Randomized clinical trial

Randomized clinical trial of skin closure by subcuticular suture or skin stapling after elective colorectal cancer surgery S. Kobayashi1,3,4 , M. Ito1 , S. Yamamoto2 , Y. Kinugasa5 , M. Kotake6 , Y. Saida3 , T. Kobatake7 , T. Yamanaka8 , N. Saito1 and Y. Moriya2 1 Department of Colorectal Surgery, National Cancer Centre Hospital East, Kashiwa, 2 Department of Colorectal Surgery, National Cancer Centre Hospital, 3 Department of Surgery, Toho University Ohashi Medical Centre, and 4 Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, 5 Department of Colon and Rectal Surgery, Shizuoka Cancer Centre, Shizuoka, 6 Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, 7 Department of Gastroenterological Surgery, National Hospital Organization Shikoku Cancer Centre, Matsuyama, and 8 Department of Biostatistics, Yokohama City University, Yokohama, Japan Correspondence to: Dr M. Ito, Department of Colorectal Surgery, National Cancer Centre Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277–8577, Japan (e-mail: [email protected])

Background: The best suture method to prevent incisional surgical-site infection (SSI) after clean-

contaminated surgery has not been clarified. Methods: Patients undergoing elective colorectal cancer surgery at one of 16 centres were randomized

to receive either subcuticular sutures or skin stapling for skin closure. The primary endpoint was the rate of incisional SSI. Secondary endpoints of interest included time required for wound closure, incidence of wound problems, postoperative length of stay, wound aesthetics and patient satisfaction. Results: A total of 1264 patients were enrolled. The cumulative incidence of incisional SSI by day 30 after surgery was similar after subcuticular sutures and stapled closure (8⋅7 versus 9⋅8 per cent respectively; P = 0⋅576). Comparison of cumulative incidence curves revealed that SSI occurred later in the subcuticular suture group (P = 0⋅019) (hazard ratio 0⋅66, 95 per cent c.i. 0⋅45 to 0⋅97). Wound problems (P = 0⋅484), wound aesthetics (P = 0⋅182) and postoperative duration of hospital stay (P = 0⋅510) did not differ between the groups; subcuticular sutures took 5 min longer than staples (P < 0⋅001). Patients in the subcuticular suture group were significantly more satisfied with their wound (52⋅4 per cent versus 42⋅7 per cent in the staple group; P = 0⋅002). Conclusion: Compared with skin stapling, subcuticular sutures did not reduce the risk of incisional SSI after colorectal surgery. Registration number: UMIN000004001 (http://www.umin.ac.jp/ctr). Paper accepted 16 January 2015 Published online 26 February 2015 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9786

Introduction

Surgical-site infection (SSI) is a common postoperative complication, with a reported incidence of 500 000 cases per year in the USA1 . SSIs account for 15 per cent of all nosocomial infections and for up to 38 per cent of such infections in surgical patients2 . Furthermore, in a survey conducted in 19923 they accounted for 7.3 extra days of hospital stay and for US$3152 (€2740; exchange rate 21 January 2015) in additional costs. Most importantly, 77 per cent of postoperative deaths are related to SSI4 . Therefore, preventing SSIs is crucial to safeguarding patients and containing medical costs. Subcuticular suture was first described by Halsted5 in 1890, and is the preferred method of skin closure in clean surgery. Because no foreign material reaches beyond the © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

epidermis, this method of closure causes no undue skin inflammation, obviates the need for postoperative suture removal, and enhances wound aesthetics6 – 8 . The reported rate of incisional SSI is lower with subcuticular sutures than with staple closure in clean surgery6,9,10 . In a recent study of infection following gastroenterological surgery11 , the incidence of incisional SSI following skin closure by subcuticular sutures was reduced, particularly after colorectal surgery. However, the sample group was relatively small, and all the procedures were open. It was concluded that there is a need for a large randomized clinical trial that includes both open and laparoscopic surgery. Thus, the present multicentre study was conducted to examine whether subcuticular skin suture, in comparison with metal staple closure, reduces BJS 2015; 102: 495–500

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S. Kobayashi, M. Ito, S. Yamamoto, Y. Kinugasa, M. Kotake, Y. Saida et al.

the incidence of incisional SSI after surgery for colorectal cancer. Methods

Patients were eligible if they: were scheduled for elective colorectal cancer surgery with, or without ileostomy or colostomy; had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; had adequate organ function according to laboratory data (white blood cell count above 3000/μl and below 10 000/μl, neutrophil count at least 1500/μl, haemoglobin at least 9⋅0 g/dl, platelet count at least 70 000/μl, total bilirubin 1⋅5 mg/dl or less, aspartate aminotransferase 100 units/l or less, alanine aminotransferase 100 units/l or less, serum creatinine 1⋅5 mg/dl or less, serum albumin at least 2⋅8 g/dl); and provided written informed consent. Eligible patients were assigned randomly to skin closure by subcuticular suture or by skin stapling. The primary endpoint was postoperative incisional SSI. Other endpoints of interest were: wound problems, especially excessive exudate or dehiscence; length of postoperative hospital stay; time required to close the wound; wound aesthetics; and patient satisfaction. This study was approved by the institutional review board of each centre and registered in the UMIN Clinical Trials Registry (UMIN000004001).

Randomization and masking Patients were recruited by participating surgeons and enrolled before surgery. Randomization was done in a 1 : 1 allocation ratio to balance treatment over the following factors: institution, type of surgery (open versus laparoscopic) and tumour location (colon versus rectum). Surgeons were notified of the allocation by telephone before surgery. Neither the patient nor the investigators were blinded to the allocation. These processes were managed by the data centre located at National Cancer Centre Hospital East, Kashiwa, Japan.

Surgical procedure On completion of the surgical procedure and after fascial closure, the incision was irrigated with warm saline, approximately 500 ml for open surgery and 100 ml for laparoscopic surgery. The incision was then closed with either subcuticular sutures or skin staples. When subcuticular sutures were used, the dermal layers of each edge were attached to one another with suture strings buried beneath the skin surface (Fig. 1a); 4/0 or 5/0 absorbable monofilament suture material was used. When skin staples © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

Epidermis Dermis Adipose tissue

a

Subcuticular suture

Epidermis Dermis Adipose tissue

b

Skin stapling

Schematic drawings of skin closure. a Subcuticular suturing: the opposing skin layers are attached correctly to one another by subcuticular suture. b Skin stapling: the opposing skin layers are attached to one another with skin staples

Fig. 1

were used, the dermis of each edge was attached correctly at intervals of 10–15 mm (Fig. 1b). For standardization, participating surgeons were requested to learn the procedures described above by means of lectures, and by viewing an instructional video provided by the authors before the start of the study.

Perioperative care Because the study was multi-institutional, perioperative care was not standardized between centres. The institutions were surveyed before the trial by questionnaire, and it was confirmed that each institution largely follows the Centers for Disease Control and Prevention (CDC) guideline for perioperative care4 . The approach to standard perioperative care, as described in the CDC guideline, was also provided to each institution at conferences and in the study protocol.

Surveillance for surgical-site infection Surgical wounds were inspected daily during the hospitalization. Incisional SSI was suspected if there was any purulent discharge, pain or tenderness, localized swelling, redness or heat. The fluid or tissue was obtained aseptically and cultured; if infectious organisms were isolated, SSI was diagnosed and the superficial incision was opened by the surgeon4 . Each SSI was diagnosed and confirmed www.bjs.co.uk

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Skin closure by subcuticular suture or stapling after colorectal cancer surgery

Allocated to staples n = 629 Received stapling closure n = 628 Did not receive stapling closure n = 1 Operation cancelled n = 1

Follow-up

Allocation

Enrolment

Assessed for eligibility and randomized n = 1264

Allocated to subcuticular sutures n = 635 Received subcuticular suture closure n = 631 Did not receive subcuticular suture closure n = 4 Operation cancelled n = 2 Patient withdrew consent n = 1 Patient ineligible n = 1

Excluded n = 11 Reoperation n = 8 Protocol violation n = 3

Excluded n = 16 Reoperation n = 16

Analysis Fig. 2

497

Analysed n = 612

Analysed n = 620

CONSORT diagram for the trial

Table 1

Patient characteristics Staples (n = 612)

Age (years)* Sex ratio (M : F) Body mass index (kg/m2 )* ECOG performance status 0

67 (25–91) 335 : 277 22⋅6 (14⋅3–38⋅2)

Subcuticular suture (n = 620) 65 (30–91) 335 : 285 22⋅3 (14⋅6–34⋅3)

569 (93⋅0)

577 (93⋅1)

595 (97⋅2)

600 (96⋅8)

ASA fitness grade I or II III

17 (2⋅8)

20 (3⋅2)

Diabetes mellitus

47 (7⋅7)

64 (10⋅3)

History of smoking

80 (13⋅1)

66 (10⋅6)

Type of surgery Open

121 (19⋅8)

121 (19⋅5)

Laparoscopic

491 (80⋅2)

499 (80⋅5)

Colon

462 (75⋅5)

457 (73⋅7)

Rectum

150 (24⋅5)

163 (26⋅3)

35⋅8 (31⋅9–37⋅2)

35⋅9 (31⋅9–37⋅7)

Tumour location

Lowest body temperature during surgery (∘ C)* Surgical drains

467 (76⋅3)

469 (75⋅6)

Prophylactic cephalosporin

609 (99⋅5)

619 (99⋅8)

Depth of subcutaneous fat tissue (cm)*

1⋅8 (0–5)

1⋅8 (0–5)

Duration of operation (min)*

206 (60–690)

213 (81–621)

29 (0–4700)

25 (0–3575)

Blood loss (ml)*

Values in parentheses are percentages unless indicated otherwise; *values are median (range). ECOG, Eastern Cooperative Oncology Group; ASA, American Society of Anesthesiologists.

by a surgeon other than the patient’s primary surgeon, or by the institution’s infection control team. Each participating surgeon attended lectures, meetings and discussions to learn to identify SSIs on the basis of the CDC criteria. © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

At hospital discharge, each patient was asked to respond to a questionnaire regarding their wound, and the incision was reinspected in outpatients approximately 30 days after surgery. Thus, postdischarge SSI was tracked by both questionnaire and outpatient examination.

Evaluation of other factors Wound problems, particularly exudation and dehiscence, were surveyed in the same way as SSI. The total number of patients with excessive exudate or dehiscence within 30 days of operation, both during and after hospitalization, was recorded. Each wound was inspected for aesthetics in the outpatient clinic 30 days after surgery by the nurse and surgeon, and judged in accordance with a validated scar evaluation scale ranging from 1 (least aesthetic) to 6 (most aesthetic)12 . Patient satisfaction was self-reported on a scale ranging from 1 (least possible satisfaction) to 5 (greatest possible satisfaction)13 .

Statistical analysis The study was first designed to detect a 6⋅0 per cent reduction in the rate of SSI, from 14⋅0 per cent in the staple group to 8⋅0 per cent in the subcuticular suture group, with a two-sided significance level of 0⋅100 and power of 80 per cent. Accordingly, the initial target sample size was 800 patients. However, targeting a definitive result by a decrease in type I and II errors due to more rapid accrual than expected, the two-sided significance level and power www.bjs.co.uk

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Table 2

S. Kobayashi, M. Ito, S. Yamamoto, Y. Kinugasa, M. Kotake, Y. Saida et al.

Postoperative outcomes according to type of skin closure Staples (n = 612)

Time to close wound (min)* Incisional SSI Wound problem Postoperative hospital stay (days)* No. of patients with highest score for wound aesthetics No. of patients with highest score for satisfaction*

Subcuticular suture (n = 620)

1 (0⋅5–25) 60 (9⋅8) 42 (6⋅9) 9 (4–77) 475 (77⋅6) 211 of 494 (42⋅7)

P† < 0⋅001‡ 0⋅576 0⋅484 0⋅510‡ 0⋅182 0⋅002

6⋅5 (0⋅5–30) 54 (8⋅7) 36 (5⋅8) 9 (5–76) 500 (80⋅6) 268 of 511 (52⋅4)

Values in parentheses are percentages unless indicated otherwise; *values are median (range). SSI, surgical-site infection. †χ2 test, except ‡Mann–Whitney U test.

Proportion of incisional SSIs (%)

10 8 6 4 Staples Subcuticular suture

2

0

3

6

9

12

15

18

21

24

27

30

Time after surgery (days) No. at risk Staples

612

611

590

571

563

558

554

554

553

553

553

Subcuticular suture 620

620

604

589

583

577

573

572

570

568

567

Cumulative risk of incisional surgical-site infection (SSI) within 30 days of surgery (hazard ratio 0⋅66, 95 per cent c.i. 0⋅45 to 0⋅97; P = 0⋅019, log rank test)

Fig. 3

were changed to 0.050 and 90 per cent respectively, and the sample size was revised to 1240 patients. Between-group difference in the rate of incisional SSI was analysed with the χ2 test. Differences between numerical variables and binary variables were analysed with the Mann–Whitney U test and χ2 test respectively. Between-group difference in the incidence of incisional SSI over time was analysed using the log rank test. All P values are two-tailed, and P < 0⋅050 was considered statistically significant. Statistical analyses were performed with SAS® for Windows® version 9⋅3 (SAS Institute, Cary, North Carolina, USA) and SPSS® for Windows® version 11⋅0 J (IBM, Armonk, New York, USA). Results

In total, 1264 patients were enrolled from 16 centres in Japan between August 2010 and April 2012. Of these patients, 629 were allocated to abdominal closure by stapling and 635 to closure by subcuticular suture. Thirty-two patients were excluded owing to: reoperation (staples, © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

16; subcuticular sutures, 8), major protocol violation (subcuticular sutures, 3), cancelled operation (staples, 1; subcuticular sutures, 2), withdrawn consent (subcuticular sutures, 1) or ineligibility (subcuticular sutures, 1) (Fig. 2). The ineligible patient had anaemia (haemoglobin level below 9⋅0 g/dl). Thus, the final analysis included 612 patients in the staple group and 620 in the subcuticular suture group. Baseline demographics, and operative and postoperative characteristics were well balanced (Table 1). The rate of incisional SSI at 30 days after surgery was 9⋅8 per cent in the staple group and 8⋅7 per cent in the subcuticular suture group (Table 2). This difference was not statistically significant (P = 0⋅576). However, the onset of SSI tended to be delayed after subcuticular sutures (P = 0⋅019), with a hazard ratio of 0⋅66 (95 per cent c.i. 0⋅45 to 0⋅97) (Fig. 3). The rate of all wound problems (6⋅9 versus 5⋅8 per cent; P = 0⋅484), postoperative duration of hospital stay (median 9 versus 9 days; P = 0⋅510) and wound aesthetics (proportion of patients with highest possible score 77⋅6 versus 80⋅8 per cent; P = 0⋅182) did not differ www.bjs.co.uk

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Skin closure by subcuticular suture or stapling after colorectal cancer surgery

significantly between the two groups. It did take longer to insert subcuticular sutures than staples (1 versus 6⋅5 min respectively; P < 0⋅001). Regarding patient satisfaction, the proportion of patients giving the highest possible score was greater for subcuticular sutures than for staples (P = 0⋅002). The response rate to the patient questionnaire was 81⋅6 per cent, and was similar in the two groups (P = 0⋅442). Discussion

Subcuticular suture for skin closure is widely accepted as the procedure of choice in clean surgery; it is good for simple postoperative care and wound aesthetics, and there is no need to remove the stitches5 – 7,14 . The present randomized trial was conducted in patients undergoing elective colorectal surgery because the incidence of incisional SSI may be higher than in other gastrointestinal procedures. Wound healing involves re-epithelialization, which is completed within 24–48 h of skin closure, and dermal reconstruction takes place through angiogenesis and fibrogenesis within 3–4 days15 – 17 . Subcuticular suture promotes attachment of each dermal layer, supports dermal reconstruction, and subsequently enhances wound healing. It may reduce the risk of incisional SSI in colorectal surgery compared with standard staple closure. In the present study, the rate of incisional SSI after subcuticular suture by postoperative day 30 was similar to that after stapling (8.7 versus 9⋅8 per cent respectively). The cumulative risk suggested that SSI was delayed in the subcuticular suture group. It is not clear what might have developed if the incision had been followed for more than 30 days. At least, the results suggest that subcuticular suture skin closure is an acceptable alternative after colorectal surgery, for which the incidence of incisional SSI is relatively high. Other wound problems including exudate and dehiscence, wound aesthetics and postoperative hospital stay were all similar after the two methods. However, patient satisfaction, judged by the proportion of patients giving the highest possible score, was greater in the subcuticular suture group (P = 0.002), probably because it was not necessary to remove any stitches. The longer time required to close the skin by subcuticular suture was not unexpected, but the difference was only 5 min in an operation that was generally longer than 200 min. In the randomized clinical trial conducted by Tsujinaka and colleagues11 , all procedures were open. The present study included colorectal procedures that are considered higher risk for SSI18,19 . In addition, the proportion of laparoscopic procedures was high in the © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

499

present study, which reflects current surgical practice. Both this study, and the trial by Tsujinaka et al.11 , suggest that subcuticular suture is equivalent to skin stapling in terms of the risk of incisional SSI after gastrointestinal surgery. One of the limitations of the study is postdischarge surveillance. Delgado-Rodriguez and co-workers20 reported development of SSI in as many as 103 (45⋅6 per cent) of 226 patients after discharge. In some centres, postdischarge SSI surveillance is based solely on a review of medical records or on a one-time medical examination in outpatients6 – 10,14,21 . With the trend towards shorter hospital stays, some infections may be missed unless special attention is paid to postdischarge surveillance. In the present study, postdischarge SSI surveillance was achieved by patient questionnaire, outpatient medical examination and review of patients’ medical records, which increased the reliability of the results. The response rate to the patient questionnaire was 81⋅6 per cent, which is fairly high in comparison with that of other randomized trials in surgery22 – 24 . Therefore, the authors believe this limitation should not affect interpretation of the study results. Another limitation was that perioperative risk factors for SSI were not exactly the same among the participating institutions. However, each institution was involved in meetings to standardize the suture techniques, perioperative care and SSI surveillance. Furthermore, patients were stratified by institution before randomization. Therefore, the effects of interinstitutional inconsistencies were minimized. Collaborators

The following were collaborators in this study: M. Sugito, A. Kobayashi, Y. Nishizawa (National Cancer Centre Hospital East), S. Fujita (National Cancer Centre Hospital), S. Kusachi, T. Enomoto (Toho University Ohashi Medical Centre), H. Bando (Ishikawa Prefectural Central Hospital), M. Ohue, S. Noura, T. Shingai (Osaka Medical Centre for Cancer and Cardiovascular Diseases), A. Shiomi, T. Yamaguchi (Shizuoka Cancer Centre), Y. Kubo (Shikoku Cancer Centre), K. Komori, Y. Kanemitsu, K. Kimura, T. Kinoshita (Aichi Cancer Centre), K. Ootsuka (Iwate Medical University), T. Sato (Yamagata Prefectural Central Hospital), K. Takahashi (Tokyo Metropolitan Komagome Hospital), T. Shimizu (Shiga University of Medical Science Hospital), K. Yoshimatsu (Tokyo Women’s Medical University Medical Centre East), M. Nakanishi, Y. Murayama (Kyoto Prefectural Medical University), M. Hamada (Kansai Medical University Hirakata Hospital) and Y. Takii (Niigata Cancer Centre Hospital). www.bjs.co.uk

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Acknowledgements

The authors thank the above colleagues for discussion and suggestions; they also thank Y. Tanabe, M. Noguchi, T. Murakoshi, Y. Takahashi and N. Okada for data management. This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan. Disclosure: The authors declare no conflict of interest. References 1 Nichols RL. Preventing surgical site infections: a surgeon’s perspective. Emerg Infect Dis 2001; 7: 220–224. 2 Emori TG, Gayues RP. An overview of nosocomial infections, including the role of the microbiology laboratory. Clin Microbiol Rev 1993; 6: 428–442. 3 Martone WJ, Jarvis WR, Culver DH, Haley RW. Incidence and nature of endemic and epidemic nosocomial infections. In Hospital Infections (3rd edn), Bennett JV, Brachman PS (eds). Little, Brown and Co: Boston, 1992; 577–596. 4 Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1999; 20: 247–278. 5 Halsted WH. Radical cure of hernia. Johns Hopkins Hospital Medical Journal 1890; 1: 13. 6 Angelini GD, Butchart EG, Armistead SH, Breckenridge IM. Comparative study of leg wound skin closure in coronary artery bypass graft operations. Thorax 1984; 39: 942–945. 7 Lubowski D, Hunt D. Abdominal wound closure comparing the proximate stapler with sutures. Aust N Z J Surg 1985; 55: 405–406. 8 Ranaboldo CJ, Rowe-Jones DC. Closure of laparotomy wounds: skin staples versus sutures. Br J Surg 1992; 79: 1172–1173. 9 Johnson RG, Cohn WE, Thurer RL McCarthy JR, Sirois CA, Weintraub RM. Cutaneous closure after cardiac operations. Ann Surg 1997; 226: 606–612. 10 Johnson A, Young D, Reilly J. Caesarean section surgical site infection surveillance. J Hosp Infect 2006; 64: 30–35. 11 Tsujinaka T, Yamamoto K, Fujita J, Endo S, Kawada J, Nakahira S. Subcuticular sutures versus staples for skin closure after open gastrointestinal surgery: a phase 3, multicenter, open-label, randomized controlled trial. Lancet 2013; 382: 1105–1112.

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