Chang, Chun-Shin M.D.; Wallace, Christopher Glenn M.D., M.S.; Hsiao, Yen-Chang M.D.; Chang, Chee-Jen Ph.D.; Chen, Philip Kuo-Ting M.D.
Upper lip scars that lie perpendicular to the relaxed skin tension lines are conspicuous and difficult to conceal. Unfortunately, cheiloplasty scars are unavoidably orientated this way, and mark the patient for life as having been born with a cleft lip deformity. Hypertrophic scarring is a recognized complication of cheiloplasty, and its incidence appears to vary most significantly with ethnicity.1 Soltani et al. recently reviewed the incidence of hypertrophic scarring in a single-surgeon cohort of 180 cleft lips repaired using a variant of the Millard technique.1 Overall, hypertrophic scars arose in 25 percent of their patients, but Asian patients were the most susceptible (36.3 percent), followed by Hispanics (32.2 percent) and Caucasians (11.8 percent). They recommended that prophylaxis against hypertrophic scarring should be considered in susceptible ethnicities undergoing cheiloplasty.1
In 2006, Tollefson et al. first published the use of botulinum toxin to chemodenervate the orbicularis oris muscle and immobilize the upper lip before primary cheiloplasty.2 In 2002, Galárraga confirmed with postoperative electromyography that botulinum toxin injection during cheiloplasty inhibited the action of the orbicularis oris muscle; he published these findings in 2009.3 Although both articles reported the feasibility of this treatment and suggested that it might decrease wound tension, neither reported any surgical or scarring outcomes caused by the intervention. To our knowledge, there remains no objective or subjective scar evaluation study following botulinum toxin chemoimmobilization of the upper lip for cheiloplasty. Accordingly, the objective of this study was to determine whether upper lip chemoimmobilization with botulinum toxin type A could improve primary cheiloplasty scars in a Taiwanese population.
PATIENTS AND METHODS
This was a prospective, randomized, vehicle-controlled, double-blind clinical trial designed to investigate whether the injection of botulinum toxin into the bilateral orbicularis oris muscles immediately after completion of cheiloplasty affected the quality of the resultant scar. The trial was approved by the Chang Gung Memorial Hospital Institutional Review Board.
Patient Sample Size
The sample size was calculated based on the results of a pilot study. Ten consecutive outpatients underwent upper lip scar evaluation in March of 2009 using the Vancouver Scar Scale and presented a mean score of 4.6 ± 1.26. If treatment could improve the Vancouver Scar Scale score by 1, which was considered clinically significant, approximately 26 patients per group would have been necessary to provide a result with real significance (using the same standard deviation, considering the standard type 1 α error of 0.05 and a power of 0.8). Assuming a 10 percent noncompliance rate for follow-up evaluation, the sample size was increased to 30 per group.
Patients and Randomization
Between August of 2011 and June of 2012, 60 consecutive patients were enrolled for randomization having satisfied the following criteria. Inclusion criteria were the following: baby born with a unilateral cleft lip planned for primary cheiloplasty at approximately 3 months of age, and valid written informed consent provided for surgery and trial inclusion. Exclusion criteria were the presence of other craniofacial anomalies and nonconsenting patients or legal guardians. All cheiloplasties were performed at the Craniofacial Center of Chang Gung Memorial Hospital.
Patients were randomized, by a third-party specialized nurse who was independent of the study, into the experimental or vehicle-control group using secure randomization envelopes. Randomization codes were not revealed to anyone until after completion of the entire study; patients, investigators, study personnel, and outcomes assessors therefore remained blinded throughout the investigation.
Encoded treatment vials were prepared. Experimental group vials contained botulinum toxin in normal saline [each 0.1 ml of solution contained 2.5 units of botulinum toxin (Botox; Allergen, Inc., Irvine, Calif.)]. Vehicle-control group vials contained the same volume of normal saline only. Dosage was calculated according to the baby’s weight (1 unit/kg) and thus the amount of solution administered from the vial was calculated as if the vial contained the botulinum toxin (although it was unknown whether the vial contained botulinum toxin or vehicle alone).
Primary Cheiloplasty and Injection of Vial Contents
All operations were performed by two craniofacial cleft surgeons (C.S.C. and P.K.T.C.) following presurgical nasal molding. The cleft gap was measured at its narrowest point, and a modified rotation-advancement cheiloplasty was performed for all patients as described previously.4,5 For the medial rotation flap, the Mohler line was incised, which is a curved line passing upward into the columella base and then turning back to the nasolabial junction of the noncleft-side philtral column. Lateral to the curved incision line, the skin overlying the premaxilla to the base of the columella was elevated with the C flap. The mucosa of the noncleft side was elevated as the C-mucosa flap. On the cleft side, the advancement flap incision passes along the cleft margin. The buccal mucosa L flap is elevated during lateral lip dissection. The nasal floor was reconstructed with a combination of an inferior turbinate flap, an L flap, and a C-mucosa flap. The columella base defect was reconstructed with the C flap. The orbicularis oris muscle on both medial and lateral sides was released and repositioned. The first stitch taking lateral orbicularis muscle was sutured to the nasal septum; thereafter, the lateral orbicularis oris muscle was sutured overlapping the medial orbicularis oris muscle to increase muscle bulk and thereby reconstruct the philtral column. The muscle repair, which bears the majority of the tension across the wound, was performed with 5-0 polydioxanone (PDS II; Ethicon/Johnson & Johnson, New Brunswick, N.J.). Overlying skin laxity results from this muscle repair and allows for the construction of a philtral column. Wound closure was performed in two layers: first, subcutaneous 5-0 polydioxanone (PDS II); and second, a running 7-0 polyglactin (Vicryl; Ethicon/Johnson & Johnson). Finally, injection of the randomized vial contents was performed at four points, each 0.5 cm away from the surgical wound edge.
Oral amoxicillin was routinely prescribed for 7 postoperative days. Wound dressings were performed twice daily. Cutaneous sutures were removed on the sixth postoperative day. Nasal stents were worn by all patients for 6 months. Parents or guardians were instructed how to place Micropore tapes (3M, St. Paul, Minn.) across the upper lip wound and both cheeks to reduce wound tension caused by the adjacent risorius, zygomaticus major, and zygomaticus minor muscles. Taping remained in place throughout the day and silicone sheeting was added during sleep. Compliance with taping, silicone sheeting, and nasal stenting was recorded according to the caregivers. All complications, such as hematoma, infection, wound dehiscence, oral incompetence, feeding dysfunction, and drug allergy, were logged if encountered.
Records and Measurements
Primary endpoints were Vancouver Scar Scale score (consisting of the following components: pigmentation, vascularity, pliability, and scar height) and scar width. At 6-month follow-up, two plastic surgeons (C.S.C. and P.K.T.C.) examined the patients. The two raters were blinded regarding which group patients belonged to. Scars were assessed using the Vancouver Scar Scale and assigned the mean score of the two observers.
For photographs, a standard surgical ruler was placed over the lower lip, and a frontally orientated photograph of the patient was taken. The same professional craniofacial medical photographer took all photographs. Objective scar width measurements were obtained from the photographs by two independent raters in duplicate and averaged; both were blinded regarding which group each patient belonged to. The scar was measured at two points with Photoshop (CS5 extended version 12.0; Adobe Systems, Inc., San Jose, Calif.) using the ruler as a control reference. The first point was 1 mm above the white roll and the second point was 1 mm below the C-flap suture line. In addition, the scars were assessed subjectively by five examiners (two attending plastic surgeons and three laypersons). All examiners were both independent of the patients’ care and blinded to their treatments. They were asked to score the scars on the photographs using a standard visual analogue scale graded from 0 (worst possible scar) to 10 (best possible scar).
Interobserver and Intraobserver Consistency of Assessments
Interobserver reliability of the Vancouver Scar Scale and visual analogue scale were tested using Cronbach α. Interobserver reliability of photographic measurements was assessed with Pearson correlation by comparing two sets of measurements performed by two independent raters.
All statistical analyses were conducted using SPSS software (version 17.0; SPSS, Inc., Chicago, Ill.). Differences between Vancouver Scar Scale scores, visual analogue scale scores, and scar widths obtained photographically were compared. The independent t test was used to compare groups. The chi-square test was used to compare demographic data of both groups (sex and cleft side). Statistical significance was defined for values of p < 0.05.
Thirty patients in the experimental group received botulinum toxin injections and 30 patients in the vehicle-control group received normal saline injections immediately after completion of cheiloplasty. Fifty-nine patients attended their 6-month follow-up appointment; one patient in the vehicle-control group failed to attend. Patients’ demographics, cleft gap before surgery, mean dosage of botulinum toxin, compliance with lip taping and silicone sheeting, and distribution of surgeons are listed in Table 1. No complications (i.e., infection, bleeding, wound dehiscence, oral incontinence, or feeding dysfunction) were encountered.
The Vancouver Scar Scale score in the experimental and vehicle-control groups were similar (2.70 ± 1.29 versus 2.76 ± 1.44 for experimental and vehicle-control groups, respectively; p > 0.05). Interobserver consistency in using the Vancouver Scar Scale score was high (Cronbach α = 0.98).
The visual analogue scale score in the experimental group was significantly better than in the vehicle-control group (8.43 ± 0.56 versus 7.19 ± 0.95; p < 0.001). Interobserver consistency was high (Cronbach α = 0.890).
The widths of scars in the experimental group were significantly better than in the vehicle-control group at both the first (0.33 ± 0.11 versus 0.45 ± 0.11 for experimental and vehicle-control groups, respectively; p < 0.001) and second points (0.33 ± 0.13 versus 0.47 ± 0.13; p < 0.001). Interobserver consistency was high for photographic measurements (r = 0.897 and p < 0.001 for first points; and r = 0.943 and p < 0.001 for second points).
A scar represents dermal fibrous replacement tissue and results from a wound that has healed by resolution rather than regeneration. Undesirable scars, such as hypertrophic or keloid scars, occur most frequently over the anterior chest, shoulders, scapular area, lower abdomen, and suprapubic region.6 The skin of the upper lip is also at risk of hypertrophic scars because of the repetitive movements of the underlying orbicularis oris muscle during speech, eating and drinking, and facial expression that transmit tension forces that distract and widen the healing wound. The incidence of hypertrophic upper lip scars ranges between 12 and 27 percent in the mixed population but increases when controlled for ethnicity to 32.2 percent in Hispanics and 36.3 percent in Asians.1,7,8 In addition, primary cheiloplasty scars are more conspicuous because they do not align with the relaxed skin tension lines of the face.
A patient’s cheiloplasty scar is a lifelong marker that he or she was born with a cleft lip. The position of a cheiloplasty scar makes it difficult to conceal, and its conspicuity can inflict significant psychological impact on its bearer. According to a structured semiquantitative survey of 97 elective/aesthetic surgical patients, 91 percent would value even a small improvement in the quality of their scar.9 Patients were dissatisfied with surgical scars irrespective of their sex, age, ethnicity, or geographic location, and wished their scars were less noticeable. With current cheiloplasty techniques, the anatomy of the lip can be restored adequately.10 As a result of charitable funding from the Noordhoff Craniofacial Foundation, almost all patients presenting to our center with cleft lip are able to undergo cheiloplasty at approximately 3 months of age. Our own survey of patients treated at our center revealed that more than 90 percent would regard even a small improvement in their cheiloplasty scar to be worthwhile (unpublished data). This is despite our use of several established strategies to attempt to optimize cheiloplasty scars in our center.
First, we repair the orbicularis oris muscle so that it bears the majority of the tension of the wound. This causes the overlying skin to become slightly redundant (and therefore tension-free), which allows enough skin for philtral column reconstruction on the cleft side. Second, we strictly use wound taping to minimize tension across the lip. These tapes span across the upper lip from cheek to cheek and are placed purposefully so that the nasolabial folds are deepened (and thus the skin is redundant) and the upper lip protrudes. Adhesive tape has been used by plastic surgeons for decades, with or without sutures, to reduce wound tension to prevent hypertrophic scar formation.11–13 Third, we strictly use silicone gel sheeting over the scar when the baby is asleep. Topical silicone preparations have been recommended in the management of hypertrophic and keloid scars and are known to reduce the recurrence of hypertrophy following scar revision surgery in patients at higher risk of hypertrophic scarring.14,15 The benefit of topical silicone is less clear in patients who lack a history of abnormal scarring.15 Although there remains a lack of consensus as to whether topical silicone gel sheets should be applied routinely for upper lip cheiloplasty scars, this has remained routine practice at our center for many years.10 The compliance with lip taping and silicone sheets is very high in our population. The parents are well supported in this regard both by each other (many, if not most, of the parents of our children who have been operated on are routinely in contact on social media groups to encourage compliance) and by our Noordhoff Craniofacial Foundation social workers. The use of taping and topical silicone and the method of lip repair were all constant in this study; the only variable, which was blinded, was whether the vial for injection contained botulinum toxin or vehicle alone.
The contraction of the muscles of facial expression cause increased skin tension and the accentuation of dynamic rhytides that are often considered cosmetically undesirable. Carruthers et al. first realized that patients treated with botulinum toxin chemodenervation for blepharospasm experienced concurrent improvements in their dynamic glabella rhytides, sparking its widespread use in aesthetic practices ever since. Similarly, Gassner et al. injected botulinum toxin around frontal wounds to chemoimmobilize underlying musculature and therefore reduce wound tension during scar formation, with resultant improvements in cosmetic outcomes in an animal study.16 Several human studies have since demonstrated that the injection of botulinum toxin can improve facial scars.17–20 Tollefson et al. first published the use of botulinum toxin to immobilize the upper lip for cheiloplasty in three cleft infants aged 3 to 6 months.2 However, it was unknown whether the botulinum toxin was responsible for the satisfactory aesthetic results that they reported. Galárraga injected the upper lips of five children undergoing cheiloplasty intraoperatively.3 Electromyographic tracings proved that significant reductions in orbicularis oris muscular activity were resulting from the botulinum toxin treatment. Again, although the author hypothesized that this chemoimmobilization might benefit scarring, no direct evidence for the benefit of botulinum toxin was provided.
We investigated botulinum toxin injection as an additional potential intervention that might further improve our cheiloplasty scars over and above our established protocolized techniques. To our knowledge, this current study represents the first objective and subjective evaluation of scars following botulinum toxin injection into the upper lip during cheiloplasty. Although there was no significant difference in Vancouver Scar Scales between the experimental and control groups, photographic visual analogue scale and photographic measurements both revealed consistently better appearing and narrower scars as a result of botulinum toxin treatment compared with vehicle controls (Fig. 1).
No complications (i.e., infection, bleeding, wound dehiscence, oral incontinence, or feeding dysfunction) were found. Pascual-Pascual and Pascual-Castroviejo studied the safety of botulinum toxin type A in children younger than 2 years. The dosage used for obstetric brachial plexus palsy and cerebral palsy of 6.55 units/kg, which is much higher than the dosage required for chemodenervation of the orbicularis oris muscle, was considered safe.21 Moreover, neither of the previous studies that used botulinum toxin type A injection into the orbicularis oris muscle reported complications such as feeding difficulties.
These results indicate that our established method of upper lip repair and mechanical immobilization by taping is controlling well against wound tension in infants caused by orbicularis oris but that botulinum toxin has an additional beneficial effect on scar width that, although small, is subjectively noticeable. According to the Vancouver Scar Scale, however, botulinum toxin provided no additional benefits for scar pigmentation, vascularity, pliability, or height of cheiloplasty scars.
This project was supported by Chang Gung Memorial Hospital Research Grant CMRPG 390731. The authors are grateful to Cheung Lim Kwong, B.D.S., Ph.D. (United Christian Hospital, Hong Kong) and Stephen Warren, M.D. (New York University, New York, N.Y.), who visited our center and participated in discussions regarding this trial.
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