SUBMITTED 7 JUL 21 1 REVISION REQ. 7 SEP 21; REVISION RECD. 2 NOV 21 2 ACCEPTED 25 NOV 21 3 ONLINE-FIRST: JAN 2022 4 DOI: https://doi.org/10.18295/squmj.1.2022.005 5 6 Comparison of Tissue Adhesive Glue with Subcuticular Absorbable Suture 7 for Skin Closure Following Thyroid Surgery 8 A single blinded randomized controlled trial 9 Aditya Musham,1 Evangeline M.K. Samuel,2 Ashok K. Sahoo,3 10 *Elamurugan TP,2 Manwar A.S.4 11 12 1Department of Paediatric Surgery, Lady Hardinge Medical College, New Delhi, India; 13 2Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education and 14 Research, Pondicherry, India; 3Department of Surgery, S.C.B Medical College and Hospital, 15 Cuttack, India; 4Department of Surgery, All India Institute of Medical Sciences, 16 Bhuvaneshwar, India. 17 *Corresponding Author’s e-mail: elamurugantp@gmail.com 18 19 Abstract 20 Objectives: The objective of this study was to compare the skin closure time, postoperative 21 pain and the scar outcome between tissue adhesive and sub-cuticular sutures in thyroid 22 surgery. Methods: This was a prospective, single-blinded, randomized controlled trial. A 23 sample size of 64 in each group was calculated. Adult patients undergoing thyroid surgery 24 were included while those with previous neck surgery, history of keloids/hypertrophic scars 25 and those undergoing concomitant neck dissections were excluded. Following platysma 26 closure, they were randomised into two groups - tissue adhesive or subcuticular sutures, using 27 Serially Numbered Opaque Sealed Envelopes technique. The primary outcome was the skin 28 closure time. The secondary outcomes were postoperative pain at 24 hours and scar scoring at 29 1st and 3rd post-operative month. Statistical analysis was done using SPSS software version 30 19.0 for Windows. Results: The median skin closure time and postoperative pain was 31 significantly lower in the tissue adhesive group as compared to the suture group (p<0.01). 32 However, there was no statistically significant difference in scar outcome at 1st month 33 mailto:elamurugantp@gmail.com (p=0.088) and in 3rd month (p=0.137) between the two groups. There were no wound-related 34 complications in either group. It was seen on a subgroup analysis that there was no difference 35 in the scar outcome or wound-related complications in patients with comorbidities. There 36 were no instances of allergic contact dermatitis to the tissue adhesive. Conclusion: The use 37 of tissue adhesive leads to lower operative time and less post-operative pain in thyroid 38 surgeries. The scar outcome is comparable between tissue adhesives and subcuticular sutures. 39 Keywords: Thyroidectomy; scar; tissue glue; subcuticular sutures 40 41 Advances in Knowledge 42  There is a decrease in operating time when tissue adhesive is used for skin closure as 43 compared to sutures 44  There is lower immediate postoperative pain when tissue adhesive is used, as 45 compared to sutures. 46  There is no difference in scar outcome or wound complications between tissue 47 adhesive and sutures, irrespective of patients’ comorbidities 48  There is an increase in cost when tissue adhesives are used. 49 50 Applications to Patient Care 51  During thyroidectomy, tissue adhesive can be an attractive option to use, instead of 52 sutures, in order to decrease operative time and post-operative pain. 53  The patient must be counselled that the scar outcome is not likely to improve by using 54 tissue adhesive as compared to sutures. 55  The patient must be made aware of the increase in cost, if tissue adhesives are used. 56 57 Introduction 58 Thyroid diseases are more common in women and in younger age groups, which makes them 59 the main population group to undergo thyroid surgeries.1 Conventional thyroid surgeries are 60 done via a collar-neck incision, which is in the anterior aspect. Such incisions have the 61 potential to leave a conspicuous scar, if skin closure is not optimal. Advances such as 62 minimally invasive thyroidectomies were designed in order to achieve a better cosmesis.2 63 However, these surgeries require sophisticated surgical equipment and expertise.3,4 Hence, 64 conventional thyroid surgery is still the standard procedure in most patients. 65 66 The ideal method of skin closure is a rapid, easy-to-apply technique with a good cosmetic 67 outcome. Initially, simple sutures were used, but was found to have a poor scar outcome due 68 to railroad tracking.6 Subsequently, subcuticular sutures were used, which showed a better 69 scar outcome with less post-procedure pain.6 However, it needs meticulous work, time to gain 70 expertise7,8 and has the risk of needlestick injuries9. 71 72 Tissue adhesive glue was introduced as an ideal system of wound closure.10 It is composed of 73 monomeric cyanoacrylate which polymerizes on contact with moisture to form an adhesive 74 layer over the skin.10 It is an attractive choice for thyroidectomies as it is easy to apply8 and 75 takes less time. Its main disadvantage is contact dermatitis11, which has been purported to 76 vary with the climate.12 This is because the antigen presenting cells identify the monomeric 77 form of cyanoacrylate. In arid climates, it takes time for polymerization thus increasing the 78 chance of reaction.12 79 80 Studies have been performed, comparing subcuticular sutures to tissue adhesives in thyroid 81 surgeries but differences in postoperative pain, wound dehiscence rates and operative time 82 has not been clearly elucidated. In our study, we aim to study the effects of both methods of 83 repair on post-thyroidectomy patients in a South Asian country, with equatorial climate as 84 well as a wide variation in the skin type of its population. 85 86 Methodology 87 Study design 88 The study was designed as a prospective, single-blinded, randomized controlled trial. It was 89 conducted from March 2017 to December 2019 in the Department of General Surgery in a 90 tertiary care hospital after obtaining approval from Institute Ethics Committee 91 (JIP/IEC/2017/0213) and registration in CTRI (CTRI/2018/02/011698). 92 93 Sample size and patient enrolment 94 The sample size was calculated based on a similar study conducted by Consorti et al.13 Using 95 Open Epi software, a sample size of 64 in each group was calculated, taking the difference in 96 time required for skin closure as the primary criterion, with level of significance as 5% and 97 the power of study set to 90% expecting a dropout rate of 10%. All patients between 18 to 80 98 years of age undergoing thyroid surgery during the study period were included. Patients with 99 previous neck surgery, history of keloids or hypertrophic scars and those undergoing 100 concomitant neck dissections were excluded. Written informed consent was obtained from 101 the participants. 102 103 All patients received an intravenous dose of prophylactic antibiotic (Inj. Cloxacillin 500mg) 104 within 30 minutes from the time of skin incision, as per the departmental policy at our centre. 105 The surgery was done as per the standard operating procedure. Once the resection was done, 106 a 14 F closed-suction drain was placed in all patients, which is part of the operative policy at 107 our centre. The strap muscles and platysma were approximated using 2-0 and 3-0 round-108 bodied vicryl simple sutures respectively. Following platysma closure, the patients were 109 randomised into the two groups. Tissue adhesive (Octyl 2-cyanoacrylate)- DERMABOND® 110 from ETHICON Inc, Johnson and Johnson (San Lorenzo, Puerto Rico) was used in the study 111 while 3-0 sized monocryl suture, from Lotus Surgicals Pvt Limited (Uttarakhand, India) was 112 used for subcuticular suturing. For each patient, one unit was used, according to the group 113 allotted. 114 115 Postoperative analgesia was standardized in both groups, with all patients receiving 116 intravenous tramadol and ketorolac alternately every 4th hourly for first 24 hours in the 117 postoperative period. Scar assessment was done at the first and third postoperative month. 118 119 Randomisation details 120 Randomisation was done using computer generated random numbers and allocation was done 121 using Serially Numbered Opaque Sealed Envelopes (SNOSE) technique, which were opened 122 after platysma closure. 123 124 Outcome assessment 125 The primary outcome measured was the skin closure time (minutes). In the tissue adhesive 126 group (Group A), after closing the platysma, the skin closure start time was noted once the 127 skin edges were dry. The tissue adhesive was applied slowly in 2 layers, using a brushing 128 motion. A gap of 15 seconds was given between the applications and the adhesive was 129 allowed to set for 60 seconds, at which point the skin closure end time was noted. Dressing 130 was not applied. 131 132 In the subcuticular suture group (group B), after closing the platysma, the skin closure start 133 time was noted. The skin was closed by subcuticular absorbable suture and a dressing was 134 applied. Once done, the skin closure end time was noted. 135 136 The secondary outcomes measured were postoperative pain at 24 hours and scar scoring at 137 1st and 3rd post-operative month. Post-operative pain was assessed using a 10-point Visual 138 Analog Scale.14 The scar cosmesis was assessed by a person who was blinded regarding the 139 method of skin closure, using the Manchester Scar Scale.15 The cost per unit used was also 140 compared between the two groups. 141 142 Statistical analysis 143 Statistical analysis was done using SPSS software version 19.0. Continuous variables were 144 expressed as mean or median based on the distribution. Ordinal variables were expressed as 145 median. Categorical variables were expressed as proportions, frequencies or percentages. 146 Continuous variables were compared using unpaired t-test. Ordinal variables were tested 147 using Pearson Chi-Square test. The difference of medians of skin closure time, pain, scar 148 scores at 1st and 3rd postoperative months between both the groups were tested using Mann-149 Whitney U test. 150 151 Results 152 Among the 143 patients who underwent thyroid surgery during this study period, 124 patients 153 were included in the study based on the inclusion criteria. The schematic representation of the 154 study as per the CONSORT 2010 (Consolidated Standards of Reporting Trials) flow diagram 155 is shown in Figure 1. As shown in table 1, the baseline characteristics were comparable 156 between the two groups. The mean age of patients in the suture group was 42.62 ± 12.28 157 years and of tissue adhesive group was 42.03 ± 11.8. The majority of the study participants 158 were female, both in the suture group and in the tissue adhesive group (72.13% and 82.53% 159 respectively). The preoperative diagnosis distribution and type of surgery done in both the 160 groups were similar. 161 162 The median skin closure time in suture group and the adhesive group was 390 and 250 163 seconds respectively and the difference was found to be statistically significant (p<0.01) by 164 Mann-Whitney test, as shown in Table 2. The median pain score between the two groups also 165 showed significant difference (p<0.01), as shown in Table 3. However, there was no 166 statistically significant difference in scar outcome at 1st month (p=0.088) and in 3rd month 167 (p=0.137) between both the groups, as shown in Table 4 and Table 5. There were no wound-168 related complications in either group. The cost of one unit of tissue adhesive was found to 169 2000 INR and one unit of suture was 899 INR. 170 171 Discussion 172 The use of tissue adhesives has gained significance in recent days owing to the concept of no-173 suture cosmetic surgery. Previously, subcuticular suturing was a standard technique used for 174 skin closure especially in areas of cosmetic interest. Studies comparing subcuticular suturing 175 and tissue adhesive are few in number with contradicting results. Therefore, we conducted 176 this study to add to the body of existing knowledge. 177 178 The present study showed that there was a significant difference in skin closure time between 179 the tissue adhesive group and suture group. Tissue adhesive reduced skin closure time by 180 36% to that of subcuticular suture. Saving theatre time is essential to avoid wastage of 181 hospital resources and to avoid dissatisfaction of staff, which would affect the quality of 182 work.16 Bozkurt17 and Consorti13 also came to the same conclusion as this study. 183 184 Postoperative pain between the two groups has been analysed in our study, which showed a 185 significant difference on the first postoperative day between the suture and tissue adhesive 186 group, which is a novel finding. In the available literature, there is no clear evidence that 187 postoperative pain in affected by using tissue adhesive, as compared to sutures. In a 188 randomized cohort study by Chamariya et al in 2016, it was found that using a tissue 189 adhesive causes less pain after closure of the episiotomy wound as compared to suturing.18 190 However, the skin closure technique was mattress suturing and the area of interest was the 191 perineum. With respect to thyroid surgeries, Pronio et al20 mentioned that 26.3% of 192 patients in the control group and 9.3% of the study group, which was a significant difference; 193 however, they compared between staples and tissue adhesives. Amin et al21 compared pain 194 at first and tenth postoperative day using the visual analogue scale and concluded that there 195 is no difference between both the groups (p=0.829 and p=0.931). Our findings can be 196 explained by the fact that there was a lower amount of tissue handling and dissection, no 197 needle pricks and no suture lying within the skin postoperatively in the tissue adhesive 198 group. 199 200 Scar outcome is one another important factor for assessing a skin closure technique. 201 Consorti13 have assessed scar outcome at 6 weeks using Patient and Observer Scar 202 Assessment Scale (POSAS) score. Based on observer assessment, subcuticular suture was 203 favoured above tissue adhesive, but there was no difference on the patients’ assessment. This 204 study was, however, criticized for assessing scars at 6 weeks as it may be too early to assess 205 scar outcome with most surgical scars taking an optimal time of 3 months to mature. Ciufelli 206 et al concluded that there was better scar in tissue adhesive group than suture group at tenth 207 day, but at three months, there was no difference.19 Pronio20, Amin21 and Yang22 also showed 208 that there was no significant difference in the scar outcome at the 3rd month between both the 209 groups. We found concordant results in our study with there being no difference in the scar 210 outcome both at 1st month and at 3rd month between the groups. 211 212 In the Cochrane review published by Dumville, it was stated that sutures were significantly 213 better than tissue adhesives for minimising dehiscence, but the available evidence was of a 214 low quality. A need to study a subset of the population that have comorbidities that influence 215 the rates of wound breakdown was also noted.9 In our present study, we have tried to bridge 216 this gap in knowledge by taking comorbidities into account with 16.39% patients in suture 217 group and 15.87% patients in the tissue adhesive group having comorbidities. It was seen on 218 a subgroup analysis that there was no difference in the scar outcome or wound-related 219 complications in these patients. However, the validity of this statement was questionable due 220 to the small subgroup size (15-16%) and this statement requires larger studies to reinforce 221 this conclusion. 222 223 Regarding the time for closure of the skin incision, it would depend on the skin incision 224 length which depends on the extent of surgery. Pronio20 and Ciufelli19 did not differentiate 225 between the different types of thyroid surgeries. Consorti13 had only taken patients 226 undergoing total thyroidectomy patients, whereas Bozkurt17 had taken all head and neck 227 surgeries into account. In our study, we have taken patients undergoing different extents of 228 thyroid surgeries and randomized them into both groups, and as table 1 demonstrates, were 229 equally distributed into either arm. Our study shows that hemithyroidectomy took 230 significantly less time in both groups, which may be attributed to the incision length. As all 231 types of thyroid surgeries were included in our study, this was prevented from being a 232 confounding factor. 233 234 In the present study, each patient required one package of 3-0 monocryl suture which costs 235 899 INR or one vial of tissue adhesive which costs 2000 INR. This showed that the tissue 236 adhesive was twice as expensive as a suture. However, there was no need of dressing or 237 follow-up visits for suture removal in tissue adhesive. Hence, the overall cost involved in 238 both groups was difficult to estimate and compare. Bozkurt and Saydam17 also had similar 239 results in their study done in 2008. 240 241 The disadvantages of cyanoacrylate were mainly technical, and care should be taken to 242 prevent them. In literature, it was seen that the adhesive can seep into the wound edges, 243 impairing the wound healing and affecting the scar cosmesis by causing a foreign body 244 reaction.23 Asai et al reported that 9/577 patients had developed allergic contact dermatitis 245 after the first application of cyanoacrylate tissue adhesive.11 Bitterman et12 reported a 246 papulovesicular rash at the application site, 2 weeks postoperatively, which on close 247 examination, showed residual glue found at the incision site, which improved once the glue 248 was washed off. None of these effects were noted in any of our patients. 249 250 Another advantage of tissue adhesive is the antimicrobial nature. Cyanacrylate, in the 251 unused form, is manufactured in the monomeric state. When it encounters moisture, it 252 polymerizes forming a layer of waterproof material, which forms a physical barrier to the 253 entry of microbes, obviating the need for dressing. It can also inhibit microbial growth in 254 vitro. This is thought to be due to high electronegative charge on the cyanoacrylate monomer 255 which reacts with the positively charged polysaccharide capsule of organisms.24 256 257 The present study was not without limitations of its own. It was a single institutional study. 258 The skin closure was not done by a single surgeon in all patients. Thus, the experience of the 259 surgeon with the technique may have affected our results especially skin closure time and 260 scar outcome. The length of the skin incision was not measured which can affect the skin 261 closure time. Scar outcome was assessed by a blinded observer using Manchester scar score 262 which is a subjective score. Patient satisfaction and their assessment of the scar were not 263 evaluated which can tell us the patient’s preference which may affect the choice of skin 264 closure. 265 266 Conclusion 267 Tissue adhesive is faster to apply than subcuticular sutures in all types of thyroid surgeries. 268 They also result is less immediate postoperative pain and the two groups have a comparable 269 scar cosmesis. There was no difference seen in the wound-related complications between the 270 two groups, even among patients with comorbidities. However, the cost involved in tissue 271 adhesives is significantly higher as compared to sutures. Hence, we propose that the use of 272 tissue adhesives can replace subcuticular sutures in thyroid skin closure, if the patient is able 273 to afford it. 274 275 Conflict of Interest 276 The authors declare no conflicts of interest. 277 278 Funding 279 No funding was received for this study. 280 281 Authors’ Contribution 282 AM was involved in the formulation of the protocol and of its execution. EMKS was 283 involved in the data collection and the writing of the final manuscript. AKS was involved in 284 protocol creation and the editing of the manuscript. ETP and MAS were involved in the 285 overall process of supervising the study and editing the manuscript. 286 287 References 288 1. Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, et al. 289 Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 290 2018 May;14(5):301–16. https://doi.org/10.1038/nrendo.2018.18 291 2. Ohgami M, Ishii S, Arisawa Y, Ohmori T, Noga K, Furukawa T, et al. 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In: Active 361 Implants and Scaffolds for Tissue Regeneration. 2011. p. 39–56. https://doi.org/ 362 10.1007/8415_2010_48 363 364 https://www.ncbi.nlm.nih.gov/pubmed/25762833 https://doi.org/10.1007/s00238-010-0477-6 https://doi.org/10.1016/j.otohns.2009.01.003 https://doi.org/10.1177/1457496913490610 https://doi.org/10.1016/0022-3468(95)90760-2 http://dx.doi.org/10.1007/8415_2010_48 365 Figure 1: CONSORT 2010 Flow Diagram 366 367 Table 1: Demographic and clinical parameters comparison between the two groups 368 Parameters Subcuticular suture Tissue adhesive P value Mean Age 42.62 ± 12.28 42.03 ± 11.8 0.785 Gender Male [n(%)] 17(27.87) 11(17.46) 0.166 Female [n(%)] 44(72.13) 52(82.54) Preoperative diagnosis Benign [n(%)] 44(72.13) 46(73.02) 0.912 Malignant [n(%)] 17(27.86) 17(26.98) Type of surgery Hemithyroidectomy [n(%)] 29(47.54) 30(47.62) 0.993 Subtotal and Total thyroidectomy [n(%)] 32(52.46) 33(52.38) 369 Table 2: Comparison of Skin closure time in each group 370 Group Median (in seconds) Minimum (in seconds) Maximum (in seconds) p-value# Suture 390 130 750 <0.01* Tissue adhesive 250 90 720 #Mann-Whitney U test 371 *statistically significant with 1% level of significance 372 373 Table 3: Comparison of post-operative pain score in each group 374 Group Median Minimum Maximum p-value# Suture 6 1 9 <0.01* Tissue adhesive 5 1 9 #Mann-Whitney U test 375 *statistically significant with 1% level of significance 376 377 Table 4: Comparison of scar score in the 1st postoperative mont 378 Group Median Minimum Maximum p-value# Suture 10 6 15 0.088 Tissue adhesive 9 5 15 #Mann-Whitney U test 379 380 Table 5: Comparison of scar score in the 3rd postoperative month in each group 381 Group Median Minimum Maximum p-value# Suture 8 6 13 0.137 Tissue adhesive 8 5 13 #Mann-Whitney U test 382