals.org/ by guest on March 1, 2016
DISCUSSION
1.
Skin Necrosis Following Adipocitolitic Solution Injections
Aesthetic Surgery Journal 2016, Vol 36(2) NP74–NP76 © 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: [email protected] DOI: 10.1093/asj/sjv183 www.aestheticsurgeryjournal.com
Giuseppe Di Toro, MD; and Raffaele Rauso, MD, PhD Accepted for publication August 5, 2015; online publish-ahead-of-print October 26, 2015.
CLINICAL EXPERIENCE Rauso and Salti8 described their 4-year experience with Aqualyx injection alone. Ultrasonography (step 2) was not performed. Four trained physicians treated a total of 186 patients, and no patient experienced skin necrosis. All patients had mild to moderate swelling and reddening of the skin, which resolved 3 to 5 days after injection. Rates of transient events were as follows: hematoma, 1.61%; paresthesia, 1.07%; and ecchymosis, 6.45%. Pruritus was reported by 21.5% of patients, which began 3 to 7 days following injection.8 Subcutaneous nodules were noted in 1.61% and resolved within 4 months of injection. A transitory “strange feeling” was reported by 12.9% of patients, which lasted up to 2 months after final injection. Aesthetic outcomes were considered “very good” (score: 8/10) for 60.2% of the patients.8 Pinto et al7 of Spain retrospectively analyzed 331 sessions of Aqualyx injections performed in a total of 145 patients. There were no reports of skin necrosis, and the most common side effects were mild to moderate swelling and reddening of the skin, which were transitory.7 The next most common complication was subcutaneous nodule (61 cases among 145 patients). The authors surmised that the nodule occurrence likely related to limited physician experience: of the 61 sessions that resulted in a nodule(s), 53 of them (19 patients) were performed in a medical center where the physician had little or no previous experience with intralipotherapy.7 (Per the manufacturer’s information, this is the only injection technique to be used for Aqualyx.5,7) Dr Di Toro is a private practitioner in Milazzo, Italy. Dr Rauso is an Assistant Professor, Department of Dentistry, University of Foggia, Foggia, Italy. Corresponding Author: Dr Raffaele Rauso, c/o Centro Polispecialistico Santa Apollonia, Via Martiri del Dissenso 47, 81055 S. Maria C.V. (CE), Italy. E-mail: [email protected]
Downloaded from http://asj.oxfordjournals.org/ by guest on March 1, 2016
Injectable fat-reduction techniques emerged in the world literature in 2001, when Patricia Rittes, a dermatologist in São Paulo, Brazil, reported reduction of infraorbital fat after direct, transcutaneous injection of phosphatidylcholine (PC) combined with sodium deoxycholate (DC) solution.1 Despite lack of approval by any regulatory body, PC/DC combinations have been used off-label by healthcare practitioners to reduce subcutaneous fat in selected patients.2,3 In Europe, the only drug with CE marking (approval) for the reduction of localized fat is Aqualyx (Marllor International; San Giovanni in Marignano, Italy).4 Currently, it is approved in approximately 50 countries. Aqualyx is a DC-based solution with a lactose-based delivery system, formulated to control and enhance the action of external ultrasound waves for the microcavitation of adipose tissue.5 It does not contain PC. Aqualyx was designed for the medical treatment (reduction) of localized adipose tissue5 and is sold exclusively to physicians trained in intralipotherapy, the injection technique for its insertion.6 The product has been in clinical use since 2009 for the nonsurgical reduction of localized adiposity, lipohypertrophy, subcutaneous lipohyperplasia, and “buffalo hump”.6-8 Aqualyx is an aqueous microgelatinous solution comprised of the following: polymer of 3:6-anhydro-L-galactose and D-galactose; buffer systems; 3-alpha-12alpha-dihydroxy-5-beta24-oico cholanic acid sodium salt; and saline solution.7,8 The solution appears similar in composition to DC, but it is considered a medical device—not a drug. A claim regarding this matter has been submitted to the Italian Ministry of the Health.8 Aqualyx is marketed as a 2-step product: immediately following injection (step 1), it is recommended that external ultrasonography be performed (step 2).5 However, various physicians have demonstrated that Aqualyx solution is safe and effective without the application of external ultrasonography.9-12
Di Toro and Rauso
NP75
INTRALIPOTHERAPY TECHNIQUE Although intralipotherapy differs completely from liposuction, a similar instrument is utilized. Intralipotherapy is performed with a long (10 cm) 24-G needle supplied by the manufacturer of Aqualyx. This needle releases the solution into the subcutaneous fat only in retrograde fashion and in a continuous “streaming” manner, not in a “string-of-pearls” interrupted depot manner.7 Thus, the distribution of the product is as homogeneous as possible.8 The entire length of the needle must be inserted into the subcutaneous adipose tissue, parallel to the skin surface, but the injections must not be too superficial (in the skin) or too deep (into the muscles) (Figure 1).8 Multi-depth injections are required to achieve optimal results.8 The ray-type distribution pattern is similar to that of liposuction, and the multi-level effect helps to address thick layers of adipose tissue. The technique requires many inward and outward movements. Each time the needle is moved outward, 0.5 mL of the solution must be released in a retrograde fashion. This outward motion is similar to that performed with liposuction cannulae.8 Intralipotherapy also differs from mesotherapy, which is the most common injection technique for lipolysis. Duncan et al11 investigated various aspects of lipolysis, including how modifications of the formula and technique change the outcome; the role of each constituent of various formulas; and the degree of fat reduction and skin retraction attainable with these treatments. In addition, they evaluated the influence of injection depth, the distance between injection points, volume injection, and ratios of formula constituents, and provided update recommendations for the
clinical practice of injection lipolysis. The intralipotherapy technique was not considered in their study.11 When performing intralipotherapy technique, the released solution must be spread throughout the subcutaneous adipose tissue requiring reduction, in width as well as depth, and therefore numerous passes are necessary.7 Local anesthesia is not required because the needle is very sharp and the solution must be premixed with lidocaine (as noted by the manufacturer). Before injection, we add 0.2 mL of lidocaine 2% to each 8 mL vial of Aqualyx.8
CASE PRESENTATION This case is believed to be the first published report of skin necrosis following injection of Aqualyx. In September 2013, a 46-year-old Caucasian woman was referred to a private physician in Milazzo (Sicily, Italy) for noninvasive treatment of localized adiposity of the anterior thighs. The pinch-test result for each leg was 2.5 cm. One vial (8 mL) of Aqualyx was injected into each anterior thigh with the intralipotherapy technique. External ultrasonography was not applied after injection. Immediately after completion of the injections, reddening and swelling of the area appeared. During the initial posttreatment days, the clinical condition of treated areas worsened. A prolonged localized inflammatory phenomenon occurred. Palpation of the treated areas revealed hardened tissues, and the patient experienced pain during palpation. Approximately 3 weeks after the Aqualyx injections, an area of skin necrosis developed on each thigh. (Figure 2 shows the appearance of the thighs 40 days after Aqualyx treatment.) The necrotic
Downloaded from http://asj.oxfordjournals.org/ by guest on March 1, 2016
Figure 1. (A, B) Intralipotherapy is performed with the long (10 cm) 24-G needle supplied by the manufacturer. The entire length of the needle must be inserted into the subcutaneous adipose tissue, parallel to the skin surface.
Aesthetic Surgery Journal 36(2)
NP76
Figure 2. Anterior thighs of a 46-year-old Caucasian woman who experienced skin necrosis shortly after Aqualyx injections. This photograph was obtained 40 days after the injections.
Figure 3. Fourteen months after surgical revision, during which the scar tissue was removed. Wound closure was achieved with local flaps. (A) Right thigh. (B) Left thigh.
areas were treated with surgical curettage and antibiotics ointment medications. The skin healed in 3 months, with depressed scar tissue. Six months later, the scar tissue was surgically removed and the wounds were closed, undermining the surrounding tissues, with local flaps (Figure 3).
REFERENCES
This case corroborates the notion that not all DC-based solutions are fat-tissue selective, as evidenced elsewhere.2,3,12 Therefore, injecting such products (eg, Aqualyx) to reduce localized adiposity can result in adverse events such as skin necrosis, which was demonstrated recently by a multiplex assay performed by Duncan.4 As emphasized previously by Rauso et al,8 because the safety of DC itself is still under investigation, it is surprising that this DC-based solution could have gained approval as a medical device. Even though this instance of post-Aqualyx skin necrosis appears to be the only documented case worldwide, it strongly suggests that more investigations on the merchantability of this product are warranted.
Disclosures Dr Rauso received grants from Healthxchange (Manchester, UK) and Marllor (S. Giovanni in M., Cattolica, Italy), the company that distributes the drug solution in the United Kingdom and the drug’s manufacturer, respectively. Dr Di Toro has no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Funding The authors received no financial support for the research, authorship, and publication of this article.
Rittes PG. The use of phosphatidylcholine for correction of lower lid bulging due to prominent fat pads. Dermatol Surg. 2001;27:391-392. 2. Duncan D, Rotunda A. Injectable therapies for localized fat loss: state of the art. Clin Plast Surg. 2011;38:489-501. 3. Rotunda A. Injectable treatments for adipose tissue: terminology, mechanism, and tissue interaction. Lasers Surg Med. 2009;41:714-720. 4. Duncan D. Response to “Injection lipolysis with phosphatidylcholine and deoxycholate”. Aesthet Surg J. 2013;33 (7):1073-1075. 5. Aqualyx package leaflet. Motolese’s solution. CE 0373. LELX0010 Rev.00. 6. Salti G, Rauso R. Comments on “Injection lipolysis with phosphatidylcholine and deoxycholate”. Aesthet Surg J. 2014;34(4):639-640. 7. Pinto H, Hernandez C, Turra C, Manzano M, Salvador L, Tejero P. Evaluation of a new adipocitolitic solution: adverse effects and their relationship with the number of vials injected. J Drugs Dermatol. 2014;13(12):1451-1455. 8. Rauso R, Salti G. A CE marked drug used for localized adiposity reduction: a 4-year experience. Aesthet Surg J. 2015;35(7):850-857. 9. Rauso R. Non surgical reduction of buffalo hump deformity. Case report and literature review. Eur J Aesthet Med Dermatol. 2011;1(1):29-34. 10. Rauso R, Rusciani A, Curinga G. An adipocitolitic aqueous micro-gelatinous solution for buffalo hump deformity reduction. J Drugs Dermatol. 2014;13(10):1282-1284. 11. Duncan D, Rubin JP, Golitz L, et al. Refinement of technique in injection lipolysis based on scientific studies and clinical evaluation. Clin Plast Surg. 2009;36(2):195-209, v-vi; discussion 211-213. 12. Rotunda AM, Suzuki H, Moy RL, et al. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution. Dermatol Surg. 2004;30:1001-1008.
Downloaded from http://asj.oxfordjournals.org/ by guest on March 1, 2016
DISCUSSION
1.
