Literature review of adverse events associated with cryolipolysis

Cryolipolysis is a noninvasive procedure for localized fat reduction and body contouring. This technique utilizes controlled cooling to induce adipocyte apoptosis without damage to overlying skin and other tissue. Although the procedure was once thought to be relatively harmless, recent studies have shed light on the risks of adverse effects (AEs).


| INTRODUC TI ON
It is well-established that excessive body fat can induce a variety of health issues and increase the risk of metabolic diseases such insulin resistance and Type 2 diabetes. 1Noninvasive body contouring has seen rapid growth in recent years.In 2019, the American Society for Dermatologic Surgery reported a five times increase over 8 years in body contouring procedures. 2 Out of more than 1 000 000 body contouring procedures performed in 2019, 25% were cryolipolysis or "fat-freezing." 2 Cryolipolysis is growing in popularity as a noninvasive procedure for localized fat reduction and body contouring.
This technique utilizes controlled cooling to induce adipocyte apoptosis without damage to overlying skin and other tissue. 3,4These adipocytes are eventually engulfed by macrophages and cleared out naturally by the immune system over several months. 3,4Other FDAapproved noninvasive body contouring modalities include low-level laser therapy (LLLT), radiofrequency (RF), high-intensity focused ultrasound (HIFU), and high-intensity focused electromagnetic field (HIFEM). 1,5ntraindications of cryolipolysis include scars, hernias, coldrelated disorders such as cryoglobulinemia, cold urticaria, and paroxysmal hemoglobinuria.[8] Although the safety profile of cryolipolysis has generally been considered low-risk after evaluation in thousands of research subjects, serious and long-term adverse effects (AEs) have been reported since its FDA approval for cosmetic use in 2010. 9,10Some of these concerning complications, like paradoxical adipose hyperplasia (PAH) (Figure 1A,B) have recently gained widespread media attention.Former supermodel Linda Evangelista reported that her experience with CoolSculpting resulted in PAH, leaving her "permanently deformed"-the model settled with Zeltiq Aesthetics, a division of Allergan Aesthetics, in a $50M lawsuit in 2022. 10,124][15] As the use of noninvasive procedures to reduce body fat continues to grow, both in and out of the cosmetic world, it is important to continuously review and appropriately document adverse events and complications in clinical practice.Healthcare professionals must stay abreast of these new insights so that they can inform their patients about these potential risks.

| MATERIAL S AND ME THODS
To conduct this review, a comprehensive search was performed in PubMed, using relevant keywords such as "cryolipolysis," "CoolSculpting," "adverse effects," "complications," and "side effects" with no set data range.The search was limited to studies published in English.The selected studies encompassed a variety of study designs, including randomized controlled trials, prospective cohort studies, case series, case reports, and reviews.(55.2%) and exacerbation of preexisting hernia (44.8%), with over 25% of patients requiring surgery to repair. 5terestingly, even though hernias accounted for 10% of all cryolipolysis-related MDRs, a literature search found no such cases reported in scientific literature.Other AEs associated with cryolipolysis discussed in the Nguyen et al paper include burn/blister, fat necrosis, cold panniculitis, clots, diastasis Recti, systemic inflammation, hematuria, fat embolism, colon obstruction, systemic infection, brain aneurysm, ruptured breast implant, lipoma, organ prolapse, Crohn's disease flare, and hearing changes. 5 a similar review of the MAUDE database from 2015 to 2021,  (11,   1.6%), and neuropathy (11, 1.6%), and that all reports of PAH and abdominals hernias came specifically from CoolSculpting procedures. 16systematic review of adverse events associated with cryolip- (n = 269), "stiff skin" (n = 248), bruising (n = 124), and edema (n = 82). 9ss common AEs found were dysesthesia (n = 59), delayed, persistent, or severe pain (n = 49), PAH (n = 30), skin blanching (n = 15), vasovagal reactions (n = 14), diffuse or nodular infiltration of the skin within days of the procedure (n = 12), post-inflammatory skin hyperpigmentation (n = 8), contour irregularities (n = 3), and skin necrosis (n = 2, one reported with use of a non-FDA-approved cryolipolysis device, one reported with an at-home device). 17Additionally, coldinduced blisters (n = 1), painful indurations (n = 4), cold panniculitis (n = 1), localized scleroderma (n = 1) were noted in case reports and case series. 17[20][21][22] When reviewing the AEs of medical procedures, it is important to consider that not every machine is created or used equally.For example, "cryolipolysis" is the general term for the procedure of freezing fat, and in the United States, the "CoolSculpting" device (manufacturer ZELTIQ Aesthetics, Inc., a subsidiary of Allergan Aesthetics) was cleared by the FDA in 2010 for cryolipolysis; however, the terms are often used interchangeably by providers, patients, and in medical literature worldwide. 23This can lead to confusion as there are a number of different devices both in the United States and abroad that are used for cryolipolysis in medical and aesthetic facilities, as well as at-home products directly by consumers.Even the FDA-approved CoolSculpting line itself has multiple devices with varying cup shapes or mechanisms, such as CoolCore, CoolCurve, CoolMax, CoolFit, CoolSculpting Elite (the most up-to-date applicator), and CoolMini (used for the submental region).More research is needed to determine if there are major differences in AEs based on specific CoolSculpting device or region (abdomen, submental, etc.) MDRs can be reported from outside the United States, so adverse event data in the MAUDE database for cryolipolysis includes a mix of US and non-US devices, which may not all meet the same safety standards. 5Other limitations of the MAUDE database include under-reporting of AEs to the FDA, the fact that reports are not subject to review to determine a true link between a device and an AE; and that sources are not prescreened, with one study showing that 17.8% of submissions between 1997 and 2018 were from physicians, and only 0.5% of these reports were submitted directly to the FDA, while the manufacturer submitted 99% of the physician reports. 16,24ditionally, machine users may have different levels of experience, licensure, and up-to-date knowledge of optimal machine settings for effectiveness and safety.In fact, there are limited regulations on who can purchase or use a cryolipolysis device in the United States.A search on eBay for "coolsculpting" yielded thousands of results, from used ZELTIQ's CoolSculpting to non-US regulated devices from China marketed as "cool sculpting." 25These variables can make it more difficult to quantify the risks of cryolipolysis accurately.

| Paradoxical adipose hyperplasia
In recent years, it has become increasingly evident that PAH may not be as rare as once believed. 17PAH is believed to be underreported, and because the manufacturers' reported risks may be based on number of cycles instead of number of patients (with patients typically undergoing multiple cycles), the perceived risk of developing PAH was low. 5,9,10As the New York Times wrote to simplify how the risk of developing PAH can be represented in dramatically different ways: if 2 patients received 10 treatments of CoolSculpting, and 1 developed PAH, the manufacturer would report 1 in 20 (5%) treatments as the risk of developing PAH, whereas physicians would report 1 in 2 patients, so 50%. 10A multicenter study of 8658 cycles in 2114 patients showed an incidence of PAH between 0.05% and 0.39%, which is greater than the 0.025% risk originally stated by the CoolSculpting manufacturer.In other words, the rate of PAH incidence in the multicenter study was found to be at least 2 times to at most 15.6 times greater than originally suggested by the manufacturer. 9A recent retrospective case series of 4 patients diagnosed with PAH after cryolipolysis at a large academic medical center calculated the incidence of PAH as 0.67. 26These kinds of discrepancies and different approaches to defining certain risks complicate the understanding of AEs in cryolipolysis, and thus patients may not have a true understanding of their risks before undergoing treatment.
After FDA approval of cryolipolysis in 2010, the first reported case of PAH in medical literature, which coined the term itself, was published in 2014.As of July 16, 2023, 23 articles were found related to PAH on PubMed.This suggests that incidents of PAH may have occurred prior to this case, however, may not have been officially reported.It has been found to disproportionately impact men more than women, may have an increased prevalence in Hispanic people, and has also been linked to the abdominal region and larger handpieces. 9,27,28There may also be a genetic predisposition, as one study found PAH in twins who underwent the procedure in different centers. 28,29A study of the MAUDE database found that PAH was the most common AE accounting for 483 (73.2%) of the cryolipolysis MDRs from 2015 to 2021. 16 mentioned earlier, due to the nature of the MAUDE database having MDRs reported from both US and non-US users, the exact device not always known or reported, and the underreporting of AEs to the FDA in general, it is not quite clear what percentage of PAH incidences are due to CoolSculpting in the United States, CoolSculpting outside the United States, cryolipolysis with non-FDA-approved devices, and even cryolipolysis with counterfeit machines. 5This further complicates our understanding of the true risk of developing PAH post-procedure.
It is worth nothing that PAH may not be limited to postcryolipolysis fat reduction.One case reported a 57-year-old male patient developing PAH in the abdomen after undergoing noninvasive treatment with RF (Vanquish). 30The mechanism of action of PAH is not well understood, therefore further research is needed to understand the risks and mitigations of a diagnosis.

| Severe frostbite
One rare cryolipolysis AE found in the literature was frostbite.A 61-year-old woman developed severe, full-thickness frostbite on her abdomen with unbearable pain requiring hospitalization 2 days after undergoing cryolipolysis treatment by a beautician in a nonmedical center.The device was brand-new and used for the first time on this patient with manufacturer settings and it is not a US FDA-approved device (YetiⒸ, ITS Group).It was noted that the patient was clearly in pain within the first minute of treatment, but treatment was not interrupted. 19

| Cold burns
In 2023, Barry et al. published the world's first case series on cold burns caused by cryolipolysis to challenge the once perceived safety of the treatment. 31In this retrospective review of the New South Wales (NSW) Statewide Burn Injury Service Registry, a database of all patients treated by NSW burn units, 8 female and 2 male patients (mean age 37; range 22-61) with cold burns sustained from cryolipolysis treatment between 2012 and 2020 were included.Locations included abdomen (most common), limbs, neck, flank, and buttock; mean total body surface area injury was 1%, burn depth ranged from superficial partial thickness to full thickness, with two patients requiring inpatient management and skin grafts.The study did not specify if the NSW Statewide Burn Injury Service Registry included device manufacturer details. 31

| Cold panniculitis
The first known case of cold panniculitis after cryolipolysis to the abdomen was published in 2018.The patient was a 69-year-old woman who received CoolSculpting on the right and left upper abdomen and returned 7 days later with edema, large nontender erythematous plaques on right and left lateral abdomen, and tender erythematous subcutaneous nodules periumbilically which developed 3 days post-procedure.The patient experienced adipocyte necrosis and was treated with systemic corticosteroids and levofloxacin, and the inflammation resolved after 6 weeks with residual postinflammatory hyperpigmentation.After this event, the patient wanted to continue with noninvasive body contouring and it was decided to treat with RF instead.The authors also noted that the patient had many superficial varicose veins across her abdomen, which may have put her at an increased risk of localized ischemia, reperfusion injury, and cold panniculitis post-cryolipolysis. 22

| Submental considerations
The FDA approved the use of cryolipolysis for treatment of submental adipose tissue in 2015. 8Knowledge of the anatomy of the submental region is critical in avoiding injury to the marginal mandibular nerve.This could leave patients at a greater risk of injury if undergoing cryolipolysis with a non-medically trained provider.A 2017 review of submental cryolipolysis literature found no cases of PAH, but cases have emerged since then. 8,32As the use of submental cryolipolysis grows, the medical community will benefit from providers sharing experiences and cases of AEs in their patients.
In one case of cryolipolysis to the submental region using the CoolSculpting CoolMini applicator, a 60-year-old woman developed a marginal mandibular nerve injury.The patient tolerated the procedure but immediately after she noted dysesthesia (tingling), which responded to Ibuprofen, decreased sensation of bilateral submandibular area and cheeks (between the zygoma and mandible, more pronounced on the left), and asymmetrical smiling after 8 h.After 2 weeks, she had residual dysesthesia of the left cheek and left submandibular, while the symptoms on the right had completely resolved and asymmetry of smile persisted.At the 1-month follow-up, she had complete resolution of sensory symptoms but still had an asymmetrical smile, due to left marginal mandibular nerve damage.
After 8 weeks, all motor and sensory symptoms had resolved.The authors hypothesize that cryolipolysis injured the myelin sheath of the nerve leading to temporary impedance of nerve conduction. 21n another case, a 52-year-old woman presented with PAH after undergoing cryolipolysis to the submental region 4 years prior.The case did not specify if the device manufacturer was known or where the patient had received the prior treatment of cryolipolysis.The patient was treated with direct excision of the preplatysmal fat with concurrent tumescent liposuction and had improved contour at the 7-week follow-up.The authors also discuss that cytolytic therapy, such as Kybella, can also serve as a powerful adjunct in treating submental PAH. 32

| RECOMMENDATIONS/S TR ATEG IE S TO AVOID OR TRE AT AE s
Some studies have assessed combined treatments, such as HIFU with cryolipolysis, for safety and efficacy.One such study found cryolipolysis reduced pain after use of HIFU versus HIFU alone, but did not state whether there was a difference in other AEs such as erythema and bruising between the two treated sides. 33e study explored the use of shockwave therapy (SWT) for prevention of PAH after cryolipolysis.Their center reports performing 2291 treatment cycles of cryolipolysis followed by SWT between April 2017 and mid-January 2021 with no documented cases of PAH.
However, this use of SWT has been challenged and questioned as to whether there is an additional benefit of SWT over manual massage following cryolipolysis. 34More research is needed to understand if SWT does in fact aid in fat removal after cryolipolysis, and whether or not its adjunct use can reduce or prevent incidence of PAH.
A retrospective chart review performed for post-cryolipolysis PAH between May 2013 and May 2016 in one Florida practice.The authors identified 11 cases, 7 of which were treated surgically with either liposuction alone or liposuction plus abdominoplasty, yielding patient satisfaction with their final appearance.The authors recommend treatment of PAH be delayed until the affected area is softened, which typically occurs within 6-8 months. 35 one study, 25 subjects had one session of cryolipolysis of the lower abdomen, and were a randomized side of the region (right or left) was subsequently treated with a heating mud pack and determined that side effects of edema, erythema, and hypesthesia were reduced on the heated side, as was the effectiveness of the cryolipolysis.The cryolipolysis device used was the CE-certified device KryoShape® (Swiss-Med-Tech, Switzerland), applicator size 4 (220 × 55 × 70 mm) with negative pressure around 20 kPa and protective gelpad (coolpas™, 25 × 50 mm).Due to the heated sites having a reduced mean sonographic reduction of local adipose tissue after 12 weeks (9.6% vs. 14.1%;p = 0.0003), the investigators do not recommend the use of active heating following cryolipolysis. 36few cases have been published of patients who previously underwent cryolipolysis and if there was any impact on subsequent surgeries in the treated area.One such case presented a patient undergoing surgical treatment for breast cancer who had previously undergone multiple cycles of cryolipolysis of the abdomen.
Deep inferior epigastric artery perforator (DIEP) flap was used as an autologous breast reconstruction in the patient without any reported complications. 37More research is needed to understand long-term effects of cryolipolysis and if patients are at risk when undergoing subsequent surgical procedures.
The first systematic review on cryolipolysis from 2015 found that the procedure "appears to be safe in the short term, with a limited side effect profile." 38 Since then, the medical community has expanded its knowledge on the potential risks and complications associated with cryolipolysis.Continued post-market surveillance of medical devices like NIBC devices is partially due to the Safe Medical Device Act (SMDA) in 1990, which created the MAUDE database as a registry to report device-related deaths, injuries, and malfunctions dating back to 1993. 16,39Manufacturers, patients, and user facilities can submit AEs to MAUDE; however the information may not always be complete or accurate, and the number of AEs may not be truly encompassing as medical device AEs are underreported for a variety of reasons. 16erefore, it is critical for providers of such services as NIBC to document and share AEs through scientific literature as well.Further research is needed to understand if AEs such as PAH that occur outside the United States are CoolSculpting cases or other devices.Additionally, further studies are needed to better understand the pathophysiology of such sequelae as PAH, and to better recognize the risks and potential complications associated with cryolipolysis, so that we can treat our patients better through informed participation.

ACK N OWLED G M ENTS
The editorial assistance was provided by Angela N. Brown.

CO N FLI C T O F I NTER E S T S TATEM ENT
Dr. Michael Gold is a consult for Allergan Aesthetics, an AbbVie Company.

F
I G U R E 1 (A) Before one cryolipolysis treatment.(B) After one cryolipolysis treatment with PAH.Photos courtesy Singh et al.

11
olysis published in 2020 by Hedayati et al. included 53 studies and 3312 patients.Their literature search found the most common AEs that developed within a week of treatment and resolved spontaneously, and include erythema at the treatment site (the most common side effect found, n = 871), numbness/paresthesia (n = 301, with 114 patients' numbness lasting longer than a week, 25 patients' lasting longer than a month, 1 patients lasting 132 days), "clay-like skin" Lim et al found 660 MDRs on NIBC treatments, and that 85.7% of those MDRs were from CoolSculpting by Zeltiq, followed by 6.2% from SculpSure by Cynosure, which utilizes laser lipolysis, and 2.4%