Antimicrobiële afdichtingsmiddelen

Beoordeeld: 01-12-2024

Uitgangsvraag

Wat is de plaats van antimicrobiële afdichtingsmiddel voor de preventie van postoperatieve wondinfecties?¹

^{Disclaimer: Dit is een adaptatie van een origineel werk ‘Global guidelines for the prevention of surgical site infection, second edition. Geneva: World Health Organization; 2018. License: CC BY-NC-SA 3.0 IGO.’ (https://www.who.int/publications/i/item/9789241550475). Deze adaptatie is niet uitgevoerd door de WHO. De WHO is niet verantwoordelijk voor de inhoud of nauwkeurigheid van deze adaptatie. De originele uitgave is de bindende en authentieke uitgave.}

^{1 De WHO-richtlijn beschrijft geen uitgangsvragen. De uitgangsvragen voor deze module zijn opgesteld in overeenstemming met de standaardprocedures van het Kennisinstituut van de Federatie Medisch Specialisten.}

Aanbeveling

Het gebruik van een antimicrobieel afdichtingsmiddel bij chirurgische ingrepen wordt niet aanbevolen in aanvulling op standaard huiddesinfectie ter preventie van postoperatieve wondinfecties [WHO 2018].

^{Disclaimer: This is an adaptation of an original work “Global guidelines for the prevention of surgical site infection, second edition. Geneva: World Health Organization; 2018. License: CC BY-NC-SA 3.0 IGO.” (https://www.who.int/publications/i/item/9789241550475). This adaptation was not created by WHO. WHO is not responsible for the content or accuracy of this adaptation. The original edition shall be the binding and authentic edition.}

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

Er is literatuuronderzoek verricht naar het effect van antimicrobiële afdichtingsmiddelen na huiddesinfectie in vergelijking met standaard huiddesinfectie bij patiënten die een chirurgische procedures ondergaan. Postoperatieve wondinfecties (POWI) werden als cruciale uitkomstmaat gedefinieerd en POWI-attributieve sterfte als belangrijke uitkomstmaat. Een relatief verschil van 25% (relatief risico kleiner dan 0.80 of groter dan 1.25) in het optreden van POWI en 5% (relatief risico kleiner dan 0.95 of groter dan 1.05) in het optreden van POWI-attributieve sterfte tussen beide interventies werd als klinisch relevant beschouwd.

Er werden negen studies geïncludeerd. De kwaliteit van het bewijs was zeer laag. Analyse van de gerandomiseerde studies liet geen klinisch relevant verschil zien in het optreden van POWI tussen het toepassen van een afdichtingsmiddel en de standaardmethode (RR 0.73; 95% CI 0.43 - 1.23). Er was variatie in de definitie van POWI tussen de studies en tevens was er inconsistentie in de gevonden effecten op POWI’s. Opmerkelijk was dat er meerdere studies werden gefinancierd door fabrikanten, dat blindering onduidelijk was en dat er sprake was van onvolledige en selectieve rapportage van gegevens en uitkomsten.

Samenvattend betekent dit dat het erg onzeker is wat het effect is van het gebruik van een antimicrobieel afdichtingsmiddel op het voorkomen van POWI’s.

Er is geen conclusie te trekken met betrekking tot het effect van antimicrobiële afdichtingsmiddelen op POWI-attributieve sterfte, omdat geen van de geïncludeerde studies POWI-attributieve sterfte als uitkomst heeft gerapporteerd.

Bijwerkingen

Antimicrobiële afdichtingsmiddelen kunnen mogelijke schadelijke effecten hebben op de huid doordat de huid langere tijd bedekt blijft. Het is belangrijk hiermee rekening te houden.

Slechts één van de geïncludeerde studies rapporteerde huidirritatie bij één patiënt in de interventiegroep – mogelijk ten gevolge van het toepassen van het afdichtingsmiddelen. Aanvullende behandeling bij deze patiënt was echter niet nodig (Towfigh, 2008).

Eerdere onderzoeken hebben echter aangetoond dat middelen op basis van cyanoacrylaat bijwerkingen kunnen veroorzaken bij pediatrische patiënten, waaronder huidreacties (Towfigh, 2008, Roy 2014).

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Er zijn geen studies gevonden naar de waarden en voorkeuren van patiënten met betrekking tot het gebruik van antimicrobiële afdichtingsmiddelen. Het is belangrijk dat de patiënt wordt geïnformeerd wordt met betrekking tot de voor- en nadelen van het gebruik van deze middelen. Tevens is het van belang de patiënt te informeren over kans op infectie, hoe deze te herkennen en hoe dan te handelen.

Kosten (middelenbeslag)

Voor zover bekend bij de werkgroep zijn er geen studies die de kosteneffectiviteit van afdichtingsmiddelen rapporteren (Lipp 2013). Additioneel gebruik van antimicrobiële afdichtingsmiddel brengt extra kosten met zich mee.

POWI is geassocieerd met extra morbiditeit, langdurige ziekenhuisopname en een aanzienlijke stijging van de gemiddelde kosten voor gezondheidszorg (de Lissovoy, 2009). Een interventie die aantoonbaar de kans op POWI verminderd kan daarom bijdragen aan het verminderen van de kosten voor behandeling van chirurgische patiënten.

Aanvaardbaarheid, haalbaarheid en implementatie

Het toepassen van antimicrobiële afdichtingsmiddelen voorafgaand een chirurgisch ingreep wordt in de praktijk slechts beperkt toegepast. De werkgroep verwacht dan ook geen belemmeringen m.b.t. de haalbaarheid en implementatie van de aanbeveling waarbij het toepassen afgeraden wordt.

Duurzaamheid

Duurzaamheid is niet benoemd in de WHO-richtlijn en er is niet aanvullend naar gezocht.

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Het bewijs uit de geïncludeerde acht RCTs en één quasi-gerandomiseerde studie is van zeer lage kwaliteit en toont aan dat de preoperatieve toepassing van antimicrobiële afdichtingsmiddelen, naast de standaard huiddesinfectie/voorbereiding van de operatieplaats geen voor- of nadeel oplevert bij het verlagen van de kans op POWI.

Onderbouwing

Achtergrond

Endogene bacteriën op de huid, slijmvliezen en holle organen van een patiënt vormen de belangrijkste bron van verwekkers voor het ontstaan van postoperatieve wondinfecties (POWI) (Mangram 1999). Bij chirurgische ingrepen wordt, voorafgaand aan de incisie, de huid behandeld met antiseptische middelen. De middelen worden effectief beschouwd tegen een breed scala aan bacteriën, schimmels en virussen.

Antimicrobiële afdichtingsmiddelen zijn filmvormende middelen op basis van cyanoacrylaat. Deze worden na desinfectie en voorafgaand aan de incisie aangebracht om de migratie van bacteriën te neutraliseren en daarmee de contaminatie te beperken. Het is echter onduidelijk wat de toegevoegde waarde van deze middelen is in het voorkomen van een POWI.

Deze module betreft een adaptatie van de module ‘Antimicrobial Sealants’ van de World Health Organization (WHO)-richtlijn ‘Global guidelines for the prevention of surgical site infection, second edition. 2018’ (WHO, 2018A; WHO, 2018B). Voor een toelichting op de procedure van adapteren wordt verwezen naar de Bijlage Adapteren.

Conclusies

Surgical site infections¹

Very low GRADE

The evidence is very uncertain about the effect of sealants (in addition to standard surgical site skin preparation) on surgical site infections when compared with standard surgical site skin preparation in patients undergoing surgical operations (any type of procedure).

Sources: (Daeschlein 2014, Doorly 2015, Dromzee 2012, Falk-Brynhildsen 2014, Iyer 2011, Twofigh 2008, Vierhout 2014, von Eckardstein 2011, Waldow 2012)

Mortality¹

No GRADE

No evidence was found about the effect of sealants (in addition to standard surgical site skin preparation) on surgical site infection attributable mortality when compared with standard surgical site skin preparation in patients undergoing surgical operations (any type of procedure).

Sources: -

^{1 The conclusions of the literature analysis were formulated in accordance with the standard procedures of the Knowledge Institute of the Federation of Medical Specialists.}

Samenvatting literatuur

Description of studies

Eight randomized clinical trials (RCTs) (Daeschlein 2014, Doorly 2015, Dromzee 2012, Falk-Brynhildsen 2014, Iyer 2011, Twofigh 2008, Vierhout 2014, von Eckardstein 2011) and one prospective, quasi-randomized trial (Waldow 2012) with surgical side infection (SSI) outcome were identified. They evaluated sealants compared to standard surgical site preparation with antiseptics for the prevention of SSI. All 9 studies compared a cyanoacrylate-based sealant to standard antiseptic preparation without sealant.

One study (Dromzee 2012) included children and adults, while the remaining 8 included adult patients only. Both elective and emergency procedures were included; the types of surgery were cardiac, vascular, colorectal, hernia repair, scoliosis correction and trauma. In each study, the intervention and control groups received the same surgical site skin preparation with the addition of sealant in the intervention groups. The type and concentration of skin preparation varied. Some studies used chlorhexidine gluconate, while others used povidone iodine, all in an alcohol-based solution.

Results

The effects of the intervention on the prevention of SSI varied among studies. One study (Iyer, 2011) reported that sealants may have some benefit compared to standard skin preparation. Five studies (Falk-Brynhildsen 2014, Twofigh 2008, Vierhout 2014, von Eckardstein 2011, Waldow 2012) showed some effect of sealants, but the effect estimate was not clinically relevant compared to the effect of standard skin preparation. Two studies (Doorly 2015, Dromzee 2012) found that sealants may cause harm, but this effect was also not clinically relevant. Meta-analysis of the 8 RCTs and the quasi-randomized trial showed that there was no overall difference between sealants and standard surgical skin preparation in reducing the incidence of SSI (odds ratio (OR): 0.69; 95% confidence interval (CI): 0.38 to 1.25/ RR 0.43; 95% CI 0.43 to 1.23/ RD -0.03; 95% CI -0.03 to 0.01) (Figure 1a, Comparisons). In a sensitivity analysis comparing the overall effect of the included studies with or without the quasi-randomized trial, there was no difference in the results if the trial was included or not (P=0.658).

Figure 1a. Forest plot of surgical site infections for sealants versus standard surgical site skin preparation, randomized controlled trials randomized controlled trials (pooled

Level of evidence of the literature

For SSIs, the quality of evidence of the identified studies started at high and was downgraded to very low because of study limitations, including serious risk of bias (mainly due to unclear blinding, incomplete outcome data and selective outcome reporting) and very serious imprecision (risk of bias; -1, imprecision; -2) (GRADE tables).

For SSI-attributable mortality, the level of evidence could not be assessed due to the absence of relevant studies.

Zoeken en selecteren

A systematic review of the literature was performed to answer the following (search) question:

What is the effect of sealants (in addition to standard surgical site skin preparation) vs. standard surgical site skin preparation for the prevention of SSI and SSI-attributable mortality in surgical patients.¹

P: Inpatients and outpatients of any age undergoing surgical operations

(any type of procedure)

I: Sealant in addition to standard surgical site skin preparation

C: Standard surgical site skin preparation

O: SSI, SSI-attributable mortality

Relevant outcome measures²

The working group considered surgical site infections as a critical outcome and SSI-attributable mortality as an important outcome for decision making.

The working group defined a 25% relative difference (RR<0.8 or >1.25) in SSI rate and a 5% relative difference (RR<0.95 or >1.05) in SSI-attributable mortality as minimal clinically (patient) important difference.

Search and select (Methods)

The WHO searched the following databases: Medline (PubMed); Excerpta Medica Database (EMBASE); Cumulative Index to Nursing and Allied Health Literature (CINAHL); Cochrane Central Register of Controlled Trials (CENTRAL); and the WHO Global Health Library. The time limit for the review was between 1 January 1990 and 31 March 2015. Language was Page 2 of 22 restricted to English, French and Spanish. A comprehensive list of search terms was used, including Medical Subject Headings (MeSH). The detailed search strategy is available under the "Evidence tabellen" tab.

Two independent WHO-reviewers screened the titles and abstracts of retrieved references for potentially relevant studies. The full text of all potentially eligible articles was obtained and then reviewed independently by two WHO authors for eligibility based on inclusion criteria. Duplicate studies were excluded. Data were extracted in a predefined evidence table (Evidence tables) and retrieved studies were critically appraised. Quality was assessed using the Cochrane Collaboration tool (Higgins, 2011) to assess the risk of bias of randomized controlled studies (Risk of bias tables). Any disagreements were resolved through discussion or after consultation with the senior WHO-author, when necessary.

Meta-analyses of available comparisons were performed using Review Manager v5.3 as appropriate (Cochrane Collaboration, 2014) (Comparisons).

The WHO extracted and pooled adjusted odds ratios (OR) with 95% confidence intervals (CI) for each comparison with a random effects model. In addition to the WHO meta-analyses, relative risks (RR) and risk differences (RD) with 95% confidence intervals (CI) were extracted and pooled with a random effects model and added to the current literature analysis.

The WHO used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (GRADE Pro software) (GRADE Working Group, 2015) to assess the quality of the body of retrieved evidence (GRADE tables).

The WHO systematic literature search resulted in 884 (non-duplicate) hits. 32 studies were initially selected based on title and abstract screening; after reading the full text, 23 studies were excluded, and nine studies were included in the analysis (Study selection).

Results³

Nine studies were included in the analysis of the literature, eight RCTs and one prospective, quasi-randomized trial (Summary of literature). Important study characteristics and results are summarized in the evidence tables (Evidence tables). The assessment of the risk of bias is summarized in the risk of bias tables (Risk of bias tables).

^{1 The working group modified the WHO-search question by including all WHO-defined outcomes.}

^{2 The WHO-guideline did not distinguish between crucial and important outcome measures and did not define thresholds for clinical decision making.}

^{3 The WHO-guideline did not report risk ratios and risk differences.}

Referenties

Daeschlein G, Napp M, Assadian O, Bluhm J, Krueger C, von Poedwils S, et al. Influence of preoperative skin sealing with cyanoacrylate on microbial contamination of surgical wounds
following trauma surgery: a prospective, blinded, controlled observational study. Int J Infect Dis. 2014;29:274-8.
Doorly M, Choi J, Floyd A, Senagore A. Microbial sealants do not decrease surgical site infection for clean-contaminated colorectal procedures. Tech Coloproctol. 2015;19:281- 5.
Dromzee E, Tribot-Laspiere Q, Bachy M, Zakine S, Mary P, Vialle R. Efficacy of integuseal for surgical skin preparation in children and adolescents undergoing scoliosis correction. Spine. 2012;37:E1331-5.
Falk-Brynhildsen K, Soderquist B, Friberg O, Nilsson U. Bacterial growth and wound infection following saphenous vein harvesting in cardiac surgery: a randomized controlled trial of the impact of microbial skin sealant. Europ J Clin Microbiol Infect Dis. 2014;33:1981-7.
GRADEpro Guideline Development Tool. Summary of findings tables, health technology assessment and guidelines. GRADE Working Group, Ontario: McMaster University and Evidence Prime Inc.; 2015 (http://www.gradepro.org, accessed 5 May 2016).
Higgins JP, Altman DG, Gotzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
Iyer A, Gilfillan I, Thakur S, Sharma S. Reduction of surgical site infection using a microbial sealant: a randomized trial. J Thorac Cardiovasc Surg. 2011;142:438-42.
Lipp A, Phillips C, Harris P, Dowie I. Cyanoacrylate microbial sealants for skin preparation prior to surgery. Cochrane Database Syst Rev. 2013;(8):CD008062
de Lissovoy G, Fraeman K, Hutchins V, Murphy D, Song D, Vaughn BB. Surgical site infection: incidence and impact on hospital utilization and treatment costs. Am J Infect Control. 2009;37:387-97. Page 22 of 22
Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection
Control Practices Advisory Committee. Am J Infect Control. 1999;27:97- 132; quiz 3-4; discussion 96.
The Nordic Cochrane Centre TCC. Review Manager (RevMan). Version 5.3. Copenhagen: The Cochrane Collaboration; 2014.
Roy P, Loubiere A, Vaillant T, Edouard B. [Serious adverse events after microbial sealant application in paediatric patients]. [Article in French] Ann Pharm Fr. 2014;72:409-14.
Towfigh S, Cheadle WG, Lowry SF, Malangoni MA, Wilson SE. Significant reduction in incidence of wound contamination by skin flora through use of microbial sealant. Arch Surg. 2008;143:885-91; discussion 91.
Vierhout BP, Ott A, Reijnen MM, Oskam J, Ott A, van den Dunggen JJ, et al. Cyanoacrylate skin microsealant for preventing surgical site infection after vascular surgery: a discontinued
randomized clinical trial. Surg Infect (Larchmt). 2014;15:425-30.
von Eckardstein AS, Lim CH, Dohmen PM, Pêgo-Fernandez PM, Cooper WA, Oslund SG, et al. A randomized trial of a skin sealant to reduce the risk of incision contamination in cardiac surgery. Ann Thorac Surg. 2011;92:632-7.
Waldow T, Szlapka M, Hensel J, Plotze K, Matschke K, Jatzwauk L. Skin sealant InteguSeal® has no impact on prevention of postoperative mediastinitis after cardiac surgery. J Hosp Infect. 2012;81:278-82.
World Health Organization. Global guidelines for the prevention of surgical site infection, second edition. Geneva: World Health Organization; 2018. (https://www.who.int/publications/i/item/global-guidelines-for-the-prevention-of-surgical-site-infection-2nd-ed/, accessed 12 June 2023). A
World Health Organization. Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018. Web Appendix 9, Summary of a systematic review on antimicrobial skin sealants. (Summary of a systematic review on antimicrobial skin sealants - Global Guidelines for the Prevention of Surgical Site Infection - NCBI Bookshelf (nih.gov), accessed 13 June 2023).

Evidence tabellen

Author, year	Design, scope, setting, population	Objective	SSI definition	Type of surgery	Study methods	Intervention	Results
Daeschlein, 2014	Prospective, blinded RCT Germany Population: 128 adults (male and female) receiving trauma surgery Exclusion criteria: infected wounds, AIDS, HBV/HCV, known drug users	To measure the number of bacteria at the base of the wound, along the wound margin, and on the wound sutures in patients undergoing surgery with and without the use of a cyanoacrylate-based adhesive sealant.	Modified CDC definition, observed by the attending surgeon; not primary study measure. Follow-up: 3 months postoperatively.	Trauma surgery	After assessing eligibility, patients were randomized by opening a sealed envelope, which contained pre-set computer generation number sequence. Skin antisepsis was performed using a 70% propanol-based product for 1-3 minutes. The control group was covered with a sterile drape prior to incision. The intervention group received an application of cyanoacrylate sealant (InteguSeal®) after antisepsis, but before draping. Follow-up: 3 months. Three intraoperative swabs were taken from each surgical site and incubated for colony-forming unit data.	Group 1: no sealant Group 2: cyanoacrylate sealant	SSI: Group 1: 0/66 Group 2: 0/62 OR: NA CI: NA This study was financed through the routine research grant of the Institute for Hygiene and Environmental Medicine. The authors have no competing interests to report.
Doorly, 2015	Prospective, randomized trial Single institution, multicentre; USA Population: patients undergoing clean contaminated colorectal procedures Exclusion: less than 18 years, pregnancy, history of hypersensitivity to cyanoacrylate formaldehyde-acetone, emergent surgery, laparotomy within 60 days (or planned), sepsis, neutropenia, previous abdominal wound infection, serum creatinine > 3mg/dL, chemotherapy/radiation within 30 days, steroid use, HIV	To assess the role of a skin antimicrobial sealant for reducing the rate of superficial and deep wound SSI in a blended case mix of open and laparoscopic cleancontaminated procedures.	CDC criteria	Clean contaminated colorectal procedures	Consenting patients were blinded to allocation; randomization occurred via sealed envelopes containing either “InteguSeal®” or “Control”. Enrolled patients received the same mechanical bowel preparation and prophylactic antibiotics. Abdomen was prepped with hair removal by clippers and ChloraPrep® (chlorhexidine gluconate 2%, isopropyl alcohol 70%; CareFusion, San Diego, CA, USA) prior to sealant application (in the intervention group). SCIP and a standardized enhanced recovery protocol implemented for all. Follow-up at 4 weeks.	I: cyanoacrylate sealant C: no sealant The sealant was provided by the InteguSeal® manufacturer.	SSI: I: 7/50 C: 5/50 P=0.545
Dromzee, 2012	Prospective randomized trial June 2010 – June 2011; paediatric orthopaedic unit, France Population: children and adolescents undergoing scoliosis correction Exclusion criteria: previous spinal surgery and surgery indicated for anterior or combined procedures.	To explore the use of a antimicrobial sealant applied before the surgical incision to reduce SSI in patients with scoliosis.	Not specified	Spine	Randomization by random number table; impossible to blind surgical attendants. All patients showered with povidone-iodine the day before and the morning of surgery. Skin was cleaned and prepared in the operating room with 2 consecutive applications of one-step alcohol povidone-iodine 5% solution. Patients were draped either after skin preparation (control) or after the sealant dried (intervention).	Group 1: drape only after skin preparation (n=28) Group 2: drape after sterile, film-forming cyanoacrylate liquid application (InteguSeal®; n=28)	SSI: Group 1: 1/28 Group 2: 5/28 P=0.096 “No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.”
Falk-Brynhildsen 2014	RCT May 2010-October 2011; Sweden Population: patients scheduled for elective CABG, with the saphenous vein used for at least two CABG with or without another concomitant cardiac procedure. Exclusion: emergency operation, previous cardiac surgery, longterm corticosteroid treatment and/or antibiotic treatment within 14 days preoperatively skin disease, infection, or preoperative use of an intra-aortic balloon pump.	To compare the use of microbial skin sealant vs. bare skin at the saphenous vein harvesting site in patients undergoing CABG with regard to bacterial growth on the skin and in the surgical wound, including the postoperative wound infection rate.	Primary endpoint was bacterial growth on the wound-adjacent skin or from the subcutaneous wound tissue. Secondary endpoint – SSI: defined as wound complications requiring physician-prescribed antibiotic treatment (telephone call via dedicated nurse) Follow-up: 2 months	Coronary artery bypass graft with saphenous vein harvesting site	Patients were randomized via computer-generated block randomization by an external statistician allocated to two groups: bare skin (control) or microbial skin sealant (intervention). After preoperative disinfection with chlorhexidine 0.5% in ethanol 70%, or nurseapplied microbial skin sealant (InteguSeal®) on the saphenous vein harvest site (in intervention group) prior to incision.	Sealant group: cyanoacrylate sealant Control: no sealant	SSI: I: 7/61 C: 14/64 P=0.120 Kimberly Clark Health Care supported the investigators by providing InteguSeal® to be studied in an elective cardiac surgery population. Kimberly Clark provided no financial support to any author.
Iyer, 2011	Prospective RCT 2008; New Zealand Population: patients undergoing CABG	To report the effect of pretreatment with an n-butyl cyanoacrylate-based microbial skin sealant in a population undergoing cardiac surgery and discuss its potential use in decreasing infections in other kinds of surgical procedures.	Southampton score divides wounds into 5 grades: 0=normal healing; 1= normal with bruising or erythema; 2=erythema with other signs of inflammation; 3=haemoserous discharge; 4=purulent discharge; 5=deep or severe infection with or without tissue breakdown.	CABG	Hair removal was performed using an electric clipper the day before surgery. Patients washed with soap on the morning of surgery and the skin was disinfected with an alcohol-based povidone-iodine solution and left to dry for 3 minutes before a one-layer application of antimicrobial sealant, which was applied on the intervention leg on a random basis. No sham application was applied on the other leg. Wounds were examined daily during postoperative stay. In the case of infection, swabs were taken; if no infection was present, a culture swab was applied to a segment of the incision before discharge. Findings were recorded and 1-2 blinded assessors followed up at 4 weeks	Group 1: Cyanoacrylate-based sealant (InteguSeal®) Group 2: No sealant	SSI: Group 1: 1/47 Group 2: 12/47 P=0.0011 “Authors have nothing to disclose with regard to commercial support.”
Towfigh, 2008	Prospective randomized multicentre trial Six teaching hospitals; USA Population: adult patients undergoing open inguinal hernia repair. Exclusion criteria: sensitivity to cyanoacrylate, existence of infection or use of antibiotics, chemotherapy, diabetes with HbA > 7 within 90 days, pregnant, nursing, participation in other studies.	To compare the safety and effectiveness of antimicrobial sealant in reducing the incidence of surgical incision bacterial contamination relative to surgical skin preparation alone	Not specified	Hernia repair	Patients were randomized using a 1:1 allocation; each site was supplied with sealed envelopes and the schedule was blocked within the centre to ensure an even distribution. It was not possible to blind the surgeon to the assigned study group. All patients underwent intraoperative microbial wound sampling at 2 stages during the operation; colony-forming units were quantified. Follow-up at 2 and 4 weeks postoperatively for signs of infection.	Group 1: cyanoacrylate sealant Group 2: control	SSI: Group 1: 0/68 Group 2: 3/80 OR: 0.45 95% CI: 0.238- 0.88 P=0.02 Funding given for InteguSeal® applicator, standardized microbial sampling supplies and facility reimbursement of study-related costs.
Vierhout, 2014	Discontinued RCT The Netherlands Population: patients undergoing vascular reconstruction Exclusion: thrombectomies through inguinal incision, patients under 18 years and those with a previous groin incision or vascular reconstruction done cranially to the site of incision.	To investigate whether the use of cyanoacrylate skin sealant at the site of surgery could reduce the incidence of SSI in the groin after vascular procedures.	Southampton wound asssessment scale greater than grade III, erythema plus inflammation and clear or serosanguinous discharge (G3) or pus (G4).	Vascular reconstruction	Randomization was completed in a 1:1 ratio by the drawing of a sealed envelope in the operating room 30 minutes before surgery by the surgeon. All patients received cefazolin (2 g intravenous) before incision. Hair removal by clipper done before disinfection with chlorhexidine (0.5% in 70% isopropyl alcohol) and draped with sterile disposable drapes. Intervention group patients received application of cyanoacrylate-based sealant (InteguSeal®) prior to draping and after skin preparation.	Group 1: control Group 2: cyanoacrylate sealant	SSI: Group 1: 2/22 Group 2: 1/25 P = NS
Von Eckardstein, 2011	Randomized, controlled, parallelgroup, multi-centre, open-label clinical trial April 2006 to February 2009; 5 centres in Asia, Europe, Latin America and the USA Population: adult patients undergoing CABG Exclusion criteria: complex procedures, sensitivity to cyanoacrylate, isopropyl alcohol or iodine; abnormal skin condition; antimicrobial impregnated incise drapes; chemotherapy, immunosuppressive therapy; steroid therapy; use of antibiotics for an active infection, HIV infection with CD4 count <350 mm³; therapeutic radiation or renal dialysis; morbid obesity (body mass index [BMI] > 37 kg/m²); neutropenia; intraaortic balloon pump or mechanical assist device in place preoperatively; and hospital stay greater than 14 days.	To determine if the use of this skin sealant before CABG could reduce surgical wound contamination by skin microflora and decrease postprocedure infections	CDC criteria	Cardiac	Randomization in a 1:1 ratio using a computer-generated randomization schedule balanced by randomly permuted blocks; allocations were concealed in a sealed envelope. Surgical site was prepared with either povidone-iodine or iodine 0.7% in isopropyl alcohol. In the experimental group, sealant was applied after drying. Microbial samples were tested for the total bacterial burden and all patients were monitored 30 days postoperatively for SSI.	Group 1: cyanoacrylate sealant (InteguSeal®) Group 2: control	SSI: Group 1: 9/146 Group 2: 14/147 Risk reduction: 35.3% This clinical study was initiated and funded by the Kimberly Clark Corporation.
Waldow, 2012	Single-centre quasi-randomized prospective trial October 2010-April 2011; Germany Population: 998 consecutive adult patients undergoing elective cardiac surgical procedures with median sternotomy	To evaluate the prophylactic effect of a cyanoacrylatebased antimicrobial skin sealant on the incidence of postoperative mediastinitis or any other form of chest skin incision SSI after elective cardiac surgery.	CDC criteria	Elective cardiac	Hair removal by hair clipping and the application of an antiseptic alcohol-based (chlorhexidine-free) solution on the skin surface prior to incision. All measures were performed according to written internal hygienic and perioperative standards valid in the institution. Group assigned to receive a cyanoacrylate-based antimicrobial skin sealant (InteguSeal®) as a drape accessory. All patients were prospectively subdivided into two registries by alternating administration of the antimicrobial sealant every second day of surgery regardless of the operation schedule. SSI follow-up: 30 days	Group 1: cyanoacrylate-based sealant included with standard pre-operative disinfection Group 2: standard preoperative preparation	SSI: Group 1: 53/488 Group 2: 57/495 P = NS The work was supported by Kimberly-Clark Health Care, which provided investigators with the original InteguSeal® product to be studied in an elective cardiac surgery population. Kimberly-Clark did not provide any financial support to any author of this publication.

SSI: surgical site infection; CDC: Centers for Disease Control and Prevention; HIV: human immunodeficiency virus; I: intervention; C: control; AIDS: acquired immunodeficiency syndrome; HBV/HCV: hepatitis B virus/hepatitis C virus; NA: not applicable; RCT: randomized controlled trial; CABG: coronary artery bypass graft; OR: odds ratio; CI: confidence interval; SCIP: surgical care improvement project; NS: not significant.

Risk of bias tables

Studies related to antimicrobial sealants

Risk of bias in randomized controlled trials (Cochrane Collaboration tool)

Author, year	Sequence generation	Allocation concealment	Participants and personnel blinded	Outcome assessors blinded	Incomplete outcome data	Selective outcome reporting	Other sources of bias
Daeschlein, 2014	Unclear	Unclear	Low	Low	Unclear	Unclear	Unclear
Doorly, 2015	Low	Low	Unclear		Unclear	Unclear	High*
Dromzee, 2012	Low	Low	Low	Unclear	Low	High	Unclear
Falk-Brynhildsen, 2014	Low	Unclear	Unclear	Unclear	Low	Unclear	High*
Iyer, 2011	Unclear	Unclear	Low	Low	Low	Low	Low
Towfigh, 2008	Low	Low	Low	Low	Unclear	Low	Unclear
Vierhout, 2014	Low	Low			Unclear	Unclear	Low
Von Eckardstein, 2011	Low	Low	Unclear	Unclear	Unclear	Unclear	High*
Waldow, 2014**	High	High	Unclear	Unclear	Low	Low	High*

* Manufacturer of intervention provided product or funding for study

** Quasi-randomized prospective trial

Flow chart of the study selection

Comparisons

In addition to the odds ratios (OR) reported by the WHO, relative risks (RR) and risk differences (RD) with 95% confidence intervals (CI) were extracted and pooled with a random effects model and added to the current literature analysis.¹

Comparison 1. Microbial cyanoacrylate sealant vs. standard surgical site preparation

Randomized controlled trials

Forest plot

GRADE tables

Comparison 1. Microbial cyanoacrylate sealant vs. standard surgical site preparation

Outcome

Quality assessment

Number of patients

Effect

Quality

No of studies

Study design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

Microbial sealant

Standard surgical site preparation

Relative

(95% CI)

Absolute (95% CI)

Surgical site infection (SSI)

RCTs*

Serious¹

Not serious

Very serious²

None

83/975 (8.5%)

108/999 (10.8%)

OR: 0.69 (0.38- 1.25)

RR³: 0.73 (0.43-1.23)

31 fewer per 1000 (from 23 more to 64 fewer)

⨁◯◯◯

VERY LOW

SSI-attributable mortality

No GRADE

* includes one quasi-randomized trial

¹ Risk of performance bias, detection bias, attrition bias and reporting bias

² Optimal information size not met and CI includes both appreciable benefit and harm

³ Supplementary to WHO-guideline

CI=confidence interval; OR=odds ratio; RCT=randomized controlled trial; RR=relative risk; NA=not applicable

¹ ^{The WHO-guideline did not report relative risks and risk differences.}

Search strategy

Medline (through PubMed)

(("tissue adhesives"[Mesh] OR "fibrin tissue adhesive"[Mesh] OR "acrylates"[Mesh] OR

“tissue adhesives” [TIAB] OR “tissue adhesive” [TIAB] OR (sealant*[TIAB] AND

(microbial*[TIAB] OR fibrin [TIAB] OR antimicrobial* [TIAB] OR skin [TIAB])) OR

Dermabond [TIAB] OR Integuseal [TIAB] OR acrylate* OR cyanoacrylate* OR

octylcyanoacrylate* OR butylcyanoacrylate* OR bucrylate* OR enbucrilate* OR (sealing

[TIAB] AND skin [TIAB]))) AND (("surgical wound infection"[Mesh] OR surgical site

infection* [TIAB] OR "SSI" OR "SSIs" OR surgical wound infection* [TIAB] OR surgical

infection*[TIAB] OR post-operative wound infection* [TIAB] OR postoperative wound

infection* [TIAB] OR wound infection*[TIAB]))

EMBASE

'fibrin tissue adhesive'/exp OR 'fibrin tissue adhesive' OR 'acrylates'/exp OR 'acrylates' OR

'tissue adhesives'/exp OR 'tissue adhesives' OR 'tissue adhesive'/exp OR 'tissue adhesive' OR

(sealant* AND (microbial* OR 'fibrin'/exp OR fibrin OR antimicrobial* OR 'skin'/exp OR

skin)) OR 'dermabond'/exp OR dermabond OR 'integuseal'/exp OR integuseal OR acrylate*

OR cyanoacrylate* OR octylcyanoacrylate* OR butylcyanoacrylate* OR bucrylate* OR

enbucrilate* OR (sealing AND ('skin'/exp OR skin)) AND ('surgical wound infection'/exp

OR 'surgical wound infection' OR surgical AND site AND infection* OR 'ssi' OR 'ssis' OR

surgical AND ('wound'/exp OR wound) AND infection* OR surgical AND infection* OR

'post operative' AND ('wound'/exp OR wound) AND infection* OR postoperative AND

('wound'/exp OR wound) AND infection* OR 'wound'/exp OR wound) AND infection* AND

[embase]/lim AND [1990-2015]/py

CINAHL