Cyanoacrylate microbial sealants for skin preparation prior to surgery

Abstract

Background

Surgical site infections (i.e. incisions that become infected) are a continuing concern in health care. Microbial sealant is a liquid that can be applied to the skin immediately before surgery and is thought to help reduce the incidence of surgical site infections (SSIs) by sealing in the skin flora, thus preventing contamination and infection of the surgical site.

Objectives

To assess the effects of the preoperative application of microbial sealants (compared with no microbial sealant) on rates of SSI in people undergoing clean surgery.

Search methods

For this second update we searched the following electronic databases in May 2015: the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations); Ovid EMBASE and EBSCO CINAHL. There were no restrictions based on language or date of publication or study setting.

Selection criteria

Randomised controlled trials (RCTs) were eligible for inclusion if they involved people undergoing clean surgery (i.e. surgery that does not involve the breathing system, gut, genital or urinary tract, or any part of the body with an existing infection) in an operating theatre and compared the use of preoperative microbial sealants with no microbial sealant.

Data collection and analysis

All review authors independently extracted data on the characteristics, risk of bias and outcomes of the eligible trials.

Main results

Seven trials (859 participants undergoing clean surgery) met the inclusion criteria. The trials all compared cyanoacrylate microbial sealant with no sealant. We found there were fewer SSIs with the use of microbial sealant (23/443 participants) than with the control comparison (46/416 participants). There was no evidence of a difference between the two groups in surgical site infection rates following the use of microbial sealants when the results were pooled (risk ratio (RR) 0.53, 95% CI 0.24 to 1.18). There were adverse events in three studies, but these were not judged to be a result of the use of microbial sealant.

Authors' conclusions

In this second update there is still insufficient evidence available to determine whether the use of microbial sealants reduces the risk of surgical site infection or not. Further rigorous, adequately‐powered RCTs are required to investigate this properly.

Plain language summary

Cyanoacrylate microbial sealants for skin preparation prior to surgery

Question 
 We aimed to find evidence from randomised studies of people undergoing surgery to demonstrate whether or not microbial sealants make a difference to the number of surgical site infections.
 Background 
 Surgical site infection is a serious complication of surgery, where bacteria contaminate the surgical wound, preventing effective healing and in some cases spreading to other parts of the body. Research suggests that for every twenty people who have surgery, one will develop such an infection. Microbial sealant is a liquid applied to the surface of the skin immediately before surgery to seal in any bacteria living on the skin. Before applying the sealant, the skin at the operating site is usually prepared with an antiseptic solution of 10% povidone‐iodine.
 Characteristics 
 We found seven trials, which in total included 859 people. Four trials involved heart surgery, one involved inguinal hernia repair, one concerned spinal correction and another looked at surgical repair of arteries in the leg.
 Findings 
 When the findings from these trials were added together, they showed that there was no difference in surgical site infection rates following the use of microbial sealants. On average, for every hundred patients who had surgery, there were six fewer surgical site infections when a microbial sealant was used compared to when no such sealant was used.
 Adverse effects 
 None of the studies commented on any dangerous side effects or reactions resulting from use of microbial sealants, so we cannot be certain about the risks of using microbial sealants.
 Limitations 
 The risk of bias varied across the seven studies we reviewed. In some there was a high risk of bias because the methods used to design the study may have given participants and care providers knowledge of whether patients were in the comparison group or the control group. In others studies, the authors took a number of steps to minimise this risk. Overall we cannot say that any of the studies was completely free from bias.

Background

Description of the condition

Surgical site infections (SSIs) are a continuing concern in health care. An SSI is defined as an infection that occurs within 30 days of surgery as the result of a surgical incision, manifesting as pus or a swab with more than 10⁶ colony forming units (cfu) per mm³ tissue, and at least one of the following signs or symptoms: pain, localised swelling, redness or heat (Mangram 1999). Surgical incisions cause 25% to 38% of hospital‐acquired infections in surgical patients (Mangram 1999; Neumayer 2007). In clean surgery, the patient's own skin flora is highly likely to be the source of bacteria that lead to SSI (Dohmen 2008a) (see Appendix 1).

The Scottish Surveillance of Healthcare Associated Infection Programme in the UK estimated that SSI occurs in one in 20 cases of surgery (SSHAIP 2004), with an associated National Health Service (NHS) expenditure of GBP 1 billion annually. It also highlighted that the true cost of SSIs is much higher than figures would suggest, due to variations in the conduct of audits and collection of data. The reported incidence of SSI depends on a variety of factors, including: the definition of infection used, the intensity of surveillance, the nature and duration of patient follow‐up and the prevalence of risk factors in the population studied (Smyth 2000). In the UK, the National Audit Office 2004 noted that cases of infection can prolong a patient's stay in hospital by six days.

Preventative measures that can minimise SSI risk include patient skin preparation (Dumville 2015), preoperative hair removal (Tanner 2011), prophylactic antibiotics and the use of sterile disposable materials (Webster 2015).

The risk of SSI infection is influenced heavily by the nature of the surgery undertaken, and there is a widely used classification system that indicates the likelihood of SSI infection according to the risk of contamination during surgery (Appendix 1) (McLaws 2000). This review will be limited to clean surgery as SSI is least likely to occur after this type of surgery (infection rate of 3% to 5%), however, when surgery involves body cavities with infected, dead or dirty tissue ‐ for example in colorectal surgery (contaminated surgery) ‐ then SSI rates are typically higher, at between 10% and 30%.

Description of the intervention

Microbial sealants are liquids applied to the skin in the operating theatre, using an aseptic (sterile) technique, prior to surgery. The microbial sealant is applied to the surgical site immediately before surgery, after the usual preoperative skin preparation (cleansing and draping) is complete. The sealants dry to form a continuous barrier that prevents microbial migration and can be used in any type of surgery apart from that involving mucous membranes or the eyes. Instances of allergy and hypersensitivity to cyanoacrylate have been noted, and, since cyanoacrylate is an adhesive, it is suggested that accidental prolonged contact should be avoided . Cyanoacrylate sealants are supplied as a single‐use sterile pack. Integuseal is a proprietary cyanoacrylate sealant system designed to be administered via a ready‐to‐use applicator supplied in a single‐use sterile pack, with applicators offered in differing sizes depending on the surgery involved (Kimberly‐Clark 2008).

The use of cyanoacrylate microbial sealants to reduce SSI is relatively new. Cyanoacrylate forms the basis of current products that come under the term of microbial sealants. Recently the US Food and Drug Administration (FDA) gave regulatory approval for the use of topical skin adhesives, therefore, technological advances in the development of products such as cyanoacrylate may result in a number of types becoming available (Singer 2008). The focus of this review will be on cyanoacrylate‐based liquid microbial sealants.

How the intervention might work

Since the patient's own skin flora is the most common source of bacteria that cause SSIs (Nichols 1996), the aim of preoperative skin preparation is to ensure that the skin around the intended surgical site is as free as possible from endogenous bacteria, that may enter the surgical wound. Skin disinfection prior to surgery significantly reduces the number of bacteria on the skin surface, however, re‐colonisation with bacteria from deeper skin layers and hair follicles may occur during the operation (Fleischmann 1996). Cyanoacrylate‐based microbial sealant is applied before surgery in order to seal the skin flora beneath a breathable film.

Why it is important to do this review

Microbial sealants are currently being used as a method of skin preparation prior to surgery, and no systematic review exists to determine their effect on patient outcomes. Therefore, it is important to identify evidence associated with the use of microbial sealants on important outcomes such as rates of surgical site infection (SSI), the time wounds take to heal, length of stay in hospital and cost effectiveness. This review is important in determining the strength of evidence associated with the use of microbial sealants for skin preparation prior to surgery.

Objectives

To assess the effects of the preoperative application of microbial sealants (compared with no microbial sealant) on rates of SSI in people undergoing clean surgery.

Methods

Criteria for considering studies for this review

Types of studies

All published and unpublished RCTs that allocate surgical participants individually either to receive microbial sealants in the immediate preoperative phase or to receive no microbial sealant. Trials were eligible for inclusion whether or not participants received usual preoperative skin preparation (e.g. chlorhexidine, povidone iodine). Quasi‐randomised trials were not included (e.g. trials that allocate treatment by sequential record number, sequential admitting number, day of the week).

Types of participants

Trials involving participants undergoing any type of clean surgery in an operating theatre.

Types of interventions

Microbial sealant applied to the surgical incision site immediately before surgery compared with no application of microbial sealant, with or without the use of traditional preoperative preparation solutions such as povidone iodine or chlorhexidine.

Types of outcome measures

Primary outcomes

Rates of SSI as defined by Mangram 1999, or by the study authors.

Secondary outcomes

• All‐cause mortality.

• Adverse reactions (e.g. contact dermatitis, anaphylaxis).

• Other serious infection or infectious complication such as septicaemia or septic shock.

• Length of hospital stay.

• Rates of hospital re‐admissions.

• Costs.

• Postoperative antibiotic use.

Search methods for identification of studies

Electronic searches

For this update we searched the following electronic databases:

• The Cochrane Wounds Specialised Register (searched 22 May 2015);

• The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 4);

• Ovid MEDLINE & Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations) (2013 to May 21 2015);

• Ovid EMBASE (2013 to May 21 2015);

• EBSCO CINAHL (2013 to May 22 2015).

The search strategies used for CENTRAL, Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL can be found in Appendix 2, Appendix 3, Appendix 4 and Appendix 5 respectively. The Ovid MEDLINE search was combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision) (Lefebvre 2011). The Ovid EMBASE and EBSCO CINAHL searches were combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2015). There were no restrictions on the basis of date or language of publication.

Searching other resources

We searched reference lists of potentially eligible reports and review articles for further references.

We undertook the following to obtain any further data, published or unpublished for the original review but did not engage with these organisations again for the updates of this review.

• We contacted wound care product manufacturers including Kimberly Clark, Smith & Nephew, Johnson & Johnson and 3M.

• We contacted professional organisations including the Association of Perioperative Practitioners, the American Operating Room Nursing Organisation and the Australian College Operating Room Nurses.

Data collection and analysis

Selection of studies

All the review authors independently assessed the titles and abstracts of references identified by the search strategy, according to selection criteria, and obtained full versions of any articles that, from this initial assessment, satisfied the inclusion criteria. Independently we checked full papers to identify those that met the inclusion criteria, and resolved any disagreements by discussion. We screened reference lists of retrieved studies to identify further studies, and obtained full‐text copies for assessment. We settled any differences of opinion by consensus, or by referral to Cochrane Wounds editorial base.

For this second update one review author screened the search output, identified potential relevant studies and these were checked by a member of Cochrane Wounds editorial base.

Data extraction and management

We extracted and summarised study details using a piloted data extraction sheet. All review authors independently undertook data extraction and then discussed the findings to resolve any disagreement. If data were missing from reports, we contacted the study authors to request the missing information. Studies that had been published in duplicate we included only once, but extracted the maximum amount of data from all the study reports.

We extracted the following data from each study: study setting, number of participants, gender, mean age, predisposing risk factors, type of microbial sealant, use of prophylactic antibiotics, procedure and timing of adhesive application, period of postoperative follow‐up, all primary and secondary outcome descriptions and outcome measures reported, including infection rates and study authors' conclusions.

For this second update one review author extracted data from relevant studies and these data were checked by a member of Cochrane Wounds editorial base.

Assessment of risk of bias in included studies

In the original review and first update, all review authors independently assessed each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011). This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues (e.g. extreme baseline imbalance) (see Appendix 6 for details of criteria on which the judgement was based). We assessed blinding and completeness of outcome data for each outcome separately. We discussed any disagreement amongst all review authors to achieve a consensus.

For this second update one review author assessed risk of bias and discussed the judgements with a member of Cochrane Wounds editorial base.

We presented assessment of risk of bias using a 'Risk of bias' summary figure, which presents all of the judgements in a cross‐tabulation of study by entry (Figure 1). This display of internal validity indicates the weight the reader may give the results of each study.

1.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Measures of treatment effect

We entered data into Cochrane Review Manager 5 software (RevMan 2014), and used this programme for the analysis. We planned to present effect measures for dichotomous outcomes (e.g. rates of infection) as risk ratio (RR) with 95% confidence intervals (CI). For continuous outcomes, we planned to use the mean difference (MD) or, if the scale of measurement differed across trials, standardised mean difference (SMD), each with 95% CI.

Assessment of heterogeneity

We planned to assess heterogeneity by first inspecting the graphical display of the estimated treatment effects. In addition we calculated the Chi² statistic with significance set at P value less than 0.10. Any data below this threshold show evidence of heterogeneity of intervention effects. In addition, the degree of heterogeneity would have been investigated by calculating the I² statistic, which examines the percentage of total variation across studies due to heterogeneity rather than to chance. Values of I² over 75% indicate a high level of heterogeneity (Higgins 2003).

Data synthesis

Results are presented with 95% confidence intervals (CI). Estimates for dichotomous outcomes (e.g. rates of infections ‐ yes or no) were reported as risk ratio (RR). The method of synthesising the studies was dependent on the quality, design and heterogeneity of the studies identified. In addition to the statistical synthesis of data we conducted a narrative review of the eligible studies.

Subgroup analysis and investigation of heterogeneity

If sufficiently similar studies had been identified, and I² was less than 30%, a meta‐analysis would have been undertaken using a fixed‐effect model. This updated review identified four additional trials which were pooled using a random‐effects model (I² = 42%).

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies.

Results of the search

The initial search identified 220 records, which included two that were identified through contact with manufacturers (Dohmen 2008b; Dohmen 2008c), and one obtained through accessing the ClinicalTrials.gov. web site (Owens 2010). We identified no additional trials through scanning reference lists. The majority of papers referred to the use of cyanoacrylate as a method of wound closure, and were not relevant to this review. Nine citations were reviewed in full, one of which was eligible for inclusion (Towfigh 2008). One citation by Wilson presented data reported in the included study and has been recorded as a secondary citation to the included study (Towfigh 2008). A study awaiting assessment in the initial review (Owens 2010) was subsequently published and included in the first update (von Eckardstein 2011). In addition we identified two further trials for the first update: one was included (Iyer 2011), and the other excluded (Dohmen 2011), as it was not randomised.

This second update identified 65 records, of which three met the inclusion criteria (Falk‐Brynhildsen 2014; Hanedan 2014; Vierhout 2014). We identified no additional trials through scanning reference lists. Four studies were awaiting assessment in the previous update; of which Dromzee 2012 was assessed and included; the three remaining studies were assessed but not included (Dohmen 2012; Doorly 2013; Waldow 2012).

Included studies

Seven studies met the inclusion criteria for the review (Dromzee 2012; Falk‐Brynhildsen 2014; Hanedan 2014; Iyer 2011; Towfigh 2008; Vierhout 2014; von Eckardstein 2011).

Setting

All studies took place in the operating department. One was a multi‐centred US study (Towfigh 2008), one an international multi‐centred study (von Eckardstein 2011). The remainder took place in single hospitals in France (Dromzee 2012), Turkey (Hanedan 2014), Australia (Iyer 2011), or the Netherlands (Vierhout 2014). The setting of one study was not made explicit (Falk‐Brynhildsen 2014).

Participants

Dromzee 2012 included 56 participants undergoing posterior spinal correction for scoliosis. Participants had a mean age of 15 years. Falk‐Brynhildsen 2014 recruited 140 patients undergoing elective CABG with harvesting of the saphenous vein for at least two coronary arterial grafts: 110 participants were males and the mean age of all participants was 67 years. The venous harvest wound on the leg was used as the site of interest. Hanedan 2014 included 96 people undergoing cardiac surgery (specifically CABG, valve repair or repair of congenital heart disease), the mean age was 51 and 63 of the participants were male. The sternal wound site was assessed for infection. Iyer 2011 included 47 participants with a mean age of 67 years, 39 of whom were male, undergoing coronary artery bypass grafting (CABG). Randomisation was by leg, rather than by patient. The long saphenous vein site on both legs was chosen as the site of interest. Recruitment was halted at 47 participants after further ethical committee review. Towfigh 2008 included 177 participants, 170 of whom were male, undergoing an elective hernia repair in the operating theatre. The mean age was 53 years. The trial design had been informed by a sample size calculation based on the results from a porcine study, and it was estimated that 206 participants were required to demonstrate a 23% difference in wound contamination between groups, with 90% power. An interim analysis, however, was conducted after 104 participants had been recruited, and the sample size was revised to 742 participants required to detect a 10% difference in wound contamination with 80% power. The trial, however, was stopped prematurely having recruited only 177 participants, when the FDA granted regulatory approval for the product as a class II investigational device. The Vierhout 2014 study recruited 50 participants undergoing femoro‐popliteal, femoro‐crural or femoro‐femoral crossover bypass graft insertion; of these 28 participants were male and the mean age was 71. For this study an initial sample size calculation worked on the assumption of a 12% incidence of surgical site infection, meaning 180 patients would be required in both groups. However an interim analysis recorded an SSI incidence at 6% and as a result subsequent power calculations required the recruitment of 748 patients to both groups. At this point the review board giving ethical approval deemed this number of participants too large and the trial was stopped. von Eckardstein 2011 randomised 293 participants for CABG. One‐hundred and forty‐nine were male. The mean age of patients in this trial was 63 years. Both sternal and leg wounds were used as surgical sites for the study.

Experimental intervention

Two studies used the InteguSeal IS 200 applicator to administer the sealant (Dromzee 2012; Vierhout 2014). This applicator was used following standard preoperative skin preparation, namely 5% alcoholic povidone‐iodine solution in Dromzee 2012 and 0.5% chlorhexidine in 70% isopropyl alcohol in Vierhout 2014.

In Falk‐Brynhildsen 2014, an operating room nurse used the InteguSeal IS100 applicator to apply the microbial skin sealant on the patient’s leg (at the venous harvest site) just before the surgical incision but after preoperative skin preparation (which consisted of 0.5% chlorhexidine in 70% ethanol). Iyer 2011 used the InteguSeal IS 100 applicator to apply microbial sealant to saphenous vein harvest sites on one of the legs on a random basis (the other leg acted as the participant's control). This followed application of alcoholic povidone‐iodine solution. Both substances were allowed to dry after application.

In the Towfigh 2008 trial, a microbial, film‐forming, liquid sealant was applied via a disposable sponge, to the surgical sites of participants undergoing elective hernia repair. Application was immediately prior to the surgical incision and followed the standard preoperative skin preparation procedure of an application of 10% povidone‐iodine. In Hanedan 2014 cyanoacrylate microbial (InteguSeal) was applied after standard skin preparation (10% povidone‐iodine solution).

In the von Eckardstein 2011 trial, a microbial skin sealant (InteguSeal) was applied following standard surgical preparation. The sealant was considered dry when a film formed on the skin.

Control intervention

In all studies the standard preoperative skin preparation was used in the experimental and control sites: that is, 10% povidone‐iodine (Hanedan 2014; Towfigh 2008), alcoholic povidone‐iodine solution (Iyer 2011), 0.5% chlorhexidine solution in 70% ethanol (Falk‐Brynhildsen 2014), chlorhexidine 0.5% in 70% isopropyl alcohol (Vierhout 2014) or povidone iodine or 0.7% available iodine in isopropyl alcohol 74% weight/weight (w/w) (von Eckardstein 2011). In Dromzee 2012 5% povidone‐iodine was used for standard surgical skin preparation followed by 3M Steri‐Drapes in the control group. Drapes were also used in the control group in the Hanedan 2014 trial. In the text of Hanedan 2014 the phrase "control group" is at one point used to describe the use of sealants and vice versa ‐ correspondence with the author clarifies that the control group was indeed the group receiving drapes and skin preparation but no sealants, and that cyanoacrylate microbial sealants were used only in the intervention group.

Outcome measures

In Dromzee 2012 the primary outcome measure was surgical site infection, though it is unclear from the study text how this has been defined. Secondary outcomes in Dromzee 2012 were intraoperative blood loss, intraoperative time and number of vertebral levels fused.

The primary outcome measure reported by four trials was bacterial contamination (Falk‐Brynhildsen 2014; Hanedan 2014; Towfigh 2008; von Eckardstein 2011). Falk‐Brynhildsen 2014 measured postoperative skin contamination as a primary outcome measure; secondary end‐points were time to recolonisation and surgical site infection, defined as participants being given a prescription by a doctor for antibiotics to treat wound infection. In Hanedan 2014 primary outcome measures were bacterial contamination of wound site and postoperative white blood cell (WBC) count; rates of SSI (defined as any evidence of sternal wound infection at follow‐up) were a secondary outcome measure, and adverse events and mortality were also reported. Towfigh 2008 measured secondary outcomes that included: prevalence of antibiotic‐resistant Staphylococcus aureus in the wound during surgery; any difference in postoperative SSI rates; and safety outcomes associated with microbial sealant, including adverse events. In von Eckardstein 2011 secondary outcomes were comparison of bacterial count pre‐ and post‐CABG and the proportion of SSIs in both groups according to the Centers for Disease Control Prevention National Nosocomial Infections Surveillance (NNIS) criteria.

In two studies (Iyer 2011; Vierhout 2014) the primary outcome measure was surgical wound infection graded according to the Southamption wound grading system (Bailey 1992). Secondary outcomes in Iyer 2011 were irritation and allergies. Secondary outcomes in Vierhout 2014 were not described in the methodology section but all‐cause mortality and serious complications were reported.

Two studies were funded by Kimberly‐Clark Health Care, the manufacturers of the microbial sealant (Towfigh 2008; von Eckardstein 2011). In the von Eckardstein 2011 study two authors disclosed that they had a financial relationship with Kimberly‐Clark Corporation. Kimberly‐Clark Health Care provided applicators for experimental use in one study (Falk‐Brynhildsen 2014). Other studies disclosed no relationship with a manufacturer (Dromzee 2012; Hanedan 2014; Iyer 2011; Vierhout 2014).

Excluded studies

See Characteristics of excluded studies.

We excluded ten citations (not RCTs): Dohmen 2007 was a review article; Dohmen 2008b, Dohmen 2008d, and Dohmen 2009 were multiple publications of the same case‐control study; Dohmen 2008c was available in abstract form only with limited data ‐ the author was contacted but no reply was received; Pekar 2009 used unmatched cases and controls; Dohmen 2011 was a before/after trial, Dohmen 2012 was a letter, Doorly 2013 did not look at clean surgery and Waldow 2012 was not a RCT.

Risk of bias in included studies

Risk of bias in included studies

No trials were overall at low risk of bias.Though randomisation was performed well across the studies, allocation was infrequently concealed and blinding of care providers was mostly not done. See Figure 1; 'Risk of bias' summary and Figure 2 'Risk of bias' graph and Characteristics of included studies.

2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Sequence generation

The method of generating the randomisation sequence was reported in six studies (Dromzee 2012; Falk‐Brynhildsen 2014; Hanedan 2014; Towfigh 2008; Vierhout 2014; von Eckardstein 2011 ) but not reported in Iyer 2011.

Allocation concealment

The method of allocation concealment was not stated in four studies (Dromzee 2012; Falk‐Brynhildsen 2014; Hanedan 2014; Iyer 2011). In Towfigh 2008 the sealed envelopes were not confirmed as opaque and sequentially‐numbered. In Vierhout 2014 envelopes were "blinded" but opacity and sequential numbering was not confirmed. von Eckardstein 2011 conducted allocation concealment and reported the method.

Blinding

Participant blinding was unclear in one study (Iyer 2011), and in three studies participants were blinded (Falk‐Brynhildsen 2014; Hanedan 2014; Towfigh 2008). In Vierhout 2014 patients were blinded to their allocation until 48 hours postoperatively, at which point dressings were taken down and the use of sealants inevitably revealed to the patient. No report of blinding of participants was made in Dromzee 2012. The von Eckardstein 2011 trial was described as an "open label" and therefore participants were not blinded. In five studies outcome assessors were blinded to the intervention (Falk‐Brynhildsen 2014; Hanedan 2014; Iyer 2011; Towfigh 2008; Vierhout 2014). Dromzee 2012 does not describe blinding of care providers or outcome assessors. von Eckardstein 2011 was described as an open label trial therefore blinding of care providers or outcome assessors did not take place. The nature of the intervention may make blinding of care providers (viz., surgeons) quite difficult. This is acknowledged by both Dromzee 2012 and Towfigh 2008.

Incomplete outcome data

There were no drop outs in three studies (Dromzee 2012; Hanedan 2014; Iyer 2011). In Towfigh 2008 29 participants were lost to follow‐up, and data were not analysed on an intention‐to‐treat basis. Data were analysed by intention‐to‐treat analysis in von Eckardstein 2011, but 31 participants were described as ineligible for the per protocol analysis. Ten patients were lost to follow‐up (Falk‐Brynhildsen 2014), eight due to postoperative death and two due to language difficulties ‐ it is not clear from the study text that data were analysed on an intention‐to‐treat basis. There was a single postoperative death and no other drop outs in Hanedan 2014. In Vierhout 2014 three patients died postoperatively and though in the study text authors describe calculating power "on the basis of an intention‐to‐treat principle", these early postoperative deaths were excluded from subsequent analysis.

Selective outcome reporting

The presence of selective outcome reporting was unclear for all studies. Prespecified outcomes as stated in the studies were reported, but we were only able to access the study protocol for one study, Falk‐Brynhildsen 2014, which described a somewhat broader inclusion criteria and listed calculation of an ASEPSIS score as an outcome measure, though this calculation did not appear in the published report and no account was given for these differences in the study text.

Other potential sources of bias

In one study there was a baseline imbalance with a significantly longer operation time in the control group (Hanedan 2014). In two studies there was baseline imbalance between the groups in relation to obesity, with no apparent adjustment for this (Towfigh 2008; von Eckardstein 2011). In both studies there were more obese participants in the intervention group. No baseline imbalance was described in Dromzee 2012, Towfigh 2008 or Vierhout 2014.

Three trials were stopped prematurely (Iyer 2011; Towfigh 2008; Vierhout 2014). In Iyer 2011 the study was halted after further ethical review. The Towfigh 2008 trial was stopped prematurely when the FDA granted regulatory approval for InteguSeal (microbial sealant) as a class II medical device. The trial reports this as 'additional information' in the published paper. Neither Iyer 2011 nor Towfigh 2008 mentioned the effect of this early stopping on either the findings (up to the point of stopping), or on the risk of bias, neither was this event discussed in the papers. On this basis we would suggest that the studies were at high risk of bias. In Vierhout 2014 an interim analysis of SSI rates lead to an upwards revision of the sample size needed to yield adequate power, at which point the study's ethics committee halted the trial. There is no discussion of the effects of early stopping in the text, though the halting of the trial and the reasons behind this were addressed in the paper.

Effects of interventions

We identified seven trials, with 859 participants, that compared the use of microbial sealant with standard skin preparation in people undergoing clean surgery (Dromzee 2012; Falk‐Brynhildsen 2014; Hanedan 2014; Iyer 2011; Towfigh 2008; Vierhout 2014; von Eckardstein 2011).

Primary outcome: Surgical site infection (SSI)

All seven trials reported surgical site infection (SSI) as an outcome measure, but definitions differed between trials (Dromzee 2012; Falk‐Brynhildsen 2014; Hanedan 2014; Iyer 2011; Towfigh 2008; Vierhout 2014; von Eckardstein 2011). Overall 23/443 people developed a SSI in the groups where microbial sealant was applied compared with 46/416 in the control groups. We pooled the trials using a random‐effects model (I² = 42%) and found there was no evidence of a difference between the groups in the rate of SSI reported (RR 0.53 95% CI 0.24 to 1.18) Analysis 1.1.

1.1. Analysis.

Comparison 1 Microbial sealant compared with no microbial sealant, Outcome 1 Surgical site infection.

Secondary outcomes

All‐cause mortality

Mortality was reported in one study (von Eckardstein 2011), where there were four deaths (one in the intervention group and three in the control group) of cardiac/circulatory origin; none was considered to be related to the microbial sealant. Eight deaths were reported in another study (Falk‐Brynhildsen 2014) but the causes of these deaths were not discussed in the study text. Hanedan 2014 reported one postoperative mortality, though the reasons for this are not detailed in the trial report. There were two deaths due to postoperative cardiac complications and one due to bowel ischaemia reported in Vierhout 2014.

Adverse reactions

No adverse events were reported by Falk‐Brynhildsen 2014 or Iyer 2011. Towfigh 2008 reported adverse events in both groups but none were considered to be due to the microbial sealant. von Eckardstein 2011 reported adverse events (11 in the intervention group and 16 in the control group). Hanedan 2014 reported one case of sternal wound dehiscence (with no clinical or laboratory evidence of infection noted) in one patient in the microbial sealant group, requiring surgical management. Vierhout 2014 reported noninfectious lymphatic complications requiring fluid draining in two participants in the intervention group (n = 25) and two in the control group (n = 22), the authors do not state that they consider this related to the use or absence of cyanoacrylate sealants.

Other serious infection or infectious complications

In Towfigh 2008 one participant was given antibiotics for a deep infection with MRSA and was admitted to hospital for wound debridement, mesh removal and intravenous antibiotics. Four participants in Iyer 2011 required incision and drainage in the control group. In one study where wound contamination was being assessed, positive cultures were grown from samples from 38 patients, (27/68 from the microbial sealant group and 11/28 from the control group, in all of these cases there was no clinical evidence of infection (Hanedan 2014). One patient in the sealant group of the Vierhout 2014 study required further surgery at 22 days due to an infected graft following SSI.

Length of hospital stay, rates of hospital re‐admissions, costs

The above outcomes were not reported in any of the included studies.

Postoperative antibiotic use

In Falk‐Brynhildsen 2014 all patients received pre‐, intra‐ and post‐operative prophylactic antibiotics; in this trial the use of antibiotics in the two‐month postoperative period was used to define SSI. In Hanedan 2014 all patients received pre‐ and post‐operative prophylactic antibiotics. In Dromzee 2012, postoperative antibiotics and wound debridement were used to treat the six infection (event) cases. The two SSI cases amongst the control group in the Vierhout 2014 trial were treated with antibiotics (oral amoxicillin/clavulanic acid 625 mg for three days), which lead to healing of the SSI.

Discussion

Microbial sealant is thought to seal skin flora beneath a continuous film prior to skin incision, thus reducing the risk of an SSI. We decided to undertake a systematic review to establish its effectiveness, as it is a relatively new product that lacks a robust evidence base.

We identified seven trials that met the inclusion criteria for the review and investigated infection rates when microbial sealant was used compared with use of a standard preoperative method of skin preparation (Dromzee 2012; Falk‐Brynhildsen 2014; Hanedan 2014; Iyer 2011; Towfigh 2008; Vierhout 2014; von Eckardstein 2011). In five of these seven trials, participants in the intervention groups developed fewer SSIs, though there was no evidence of a difference between the two groups when the trials were pooled. All trials were at high or unclear risk of bias.

The review process was carried out with no departures from the review protocol. Although a relatively small number of studies were found in the initial review and first update, the identification of four more studies suggests that research is still ongoing in this area.

Across the trials there was unclear to high risk of bias overall. In Dromzee 2012 it was unclear who was following‐up patients and whether or not they were blinded . Amongst three of the four studies identified in this most recent (2015) update (Falk‐Brynhildsen 2014; Hanedan 2014; Vierhout 2014), randomisation was done well but allocation concealment was unclear and whilst outcome assessors were usually blinded, care providers were not. This probably represents a limitation of the study design. Randomisation and allocation concealment were unclear in one study (Iyer 2011), while in another the extent of allocation concealment was unclear and 16% of those randomised were lost to follow‐up (Towfigh 2008). In von Eckardstein 2011, there was no blinding of participants or outcome assessors, and reasons for drop outs were unclear. There were no participants lost to follow up reported in Dromzee 2012. In Falk‐Brynhildsen 2014 there were eight deaths but no explanation given. There was a single death reported in the Hanedan 2014 trial. In Vierhout 2014 there were three deaths and the reasons for these were made clear in the trial report. Three trials were stopped prematurely, one because the FDA granted regulatory approval for the product as a class II investigational device (Towfigh 2008), and two others as the result of a further review by the ethical committee (Iyer 2011; Vierhout 2014). None of these trials discussed the potential implications of this lack of power due to stopping prematurely, though in the study text Vierhout 2014 reported clearly the reasons for halting the trial. The Towfigh 2008 study was supported by the Kimberly‐Clark Corporation. The Kimberly‐Clark Corporation initiated and funded the von Eckardstein 2011 study, and two of the authors were employed by them. The same corporation provided applicators for use in the Falk‐Brynhildsen 2014 trial, but not direct financial support.

In this second update there is no robust evidence that microbial sealants may reduce the number of SSIs in clean surgery. Of the seven studies assessed, none were truly double‐blinded and overall the trials were at unclear or high risk of bias. Futhermore, these studies only involved a small number of participants and although this update included four additional studies the overall conclusion remains unchanged. We cannot draw firm conclusions about the effects of this intervention without further high‐quality evidence generated from well‐powered, double‐blinded, randomised controlled trials.

Authors' conclusions

Implications for practice.

There is insufficient evidence to guide practice with respect to the use of microbial sealant as a preoperative skin preparation for clean surgery.

Implications for research.

Randomised controlled trials are needed to establish whether applying microbial sealant prior to surgery provides any clinical benefit. Trialists should:

• follow the CONSORT statement when reporting the trial (CONSORT 2010);

• ensure that future trials have adequate statistical power;

• compare application of microbial sealant with alternative antiseptic skin preparations (possibly including a sham or placebo dressing to be used as sealant); and

• include outcomes of infection rates, adverse reactions, postoperative antibiotic use, mortality, costs and other serious infections or infectious complication such as septicaemia or septic shock;

• concomitant interventions/medications should be recorded clearly;

• internationally agreed definitions should be used where possible to ensure consistency in measurement.

What's new

Date	Event	Description
10 November 2015	New citation required but conclusions have not changed	Four new included studies included (Dromzee 2012; Falk‐Brynhildsen 2014; Hanedan 2014; Vierhout 2014). Conclusions remain unchanged.
10 November 2015	New search has been performed	Second update. Revised author team. New search.

History

Protocol first published: Issue 4, 2009
 Review first published: Issue 10, 2010

Date	Event	Description
3 July 2013	New search has been performed	First update.
3 July 2013	New citation required but conclusions have not changed	New search, two additional studies included (Iyer 2011; von Eckardstein 2011). Overall conclusions not changed.

Appendices

Appendix 1. Definition of degree of contamination of the surgical site

Type of wound	Description
Clean wound	Non‐infective operative wounds in which no inflammation is encountered, and neither the respiratory, alimentary, genitourinary tract nor the oropharyngeal cavity is entered. In addition these cases are elective, primarily closed, and drained with closed drainage systems when required.
Clean‐contaminated wound	These are operative wounds in which the respiratory, alimentary, genital or urinary tract is entered under controlled conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix, vagina and oropharynx are included in this category, provided no evidence of infection or major break in sterile technique is encountered.
Contaminated wound	These include fresh, accidental wounds, operations with major breaks in sterile technique or gross spillage from the gastrointestinal tract, and incisions in which acute, non‐purulent inflammation is encountered.
Dirty wound	These include old traumatic wounds with retained devitalised tissue and those that involve existing clinical infection or perforated viscera. This definition suggests that organisms causing postoperative infection were present in the operative field before the operation.

(McLaws 2000) 

Appendix 2. Search strategy CENTRAL

#1 MeSH descriptor Tissue Adhesives explode all trees
 #2 MeSH descriptor Fibrin Tissue Adhesive explode all trees
 #3 skin sealant*:ti,ab,kw
 #4 microbial sealant*:ti,ab,kw
 #5 MeSH descriptor Acrylates explode all trees
 #6 (acrylate* or cyanoacrylate* or octylcyanoacrylate* or butylcyanoacrylate* or bucrylate* or enbucrilate* or dermabond):ti,ab,kw
 #7 (#1 OR #2 OR #3 OR #4 OR #5 OR #6)
 #8 MeSH descriptor Surgical Wound Infection explode all trees
 #9 MeSH descriptor Surgical Wound Dehiscence explode all trees
 #10 surg* NEAR/5 infect*:ti,ab,kw
 #11 surg* NEAR/5 wound*:ti,ab,kw
 #12 surg* NEAR/5 site*:ti,ab,kw
 #13 surg* NEAR/5 incision*:ti,ab,kw
 #14 (#8 OR #9 OR #10 OR #11 OR #12 OR #13)
 #15 (#7 AND #14)

Appendix 3. Search strategy Ovid MEDLINE

1 exp Tissue Adhesives/ 
 2 exp Fibrin Tissue Adhesive/ 
 3 skin sealant*.tw. 
 4 microbial sealant*.tw. 
 5 exp Acrylates/ 
 6 (acrylate* or cyanoacrylate* or octylcyanoacrylate* or butylcyanoacrylate* or bucrylate* or enbucrilate* or dermabond).tw. 
 7 or/1‐6 
 8 exp Surgical Wound Infection/ 
 9 exp Surgical Wound Dehiscence/ 
 10 (surg* adj5 infection*).tw. 
 11 (surg* adj5 wound*).tw. 
 12 (wound* adj5 infection*).tw. 
 13 ((postoperative or post‐operative) adj5 infection*).tw. 
 14 or/8‐13 
 15 7 and 14

Appendix 4. Search strategy Ovid EMBASE

1 exp tissue adhesive/ 
 2 exp fibrin glue/ 
 3 skin sealant*.tw. 
 4 microbial sealant*.tw. 
 5 exp acrylic acid derivative/ 
 6 (acrylate* or cyanoacrylate* or octylcyanoacrylate* or butylcyanoacrylate* or bucrylate* or enbucrilate* or dermabond).tw. 
 7 or/1‐6 
 8 exp surgical infection/ 
 9 exp wound dehiscence/ 
 10 (surg* adj5 infection*).tw. 
 11 (surg* adj5 wound*).tw. 
 12 (wound* adj5 infection*).tw. 
 13 ((postoperative or post‐operative) adj5 infection*).tw. 
 14 or/8‐13 
 15 7 and 14

Appendix 5. Search strategy EBSCO CINAHL

S13 S5 and S12
 S12 S6 or S7 or S8 or S9 or S10 or S11
 S11 TI ( postoperative* N5 infection* OR post‐operative* N5 infection* ) or AB ( postoperative* N5 infection* OR post‐operative* N5 infection* )
 S10 TI wound* N5 infection* or AB wound* N5 infection*
 S9 TI surg* N5 wound* or AB surg* N5 wound*
 S8 TI surg* N5 infection* or AB surg* N5 infection*
 S7 (MH "Surgical Wound Dehiscence")
 S6 (MH "Surgical Wound Infection")
 S5 S1 or S2 or S3 or S4
 S4 TI ( acrylate* or cyanoacrylate* or octylcyanoacrylate* or butylcyanoacrylate* or bucrylate* or enbucrilate* or dermabond ) or AB ( acrylate* or cyanoacrylate* or octylcyanoacrylate* or butylcyanoacrylate* or bucrylate* or enbucrilate* or dermabond )
 S3 TI microbial sealant* or AB microbial sealant*
 S2 TI skin sealant* or AB skin sealant*
 S1 (MH "Fibrin Tissue Adhesive")

Appendix 6. Risk of bias definitions

1.  Was the allocation sequence randomly generated?

Low risk of bias

The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

High risk of bias

The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

Unclear

Insufficient information about the sequence generation process to permit judgement of whether low risk or high risk of bias to be made.

2.  Was the treatment allocation adequately concealed?

Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based and pharmacy‐controlled randomisation); sequentially‐numbered drug containers of identical appearance; sequentially‐numbered, opaque, sealed envelopes.

High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: use of an open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. envelopes were unsealed, non­opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear

Insufficient information to permit judgement of ‘Yes’ or ‘No’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

3.  Blinding: was knowledge of the allocated interventions adequately prevented during the study?

Low risk of bias

Any one of the following:

• No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.

• Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

• Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others was unlikely to introduce bias.

High risk of bias

Any one of the following:

• No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.

• Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.

• Either participants or some key study personnel were not blinded, and the non‐blinding of others was likely to introduce bias.

Unclear

Either of the following:

• Insufficient information to permit judgement of low risk or high risk of bias.

• The study did not address this outcome.

 4.  Were incomplete outcome data adequately addressed?

Low risk of bias

Any one of the following:

• No missing outcome data.

• Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).

• Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.

• For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.

• For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size.

• Missing data have been imputed using appropriate methods.

High risk of bias

Any one of the following:

• Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.

• For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is enough to induce clinically relevant bias in intervention effect estimate.

• For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes is enough to induce clinically relevant bias in observed effect size.

• ‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation.

• Potentially inappropriate application of simple imputation.

Unclear

Either of the following:

• Insufficient reporting of attrition/exclusions to permit judgement of low risk or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided).

• The study did not address this outcome.

5.  Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias

Either of the following:

• The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

• The study protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).

High risk of bias

Any one of the following:

• Not all of the study’s pre‐specified primary outcomes have been reported.

• One or more primary outcomes reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified.

• One or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).

• One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis.

• The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear

Insufficient information available to permit judgement of low risk or high risk of bias. It is likely that the majority of studies will fall into this category.

 6.  Other sources of potential bias

Low risk of bias

The study appears to be free of other sources of bias.

High risk of bias

There is at least one important risk of bias. For example, the study:

• had a potential source of bias related to the specific study design used; or

• stopped early due to some data‐dependent process (including a formal‐stopping rule); or

• had extreme baseline imbalance; or

• has been claimed to have been fraudulent; or

• had some other problem.

Unclear

There may be a risk of bias, but there is either:

• insufficient information to assess whether an important risk of bias exists; or

• insufficient rationale or evidence that an identified problem will introduce bias.

Data and analyses

Comparison 1. Microbial sealant compared with no microbial sealant.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Surgical site infection	7	859	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.24, 1.18]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Dromzee 2012.

Methods	RCT
Participants	56 patients with neuromuscular or idiopathic scoliosis. Group 1: 28 patients Group 2: 28 patients Inclusion Criteria: patients with idiopathic or neuromuscular scoliosis undergoing posterior correction and fusion. Exclusion Criteria: patients that have had previous spinal surgery; patients undergoing anterior or combined correction procedures
Interventions	Group 1: Cyanoacrylate microbial sealant (InteguSeal 200 applicator) plus 3M Steri‐Drape and standard skin preparation (5% alcoholic povidone‐iodine solution) Group 2: 3M Steri‐Drape and standard skin preparation (5% alcoholic povidone‐iodine solution)
Outcomes	Surgical Site Infection Secondary outcomes: Blood loss and operation time Number of spinal levels fused Postoperative antibiotics and wound debridement were used to treat the postoperative infection cases No adverse effects noted
Notes	Location: France
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Using a random number table, patients were administered either a 3M Steri‐Drape incise drape (3M, St. Paul, MN) alone or after a sterile, film‐forming cyanoacrylate liquid application”
Allocation concealment (selection bias)	High risk	Use of a random number table may have allowed participants to foresee assignment
Blinding (performance bias and detection bias) Participant	Unclear risk	Not stated in study
Blinding (performance bias and detection bias) Care provider	High risk	Quote: "Findings from this study may have been limited by our inability to blind surgeons and caregivers to the study group assignment."
Blinding (performance bias and detection bias) Outcome assessor	Unclear risk	Not stated in study
Incomplete outcome data (attrition bias) Drop out rates	Low risk	No drop outs, no missing outcome data
Incomplete outcome data (attrition bias) Intention to treat analysis	Unclear risk	Not stated in study
Selective reporting (reporting bias)	Unclear risk	Study protocol not accessed Outcomes addressed as described in methodology section
Other potential sources of bias	Low risk	No baseline imbalances

Falk‐Brynhildsen 2014.

Methods	RCT
Participants	140 patients undergoing CABG surgery Group 1: 70 patients Group 2: 70 patients Inclusion criteria: patients undergoing elective CABG with harvesting of the saphenous vein for at least two coronary arterial grafts. Exclusion criteria: non‐elective surgery, prior cardiac surgery, long term steroid use, antibiotic treatment within 14 days, preoperative disease of the skin including active infection, preoperative use of intra‐aortic balloon pump.
Interventions	Group 1: Cyanoacrylate antimicrobial sealant prior to incision at the venous harvest site plus standard preoperative skin preparation (0.5% chlorhexidine solution in 70% ethanol) Group 2: standard preoperative skin preparation (0.5% chlorhexidine solution in 70% ethanol).
Outcomes	Surgical wound contamination Surgical site infection Secondary outcomes: All‐cause mortality: 8 patients died in the postoperative period but no details reported as to cause.
Notes	Location: Sweden Kimberly‐Clark Health Care provided applicators for use in the study but made no financial contribution.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote:”The randomisation sequence was produced by an external statistician using computer‐generated block randomisation.”
Allocation concealment (selection bias)	Unclear risk	Not stated in study
Blinding (performance bias and detection bias) Participant	Low risk	Quote: “Patients were blind to allocation”
Blinding (performance bias and detection bias) Care provider	Unclear risk	Not stated in study, though a surgeon would be able to determine the difference in treatment between the two groups
Blinding (performance bias and detection bias) Outcome assessor	Low risk	Quote: “2‐month follow‐up data were retrieved from the center’s routine postoperative structured follow‐up, conducted by dedicated nurses not connected to this or any other study, and blinded to the allocation”
Incomplete outcome data (attrition bias) Drop out rates	Low risk	10 drop‐outs reported (8 due to postoperative deaths, 2 due to language difficulties)
Incomplete outcome data (attrition bias) Intention to treat analysis	Unclear risk	No mention of ITT in study report
Selective reporting (reporting bias)	High risk	Trial record accessed at clinicaltrials.gov. Study report conflicts with trial record as there is no mention in the study report of calculating the “ASEPSIS” score; inclusion criteria in the study report are somewhat narrower compared to the trial record. No further detail given about drop outs
Other potential sources of bias	Unclear risk	Significant baseline imbalance with males being over‐represented

Hanedan 2014.

Methods	RCT
Participants	102 patients undergoing cardiac surgery Group 1: 68 Group 2: 28 (after 6 exclusions) Inclusion criteria: patients undergoing CABG, valve repair or congenital heart surgery Exclusion criteria: previous cardiac surgery, concurrent infection, skin lesions on surgical site, BMI > 35, ASA score > 3, emergent cases
Interventions	Group 1: Cyanoacrylate antimicrobial sealant applied prior to incision after standard preoperative skin preparation (10% povidone‐iodine solution) Group 2: Plain adhesive drapes applied prior to incision after standard preoperative skin preparation (10% povidone‐iodine solution) (confirmed in correspondence with author)
Outcomes	Surgical wound contamination Postoperative WBC count Secondary outcomes: Surgical site infection All‐cause mortality ‐ one postoperative death. Adverse events ‐ one case of wound dehiscence in one patient from group 1 with no evidence of infection
Notes	Location: Turkey
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote:"patients randomised to either a standard plain adhesive drape (28 patients, control group) or a microbial sealant (68 patients, study group) " Author states: “we flipped a coin each time”
Allocation concealment (selection bias)	Unclear risk	Not stated in study
Blinding (performance bias and detection bias) Participant	Low risk	Not stated in study Author states: “care providers were not but the patients and the outcome assessors were blinded to the allocation.”
Blinding (performance bias and detection bias) Care provider	High risk	Not stated in study. Author states: “care providers were not but the patients and the outcome assessors were blinded to the allocation.”
Blinding (performance bias and detection bias) Outcome assessor	Low risk	Not stated in study. Author states: “care providers were not but the patients and the outcome assessors were blinded to the allocation.”
Incomplete outcome data (attrition bias) Drop out rates	Low risk	No drop‐outs reported
Incomplete outcome data (attrition bias) Intention to treat analysis	Unclear risk	ITT not done
Selective reporting (reporting bias)	Unclear risk	All of the outcomes stated in the methods section of the study were addressed; a study protocol could not be not accessed
Other potential sources of bias	Unclear risk	Baseline imbalance: operative period significantly longer in the adhesive drape group Patients requiring postoperative surgical exploration were excluded

Iyer 2011.

Methods	RCT
Participants	47 participants undergoing CABG surgery with bilateral long saphenous vein removal Groups 1 and 2 comprised 47 participants and 94 legs. Each leg was assigned randomly to intervention or control Inclusion criteria: undergoing CABG surgery requiring ≥ 3 lengths of long saphenous vein Exclusion criteria: participant required ≤ 2 segments of vein, so only one leg would be used Any dissimilarity between the legs included unusable veins in either leg, unilateral vascular disease, or skin lesions
Interventions	Group (leg) 1: microbial sealant plus standard pre‐operative skin preparation (alcoholic povidone‐iodine solution) Group (leg) 2: standard preoperative skin preparation (alcoholic povidone‐iodine solution)
Outcomes	SSI Secondary outcomes: irritation and allergies, none found Follow‐up: 1 month
Notes	Location: Australia Trial was halted after recruitment of only 47 participants following further ethical committee review All participants underwent systemic cooling to 32oC to 34oC
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote:"Microbial sealant was applied to one of the legs on a random basis" Comment: there was insufficient information about how the randomisation sequence was generated
Allocation concealment (selection bias)	Unclear risk	No detail given in study. No reply from author contact
Blinding (performance bias and detection bias) Participant	Unclear risk	Not stated in study. No reply from author contact
Blinding (performance bias and detection bias) Care provider	Unclear risk	It would not be possible to blind caregivers to the intervention, as no sham treatment was given
Blinding (performance bias and detection bias) Outcome assessor	Low risk	Quote: "Wounds were assessed according to the Southampton score at 30 days by two blinded observers". Comment: outcome assessor adequately blind to intervention
Incomplete outcome data (attrition bias) Drop out rates	Low risk	No drop outs reported, and potential effect on results due to early stopping not discussed
Incomplete outcome data (attrition bias) Intention to treat analysis	High risk	Not reported
Selective reporting (reporting bias)	Unclear risk	All outcomes stated in the methods section of the study were addressed, but study protocol could not be not accessed.
Other potential sources of bias	Unclear risk	Trial was stopped after recruitment of only 47 participants following further ethical committee review. Low risk of baseline imbalance as all participants acted as their own control (47 participants 94 legs).

Towfigh 2008.

Methods	RCT
Participants	177 participants undergoing an open, clean hernia repair. Group 1: 68 participants included in final analysis (88 randomised) Group 2: 80 participants included in final analysis (89 randomised) Inclusion criteria: scheduled for open class 1, clean inguinal hernia repair; aged 18 years or over; able to complete mean (SD) 30 (5) days follow‐up; able to provide written consent Exclusion criteria: known sensitivity to cyanoacrylate, formaldehyde or acetone products, or iodine or iodine‐containing products; surgical procedures involving mucous membranes or eyes; laparoscopic surgical procedures; evidence of coexistent infection at a remote body site; skin rashes or exfoliative condition on the day of surgery; history of keloid formation; currently on high‐dose steroid treatment or immunosuppressive therapy; chemotherapy treatment within 30 days of current surgery; diagnosis of diabetes with HbA1c > 7% obtained within 90 days; use of oral, IV or topical (in expected area of incision) antibiotics within 10 days prior to the day of surgery; pregnant or nursing; participation in any other study of an investigational drug or device within two weeks prior to the current surgical procedure
Interventions	Group 1: microbial sealant plus standard preoperative skin preparation of 10% povidone‐iodine Group 2: standard preoperative skin preparation of 10% povidone‐iodine
Outcomes	Surgical wound contamination Secondary outcomes: Adverse reactions: serious adverse events included one of each of the following in the control group: admission for SSI due to MRSA, groin haematoma, chest pain, dyspnoea, scrotal oedema and knee pain. There were a number of non‐serious adverse events listed in Table 6 including scrotal oedema and haematoma: three in the intervention group and two in the control group Postoperative antibiotics: given to one participant in the control group for a deep infection with MRSA Other serious infections: three participants developed SSIs, all in the control group. One was a deep infection with MRSA and was admitted to hospital for wound debridement, mesh removal and intravenous antibiotics Follow‐up: 30 days
Notes	Location: USA Setting: multi‐centred, six teaching hospitals Funding source: Quote: "This study was supported by Kimberly‐Clark Health Care to be performed at 6 academic institutions". "Funding was limited to provision of InteguSEAL applicator, standardised microbial sampling supplies, and facility reimbursement of study‐related costs, such as data collection and participant reimbursement for travel expenses at test‐of‐cure visit"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked by investigational centre to ensure equal numbers randomised to each group. Computer programme SAS version 9 used to generate randomisation sequence Quote: "Patients were randomised using a 1:1 allocation"
Allocation concealment (selection bias)	Unclear risk	Quote: "Each investigational site was supplied with sealed envelopes" Comment: Envelopes were not stated as opaque and sequentially numbered, therefore assessed as unclear
Blinding (performance bias and detection bias) Participant	Low risk	Confirmed, following contact with the author, that participants were blinded
Blinding (performance bias and detection bias) Care provider	High risk	Author stated, "it was not possible to mask the surgeon from knowledge of the assigned study group"
Blinding (performance bias and detection bias) Outcome assessor	Low risk	Quote: "Microbiological evaluation was performed by an independent microbiological core laboratory that had no knowledge of the randomised study group"
Incomplete outcome data (attrition bias) Drop out rates	High risk	29 lost to follow‐up, 20 in microbial sealant group and nine in control group
Incomplete outcome data (attrition bias) Intention to treat analysis	High risk	ITT was not performed
Selective reporting (reporting bias)	Unclear risk	All outcomes stated in the methods section of the study were addressed, but study protocol could not be accessed.
Other potential sources of bias	High risk	Early stopping: trial was stopped once regulatory approval was granted by the FDA as a class II medical device Baseline imbalance: tobacco use was lower in the intervention group (28 in intervention group and 34 in control group). The number of obese participants was slightly higher in the intervention group (27 versus 18 in control group)

Vierhout 2014.

Methods	RCT
Participants	50 patients undergoing vascular repair surgery, indications for surgery were invalidating claudication (Fontaine IIb), pain at rest, or tissue necrosis Group 1: 25 patients Group 2: 25 patients Inclusion criteria: patients Exclusion criteria: Patients undergoing thrombectomy via inguinal incision, patients under 18 years old, patients with previous groin incisions or previous vascular surgery proximal to the site of incision being studied
Interventions	Group 1: cyanoacrylate sealant applied using InteguSeal IS 200 ready‐to‐use applicator before incision but after regular disinfection (chlorhexidine 0.5% in 70% isopropyl alcohol) Group 2: regular disinfection (chlorhexidine 0.5% in 70% isopropyl alcohol)
Outcomes	Surgical site infection (defined as Southampton Wound score of III or more with positive microbial cultures) Secondary outcomes: All‐cause mortality (three deaths in group 2 due to cardiac complications (two patients) and bowel ischaemia (one patient)) Postoperative use of antibiotics (reported in two patients in group 2 for treatment for surgical site infection) Other serious infection (infected graft in one patient in group 1) Other adverse events (lymphatic complications reported in two patients from each group)
Notes	Location: Netherlands Trial was stopped after recruitment of only 50 participants following interim analysis and further ethical committee review
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Patients were randomly assigned in a 1:1 ratio to one of the two groups, with randomisation accomplished by the drawing of a sealed envelope in the operating room one‐half hour before surgery by the surgeon” Author States: “There was a 50:50 chance for allocation”
Allocation concealment (selection bias)	Unclear risk	Not stated in study Author states: “Their allocation could not have been predicted, for randomisation was performed by a blinded envelope.”
Blinding (performance bias and detection bias) Participant	High risk	Author states: “After operation, the bandage was left in place for 48 hours, after that, the allocation was obvious for the patient”
Blinding (performance bias and detection bias) Care provider	High risk	Quote: "randomisation accomplished by the drawing of a sealed envelope in the operating room one‐half hour before surgery by the surgeon performing the operation." Comment: care providers aware of allocation
Blinding (performance bias and detection bias) Outcome assessor	Low risk	Quote: “The wound evaluation was done at 2 wk and 6 wk post‐operatively by a researcher who was blinded to the randomisation” Comment: no suggestion that assessment of outcome was influenced by allocation
Incomplete outcome data (attrition bias) Drop out rates	Low risk	Quote: "3 patients died of non‐related causes" Comment: no other drop outs reported
Incomplete outcome data (attrition bias) Intention to treat analysis	Low risk	Quote: “We performed a power analysis … on the basis of an intention‐to‐treat principle” Comment: Authors intended to analyse outcomes of drop‐outs, though having died it was not possible to assess whether these patients developed an SSI
Selective reporting (reporting bias)	Unclear risk	Author states: "We did not have a study protocol published" Comment: despite unavailability of protocol, there is no suggestion that outcomes were recorded other than those reported; outcomes addressed as set out in methods
Other potential sources of bias	Unclear risk	Trial was stopped after recruitment of only 50 participants following further ethical committee review No baseline imbalances

von Eckardstein 2011.

Methods	RCT
Participants	300 participants undergoing CABG were enrolled, of this 293 were randomised Group 1: 146 participants Group 2: 147 participants Inclusion criteria: 18 years or older; scheduled, elective CABG with median sternotomy and use of saphenous vein or radial artery as one of the graft sites Exclusion criteria: participant undergoing additional procedures; sensitivity/allergy to cyanoacrylate, isopropyl alcohol, iodine, iodine‐containing products or tape, antimicrobial‐impregnated incision drapes; abnormal skin condition around the surgical incision site; chemotherapy, immunosuppressive therapy or steroids; use of antibiotics for an active infection; HIV infection with CD4 count < 350 mm3; therapeutic radiation or renal dialysis; morbid obesity (BMI > 37 kg/m2); neutropenia; intra‐aortic balloon pump or mechanical assist device preoperatively; hospital stay longer than 14 days
Interventions	Group 1: microbial sealant plus standard preoperative skin preparation of povidone‐iodine or 0.7% available iodine in isopropyl alcohol 74% w/w Group 2: standard preoperative skin preparation of povidone‐iodine or 0.7% available iodine in isopropyl alcohol 74% w/w
Outcomes	Surgical wound contamination Secondary outcomes: Proportion of surgical site infections Adverse reactions Four deaths (one in intervention and three in control group) which were cardiac/circulatory in origin, and not considered to be related to the treatment. Most adverse events were related to SSIs with 11 in the intervention group and 16 in the control group (excluding deaths) Follow‐up: 30 days
Notes	Surgical incise drapes were used in some cases Prophylactic antibiotics were administered at the surgeons' discretion and according to hospital protocol Location: USA, Europe, Asia, Latin America Setting: multi‐centred Funding source: study initiated and funded by Kimberly‐Clark. Two authors (Oslund and Kelley) had financial relationships with Kimberly‐Clark Corporation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A computer‐generated randomisation schedule balanced by permuted blocks"
Allocation concealment (selection bias)	Low risk	" . . . prepared separately by the study statistician for each center before the study". "On the day of the operation for each patient, the investigator was provided with a sealed envelope containing the randomisation number and group assignment"
Blinding (performance bias and detection bias) Participant	High risk	Quote: "open label clinical trial"
Blinding (performance bias and detection bias) Care provider	High risk	Quote: "open label clinical trial"
Blinding (performance bias and detection bias) Outcome assessor	High risk	Quote: "open label clinical trial"
Incomplete outcome data (attrition bias) Drop out rates	Unclear risk	Thirty one participants were ineligible for inclusion, 19 in the intervention group and 12 in the control group
Incomplete outcome data (attrition bias) Intention to treat analysis	Low risk	ITT data based on 293 participants randomised into the study
Selective reporting (reporting bias)	Unclear risk	All outcomes stated in the methods section of the study were addressed, but study protocol could not be accessed
Other potential sources of bias	High risk	Early stopping: no Baseline imbalance: 20 participants were obese in the control group and 40 in the intervention group

Abbreviations

≤ = equal to or less than
 ≥ = equal to or more than
 > = more/greater than
 < = less/fewer than
 ASA = American Society of Anesthesiologists
 BMI = body mass index
 CABG = coronary artery bypass graft
 FDA = US Food and Drug Administration
 ITT = intention‐to‐treat analysis
 IV = intravenous
 RCT = randomised controlled trial
 SD = standard deviation
 SSI = surgical site infection
 WBC = white blood cell
 w/w = concentration of a substance by weight or mass.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Dohmen 2007	Not an RCT, a review
Dohmen 2008b	Not an RCT, a matched case‐control study
Dohmen 2008c	Unclear from abstract and contact with author whether an RCT, or not
Dohmen 2008d	Not an RCT, a case‐control study
Dohmen 2009	Not an RCT, a case‐control study
Dohmen 2011	Not an RCT, a before/after trial
Dohmen 2012	Not an RCT
Doorly 2013	Not clean surgery
Pekar 2009	Not an RCT, unmatched case‐control study
Waldow 2012	Not randomised due to "alternate day" process of participant allocation to control and intervention arms

Abbreviation

RCT = randomised controlled trial

Differences between protocol and review

None.

Contributions of authors

CP, AL and PH co‐wrote the protocol. PH wrote to manufacturers and professional bodies for additional information. CP co‐ordinated the protocol development. CP and AL co‐wrote the review and all authors agreed the final submission. AL undertook the first update which was read and approved by CP, PH and ID.
 The second update was undertaken by CW and approved by CP.

Contributions of editorial base

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content. Approved the final protocol and review prior to submission.
 E. Andrea Nelson, Editor: approved the review update prior to submission.
 Sally Bell‐Syer: co‐ordinated the editorial process. Advised on methodology, interpretation and content. Edited the review and updated review and supervised the second update of the review.
 Ruth Foxlee: designed the search strategy and edited the search methods section. For this second update Rocio Rodriguez‐Lopez ran the searches.

Sources of support

Internal sources

• University of Glamorgan, UK.

  Time and resources to prepare the systematic review

• Department of Health Sciences, University of York, UK.

External sources

• NIHR/Department of Health (England), (Cochrane Wounds), UK.

  This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Wounds. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health

Declarations of interest

Callum Wood: none known
 Cheryl Phillips: none known

New search for studies and content updated (no change to conclusions)