Cryolipolysis in the United States—Review of the clinical data

Noninvasive body contouring is becoming more popular in the United States as an alternative to liposuction. The most popular of these methods, cryolipolysis, uses precisely controlled cooling to reduce focal adiposities. The number of cryolipolysis procedures performed annually has experienced rampant growth in United States markets, and the indications have likewise diversified. In light of this change, it is imperative to perform an updated review of available US safety and efficacy data on cryolipolysis.

most frequent concern, with 77% of consumers being bothered by excess fat on any part of the body and 70% bothered by excess fat specifically under the chin/neck. 1Based on these figures, it should come as no surprise that the number of surgical and nonsurgical fat reduction and body contouring procedures is at an all-time high and continuing to rise.
Liposuction remains the apparent gold standard for procedures intended to reduce the appearance of excess adipose tissue.From 2020 to 2021, the number of liposuction procedures performed in the United States increased by 68%, according to the Aesthetic Society. 2 Though it would be natural to assume this figure might be skewed by the sharp decline in elective surgical procedures starting in the spring of 2020 due to the effects of the COVID-19 pandemic, even when comparing the number of procedures in 2019-2021, there was an 81.4% increase in liposuction performed by plastic surgeons. 2From these figures, it is clear that liposuction remains an increasingly popular modality of fat reduction, and the 491 098 procedures in 2021 constitute a record for the greatest number performed annually over the more than 20-year period in which such data have been collected by the Aesthetic Society. 2 Despite the unparalleled popularity it currently enjoys, liposuction remains a procedure with inherent risks and drawbacks.It is invasive, and as such, it carries the implicit risks associated with surgery, including anesthetic risks.One study found an overall complication rate of 2.4%. 3 Although uncommon, complications, such as fat embolism, venous thromboembolism, infection, and visceral perforation, can be serious and sometimes fatal. 3,4Less serious but still concerning complications include contour irregularities, hyperpigmentation, and scarring.[5] Although liposuction remains the most popular body contouring procedure among both men and women, several noninvasive body contouring (NIBC) alternatives are gaining traction in the United States, including treatments based on radiofrequency, lasers, ultrasound, injectables, and thermal energy, for example, cryolipolysis. 6According to the ASDS, dermatologists performed over 1 million body sculpting procedures in 2019, with cryolipolysis treatments constituting over a quarter of procedures. 6These data indicate that cryolipolysis is the most popular noninvasive body contouring method.It offers a nonsurgical and noninvasive alternative to traditional liposuction, making it an attractive option for patients seeking to eliminate stubborn body fat without the risks and downtime associated with surgical treatment.It is worth noting that other energy-based and injectable methods of body contouring have experienced nearly commensurate growth in popularity, with up to fivefold increases in the number of procedures performed across the 8-year period in which data were collected. 5spiration for the innovation behind cryolipolysis procedures stems from a number of isolated observations of visible cold-induced injuries made over the past century. 7,8Among these novel observations was a case of "popsicle panniculitis," documented by Epstein and Oren in 1970 after noting the appearance of a red, indurated nodule which progressed to fat necrosis in the cheek of an infant that had been sucking on a popsicle 2 days prior. 9In 1980, Beacham et al. made a similar report of cold-induced panniculitis in women who had been participating in equestrian activities consistently during the winter while wearing tightly fitting clothing. 10sed on these and several other reported clinical observations of Although incompletely understood, the theoretical principle underlying cryolipolysis treatments is based on exploitation of the relatively higher cold sensitivity of lipid-rich adipocytes as compared to surrounding water-rich tissues; this intrinsic difference allows adipocytes to be damaged or destroyed by cooling without harming the nearby skin, muscle, and nerves. 7,8During a cryolipolysis procedure, a thermal applicator consisting of a cup or parallel plates is placed on the treatment area to cause precisely controlled cooling of the tissue to a predetermined temperature for a given period of time.Many devices use a vacuum-based negative pressure system to draw the tissue into the applicator and improve contact with the cooling surface.The end result of this process is apoptosis of adipocytes followed by an inflammatory response that causes gradual digestion of lipids and cellular debris and a focal reduction in adiposity over the following weeks to months. 8e aim of this review is to examine the currently available objective clinical data generated by studies of cryolipolysis conducted in the United States with an emphasis on efficacy and safety.Previous reviews have had a similar focus on objective data, but these often included studies that varied widely in their location, type of device, user training, and specific protocol.While it is infeasible to control for protocol and device variations completely in a review of this type, by limiting the geographical area of the investigation, it is possible that greater clarity can be gained on the true status of cryolipolysis in the United States.

| MATERIAL S AND ME THODS
A systematic literature search was conducted on PubMed using the search terms "CoolSculpting" OR "cryolipolysis" OR "lipocryolysis."This search yielded 246 articles.Two investigators reviewed article titles and abstracts to identify studies that assessed the safety and/or efficacy outcomes of cryolipolysis, including prospective and retrospective studies as well as case series.Review articles and animal models were excluded.Selected articles then underwent further review to eliminate studies that were not based in the United States.
The literature search prompted 246 results.Assessment, with the exclusion of review articles, individual case reports, combination treatments, and animal studies, yielded a total of 15 distinct articles.
These consisted of 1 retrospective study and 14 prospective studies.(Table 1)

| Efficacy
The average age of cryolipolysis recipients in the reviewed studies was 46.4 years with a mean body mass index (BMI) of 26.6.
Prominently targeted areas included the flanks, inner/lateral thighs, submentum, abdomen, and male breast.The most popular target location in the reviewed studies was found to be the flank.
The duration of the studies varied between 2 and 6 months, generally settling around the 12-week mark.The number of treatment cycles ranged from one to two, depending on the treatment site.
[14][15][16][17][18][19][20][21][22][23][24][25][26] The assessment of objective outcome measures included ultrasound measurements, body caliper measurements, and 3D imaging (VECTRA).Utilizing these outcome measures, the investigated studies each exhibited statistically significant reductions in average fat content within the treated areas.The reviewed data presented the reduction of fat content as percentages of total volume or as absolute metric measurements in order to evaluate the efficacy of cryolipolysis.Outcomes, particularly those represented in absolute measurements, consequently varied widely depending on treatment location.The mean reduction in fat thickness, as measured by ultrasound, ranged from 2.0 mm to 5.1 mm and a 19.6% to 32.3% reduction across all studies that used this method.Fat caliper measurements displayed a mean reduction ranging from 2.3 mm to 7 mm and 14.9% to 21.5% reduction across all studies that used this method.Patient satisfaction rates and before/after identification assessments conducted by blinded evaluators served as subjective outcome measures.The observed satisfaction rates ranged from 82% to 100%.[14][15][16][17][18][19][20][21][22][23][24][25][26] Of note, two studies implemented a dual-session treatment approach that influenced both the satisfaction and identification and was accompanied by a corresponding increase in the correct blinded evaluator identification rate from 77% to 100%. 25milarly, Munavalli et al. reported an increase in satisfaction rate from 79% to 95% after the second round of treatment.Though the initial identification rate stood at 82%, there was no explicit mention of a change in evaluator identification rate following the second treatment session. 18
The severity of these side effects was mild to negligible.In the vast majority of cases, the symptoms displayed a transient nature, manifesting promptly after treatment and resolving within a few weeks.
Numbness, however, stood as an exception with a noteworthy persistence of up to 6 weeks in some patients, albeit with low severity. 21e incidence of persistent skin discoloration, wound formation, or infection was exceedingly low.Serum lipid levels and liver function enzymes (AST and ALT) were stable immediately after treatment and during a 12-week follow-up period. 13,24Four cases of PAH were reported in patients treated in the reviewed studies.This figure corresponds to an incidence of about 0.12% across 3445 treatment cycles in 976 patients.

| DISCUSS ION
Over the past two decades, the field of NIBC has undergone significant diversification in available treatment modalities, a phenomenon that has been accompanied and perhaps driven by rapid growth in popularity and demand for NIBC as an alternative to invasive body contouring methods, such as liposuction.By 2019, 11 cryolipolysis devices had already gained 510(k) premarket approval from the FDA for use in the United States, and the indicated treatment populations and target areas had both increased significantly in scope. 27Patients with BMI values of up to 43 kg/m 2 are now permitted to be treated using cryolipolysis devices in the submental and submandibular areas (≤ 30 kg/m 2 in all other areas), though the investigation of efficacy in these populations is still ongoing.Similarly, there are now eight treatment areas for which cryolipolysis devices have received clearance, including submental, submandibular, thigh, abdomen, flank, bra/back area, lower buttocks, and upper arm regions. 28Given the increasing momentum in the United States NIBC market and the growing number of cryolipolysis treatments performed each year nationally, it is imperative to perform an updated review of the existing clinical data on efficacy and safety from the United States.Additionally, decreased temperature causes significant vasoconstriction, a phenomenon that is compounded by direct pressure from the vacuum-based applicators used in many treatment devices.This reduces cellular perfusion and promotes intracellular acidosis as a result of compensatory glycolysis.Limited metabolic capacity stalls the production and recycling of ATP and its constituents, which rapidly degrade. 29During reperfusion injury, suddenly abundant oxygen combines with ATP degradation products to generate superoxide and other reactive oxygen species that compound cellular damage. 30ken together, these three mechanisms of injury are theorized to precipitate apoptotic pathways leading to adipocyte death and subsequent localized inflammatory response.Histopathologic evaluation following treatment has yielded evidence of increased tissue macrophage activity in these areas of inflammation; this is highly suggestive of their role in recycling adipocytes and also provides a mechanistic basis for evidence documenting a relatively negligible increase in serum levels of lipids and various lipid-associated proteins and enzymes following cryolipolysis treatments. 11,13,24Though the current understanding is fairly nuanced and appears physiologically sound, it is limited by the dearth of evidence drawn from real-world, clinical applications of cryolipolysis technology.Only a few initial animal studies and ex vivo experiments using extracted adipocytes have closely examined the process of cryolipolysis; further, more rigorous examination of this technology within its context of use is needed to achieve a concrete understanding of its mechanisms. 11,31

| Current paradigms
As with all cosmetic procedures, the selection of appropriate patients and treatment areas for cryolipolysis is of paramount importance and helps to ensure positive patient experiences and satisfactory results.In the same vein, adherence to effective protocols is often the best path to optimal treatment.However, the newness of cryolipolysis technology and the oftentimes poor quality of existing studies have contributed to a scarcity of expert consensus on numerous aspects of the treatment process.In 2022, a modified Delphi study was conducted by Altmann et al. in consultation with a number of expert practitioners in the United States and other countries.Although the total number of participants was small (n = 11), the study yielded a number of practice points that achieved a complete consensus among surveyed study participants and were echoed by existing literature and other published expert guidance. 28,32 regard to patient and treatment area selection, existing evidence and the aforementioned expert guidance indicate that optimal patients should have areas of fat that are well-localized and can be suctioned effectively into the vacuum applicator if one is used.Beyond the basic biomechanical suitability of targeted sites, there is limited evidence to suggest that regional designation, such as the thigh or abdomen, has an impact on treatment success. 8ile cryolipolysis is approved for a BMI of up to 43 kg/m 2 (in the submental and submandibular areas) and patient BMI is not itself a limiter of objective success (i.e., measurable reduction in the volume of the targeted area) following selection for treatment, patients with an excessively high BMI, large and continuous fatty regions, or loose excess skin folds are often considered as being less likely to achieve satisfactory outcomes. 32Thus, patients with obesity, particularly more severe obesity, are relatively contraindicated from receiving cryolipolysis.In the studies examined for this review, the mean patient BMI was 26.6, suggesting that patients who receive cryolipolysis are generally overweight but not obese.Other notable contraindications include a documented history of cold-induced conditions, such as cold agglutinin disease or cryoglobulinemia, or significant cutaneous or vascular lesions in the areas being targeted for treatment. 8Additionally, a history of hernia near the target area may contraindicate a patient from receiving treatment with vacuum-based devices due to the risk of hernia incarceration. 28ere are no standardized protocols for treatment with cryolipolysis devices, but the accumulated literature and expert practitioners have informed a general approach.Following a patient's selection for treatment, it may be advisable to collect standardized photographs of the treatment areas for the purpose of pretreatment and posttreatment comparison, as documentation of visible change can play a major role in patient satisfaction.Each regional designation for which cryolipolysis is cleared will usually achieve volumetric reduction following a single complete treatment cycle, but guidance suggests that a visible clinical outcome may be more easily achieved with at least two cycles. 28,32Importantly, the number of requisite treatment cycles to achieve both a visible and satisfactory outcome may vary widely between patients.There are no rigorous clinical studies comparing the necessary minimum number of treatment cycles for success in each target area, so the importance of existing guidance must be weighted appropriately in light of this limitation.Furthermore, there are some patients for whom treatment will never be practically successful, meaning that they either do not respond to treatment at all or would require a prohibitive number of treatments to achieve a satisfactory result.Patient categorization by the degree of response to initial treatment has been proposed, with individuals being identified as either "normal" responders, "slow" or "poor" responders, or "non-responders," though debate remains as to the validity and necessity of a "slow" responder category, as well as for whom it may be most appropriate. 32llowing the completion of a cryolipolysis treatment cycle, many practitioners now incorporate posttreatment manual massage of the treated area, a practice that has been reported to improve outcomes. 33In like fashion, practitioners have also begun to introduce combinations of adjunct treatments using a variety of both injectable and energy-based NIBC technologies, such as deoxycholic acid injections and focused ultrasound shockwave therapy, with the goal of improving efficacy.Preliminary studies have indicated that the practice of combination therapy is both safe and effective, but further investigation by means of prospective comparator studies or split-body trials is necessary before conclusions can be drawn as to whether combination therapy is superior to the use of cryolipolysis alone. 34

| Safety and efficacy
Across the studies examined for this review, cryolipolysis demonstrated modest but consistent reductions in focal adiposities.
Although the means by which fat reduction was measured varied between studies, a strong degree of consensus has previously been shown between the instruments used (body calipers, ultrasound, and 3D imaging), and some studies went so far as to implement multiple tools and redemonstrate their agreement. 16,17The way in which fat reduction was reported also varied, with many studies providing either quantification in absolute millimeters of reduction or the percentage reduction in the subcutaneous fat layer.Some studies included additional subjective measures, namely the evaluation and identification of standardized before and after photos by blinded evaluators, which lends credence to the production of visible results.
However, there can be a great deal of variation in the method by which study photos are standardized, and the study subjects themselves may introduce additional variation by way of interim weight change or differences in how they pose for photos.Nevertheless, patient satisfaction following cryolipolysis treatments is typically quite high, and treatments are usually considered successful by both the patient and practitioner.
Cryolipolysis is generally well-tolerated by a broad variety of patients.During the procedure, discomfort is regarded as being quite mild and manifests as localized feelings of intense cold and pressure.Side effects are mild and limited in duration, with none lasting more than a few weeks.Possible complications from cryolipolysis are few and relatively rare.However, PAH, one of the more serious complications, can be very distressing for a cosmetic patient on a body contouring journey.While the precise incidence of PAH is not yet clear, updated estimates range from 0.05% to 0.39% of treatment cycles. 35PAH does not resolve on its own and usually requires corrective liposuction in order to transform body contours to their original or desired state.There does not appear to be an anatomic predisposition for PAH at specific sites.PAH occurs more commonly in men, who comprise about 15% of treated patients and 55% of reported PAH cases.Though the mechanism by which PAH occurs is not understood, as it disproportionately affects men, it has been theorized that testosterone may play a role. 35Other serious complications, such as frostbite or skin necrosis, are incredibly rare and were not recorded as adverse events for any of the studies we reviewed.While cryolipolysis procedures do carry inherent risks and may result in side effects or complications, they are either mild or rare, and the procedure can be considered quite safe, especially when compared to any invasive alternative.

| Conclusions
As the field of noninvasive body contouring continues to mature, cryolipolysis seems firmly cemented as one of the best available treatment options.The growing number of treatments performed annually and the ever-diversifying cryolipolysis devices that debut on the market suggest that this is no passing trend.Cryolipolysis enjoys a broad-based appeal in the United States and around the world due to its relative affordability, few contraindications, low risk, minimal downtime, and appreciable results.Treatment has been made incredibly accessible because of the sheer number of providers who have been able to obtain cryolipolysis devices and be trained in their use.Though existing clinical data on both the mechanisms and efficacy of cryolipolysis, its adjunct treatments, and complications profile still have not reached the highest standards of rigor, they provide meaningful insight and direction for future studies which may yield a clearer picture of this promising method for noninvasive body contouring.
cold-induced panniculitis, Manstein et al. recognized the potential for using the application of intense cold to selectively damage adipose tissue.Their 2008 porcine study using a prototype device showed significant fat reduction in treated areas without injury to the skin or significant change in serum lipids or liver function indicators. 11 rates.The study by Friedmann et al. focused on the periumbilical abdomen, whereas the study by Munavalli et al. focused on the bilateral breasts.Following the second treatment session, Friedmann's satisfaction rate increased from 50% to 100%
Though the precise means by which cryolipolysis treatments achieve a reduction in focal adiposities are still being explored, there are three proposed mechanisms that predominate the TA B L E 1 Study methods, population characteristics, and outcomes from reviewed articles.