COSMETIC. Consensus Recommendations for Soft-Tissue Augmentation with Nonanimal Stabilized Hyaluronic Acid (Restylane) BACKGROUND AND OVERVIEW

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1 COSMETIC Consensus Recommendations for Soft-Tissue Augmentation with Nonanimal Stabilized Hyaluronic Acid (Restylane) Seth L. Matarasso, M.D. Jean D. Carruthers, M.D. Mark L. Jewell, M.D. and the Restylane Consensus Group San Francisco, Calif.; Vancouver, British Columbia, Canada; and Portland, Ore. Summary: The American Society for Aesthetic Plastic Surgery recently reported that there were nearly 12 million cosmetic procedures (2.1 million surgical and 9.7 million nonsurgical) performed in the United States in Almost 900,000 of the nonsurgical procedures were soft-tissue augmentation procedures using hyaluronic acid fillers. Restylane (Medicis Aesthetics, Inc., Scottsdale, Ariz.), nonanimal stabilized hyaluronic acid, was approved for use in the United States in December of Although the use of all fillers increased from 2003 to 2004, use of hyaluronic acid fillers increased nearly 700 percent. The dramatic increase in all cosmetic procedures reflects the growing trend, especially with increasing job competition, to maintain a youthful lifestyle and appearance. Basic recommendations for aesthetic use of Restylane were established based on short- and long-term efficacy and safety studies (Medicis Aesthetics, package insert). With the widespread and growing use of Restylane, a cross-sectional panel of experts with extensive clinical experience, including cosmetic dermatologists and surgical specialists (cosmetic, plastic, and ocular), convened to develop consensus guidelines for the use of Restylane. This supplement reviews the aesthetic affects of aging on the face, the role of fillers in facial soft-tissue volume replacement, and general principles for the use of Restylane, including patient comfort and assessment techniques. Specific recommendations for Restylane use in each potential target area, including type of anesthesia, injection techniques, volume for injection, use in combination with other procedures, and expected longevity of corrections, are provided. Techniques for optimizing patient outcomes and satisfaction and for minimizing and managing expected problems and potential complications are described. (Plast. Reconstr. Surg. 117 (Suppl.): 3S, 2006.) From the Department of Dermatology, University of California, School of Medicine, San Francisco; Department of Ophthalmology, University of British Columbia; and Department of Plastic Surgery, Oregon Health and Science University. Received for publication November 4, 2005; revised December 5, Copyright 2006 by the American Society of Plastic Surgeons DOI: /01.prs BACKGROUND AND OVERVIEW Effects of Facial Aging A hallmark of facial aging is loss of subcutaneous volume (Fig. 1). This is manifested by thinning of the dermis, with loss of elasticity and underlying atrophy of the natural fat pads. Aesthetically apparent results of the aging process include greater visibility of bony landmarks, blood vessels, wrinkles, and furrows. Transverse forehead lines become prominent and can be accompanied by lowering of the eyebrows. An early feature in the lower face is increased prominence of the nasolabial folds. Critical changes in the perioral area can include vertical rhytides, ptosis of the oral commissures, thinning of the lips, and flattening of the upper lip with less definition of the Cupid s bow. A labiomandibular groove can develop, as can a prejowl depression (marionette lines). 1 5 Treatment of Facial Aging A wide range of treatment options are available for managing volume loss in the aging face, including permanent, semipermanent, and nonpermanent solutions. A complete aesthetic evaluation of the patient and a thorough understanding of the patient s goals and preferences are crucial in any treatment plan. Interventions can include topical therapy, energy-based therapies, including laser-, radio frequency-, and light (visible and infrared)-based therapies, surgical proce- 3S

2 Plastic and Reconstructive Surgery March Supplement 2006 use and have a history of safety and reliability, disadvantages include allergic reactions (1 to 3 percent) requiring pretreatment skin tests and relatively short-lived corrections. Bioengineered human collagens derived from cell cultures of human fibrocytes are also available. 17,18 Fig. 1. The aging face. dures, and injectable products, including neurotoxins such as botulinum toxin type A and fillers. The temporally biodegradable injectable fillers include autologous fat, collagen (animal and human derived), lactic acid polymers, and animal and nonanimal stabilized hyaluronic acid. Threedimensional facial recontouring through soft-tissue augmentation with fillers can provide patients with a fuller, youthful appearance that softens the appearance of aging. Restoration of lost volume can fill out folds, improve lines and wrinkles, and provide the means to meet the aesthetic goals of both male and female patients across all ethnic groups. In some individuals, fillers will be sufficient for volume correction. Other patients may require both surgical solutions for volume redistribution and the use of fillers in areas of the face where surgery cannot produce a result. Nonpermanent Tissue Fillers The evolution, properties, and availability of softtissue fillers were extensively reviewed recently Soft-tissue fillers comprise four general categories: fat (autologous), bovine collagen (xenogenic), bioengineered human collagen (allogenic), and hyaluronic acid (animal and nonanimal based, xenogenic). Bovine collagen was approved for use in the United States in 1981, and several bovine collagen products are currently available in the United States. 7,15,16 Although bovine collagens are easy to Physical Properties of Hyaluronic Acid in the Skin Hyaluronic acid, or hyaluronan, is a glycosaminoglycan that consists of regularly repeating nonsulfated disaccharide units of glucuronic acid and N-acetylglucosamine (Fig. 2). 19 Hyaluronan is a naturally occurring biopolymer that exhibits no species or tissue specificity. It is an essential component of the extracellular matrix of all adult animal tissues and is especially abundant in early embryos. Hyaluronan normally exists in tissues as a free polymer of linked disaccharide units and is highly negatively charged. However, in some tissues, such as cartilage and bone, hyaluronan is bound to large glycoprotein structures or specific cell receptors. In healthy tissues, the average molecular weight of hyaluronan is 5 to 10 million with up to 25,000 disaccharide units, and the average adult concentration is 200 mg/kg (0.02 percent). A human body weighing 60 kg contains 12 g of hyaluronan. 20 Hyaluronan is highly hydrophilic (water-loving) and tends to form extended conformations that occupy a huge volume relative to mass; it forms gels even at very low concentrations. 19 Water drawn into the hyaluronan matrix creates a swelling pressure or turgor that enables the matrix to withstand compressive forces. These properties make hyaluronan an ideal component to maintain proper structure and function of tissues by creating volume, lubricating tissues, and affecting cell integrity, mobility, and proliferation. An essential feature of hyaluronan that makes it an ideal candidate for development of skin fillers is that the chemical structure is invariant across species, thus reducing potential for immunological reactions and implant rejection. Hyaluronan was first developed as a dermal Fig. 2. Hyaluronan. 4S

3 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation filler in 1989, when Endre Balazs appreciated its biocompatibility and lack of immunogenicity. 21 However, the process of catabolism and removal of hyaluronan is fast and efficient, mediated by receptor binding and intracellular degradation. This results in a half-life of nonstabilized hyaluronan that ranges from half a day to a few days in most tissues and less than 24 hours in skin. 20 Therefore, regardless of source (animal or bacterial), native hyaluronic acid must be stabilized through a cross-link process to produce practical forms suitable for use as skin fillers. Comparison of Hyaluronic Acid Fillers Four hyaluronan formulations have been approved by the U.S. Food and Drug Administration and are commercially available in the United States (Table 1). The approved indication is the same for all of the products. Each product is approved for mid- to deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. 2,22 24 All other uses are considered off-label. In contrast to bovine collagen fillers, no skin testing is required before treatment with any of the hyaluronan fillers. For Restylane (Medicis Aesthetics, Inc., Scottsdale, Ariz.), the manufacturing process, which includes use of the stabilizing agent 1,4-butandiol diglycidylether, results in approximately 1 percent cross-linking. 2,25-27 The manufacturing process also increases the hyaluronic acid concentration approximately four-fold to 20 mg/ml and produces the small gel particle size (400 m). These features distinguish Restylane from the other three products. Consensus panel members were asked a series of questions related to the use of hyaluronans in clinical practice. Sixty-nine percent of the consensus panel thought that product longevity is the most important factor in selecting a hyaluronan product. Panel members were then asked what factors they thought most affects product longevity. Fifty-seven percent of the panel members thought hyaluronic acid concentration contributes most to longevity. As described in the previous section, native hyaluronic acid is rapidly degraded and cleared from the skin. Restylane begins as hyaluronic acid biosynthesized and isolated to a high degree of purity from bacterial (Streptococcus) fermentation cultures. 2,14,26 A low level of impurities contributes to allowing Restylane to be produced at relatively higher concentrations of hyaluronic acid, and the manufacturing process produces hyaluronic acid with a minimal degree of cross-linking. The combination of these features results in a Restylane product that is more biocompatible with native hyaluronic acid, that has more favorable degradation kinetics, and that therefore achieves maximum implant residence time. The resulting continuous three-dimensional molecular network can also be formed into various gel shapes and bead sizes, which also contributes to product longevitiy. 26 The Restylane gel maintains volume in the skin through isovolemic degradation, a process by which each hyaluronic acid molecule binds more water as it is metabolized to maintain the gel volume. The actual amount of hyaluronic acid in a Restylane gel bead is about five times greater than what is needed to maintain its volume. 26 Therefore, the size and shape of the implant are maintained for an extended period of time. Restylane Historical Perspective Early clinical and efficacy studies of Restylane were reported from Italy and Sweden. 27,28 The Swedish study reported that, based on physician evaluations, treatment sites maintained an average of 82 percent and 69 percent correction (using a visual analogue scale of 0 to 100 percent) at 12 and 26 weeks, respectively. 28 The Italian study reported that 78 percent of patients maintained moderate to marked improvement after 8 months, with nasolabial folds and lips sustaining the best results. 27 These studies reported injection-related reactions, including redness, swelling, darkening of the treatment site, and slight pain in about 13 percent of patients. Ongoing analysis of the adverse event databases indicated that in 1999, with an estimated 144,000 patients treated with Restylane, only one of every 650 (0.15 percent) reported redness, swelling, localized granulomatous reactions, bacterial infection, or acneiform lesions. 29 Delayed implant hypersensitivity reactions were reported in several case series at low incidences (0.4 to 3.7 percent) in early (before mid-1999) non United States use of Restylane In mid-1999, a hyaluronic acid raw material with trace amounts of protein six times lower than the raw material previously used was introduced. 29 The amount of protein in the more purified product was reported to be in the range of 13 to 17 g/ml of product. 29 In contrast to 1999, reported adverse events were reduced to 0.06 percent and hypersensitivity reactions were reduced to 0.02 percent in Consensus panel members agreed that since further purification of the product in 1999, the incidence of implant-site hypersensitivity reactions has virtually eliminated hypersensitivity reactions, thereby confirming that no skin testing is required before use of Restylane. 2 The key active comparator study of Restylane versus Zyplast (bovine collagen; Inamed Aesthet- 5S

4 Plastic and Reconstructive Surgery March Supplement 2006 Table 1. Properties of Available Hyaluronic Acid Fillers Restylane Captique Hylaform HylaformPlus Source Bacterial fermentation Bacterial fermentation Nongender chicken combs Nongender chicken combs Cross-linking agent 1,4-Butandiol diglycidylether Divinyl sulfone Divinyl sulfone Divinyl sulfone Degree of cross-linking 1% 20% 20% 20% Hyaluronic acid concentration 20 mg/ml mg/ml mg/ml mg/ml Gel particle size 400 m 500 m 500 m 750 m ics, Inc., Santa Barbara, Calif.), reported in 2003, provided the basis for the approval of Restylane use in the United States. 33 One hundred thirtyeight predominantly female (93 percent) Caucasian patients (89 percent) were randomized to receive treatment of their nasolabial folds with Restylane and Zyplast on contralateral sides of the face. Patients returned at 2-week intervals for touch-ups until an optimal cosmetic result was achieved that was considered baseline. The average number of treatment sessions to achieve an optimal cosmetic result was 1.4 (range, one to three) for both products. The volume needed for optimal cosmetic correction was lower with Restylane (mean, 1.0 ml; range, 0.3 to 2.8 ml) than with Zyplast (mean, 1.6 ml; range, 0.1 to 5.0 ml). Efficacy evaluations were conducted 2, 4, and 6 months after baseline. The primary efficacy endpoint was the Wrinkle Severity Rating Scale (WSRS) at 6 months after baseline; a key secondary variable was the Global Aesthetic Improvement Scale (GAIS) rating at 2, 4, and 6 months after baseline. The Wrinkle Severity Rating Scale score for Restylane was superior at all time points, and at 6 months after baseline, Restylane was superior to Zyplast in 56.9 percent of patients, whereas Zyplast was superior in 9.5 percent of patients (p 0.001). The Global Aesthetic Improvement Scale rating was also superior for Restylane at all time points, and at 6 months, 62.0 percent of patients rated Restylane superior to Zyplast, whereas 8 percent of patients rated Zyplast superior to Restylane. Safety evaluations were conducted at each visit and recorded in patients diaries. Predominantly mild or moderate and short-lasting (7 days or less) local injection-site reactions (swelling, redness, tenderness, and bruising) occurred (as recorded in patients diaries) at similar rates for Restylane (93.5 percent) and Zyplast (90.6 percent) after the initial injections. The incidence of most reactions was lower after touch-up sessions than after the initial treatment. During the 6-month follow-up period, treatment-related adverse events, such as mild to moderate redness and swelling, were reported for 26.4 percent of Restylane sites and 39.1 percent of Zyplast-treated sites. Delayed-onset reactions were seen in 12 patients (8.7 percent). Ten adverse events were reported at Restylane-treated sites, and 11 adverse events were reported at Zyplast-treated sites. All delayed-onset reactions resolved within 2 to 3 months without treatment. None of these reactions was judged to be a hypersensitivity reaction by the investigators. 6S

5 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation Procedural Considerations Prescribing information for Restylane indicates that the safety and effectiveness of Restylane for anatomic regions other than the nasolabial folds have not been established in controlled clinical trials.2 A warning is included that the safety of Restylane for the treatment of lips has not been established in controlled clinical trials.2 This warning applies to all nonpermanent fillers Instructions for the use of Restylane further suggest that patients should be limited to 1.5 ml per treatment site.2 Some of the uses and volumes discussed are off-label uses of Restylane. There are limits to the effect of tissue fillers, and good judgment should be utilized in counseling patients in borderline cases where surgical procedures may be indicated. Restylane is a gel of 1,4-butandiol diglycidylether stabilized, terminally heat-sterilized hyaluronic acid suspended in physiologic buffer at a ph of 7 and a concentration of 20 mg/ml.2 The gel is supplied in 1.0-ml and 0.4-ml disposable syringes with Luer-lok fittings. A sterile 30-gauge halfinch needle is supplied with each syringe. Proper assembly of the needle is essential, and updated assembly instructions have recently been issued by Medicis, as described and illustrated in Figure 3.2 A label is a part of each Restylane syringe. This label is to be attached to patient records to ensure traceability of the product. Restylane can be stored at room temperature [up to 25 C (77 F)] and must not be resterilized after partial use. A pilot study was recently published that evaluated the incidence of bacterial contamination of nonanimal stabilized hyaluronic acid stored after initial patient injection.34 After use of a specific sterile sequence, nonanimal stabilized hyaluronic acid from 30 previously used syringes was stored at room temperature for 2 to 9 months. No bacteria were cultured from any samples. Another study with similar results was recently reported.35 Panel members were asked how they usually handle unused nonanimal stabilized hyaluronic acid. Fortyfour percent of panel members discard unused product, and 13 percent store it for later use in the same patient. Thirty-eight percent of the panel members use the remaining product in another area of the face during the same office visit. Additional discussion indicated a strong consensus recommendation that extra Restylane should be used in another area of the face or discarded. Reuse at a later time is discouraged. The Restylane package insert states that Restylane is packaged for single-patient use and should not be resterilized.2 ACHIEVING SUCCESSFUL OUTCOMES Cosmetic rejuvenation for any patient must take into account aesthetic and physical considerations from the viewpoint of both the patient and the physician. Soft-tissue correction with fillers must be approached in a manner that considers the important aesthetic outcomes of each individual patient. It was the consensus of the panel that Restylane can be used effectively in individuals of all skin types and ethnic origins. Successful outcomes for all patients can be achieved by fol- Fig. 3. Directions for Restylane syringe assembly. 7S

6 Plastic and Reconstructive Surgery March Supplement 2006 lowing a general plan that includes patient education and assessment, adequate informed consent, and consistent pretreatment and posttreatment guidelines. Patient Education and Assessment A clear understanding of the patients aesthetic goals is essential to achieving successful outcomes to cosmetic filler procedures. Patients goals and expectations must be consistent with realistic physician evaluations and recommendations. Consensus panel members agreed that realistic recommendations must include a discussion of all cosmetic options. For instance, expected outcomes with fillers must be compared with potential results with surgical procedures if warranted, with appropriate referrals as necessary. It should be recognized that some patients who are best served by facial surgery may not be suitable for surgery from emotional or other perspectives. Fillers, including Restylane, can provide a bridge to help patients resolve these issues. Panel members also agreed that Restylane can be used safely and effectively before, on the day of (concurrently), or after facial surgery. To improve cosmetic results, Restylane can be used to add volume with surgery. Management of Patient Expectations Management of patients treatment expectations is vitally important. Physicians should discuss the amount of filler necessary to achieve the desired correction, the costs of the filler, comfort techniques, including anesthesia, expected normal occurrences, potential complications, and the potential recuperation time. Consensus panel members identified defining, achieving, and maintaining full correction as extremely important, and agreed that an aesthetic ideal appropriate to factors such as sex, age, and ethnicity can be defined for each facial anatomic area as well as the face as a whole. However, this ideal must be balanced with the patient s goals and expectations, and full correction may be best described as optimal correction, which includes ideal aesthetic considerations and what the patient wants. Achieving full correction with Restylane is highly individualized. On a national basis, the average amount of volume needed to achieve full correction has been reported to be 2 to 3 ml. 36 Consensus panel members agreed that a second syringe (or more) can make the difference in achieving an optimal result. Furthermore, panel members considered it important to let patients know that correction achieved with the first treatment will be improved with subsequent treatments when Restylane is already present. Panel members were polled to determine how they would proceed if a patient requested less volume (fewer syringes) of Restylane than that required to provide the desired aesthetic result. Fifty-four percent agreed with choosing one specific area to optimally correct, 23 percent would attempt to persuade the patient to increase the desired volume, 12 percent would suggest no treatment, because the patient would not be satisfied, and 12 percent would use other, unspecified approaches. Panel members were also asked how many days they recommend that patients allow between social engagements and treatment with Restylane. Sixty percent would allow less than 1 week, 10 percent suggested 1 to 2 weeks, and 33 percent suggested more than 2 weeks. Because of the potential for edema and bruising, the nature and importance of the social event must be considered in making the recommendation. Sex, Ethnicity, and Age Sex, ethnicity, and age are important factors in patients perceptions of aesthetic well-being and beauty. According to the 2005 statistics on the American Society for Aesthetic Plastic Surgery s Web site, women had nearly 10.7 million cosmetic procedures in 2004 (90 percent of total), a 49 percent increase from The society also reported that men had 1.2 million cosmetic procedures in 2004 (10 percent of total), an increase of 8 percent from 2003 to The use of hyaluronic acid fillers in female and male patients who had cosmetic procedures increased more than 650 percent (to more than 838,000) and 300 percent (to more than 40,000), respectively, from 2003 to The 300 percent increase in male patients seeking to improve their aesthetics appearance may suggest that the male stereotype is shifting to a more balanced concern about self-image. That view was confirmed by the consensus panel, with 69 percent of panel members reporting that number of male patients seeking fillers had increased in their practices. However, panel members agreed that aesthetic goals may be different in male patients, who may typically consider less correction to be optimal. Racial and ethnic minorities represented 20 percent of all cosmetic procedures in They included Hispanics (8.5 percent), African-Americans (6.2 percent), Asians (4.6 percent), and other non-caucasians (1.1 percent). 1 Postinflammatory hyperpigmentation has been described as 8S

7 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation the potential pathophysiologic response to cutaneous injury in patients with skin of color and therefore raises the possible question of problems with hyperpigmentation after injection of Restylane and other soft-tissue fillers. 37 Members of the consensus panel with extensive experience treating patients of color reported effective use of Restylane without subsequent inflammatory hyperpigmentation problems, even in patients who required multiple needle insertions (e.g., serial puncture). However, because of more noticeable changes in skin tone, overcorrection in patients with darker skin can result in the aesthetic appearance of irregularities when a visible convexity is produced where a concavity was previously present. In 2004, people aged 19 to 34, 35 to 50, and 51 to 64 years had 15 percent, 47 percent, and 31 percent of the total number of hyaluronic acid procedures performed, respectively. 1 People aged 18 and under had 0.1 percent, and those aged 65 had 7 percent. 1 A special issue in older patients is their thin skin and dermal atrophy, which makes lumping and the appearance of blue deposits more likely if injection is too superficial. Prescribing information for Restylane states that the use of Restylane for use during pregnancy, in breastfeeding females, and in patients under 18 years of age has not been established. 2 Although the panel agreed that there are no contraindications for treating patients under the age of 18 with parental consent, following the Restylane prescribing information is recommended. Full Correction Full correction is a complex concept defined in terms of both physical alteration of anatomical features and the aesthetic goals of the patient. Prescribing information for Restylane recommends correction to 100 percent of desired volume. 2 Consensus panel members agreed that injecting a larger initial volume (i.e., 100 percent of desired correction) of Restylane increases the time between treatments and also reduces the volume subsequently required to maintain full correction. Table 2 summarizes factors that can affect the amount of Restylane required to achieve full correction. Age, sex, and genetics (including ethnicity) are generally related to patients goals. Physical factors, such as facial anatomy, skin elasticity, and previous facial trauma, and cosmetic treatments (prior use of fillers, facial surgery) must be considered in developing realistic goals and defining full correction for each patient. After full correction is achieved, there are a number of Table 2. Factors Affecting the Amount of Restylane Required for Full Correction Age Sex Patient goals Genetics Previous treatment history (other facial treatments) Skin elasticity Facial anatomy Facial scarring Number, type, and location of areas to be treated Depth and extent of defects Affordability factors that affect maintenance of the aesthetic results. An important issue is whether routine touch-ups should be done. Touch-ups are most often done at the request of the patient at follow-up visits, usually 2 or more weeks after the initial visit. Patients motivations for touch-ups include a desire for more volume or correction of a perceived unevenness. Panel members were asked when they recommend that patients return for touch-up treatments. Fifty-six percent of panel members routinely recommend touch-ups, whereas 44 percent seldom or never recommend touch-ups. Some panel members (28 percent) bring patients back in 1 to 2 weeks, whereas the balance of members used alternative approaches. Those who prefer touch-ups agreed that it is most important after the first session and is dependent on the facial area treated. Panel members who do not routinely schedule touch-ups emphasized the importance of using adequate volume and accurate placement of the first treatment, to avoid the need for touch-up sessions. Additive Effect of Serial Treatments Returning patients are never at their original baseline. Panel members agreed that retreatment should be done before full aesthetic correction has greatly diminished. Reinjecting a person who had previously achieved a full correction requires less Restylane to maintain the aesthetic effect. Restylane clinical trials have indicated that in cases where full correction has been achieved, more than two-thirds of the initial correction remains at 6 to 8 months after treatment. 27,28,33 Panel members were asked when they recommend that patients return for retreatment to maintain full correction. Seventy-eight percent of panel members recommend retreatment at 4 to 6 months, 7 percent recommend it at 2 to 3 months, and 15 percent utilize other timing. Again, there was general 9S

8 Plastic and Reconstructive Surgery March Supplement 2006 agreement that longevity of full correction is dependent on the facial area. For example, more mobile areas, such as the mouth, may require more frequent corrections than more stable areas, such as the facial folds. For general purposes, it was agreed that treatment lasts for up to 6 months and in some cases it lasts longer, especially when Restylane is used in combination with neurotoxins as muscle relaxants. Patient Retention Factors A number of important patient and practice management factors affect patient retention after treatment with Restylane. Patient factors include adequate informed consent to help manage patient expectations, quality of the in-office experience with little discomfort, quality of results, and before-and-after photographs. Sixty percent of consensus panel members take photographs at every visit. Before-and-after photographs can be critically important for specific facial areas, such as the tear troughs. It was suggested that photographs may not be needed after treatment with botulinum toxin type A because one can objectively appreciate that the muscle is immobile. Conversely, in-office photographs are more important when the results are more subjective in nature. Standardized photographic views are particularly helpful a few weeks after treatment, but it is recommended that photographs be taken immediately before and after treatment, in case the patient cannot return within a reasonable amount of time. Implementation of practice management procedures can increase patient satisfaction and retention. Follow-up must be handled carefully. Many patients do not want relatives to be aware that they are undergoing cosmetic procedures. Therefore, contact with patients must be handled discreetly. Most U.S. members of the panel do not routinely contact patients for follow-up, but all members agreed that a well-designed follow-up program would be beneficial to patient retention. The panel recommended that patients be asked for permission to contact them after their initial visit. To be in compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations, patients in the United States should be asked to provide signed permission. In one panel member s office, patients are asked to address a reminder card. Reminder cards should be very generic, simply asking the patient to give the office a call. Another suggestion was to request permission to the patient, since communications can be private. Offering patients additional ideas for new cosmetic practices keeps patients engaged with the process and can lead to greater patient retention and more frequent visits. Informed Consent Informed consent was universally recommended by all of the consensus panel members to ensure compliance with regulatory and legal requirements as well as to manage patient expectations. The minimum amount of information that should be included in the informed consent document includes product information, the available alternative treatments, risks, including expected normal occurrences and possible complications, and financial responsibilities. Treatment Plan and Pretreatment Recommendations A comprehensive treatment plan should be developed for each patient (Fig. 4). The comprehensive plan should include the patient s medical history, with particular attention paid to the recent use of medications and foods that can cause bleeding, allergies, including allergies to local anesthetics, and the patient s history of herpes facialis. Many patients have undergone tissue filler therapy with unknown types of fillers, so obtaining a list of prior fillers is very important. If untoward events or reactions occur, it may be easier to manage these if knowledge of prior filler use is available. Pretreatment guidelines should focus on minimizing the risk of bruising. Patients should be encouraged to avoid salicylate and anti-inflammatory drugs and herbs, including gingko biloba, St. John s Wort, and doses of vitamin E greater than 400 IU daily, for 7 to 10 days before treatment. Antiviral usage depends on whether the patient has a history of frequent versus rare cold sores. Members do not treat patients with active cold sores until the sores are healed, and then only with antiviral prophylaxis. Seventy-seven percent of panel members routinely prescribe antiviral agents when injecting patients with a history of cold sores. When those who prescribe antiviral medications were asked which antiviral regimen they typically prescribe, 21 percent responded that they prescribe valacyclovir (Valtrex; GlaxoSmith- Kline, Philadelphia, Pa.) 500 mg before treatment and again 12 hours after treatment. Twenty-six percent prescribe the same valacyclovir (Valtrex) regimen and provide patients with a prescription in case of an outbreak. Other treatment options include famciclovir and acyclovir. 10S

9 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation Fig. 4. Restylane treatment plan. Icing and Massaging The consensus panel discussed the use of ice and massage before, during, and after treatment. Both techniques were also considered from the point of view of technical benefit and patient comfort. Half of the panel members considered the most benefit from icing to be achieved after treatment (Table 3). Another 40 percent of members use ice before, during, and after treatment. More than 50 percent of panel members recommended using ice for less than 15 minutes after treatment. Many panel members noted that icing can also be related to the area treated. For instance, icing the glabella can reduce bruising, but it may not do so on the nasolabial folds. Some panel members expressed concern that preicing areas such as the Table 3. Icing and Massage Question Response Consensus (% of panel) When do you get the most benefit from icing? Before treatment 5 During treatment 0 After treatment 50 Before and during treatment 5 All of the above 40 How long do you recommend icing after treatment? 15 minutes 52 Up to 1 hour 29 None 19 When do you massage? During treatment 9 After treatment 30 During and after treatment 61 Do not massage 0 Do you have concerns regarding massaging leading to Yes 27 increased bruising? No 73 When do you recommend patient self-massages? Immediately after treatment 5 After 24 hours 35 Do not recommend self-massage 60 11S

10 Plastic and Reconstructive Surgery March Supplement 2006 nasolabial folds can change skin turgor and create problems with injection and shaping. Practitioners should be reassured that icing does not increase edema through the skin s absorption of water. While there may be some potential local water absorption, ice constricts local circulation and reduces swelling, thus balancing any absorptive effects. All panel members use massage. However, some massage every patient and some reserve massaging for irregularities. Sixty percent of panel members indicated they massage both during and after treatment (Table 3). Some patients might experience bruising, although only 27 percent of the panel members were concerned that massaging could lead to increased bruising (Table 3). Elderly patients with capillary fragility or patients with actinic damage are more susceptible to ruptured vessels. Panel members agreed that Restylane can be massaged and shaped at any time after treatment, although it is shaped most easily within the first 2 weeks. It is important to note that Restylane cannot be denatured by massaging. Most panel members (60 percent) do not recommend that patients self-massage (Table 3). Those who do recommend self-massage give specific instructions for recognizing lumpiness (only by sign, not feel) and the precise massaging technique. A third of those panel members who recommend self-massage provide their patients with written instructions. Posttreatment Patient Recommendations Table 4 lists recommended posttreatment patient guidelines. Patients should generally be discouraged from massaging treated areas. However, patients should specifically be instructed to avoid massaging the treated areas within 6 hours after treatment. Some panel members also recommend that patients avoid alcohol and red wine because of the effects of flavonoid (vasorelaxation and Table 4. Posttreatment Patient Recommendations Avoid strenuous physical activity (e.g., cardio workout) for 6 hours Avoid massaging treated area for 6 hours Avoid sun and/or cold outdoor activities until redness/ swelling disappears Sleep with head elevated for one night Use pain medications (e.g., acetaminophen and or nonsteroidal anti-inflammatory drugs) to alleviate minor pain Resume skin care products, such as retinoids and glycolic acids, the next day flushing), as well as nonsteroidal anti-inflammatory drugs, to decrease bruising postprocedure. Panel members had mixed opinions regarding the use of makeup immediately after Restylane treatment. Some panel members do not allow makeup for 24 hours after treatment, some provide patients with fresh, sterile makeup in the office (applied with sterile cotton applicators), and others let patients use their own makeup. There is no published evidence suggesting that posttreatment makeup increases the likelihood of expected reactions or complications. Patient Comfort Techniques Table 5 lists the patient comfort techniques, including anesthesia (topical, infiltrative, and nerve blocking), used to facilitate Restylane injections. Topical Anesthesia Local anesthetic agents are generally divided into ester and amide compounds and can be applied topically or injected directly into tissue (infiltratively). Local and topical anesthetics for use in dermatology and surgical procedures have been extensively reviewed In rare cases, hypersensitivity reactions have been seen with ester-based anesthetic agents, such as procaine, benzocaine, and tetracaine, due to cross-reactivity of metabolic products that can also inhibit the action of sulfonamides. 42 Amide-based topical anesthetic agents, such as lidocaine and prilocaine, are metabolized by microsomal enzymes in the liver and avoid the problems with the ester-based agents. However, amidetype anesthetics should be used with care in patients with severe liver disease and patients taking medications that interfere with metabolism of the anesthetic. 38 Epinephrine is included in some local anesthetic preparations. The vasoconstrictive effects of epinephrine can provide several advantages when it is added to the anesthetic solution. These can include decreased absorption of the anesthetic, which produces more efficient anesthesia with Table 5. Patient Comfort Techniques Ice Topical anesthesia Nerve block aesthesia Infiltrative anesthesia Other Distraction techniques Gate theory -massage Stress balls Talkesthesia 12S

11 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation similar volume, prolonged duration of anesthesia, reduced risk of systemic toxicity, because the rate at which the local anesthetic is metabolized in the body keeps up with the rate at which it is absorbed into circulation, and reduced bleeding at the site. 38 Table 6 lists the answers the panel members gave when they were asked what topical anesthetic preparations they typically use. A range of preferences is evident. Although 30 percent of panel members use the combination ester-amide preparation containing 20% benzocaine, 6% lidocaine, and 4% tetracaine, dermatologists on the panel were concerned about allergic reactions and cross-reactivity between para-aminobenzoic acid and sulfonamides and the ester agents. The majority of panel members agreed that ester-based topical anesthetics are problematic and should be avoided, since amide-based agents have a better safety profile. Nerve Block Anesthesia The two types of regional nerve block anesthesia used effectively for facial cosmetic filler procedures are infraorbital nerve blocks and mental nerve blocks. Nerve blocks provide effective anesthesia to a large area and reduce the chance of unacceptable distortion, which might occur with infiltration. 40 Amide-type anesthetics are used most often in nerve blocks. Forty-four percent of panel members use lidocaine with epinephrine for nerve blocks. Twenty-eight percent use plain lidocaine, 24 percent use Septocaine (Setodont, Inc., New Castle, Del.) (articaine in Canada; 4% articaine aqueous hydrochloride with epinephrine 1:100,000), and 4 percent use other preparations. Panel members also agreed that buffering the anesthetic is important in order to reduce the burning sensation on injection, and that epinephrine in the lidocaine can reduce bruising, especially if the patient has recently taken analgesic agents such as aspirin. Figure 5 illustrates the infraorbital nerve block. The infraorbital foramen can be palpated and the nerve block can be performed by two different approaches: (1) direct transcutaneous (infiltrative) injection of 0.5 to 1.0 ml of anesthetic agent or (2) intraoral injection of approximately 1.0 ml of anesthetic agent. 40 The patient s comfort can be increased for the intraoral technique by applying topical anesthetic to the mucosa before injection. Potential complications of infraorbital injection include swelling of the lower eyelid, ecchymosis, and asymmetry. The majority of panel members (56 percent) reported seeing swelling of the upper lip and ecchymosis. Patients should be warned to expect the sensation that the anesthetic is traveling back toward the eye and that lower eyelid swelling and ecchymosis may occur. The panel also discussed useful variations in the infraorbital block technique. For a complete infraorbital block, the needle is inserted, whether transcutaneously or intraorally, to the infraorbital foramen, providing a complete proximal block of the infraorbital nerve. This block is particularly useful for procedures such as tear trough corrections. Some members of the panel (20 percent) prefer this complete block in most cases, including those involving the nasolabial folds or the lips. However, the majority of panel members also use a block further down the infraorbital nerve, which is accessed intraorally (submucosally); this block is perhaps best described as a mini-dental block. The lip can be adequately numbed using a 30- gauge, half-inch needle inserted just through the intraoral mucosa. The dental anesthetic Septocaine (articaine hydrochloride 4% with epinephrine 1:100000) is a good anesthetic for this approach, because it results in little stinging. The submucosal distal block may have an advantage when correcting the nasolabial folds. Some panel members reported distortion or flattening of the folds because of weakening of the lip elevator muscle with the more complete proximal block. Figure 6 illustrates the mental nerve block. The mental nerve block can also be achieved using either the transcutaneous infiltrative or the intraoral technique. 40 The mental foramen can be palpated, and the needle should be inserted into the vicinity of, but not into, the foramen if the transcutaneous technique is being used. When the intraoral approach is used, the foramen should be Table 6. Use of Common Topical Anesthetic Agents Preparation Consensus (% of panel) Betacaine Enhanced Gel (4% lidocaine) 14 Betacaine Plus (lidocaine, prilocaine, and epinephrine) 14 BLT (20% benzocaine, 6% lidocaine, 4% tetracaine) 32 L.M.X. 4 (4% lidocaine cream) 18 EMLA (2.5% lidocaine, 2.5% prilocaine) 0 Other 23 13S

12 Plastic and Reconstructive Surgery March Supplement 2006 Fig. 5. Distribution of infraorbital nerve and area of anesthetic effect expected from an infraorbital nerve block. Photographs courtesy of J. Niamtu, III, D.N.D. Fig. 6. Distribution of mental nerve and area of anesthetic effect expected from a mental nerve block. Photographs courtesy of J. Niamtu, III, D.N.D. palpated with the middle finger of one hand and the lip should be lifted by the thumb and index finger of the same hand. The needle should be inserted at the inferior labial sulcus at the apex of the first bicuspid.40 One to 3 ml of anesthetic is usually injected. Potential complications of the mental block include swelling of the lower lip and asymmetry. Alternative and Supplemental Comfort Techniques A variety of alternative techniques have also been described for increasing patient comfort. Sixty percent of panel members use alternative techniques, including distracting techniques, massagers (vibrators), and talkesthesia (hand-holding and talking). The use of vibration anesthesia 14S in conjunction with other noninvasive patient comfort techniques has been recently reviewed.43 Injection Techniques The four techniques developed to inject fillers, including Restylane, are serial puncture, linear and serial threading, fanning, and crosshatching (Fig. 7). Serial puncture consists of making closely spaced punctures along fine lines, wrinkles, and folds. In linear threading, the filler is injected as threads, usually during needle withdrawal (retrograde) along the length of a facial defect or area of desired enhancement.6 A similar technique is the push technique, in which the filler is injected during needle insertion (anterograde). Serial threading combines the serial punc-

13 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation Fig. 7. Injection techniques: serial puncture, linear and serial threading, fanning, and crosshatching. ture and linear threading techniques. Because they have more potential for bruising, fanning and crosshatching are more advanced techniques. In the fanning technique, needle placement is similar to that in linear threading, but the direction of the needle is continually changed and new lines are injected without withdrawing the needle tip. Crosshatching utilizes two series of linear threads injected approximately 5 to 10 mm apart at right angles to each other, as shown in Figure 7, below, right. Both techniques are used for large areas and for facial shaping. A number of important factors must be considered when selecting the technique to be used, including the area to be treated, depth of the injection, volume of product injected, and technical features related to the needle. Although the needle utilized is generally the 30-gauge, half-inch needle, there are specific procedures for which various alternative needle sizes are appropriate. Other needle adaptations may include using a longer needle (1 inch), using a finer gauge needle, 32 bending the needle to access particular contours of the face, and changing the needle during the course of the procedure, particularly when using the serial puncture technique, which can dull the needle. Restylane prescribing information suggests that the needle should be inserted at an approximate angle of 30 degrees parallel to the length of the wrinkle of fold. The bevel of the needle should face upward, and the substance should be injected at the mid-dermis. If Restylane is injected too deep or intramuscularly, the duration of the effect is considered to be reduced. If injection is too superficial, there may be visible areas of excess fullness and/or blue coloration. Consensus panel members were asked whether they prefer the bevel be oriented up or down for various anatomic sites. The majority agreed that bevel orientation is not a significant issue at any site. This approach was confirmed in a study showing that the direction of the bevel does not influence the direction of flow of the material. 44 Restylane prescribing information suggests that the filler should be injected during slow withdrawal of the needle. 2 It is important to note that the Restylane gel formulation contains no anesthetic agent (e.g., lido- 15S

14 Plastic and Reconstructive Surgery March Supplement 2006 caine). Therefore, patients may experience some pain with injection, and this should be taken into account in selecting both the anesthetic and the injection technique. FACIAL ANATOMIC AREAS: SPECIAL CONSIDERATIONS Common Treatment Areas As previously discussed, Restylane is approved for mid- to deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. 2 In clinical practice, Restylane is used in all areas of the face typically considered for aesthetic improvements. Panel members responses to a series of questions related to the most common areas of the face treated with Restylane are listed in Table 7. The nasolabial folds are the most commonly treated area, followed by the lips, marionette lines, oral commissures, and tear troughs. Panel members were also asked to identify the facial area they were least comfortable treating. Tear troughs were clearly identified as the most challenging and least comfortable areas to treat, with other areas noted to lesser degrees. The facial treatment areas offer a range of challenges for injectors. Treatment of areas such as the tear troughs, glabella, and crow s feet is not recommended for novice injectors. The consensus panel suggested that experienced injectors should feel free to inject outside these consensus recommendations, according to their experience and comfort levels. Nasolabial Folds The nasolabial folds (Fig. 6) are the most commonly treated facial areas and are perhaps the ideal place to start as a novice injector, but there are important aesthetic considerations that must be addressed for nasolabial folds. Injection of too much volume in this area -overcorrection -can cause a change in animation, with long-lasting irregularities that can persist even with significant massage. Nasolabial folds display a degree of natural asymmetry. Therefore, the two sides will never be the same, and this must be discussed with patients during their aesthetic evaluation and the development of their treatment plan. In addition, in the nasolabial folds of patients with strong muscular attachments, the filler may have a tendency to be pushed to the side when these patients smile. Injection of the lateral oral commissures can soften the entire lower half of the nasolabial folds, so that only the upper two-thirds of the folds need to be injected with Restylane. An appropriate aesthetic look can be achieved without the risk of sausages appearing down the sides. Nasolabial folds and oral commissures should generally be considered together as one anatomic area. They are also often treated simultaneously with the lips. Figure 8 illustrates treatment of only the nasolabial folds in a female and a male patient. Table 8 lists the consensus panel s responses to several questions related to treatment of the nasolabial folds. The panel was nearly evenly split between using topical anesthesia and infraorbital blocks. It was noted that the techniques are often used together. Panel members who routinely use the infraorbital block suggested that the complete block provides the best comfort level for patients. The block assures coverage of the superior nasolabial folds, which is the most uncomfortable part of the procedure. An effective alternative is to use topical anesthesia on the lower parts of the folds and an intraoral infiltrative above. This is particularly effective if patients complain of pain along the alar groove. The anesthetic is injected just above the Restylane injection site, about 1 cm above the pyriform aperture (nasal opening). Panel members (58 percent) indicated that they Table 7. Facial Areas Most Commonly with Treated with Restylane Consensus (% of panel) Facial Area Most Common Second Most Common Third Most Common Least Comfortable Lips Nasolabial folds Glabellar complex Cheeks Tear troughs Brow area Chin/jaw line Depressed scar Marionette lines Oral commissures S

15 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation Fig. 8. Nasolabial folds. (Above) Correction was achieved with 1.0 ml of Restylane (0.5 ml on each side) using serial puncture in a female patient (above, left, before injection; above, right, 2 weeks after injection). (Below) Correction was achieved with 2 ml of Restylane (1 ml on each side) using serial puncture in a male patient (below, left, before injection; below, right, 2 weeks after injection). use 1 ml of anesthetic agent for the intraoral infiltration. When the oral commissures are included in the treatment, a mouth corner or commissure block can also be used. Nearly even numbers of panel members prefer the serial puncture (38 percent) and linear threading (46 percent) techniques for the nasolabial folds. A combination of techniques is often used. Fifty-five percent of panel members use a total of 1 ml (0.5 ml per side) and 45 percent use 2 ml (1.0 ml per side) of Restylane to achieve the desired aesthetic correction. When polled about Table 8. Recommendations for Nasolabial Folds Question Response Consensus (% of panel) What type of anesthetic would you use? Topical 46 Infiltrative 13 Infraorbital block 42 None 0 Which technique do you use for infraorbital blocks? Cutaneous injection: ml of anesthetic 0 Intraoral injection: 1 ml of anesthetic 58 Do not use infraorbital blocks 37 Other 5 What injection technique would you utilize? Serial puncture 38 Linear threading 46 Fanning 4 Crosshatching 0 Anterograde vs. retrograde 8 Other 4 Do you typically change the needle during treatment? Frequently 18 Infrequently 41 Never 41 Typically, how much volume do you inject for two 1.0 ml 5 sides? 1.0 ml ml ml 0 17S

16 Plastic and Reconstructive Surgery March Supplement 2006 how long Restylane lasts in the nasolabial folds based on their clinical experience, 65 percent of panel members responded that Restylane lasted up to 6 months, and 35 percent indicated that it lasted longer than 6 months. In an interventional case series of 1026 patients treated to reduce the depth of their nasolabial folds, 94 percent of physicians rated the effect at 9 months as moderate or complete improvement. 45 Ninety-three percent of the patients were satisfied or very satisfied with the results at 9 months. Lips Aesthetic Evaluation and Options The lips comprise the key aesthetic feature of the lower face, and the upper lip has a particularly important effect on the aesthetic judgment of the face. 46,47 Aesthetic evaluation of the face must first consider the goals of the patient. Does the patient want to restore the way he or she looked previously, or does the patient want a new and different look? Panel members suggested that it can be very helpful to have patients bring a photograph of themselves when they were younger or, perhaps, a magazine page showing how they would like to look. Mirroring the recent dramatic increase in all cosmetic surgical and nonsurgical procedures, lip augmentation has become increasingly common. Fuller lips have traditionally been considered more beautiful. A study recently confirmed that the lips of Caucasian fashion models were considered more aesthetically pleasing than those of Caucasian nonmodels. 48 From a practical point of view, this suggests that aesthetic correction of the lips must be done only after careful aesthetic evaluation and discussion of the patient s treatment goals. Panel members felt that the treatment approach for lips is not the same in all patients and must be individualized. A particular problem is overcorrection of the lips, which can make them look very unnatural. A number of options are available to make subtle or more dramatic changes in the structure and appearance of the lips. The height of the lips and the proportion of the upper lip to the lower lip can be altered, the Cupid s bow can be reshaped, and the philtral columns can be augmented. Injection of the vermilion border will provide structure and contour to the lip line while helping to elevate and alter the angle of both the upper and lower lip. Injection of the philtral columns will add definition to the central lip area and improve flatness. Most panel members also usually add volume to the bodies of the lip to reshape and enlarge the visible portion of the lips. Injection in the oral commissures will provide support for the overall lip structure and help define the lip angles. All of these options should be discussed with patients to develop a mutually agreed on treatment plan. Recent reviews emphasized the importance of harmonizing all areas of the lower face, including the perioral area, the chin, and the neck, to produce a globally aesthetic result. 49,50 Treatment Options and Issues The majority (65 percent) of consensus panel members typically use a combination of anesthesia, including an infraorbital block (usually intraorally, as noted earlier) supplemented with a corner block. The corner block supplements the infraorbital block in the area of the upper lip that is usually missed. Most panel members administer infraorbital blocks intraorally using approximately 1.0 ml of anesthesia. Some also supplement the anesthesia with infiltrative and topical applications. The typical volume of Restylane injected, among 70 percent of panel members, is 1.0 ml, although less or more may be injected depending on the patient and anesthetic goals. Most members (67 percent) would expect the lip correction to last 3 to 6 months, with other members expecting correction for longer than 6 months (Figs. 9 and 10). The vermilion borders were injected to create distinct borders and contour. The lip bodies were then injected to add fullness and pleasing upper and lower lip proportions. Many panel members use magnifiers (e.g., loupes) to increase the precision along the lip lines. Another technique for increasing lip line precision is to use a 32-gauge, half-inch needle to outline the upper lip lines and a 30-gauge, halfinch needle for the vermilion border and lip body. The smaller-gauge needle reduces the size of the gel particles, requires more pressure to inject, and creates more precise lines. The panel also endorsed another technique to assure precise lines. The cutaneous border can be stabilized with the nondominant thumb and index finger. This creates a lock to ensure that the linear threaded gel remains exactly at the border, and it makes it impossible to inject too high, where the filler can create an impression of swollen lips. More volume can then be added by injecting the lip body on the wet/dry border. A history of prior filler injections in any facial area is critical information to collect from 18S

17 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation Fig. 9. Lips(left) before and(right) 3 weeks after injection. Correction was achieved with2.0mlofrestylaneinjectedintothevermilionbordersandthebodyofthelips. Photographs courtesy of M. Jewell, M.D. All rights reserved. Fig. 10. Combination treatment of the lips, nasolabial folds, and oral commissures in a female patient. (Left) Before injection, (center) immediately after injection, and (right) 3 months after injection. Perioral correction was achieved with 2.0 ml of Restylane injected into the vermilion border, lip bodies, and oral commissures. Photographs courtesy of S. Matarasso, M.D. All rights reserved. patients. There was a consensus among panel members that Restylane can be used in conjunction with permanent fillers. However, documentation of use of prior fillers is critical for diagnosing problems, such as granulomas, that might occur at a later date. 3 Unfortunately, patients typically do not know what fillers have previously been implanted. Therefore, it is very important to examine the patient carefully (i.e., palpate the area to be treated) before and after treatment and to document the findings, including those considered normal. At present, there is no documented evidence of the compatibility of nonpermanent and permanent fillers or that the risk of granulomas is increased by their use in combination. The panel considered a patient history of herpetic cold sores to be very important when treating the lips. Panel members also discussed the potential use of steroids prophylactically to treat the lips. Twenty milligrams of prednisone before anesthesia or before injection of Restylane may reduce swelling. However, concern was expressed that there have been cases of avascular bone necrosis as the result of prophylactic use of steroids, although this is extremely rare. 51 The panel agreed that this should be disclosed as part of the potential complications of steroid prophylaxis. Oral Commissures, Marionette Lines, and Mandible The oral commissures, marionette lines, and mandible are generally considered to be part of 19S

18 Plastic and Reconstructive Surgery March Supplement 2006 the overall aesthetic correction of the perioral area (Figs. 11 and 12). Because of potential sensitivity at the oral commissures, panel members were asked what size needle they typically use. Nearly all panel members (95 percent) use the standard 30-gauge needle. A combination of serial puncture and linear threading is used for the oral commissures, marionette lines, and mandible. There was also consensus that crosshatching can be used effectively in the oral commissures to help fill the triangular area around the commissures. The approach in this area is to build a buttress in the triangular area of the commissures. As much as 1.5 ml of Restylane can be used on each side to provide adequate fullness. This is especially important in older patients. The majority of panel members use botulinum toxin type A in the depressor anguli oris, in combination with the filler. It is most often injected before the Restylane. The rationale for injecting it first is that there is little sensation of pain with the botulinum toxin injection, whereas there is slightly more pain during filler injection. Thus, it is better to administer the botulinum toxin first. It is also easier to have the patient animate for the botulinum toxin injection, before the patient is given anesthesia for the filler, and it can be difficult to find the depressor anguli oris after the patient is numb. Other panel members use the filler first so that, in principle, there is a reduced risk of the filler causing spread of the botulinum toxin along the lip line, and there is no possibility of the botulinum toxin causing distortion, which makes the filler more difficult to place correctly. A detailed discussion on the use of botulinum toxin can be found in a recent publication of consensus recommendations for use of botulinum toxin type A in facial aesthetics. 52 Restylane was recently reported to be effective and safe in treating the age-related downturn of the lateral lip corners in middle-aged patients. 53 Glabella The glabella is the anatomic area between the medial eyebrows. Glabellar wrinkles and furrows frequently develop during the aging process. A typical treatment protocol for moderate to severe resting glabellar rhytides would include the combined use of Restylane and botulinum toxin type A. The characteristically moderate vertical glabellar furrows shown in Figure 13 were corrected by treatment with botulinum toxin and Restylane injected during the same session. The botulinum toxin is injected first, followed by Restylane, as a general rule. However, both can be injected during the same visit, or the botulinum toxin can be given first, followed by Restylane 1 to 2 weeks later, according to the physician s preference. A prospective, randomized, parallel group study of botulinum toxin plus Restylane compared with Restylane alone in female patients with severe glabellar rhytides was reported in Thirtyeight adult female patients with deep resting glabellar folds that were deemed unlikely to have an adequate response to botulinum toxin alone were enrolled in the study. Patients assigned to the combination group were treated with botulinum toxin type A and returned 1 week later for treatment with Restylane. The combination group showed a better response both at rest and on maximum frown than the Restylane-alone group did in this selected population of female patients. The median time for return to preinjection furrow status occurred at 4.5 months in the Restylane-alone group compared with 8 months for the combination group. 54 The majority of panel members (79 percent) use topical anesthetic for glabellar injections. A small number (8 percent) use infiltrative anesthesia, and 13 percent use alternative anesthetic approaches. Alternative approaches include cryoanesthesia (use of ice, although headache can result) or simply pinching the skin in the nondominant hand and injecting the Restylane without any anesthesia. All panel members typically inject 0.4 ml of Restylane to get 100 percent correction. Sixty percent of panel members prefer the serial puncture technique, and 42 percent prefer the linear threading technique in this area. Preference and depth of furrows dictate the choice of injection method. Fifty-five percent of members orient the needle up, although, in general, the panel agreed that bevel position does not matter significantly for any facial area. Most panel members (70 percent) inject during withdrawal (retrograde) of the needle. More than half of panel members think that the correction from Restylane alone in the glabella lasts for up to 6 months, although others think it lasts longer than 6 months. Most members (96 percent) think that the effect lasts longer than 6 months when Restylane is used in combination with botulinum toxin type A. In a case series of 185 patients injected in the glabellar area with botulinum toxin type A and Restylane, 100 percent of physicians rated the effect at 9 months as moderate or complete improvement. Eighty-eight percent of the patients were satisfied or very satisfied with the results at 9 months S

19 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation Fig. 11. Combination treatment of the lips, nasolabial folds, and oral commissures in a female patient (left, before injection; right, immediately after injection). Perioral correction was achieved by injecting 1.0 ml of Restylane into the lip, 1.0 ml into the nasolabial folds, and 1.0 ml into the oral commissures. Photographs courtesy of J. Carruthers, M.D. All rights reserved. Fig. 12. Marionette lines in a female patient were corrected with botulinum toxin type A injections followed approximately 1 month later by Restylane injections. Photographs courtesy of R. Narins, M.D. All rights reserved. Fig. 13. Glabella (left) before injection and (right) immediately after injection. Correction was achieved with a combination of botulinum toxin type A and 0.4 ml of Restylane using the serial puncture injection technique. Photographs courtesy of J. Carruthers, M.D. All rights reserved. Panel members do not recommend the glabella as a treatment area for novice injectors, because of the risk of vascular occlusion or skin and tissue necrosis. These potential complications can result from inaccurate needle placement or applying too much pressure during injection. Reports of occlusion or embolism in Restylanetreated patients are extremely rare, with one case reported in Reports of necrosis are also rare. Two cases of injection-site necrosis were reported in a safety review of more than 400,000 patients treated with nonanimal stabilized hyaluronic acid in 1999 and Regardless of the rare occurrence of these events, panel members continue to recommend caution in the glabellar area based on the past history of other fillers. In 1991, necrosis caused by the use of collagen fillers was reported in nine (0.09 percent) of 10,000 21S

20 Plastic and Reconstructive Surgery March Supplement 2006 patients and was thought to be the result of local vascular disruption of the treated area. 56 More than half of the cases involved the glabella. 56 Loss of vision due to artery embolization has been observed with both bovine collagen 57 and fat injection in the glabellar area. 58 These reports suggest caution when using any filler in the glabella area. Material should flow easily from the needle during injection of the glabella. The needle should be withdrawn and reinserted properly if back-pressure is detected. A more cautious approach for less experienced injectors to decrease risk during glabella procedures is to inject Restylane to less than 100 percent correction during the initial implant. This reduces the risk of potential pressure problems. Final correction can be accomplished at a follow-up visit. The skin can also be pinched to determine whether blanching disappears, thereby indicating continued free blood flow through the area. Brow One third of consensus panel members routinely perform eyebrow injections to elevate the brow. Any unevenness or lumpiness in the brow is visible because of the relatively thinner skin in this area, particularly in older patients. Therefore, it is critical to sculpt the brow to achieve the desired look. The aging process results in the brows dropping and receding. Injection of Restylane will project the brows to the desirable arching contour. The brow should be considered in terms of the three-dimensional shape of the lateral brow fat pad. The best perspective is that the brow is being filled rather than lifted. Figure 14 shows an example of raising and projecting the brows by filling across the lateral brows. After the needle is inserted just below the cilia, the Restylane (0.2 to 0.3 ml per side) is injected using the anterograde (push-ahead) technique (anterograde threading) as the needle is pushed forward across the brow to the notch. This technique fills and raises the superolateral margin, giving a refreshed youthful look. The malleable nature of the Restylane gel allows for correction of slightly irregular contours, by squeezing the Restylane along the brow between the finger and thumb to soften the lines. It is particularly important that the patient s movements are restricted during brow injections. Sixty-five percent of the panel members use topical anesthesia for the brow, 25 percent use infiltrative anesthesia, and 10 percent use alternative anesthetic approaches. Slightly more than half of the panel members (55 percent) use 0.4 ml of Restylane for both brows, whereas 40 percent expect to inject about 1.0 ml. More than half of the panel members expect Restylane to last 6 to 9 months in the brow, and 69 percent expect the correction to last for more than 9 months when Restylane is implanted at the same time as botulinum toxin type A is injected. The majority of panel members would use Restylane and botulinum toxin type A together for the brow. The eyebrow area can be susceptible to hematomas because of the larger vessels in that area. Some panel members use an alternate deep injection technique for the brows. Restylane is injected deeper at the level of the periosteum, similar to the way fat is injected. The contour will carry down to the inferior portion of the superior orbital rim, and long-lasting results can be achieved. The need for botulinum toxin type A is then negated, because the implant is fixed along the bone and therefore is not mobile during brow movement. It is also less likely that a large-volume implant will be visible when the patient animates and raises his or her eyebrows. If this deeper (to the periosteum) injection technique is used, the area may be tender for a few weeks after the procedure. Patients should be alerted, to avoid unnecessary concern. Crow s Feet In Figure 15, left, the female patient displays crow s feet and atrophy of the malar eminence. The patient was treated with botulinum toxin type A followed by 0.75 ml of Restylane. The botulinum toxin is effective in this area, but chasing the crow s feet down the face raises the risk of reaching the zygomaticus major muscle, which would result in unwanted facial distortions comparable to hemifacial paralysis. The skin is resuspended over the zygomatic convexity induced by the adjuvant use of Restylane. A general approach to this area would be to immobilize the underlying muscle with botulinum toxin type A and then inject the residual rhytides, usually the inferior lines, with no more than 0.2 to 0.3 ml of Restylane per side. This can also be done in conjunction with injecting Restylane into both the infraocular sulcus and the superior orbital rim (brow). The serial puncture technique would be the preferred injection method; however, the anterior linear threading ( push along ) technique could also be applied. The primary complications in this area are related to the very thin nature of the periocular skin. It is not uncommon to see some occasional 22S

21 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation Fig. 14. Brow (left) before and (right) immediately after injection of approximately 0.75 ml of Restylane along the lateral brows. Photographs courtesy of J. Carruthers, M.D. All rights reserved. Fig. 15. Crow s feet (left) before and (right) 1 month after injection. This female patient was treated with 15 U of botulinum toxin type A and 0.75 ml of Restylane. Photographs courtesy of J. Carruthers, M.D. All rights reserved. contour irregularities (lumps/bumps). In addition, there is a very rich subdermal vascular plexus in this area, and this combined with the thin skin can result in significant bruising. The panel agreed that the most accurate description of this facial augmentation is reflation of the subcutaneous midface space. This is an advanced treatment concept for experienced injectors. Tear Troughs The tear trough is the medial aspect of the orbital rim hollow. Most patients have a loss of volume laterally in addition to the hollowing of the medial tear trough. Therefore correction of the whole periorbital area improves final aesthetic results and yields better patient satisfaction. The best candidates for tear trough augmentation are younger patients with thicker skin and minimal to moderate volume loss. Some younger patients do not yet have the lateral hollowing, and Restylane implanted just in the medial orbit can work very well for these patients. Concerns of the panel included embolization, prolonged edema, asymmetry, lumps, bumps, and double vision, but panel members were not aware of any documented reports of embolization resulting from the tear trough procedure. Panel members agreed that the tear trough procedure is generally a deep injection and the standard anesthesia is the infraorbital block supplemented with a topical anesthetic. The adjunctive use of epinephrine causes vasoconstriction and reduces bruising. The needle is inserted deep to the periorbital rim until it hits the bone. The implant is placed at a level below the muscle but just above the periosteum. It is important to recognize that the tear trough is at or below the rim in 100 percent of cases. Deep injection at the level of the periosteum essentially traps the gel implant, creating a long-lasting aesthetic correction (Fig. 16). A study on the use of Restylane in tear trough deformities was presented at the Annual Meeting of the American Society for Aesthetic Plastic Surgery. 59 Fifteen patients (13 women and two men) aged 36 to 59 years, with varying degrees of tear trough deformities, were treated with an average of 0.2 ml of Restylane medially and 0.05 ml laterally using the deep injection technique. In all cases, the depth and appearance of the tear trough were improved, and all patients but one were satisfied with the results. The majority of patients still had full correction at 6 months, and 60 to 70 percent still had correction at 1 year. The majority of patients had no or minimal pain, and half the patients had ecchymosis, usually limited to the 23S

22 Plastic and Reconstructive Surgery March Supplement 2006 Fig. 16. Tear troughs (left, above and below) before and (right, above and below) 9 months after injection of 1.1 ml of Restylane per side. Photographs courtesy of T. Born, M.D. All rights reserved. injection site, that resolved in 5 to 7 days. All patients had some level of edema that resolved over a period of a few weeks. 59 The panel also discussed an alternative to the deep injection technique. As the patient looks up, the tear trough can be approached with the bevel of a 30-gauge, half-inch needle facing up; the needle is inserted just through the skin and under the orbicularis. As the plunger is depressed, the needle is moved slowly across the tear trough, with the anterograde injection, rather than the needle, providing the submuscular dissection. This method has 24S

23 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation proven to be safe and effective in the hands of panel members. Panel members agreed that before-and-after photographs of tear troughs are very important. Patients easily forget what they looked like before the procedure. Members also agreed that overcorrection in this area will produce an unacceptable cosmetic result and last a long time. Massaging the tear troughs is very helpful, and the use of cotton swabs for local precise massage can be effectively applied. As in all anatomic areas, if overcorrection of the tear troughs occurs, management would consist of aspiration and expression with a small puncture wound from a no. 11 scalpel blade. Hyaluronidase can also be used to dissolve the Restylane material if the tear trough is overcorrected. Panel members cautioned against using pharmacy-compounded hyaluronidase preparations. One hyaluronidase preparation (Vitrase; ISTA Pharmaceuticals, Irvine, Calif.) is approved for use in the United States and is supplied in single-use vials containing 200 USP U/ml. 60 An injection of 20 to 30 U is usually sufficient. Vitrase is ovine (sheep) derived, so skin testing is recommended before injection. Hyaluronidase has been used to improve overcorrection in at least one patient. 61 Human Immunodeficiency Virus Facial Lipoatrophy Facial lipoatrophy results from lipodystrophy syndrome, which is part of the acquired immune deficiency/human immunodeficiency virus syndrome as well as a complication of antiretroviral therapy in individuals. Restylane was recently used to successfully treat five patients with grade 2 to 3 facial lipoatrophy. 62 Each patient was implanted with a total of 5 to 6 ml of Restylane in the malar area via intradermal injection. No adverse events were reported, and a good cosmetic result persisted at the 6-month follow-up. It was also encouraging that approximately 50 percent less implant was required to recover full correction after 6 to 8 months. Implantation depth depends on the grade of lipoatrophy. Restylane can be implanted into the deep dermal layer if the atrophy is minimal. However, higher dermal injection provides more correction, and implantation at both levels is necessary in patients with more severe atrophy. The panel noted that this is another area where a deeper injection is used with a filler that is traditionally implanted intradermally. The majority of panel members (56 percent) use topical anesthesia, while 19 percent use infiltrative or infraorbital blocks for cheek and malar fat pad procedures. The area to be augmented is outside the effective area of anesthesia induced by the infraorbital block in individuals with some preservation of fat. The topical and infiltrative techniques must be used in these patients. However, in patients with a flattening of this area, the infraorbital block works well because the area of most discomfort is covered by the anesthesia. The fanning technique (59 percent of panel members), linear threading (24 percent), and crosshatching (6 percent) can all be effectively applied for implantation of Restylane in this area. A topical anesthetic can also be used for this procedure, with the patient holding a massager on the chin during implantation. 43,63 Injection is started from below with a quarter-inch, 27-gauge needle. The needle is pushed up into the cheek and gel is injected as the needle is withdrawn. Copious emollients are then applied to the face, and the gel is vigorously massaged into place until a smooth contour is achieved. Panel members agreed that it is particularly important to let patients know that large volumes of product will be needed for this procedure. The patient in Figure 17 had grade 1/2 lipoatrophy, and 3.0 ml per side provided adequate correction. More severe cases, however, can require significantly larger volumes and cost can become an issue. Some additional concern was expressed about implant movement and balling up of the gel. Tracks that facilitate gel movement are more common in patients who may have had previous facial surgery or trauma. It has been noticed that gel can move between injection tracks, similar to air moving between the tubes of an air mattress. It was again emphasized that Restylane is subdermal and can be effectively massaged and smoothed into place. If irregularities persist, it is relatively simple to apply external pressure to crush balled up areas of gel, puncture and remove excess gel, or use hyaluronidase to dissolve the implant. It is not uncommon for patients with facial lipoatrophy to have been treated previously with permanent fillers, such as silicone oil. Silicone oil is typically injected immediately subdermally, creating an area of sclerosis or collagen formation around the implant. The layer of sclerosis can be detected with the needle when injecting Restylane. Implantation of Restylane is at a deeper level, so it creates no problems in relation to the silicone oil. A more uncertain situation may be created with a product such as Radiesse (calcium hydroxylapatite; BioForm Medical, Inc., San Mateo, Calif.), which is also injected more deeply. However, the ultramicronized particles of Radiesse will presum- 25S

24 Plastic and Reconstructive Surgery March Supplement 2006 ably be encapsulated with collagen. A careful filler injection technique and posttreatment massage should alleviate any potential problems. USE OF RESTYLANE IN NONFACIAL AREAS The primary use of Restylane and other softtissue fillers is for facial cosmetic augmentation procedures. However, consensus panel members reported successful use of Restylane to treat a variety of nonfacial body areas and cutaneous defects. Scars Augmentation and filling of postsurgical depressed scars or acne scars is an obvious potential use of Restylane (Fig. 18). A more advanced application is for postsurgical scarring after surgical repair. If the resulting contour after grafting is less than ideal, a minimally invasive technique of subcision followed by injection of Restylane has proven to be successful. Subcision was also recently reported to be effective in treating acne scars. 64 A standard subcision technique was used in which a hypodermic needle was fanned back and forth parallel to and just under Fig. 17. Facial lipoatrophy (left) before and (right) immediately after augmentation of the buccal fat pads with 3.0 ml of Restylane per side. Photographs courtesy of J. Carruthers, M.D. All rights reserved. Fig. 18. Treatment of a postsurgical scar in a female patient with 0.2 ml of Restylane: (left) before injection, (center) immediately after injection, and (right) 2 weeks after injection. Photographs courtesy of M. Jewell, M.D. All rights reserved. 26S

25 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation the dermis to release the fibrous attachments that anchor the dermis and epidermis to the subcutis. 64 Subcision of acne scars followed by injection of Restylane (e.g., 2 weeks later) has been used very successfully by members of the panel. Hands and Feet The aging process and many diseases can result in a loss of tissue volume and cushioning of bony structures. Several panel members use Restylane for cosmetic and palliative purposes in the hands and feet (Fig. 19). Restylane was injected into the hand just anterior to the wrist creases and smoothed forward to the desired contour. The hands can also be injected along the extensor tendons. The hand augmentation procedure can be accomplished without anesthetic agents by positioning a vibrating medical massager on one side of the wrist. Restylane can be injected into the foot pad to provide cushioning. Restylane is also used anecdotally in patients with calluses and corns, to reduce contact points, pain, and the risk of ulcer formation. This application has been extended to patients with diabetes, to help lower the risk of developing foot ulcers. Patients with diabetes can develop peripheral neuropathy that results in loss of protective sensation. 65 Increased pressure in the foot can result in erythema and ulcer formation at pressure points, including under calluses. 65 Augmentation of the foot in these areas can help alleviate the pressure points, thus reducing the risk of ulcer formation. Ears and Nose Irregularities of the ears and nose are often seen as impediments to the overall aesthetic beauty of the face and head. The periauricular areas that are amenable to treatment with Restylane are the vertical rhytides immediately anterior to (right in front of) the ear and the earlobe itself. The vertical linear rhytides can be the result of or independent of a rhytidectomy (face lift) and are responsive to fillers as well as resurfacing. The technique, the amount of material, and the complications are similar to those for the periocular area (i.e., topical anesthesia followed by small amounts [0.2 to 0.3 ml] of Restylane, with a combination of serial threading and serial puncture). Bruising, although minimal, can occur and can be covered easily with makeup. The earlobe becomes very atrophic and sags with senescence. Other than surgical intervention, the only viable option for correction is a filler. The material can be injected directly into the lobe and massaged into place to avoid lumping and provide fullness to the lobe. No special precautions are necessary if the lobe is pierced. The material is not extruded through the hole but actually encircles it (Fig. 20, above). Restylane can be used effectively in very small amounts in patients who want to improve the contour of the nose after surgical intervention (rhinoplasty), trauma, or scarring (acne) (Fig. 20, below). Miscellaneous Panel members reported treating a variety of additional areas successfully with Restylane. The panel agreed that Restylane is very effective in treating horizontal chin lines both alone and with subcision. Jawline softening has been effectively treated with Restylane in patients who do not want to have surgery. Panel members agreed that although Restylane can be used in the temple area, it is very difficult to do so because of the thin skin. It is very easy for lumps and bruises to appear because of the branches of the superficial temporal vein. RESTYLANE IN COMBINATION WITH OTHER COSMETIC PROCEDURES Restylane is often used with other products routinely used for soft-tissue augmentation and other cosmetic procedures, such as energybased treatments (e.g., laser) and surgery. Restylane is used most often with botulinum toxin type A. The use of energy-based treatments in addition to Restylane is not contraindicated. Restylane is very stable at temperatures well above any generated in the skin. Data are not yet available to determine whether specific wavelengths may be detrimental to Restylane, although a study is ongoing to answer that question. A study of the use of acute monopolar radiofrequency (Thermage; Thermage, Inc., Hayward, Calif.) along with Restylane is also ongoing. Early indications from both animal and human clinical studies show that using popular ablative and nonablative energy sources either before or after injection of Restylane does not adversely affect either the efficacy or persistence of the filler. 66 The panel agreed that any procedures that interrupt the epidermal barrier, including subcutaneous injection, should be performed after the energy-based procedures have been completed. This order of treatment will avoid 27S

26 Plastic and Reconstructive Surgery March Supplement 2006 Fig. 19. Hands and feet are shown (left) before and (right) immediately after injection. The extremities were augmented with 0.7 ml of Restylane. Photographs courtesy of J. Carruthers, M.D. All rights reserved. Fig. 20. Ear (above, left) before and (above, right) immediately after cosmetic augmentationwith0.2mlofrestylane(bothearsweretreated).nose(below,left)beforeand(below, right) 2 years after injection of 0.5 ml of Restylane. Photographs of the ear courtesy S. Matarasso, M.D. Photographs of the nose courtesy T. Born, M.D. All rights reserved. any possibility of driving the injected substance further through the skin. Performing energy-based procedures before injection also avoids any potential problems created by heat (energy absorption) denaturation of proteins (e.g., hemoglobin and hemosiderin) in blood present as a result of postinjection bruises. It was again emphasized that Restylane can be used before, after, or during face lift surgery. 28S

27 Volume 117, Number 3S Restylane for Soft-Tissue Augmentation MANAGING INJECTION-RELATED PROBLEMS AND ADVERSE EVENTS There is the possibility of injection-related problems or adverse events (complications) occurring during or after implantation of Restylane and other soft-tissue fillers. These complications can be caused either by the injection itself or the implanted material. Problems, such as erythema and/or edema, are expected or normal but unwanted. Adverse events are complications and conditions that have been reported as a result of filler implantation but are not normally expected. Table 9 summarizes the expected injectionrelated problems and potential complications of using Restylane and other soft-tissue fillers. Friedman et al. reported that in 2000 an estimated 262,000 patients were treated with Restylane. 29 Of those, 144 (0.06 percent) were reported as having adverse events. This was compared with 0.15 percent of patients reporting adverse events in Hypersensitivity reactions comprised 0.02 percent of the reports in This was a reduction from 0.07 percent in 1999 and was likely due to decreased amounts of protein in the Restylane preparations as a more purified formulation became available. Improvements in purification of the formulation have continued, and no sensitivity testing is required for use of Restylane in the United States. 2 There have been no confirmed reports of hypersensitivity reactions in the United States during the past 2 to 3 years. 66 A study on the hypersensitivity potential of Restylane is currently ongoing. Injection site inflammation, including erythema, swelling, pain, itching, discoloration, tenderness, and temporary palpable lumpiness at the implant site, was also reported in 0.02 percent of patients. 29 These cases typically resolved spontaneously within 1 to 2 days after injection into the skin or 1 week after injection into the lips. In two, more recent reports of inflammatory reactions in the Unites States, both cases were managed with injections of hyaluronidase. 67,68 Two cases of injection-site necrosis were reported in the glabellar area a few days after injection, but these incidents were likely secondary to compression of the vascular supply caused by excessive use of the product. 29 There have been rare reports of localized granulomatous reactions, bacterial infections, acneiform eruptions, and cystic lesions. 29,69 The majority of reactions are considered by consensus panel members to be expected sequelae of filler implantation. Panel members were asked how they manage normally occurring areas of excess fullness and asymmetry in patients. Seventy-one percent of the panel members use massage, while 14 percent generally allow areas of excess fullness and asymmetry to resolve on their own. The majority of panel members (65 percent) recommend that patients call them immediately if they experience an unexpected event. Twenty percent of the panel members recommend patients wait 24 hours to call, and 15 percent recommend that patients to wait 48 hours, unless the event falls into the category of an unexpected complication. However, most panel members subsequently agreed that 2 weeks is a reasonable follow-up time before doing anything about normally occurring areas of excess fullness and asymmetry, because they typically resolve on their own. Aspiration of a typical area of excess fullness in the lip is shown in Figure 21. In contrast to the area of excess fullness shown in Figure 21, lip swelling is a normal occurrence after any trauma or injection in the lip. This is particularly evident with Restylane, a viscous, hydrophilic substance. Patients should be made aware of this before injection and reassured that it is a normal reaction and will resolve spontaneously (i.e., it is not a sign of allergic reaction). This self-limiting reaction is usually managed by cooling measures and massage if necessary. The inflammatory nodule is a rare but potentially aggravating complication. Seventy percent of panel members reported never having seen an inflammatory nodule, while 30 percent have seen Table 9. Expected Problems and Potential Complications Expected Problems Acneiform eruptions Lumps -visible and/or palpable material Asymmetry Over or under correction Needle marks Bruising Erythema -edema Pain Complications Inflammatory nodule Tyndall effect (blue bump) Allergic reactions Vascular occlusion Granulomas 29S

28 Plastic and Reconstructive Surgery March Supplement 2006 Fig. 21. Patient is shown undergoing lump removal by aspiration. The lump was removed with a small amount of topical anesthesia, and then a no. 11 blade was inserted into the lump and clear, intact Restylane was expressed ( incision and drainage ). Views of the patient (left) 2 weeks after Restylane injection, (center) immediately after the blade pierced the skin, and (right) immediately after the Restylane was removed. Photographs courtesy S. Matarasso, M.D. All rights reserved. them infrequently. An algorithm was developed for treating inflammatory nodules. 70 Evaluation begins with determining whether the lesion is fluctuant. If this is the case, the panel agreed that incision drainage and culture would be appropriate. If it is not fluctuant, a broad-spectrum antibiotic (clarithromycin) is prescribed and an intralesional steroid may be considered. Antibiotic treatment is then initiated based on results of the culture. Blue bump is likely due to the Tyndall effect, resulting from superficial placement of the implant. Treatment for blue bump is aspiration of the gel or removal using hyaluronidase. In the one case of blue bump that was reported in the nasojugal area of a patient, 20 U of hyaluronidase was injected and then additional Restylane was added 2 to 3 days later. The panel s general recommendation was to use very small amounts of hyaluronidase (10 to 30 U) to prevent creation of a contour defect, unless the treatment plan includes reinjecting within the next few days. Patients may normally experience some areas of excess fullness and discomfort after the injection of Restylane. Although these complaints may resolve after a few days or weeks, the emotional support of patients by office staff and the physician is crucial to helping patients through this period. Much of this comes down to management of expectations regarding tissue fillers and the events that normally occur after injection. It was the group s consensus that it is better to promise less and deliver more regarding this process than to represent the use of Restylane as an instantaneous correction of soft-tissue deformities without any downtime. COSMETIC FILLERS AND THE LAW The American Society of Plastic Surgeons and the American Society of Aesthetic Plastic Surgery recently published a joint advisory on legal and risk management issues related to aesthetic cosmetic procedures. 71 The advisory noted that reimportation is the act of importing drugs/products manufactured or approved in the [United States] and approved by the [Food and Drug Administration]. The Food and Drug Administration and the U.S. Department of Health and Human Services describe re-importation as illegal and dangerous. These agencies warn physicians and consumers that drugs purchased from foreign sources may be counterfeit versions of approved drugs/products, contaminated, outdated, or improperly packaged and labeled. It is impossible to verify that drugs and devices obtained from out-of-country sources have been stored and shipped properly to avoid degradation. Physicians who directly obtain or assist patients in obtaining drugs and products from foreign countries risk increased professional liability exposure. Purchasing generic copies of brand name drug and products from compounding pharmacies is also not recommended. Counterfeit drugs are defined by the Food and Drug Administration as misbranded, diluted, contaminated, adulterated, expired, or generic copies of brand name drugs/products. Physicians who purchase and inject counterfeit drugs and products risk enforcement actions by the Food and Drug Administration and state licensing authorities. More importantly, patients are put at significant risk. Hyaluronic acid produced for topical use could potentially be repackaged as an injectable softtissue filler by an illicit compounding pharmacy, without any testing to ensure the terminal sterility of the product or its safety and efficacy. It should be noted that unless the source of the product is known and it has been purchased through an approved distribution channel, there is no way to 30S