Cyanoacrylate microbial sealants for skin preparation prior to surgery

  • Review
  • Intervention

Authors

  • Allyson Lipp,

    Corresponding author
    1. Department of Care Sciences, University of South Wales, Faculty of Health, Sport and Science, Pontypridd, Rhondda Cynon Taff, UK
    • Allyson Lipp, Faculty of Health, Sport and Science, Department of Care Sciences, University of South Wales, Glyn Taff Campus, Pontypridd, Rhondda Cynon Taff, CF37 1DL, UK. allyson.lipp@southwales.ac.uk.

    Search for more papers by this author
  • Cheryl Phillips,

    1. Department of Care Sciences, University of Glamorgan, Faculty of Health, Sport and Science, Pontypridd, Rhondda Cynon Taff, UK
    Search for more papers by this author
  • Paul Harris,

    1. Princess of Wales Hospital, Abertawe Bro Morgannwg University NHS Trust, Main Theatres, Bridgend, UK
    Search for more papers by this author
  • Iwan Dowie

    1. Department of Care Sciences, University of Glamorgan, Faculty of Health, Sport and Science, Pontypridd, Rhondda Cynon Taff, UK
    Search for more papers by this author

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 first update we searched the following electronic databases in July 2013: the Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid MEDLINE - In-Process & Other Non-Indexed Citations, Ovid EMBASE and EBSCO CINAHL.

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

Three trials (524 participants undergoing clean surgery) met the inclusion criteria. The trials all compared cyanoacrylate microbial sealant with no sealant, and, when pooled, we found there were fewer SSIs with the use of microbial sealant (10/261 participants) than with the control comparison (29/274 participants). The difference between the two groups was statistically significant (risk ratio (RR) 0.36, 95% CI 0.18 to 0.72) but given the number of participants and quality of the studies, they should be treated with caution. There were some adverse events in one study, but these were not judged to be a result of the use of microbial sealant.

Authors' conclusions

In this first 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

Surgical site infection (SSI) is a serious complication of surgery. Microbial sealant is a liquid applied to the surface of the skin immediately before surgery to seal in any bacteria living on the skin that may pose a risk of infection. Before applying the sealant, the skin at the operating site is usually prepared with an antiseptic solution of 10% povidone-iodine. Our searches discovered three eligible randomised trials, with a total of 524 participants, that compared the impact of sealant compared with no sealant on the incidence of SSIs. Two trials concerned cardiac surgery, and the third concerned inguinal hernia repair. When the results of the trials were combined they did produce a statistically significant difference in SSI rates, however, the evidence from the trials was not of high quality, so further research is needed to find out whether this intervention works.

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 (Edwards 2004), preoperative hair removal (Tanner 2006), prophylactic antibiotics and the use of sterile disposable materials (Webster 2007).

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 (Kimberly-Clark 2008). Cyanoacrylate sealants are supplied as a single-use sterile pack, with applicators in differing sizes depending on the surgery involved.

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 from endogenous bacteria, that may enter the surgical wound, as possible. 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 dry and 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 first update we searched the following electronic databases in July 2013:

  • The Cochrane Wounds Group Specialised Register (searched 3 July 2013);

  • The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 6);

  • The Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2013, Issue 6);

  • Ovid MEDLINE (2010 to June Week 3 2013);

  • Ovid MEDLINE (In-Process & Other Non-Indexed Citations, July 02, 2013);

  • Ovid EMBASE (2010 to 2013 Week 26);

  • EBSCO CINAHL (1982 to 28 June 2013)

The Cochrane Central Register of Controlled Trials (CENTRAL) was searched using the following search string: 

#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) 

The search strategies for Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL can be found in Appendix 2; Appendix 3 and Appendix 4 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 2009). The Ovid EMBASE and EBSCO CINAHL searches was combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (SIGN 2009). There were no restrictions on the basis of date or language of publication.

Searching other resources

We undertook the following to obtain any further data, published or unpublished:

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

  • We contacted wound care product manufacturers including Kimberly Clark, Smith and Nephew, Johnson and 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 the editorial base of the Cochrane Wounds Group.

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.

Assessment of risk of bias in included studies

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 5 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.

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.

Figure 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 2008), and used this program 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, in cases where the I2 was less than 30% a meta-analysis was performed using a fixed-effect model, with three RCTs there were too few studies to use a random effects model; no meta-analysis would have been performed if the I2 was greater than 60%, or if the studies were too clinically heterogeneous to make pooling appropriate.

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 2008c; Dohmen 2008d) , and one obtained through accessing the ClinicalTrials.gov. website (Owens (accessed 17 June 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). For the update a study awaiting assessment in the initial review (Owens (accessed 17 June 2010)) has now been published and included (von Eckardstein 2011). In addition, for the update we identified two further trials: one was included (Iyer 2011), and other excluded (Dohmen 2011), as it was not randomised.

Included studies

Three studies (524 participants) met the inclusion criteria for the review (Iyer 2011; Towfigh 2008; von Eckardstein 2011).

Setting

All studies took place in the operating department with one being a multi-centred US study (Towfigh 2008), one an international multi-centred study (von Eckardstein 2011), and the third took place in one hospital in Australia (Iyer 2011).

Participants

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 US Food and Drug Administration granted regulatory approval for the product as a class II investigational device. Iyer 2011 included 47 participants, 39 of whom were male with a mean age of 67 years, undergoing coronary artery bypass grafting (CABG). The long saphenous vein site on both legs was chosen as the surgical site. Recruitment was halted at 47 participants after further ethical committee review. von Eckardstein 2011 enrolled 330 participants, and randomised 293 participants for CABG. One-hundred and forty-nine were male, with a mean age of 63 years. Both sternal and leg wounds were used as surgical sites for the study.

Experimental intervention

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. 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 third study (von Eckardstein 2011), InteguSeal microbial skin sealant 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 (Towfigh 2008), alcoholic povidone-iodine solution (Iyer 2011), and povidone iodine or 0.7% available iodine in isopropyl alcohol 74% weight/weight (w/w) (von Eckardstein 2011).

Outcome measures

The primary outcome measure reported by two trials was bacterial contamination (measured as numbers of cfus) (Towfigh 2008; von Eckardstein 2011). 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 Iyer 2011 the primary outcome measure was surgical wound infection. Infection was graded according to the Southamption wound grading system (Bailey 1992). Secondary outcomes in Iyer 2011 were irritation and allergies.

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.

Excluded studies

See Characteristics of excluded studies.

We assessed and excluded seven citations (not RCTs) for the following reasons: Dohmen 2007 was a review article; Dohmen 2008b, Dohmen 2008c and Dohmen 2009 were multiple publications of the same case-control study; Dohmen 2008d 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; and Dohmen 2011 was a before/after trial.

Risk of bias in included studies

Risk of bias in included studies

Overall the risk of bias for the studies were mainly unclear or high. See Figure 1; risk of bias summary and Figure 2 risk of bias graph and Characteristics of included studies.

Figure 2.

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

Sequence generation

The randomisation sequence was reported in two studies (Towfigh 2008; von Eckardstein 2011), but not reported in one study (Iyer 2011).

Allocation concealment

Allocation concealment was not stated in Iyer 2011 and in Towfigh 2008 the sealed envelopes were not confirmed as opaque and sequentially-numbered. von Eckardstein 2011 conducted allocation concealment and reported the method.

Blinding

Participant blinding was unclear in one study (Iyer 2011), and in another participants were blinded (Towfigh 2008). In two studies outcome assessors were blinded to the intervention (Iyer 2011; Towfigh 2008). Surgeons could not be blinded due to the nature of the intervention. The third study (von Eckardstein 2011) was described as an open label trial therefore blinding did not take place.

Incomplete outcome data

There were no drop outs in one study (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.

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 not able to access the study protocols.

Other potential sources of bias

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. Two trials were stopped prematurely (Iyer 2011; Towfigh 2008). In Iyer 2011 the study was halted after further ethical review. The Towfigh 2008 trial was stopped prematurely when the US Food and Drug Administration 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 trial 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.

Effects of interventions

We identified three trials, with 524 participants, that compared the use of microbial sealant with standard skin preparation in people undergoing clean surgery (Iyer 2011; Towfigh 2008; von Eckardstein 2011).

Primary outcome: Surgical site infection (SSI)

Towfigh 2008 reported that three participants in the control group (n = 89) developed an SSI, which was defined by the study authors as pain, swelling, erythema (redness), drainage, warmth and dehiscence (wound breakdown) up to 30 days postoperatively. None of the participants in the intervention group (n = 88) developed an SSI. There was no significant difference between the two groups in the rate of SSI (risk ratio (RR) 0.17, 95% CI 0.01 to 3.19; P value 0.23) (Analysis 1.1), however, given that there were only three events, the trial was underpowered to detect a difference in infection rates. Iyer 2011 reported that 12 participants in the control group (n = 47) and one in the intervention group (n = 47) developed an SSI (non-surgical leg acted as control). There was a statistically significant difference between the groups in the SSI rate (RR 0.08, 95% CI 0.01 to 0.62) (Analysis 1.1). In the von Eckardstein 2011 trial, nine participants in the intervention group (n = 146) and 14 in the control group (n = 147) developed an SSI with no significant difference between the groups (RR 0.65, 95% CI 0.29 to 1.45).

When the three studies were pooled using a fixed-effects model, the results showed a statistically significant greater rate of SSI in the control group compared with the intervention group (RR 0.36 95% CI 018 to 0.72) (Analysis 1.1).

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.

Adverse reactions

No toxicity, allergies or adverse events were reported by Iyer 2011, though in Towfigh 2008 one of each of the following serious adverse events was reported in the control group: admission to hospital for SSI due to methicillin-resistant Staphylococcus aureus (MRSA), groin haematoma, chest pain, dyspnoea, scrotal oedema and knee pain. A number of 'non serious' adverse events occurred in both groups including three instances of scrotal oedema and haematoma in the intervention group and two in the control group. None of the adverse events in Towfigh 2008 were considered to be due to the microbial sealant. Of the adverse events (11 in the intervention group and 16 in the control group) of the von Eckardstein 2011 study, most were reported to be related to SSIs. There were four cardiac/circulatory deaths which were not considered to be related to the treatment.

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.

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

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

Post-operative antibiotic use

In Towfigh 2008 61 out of 87 patients (70.1%) in the treatment group and 70 out of 89 (78.7%) in the control group received pre-operative prophylactic antibiotics. Two studies did not state that antibiotics were used pre- or post-operatively (Iyer 2011; von Eckardstein 2011).

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 three 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 (Iyer 2011; Towfigh 2008; von Eckardstein 2011). In all trials participants in the intervention groups experienced fewer SSIs, this difference was statistically significant in only one trial (Iyer 2011). When the studies were pooled, more participants experienced an SSI in the control group (29/274) than in the intervention group (10/261), and the difference between the two groups was statistically significant, meaning there were less infections with microbial sealant. All trials, however, were at high or unclear risk of bias, as 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 the third trial, von Eckardstein 2011, there was no blinding of participants or outcome assessors, and reasons for drop outs were unclear. Two trials were stopped prematurely, one because the US Food and Drug Administration granted regulatory approval for the product as a class II investigational device (Towfigh 2008), and the other as the result of a further review by the ethical committee (Iyer 2011). Neither trial discussed the potential implications of this lack of power due to stopping prematurely. 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.

In this update, there is still little evidence of the effects of microbial sealant in reducing the number of SSIs in clean surgery. Only a small number of studies - at high risk of bias and involving a small number of participants - were available. In order to overcome the shortcomings of the three included trials, further adequately-powered, randomised controlled trials are necessary to generate evidence that can inform the use of cyanoacrylate microbial sealants for skin preparation prior to surgery.

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;

  • ensure that future trials have adequate statistical power;

  • compare application of microbial sealant with alternative antiseptic skin preparations; 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.

Acknowledgements

Thanks go to the following people who referred the protocol, or review, for readability, relevance and methodological rigour: Wounds Group editors (Susan O'Meara, Dirk Ubbink, Joan Webster and Gill Worthy) and peer referees (Duncan Chambers, Dayanithee Chetty, Iain McCallum, Jane Nadel and Kumar Samraj). Thanks you also to the copy editor Elizabeth Royle.

Data and analyses

Download statistical data

Comparison 1. Microbial sealant compared with no microbial sealant
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Surgical site infection3535Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.18, 0.72]
Analysis 1.1.

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

Appendices

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

Type of wound Description
Clean woundNon-infective operative wounds in which no inflammation is encountered, and neither the respiratory, alimentary, genitourinary tract nor the oro-pharyngeal cavity is entered. In addition these cases are elective, primarily closed, and drained with closed drainage systems when required.
Clean-contaminated woundThese 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 woundThese 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 woundThese 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 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 3. 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 4. 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 5. 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: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or 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.

What's new

DateEventDescription
3 July 2013New search has been performedFirst update.
3 July 2013New citation required but conclusions have not changedNew search, two additional studies included (Iyer 2011; von Eckardstein 2011). Overall conclusions not changed.

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. PH wrote to study authors for additional information. The review was read and approved by PH and ID.
Al is the guarantor of the review.
AL, CP, PH and ID reviewed the papers for inclusion in the update. AL undertook the update which was read and approved by CP, PH and ID.

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.
Ruth Foxlee: designed the search strategy and edited the search methods section.

Declarations of interest

None known.

Sources of support

Internal sources

  • University of Glamorgan, UK.

    Time and resources to prepare the systematic review

External sources

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

Differences between protocol and review

None.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Iyer 2011

MethodsRCT.
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 1 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 preoperative 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.

NotesTrial was halted at 47 participants following further ethical committee review.
All participants underwent systemic cooling to 32oC to 34oC.
Risk of bias
BiasAuthors' judgementSupport 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 riskNo detail given in study. No reply from author contact.
Blinding (performance bias and detection bias)
Participant
Unclear riskNot stated in study. No reply from author contact.
Blinding (performance bias and detection bias)
Care provider
Unclear riskIt 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 2 blinded observers".

Comment: outcome assessor adequately blind to intervention.

Incomplete outcome data (attrition bias)
Drop out rates
Low riskNo drop outs reported, and potential effect on results due to early stopping not discussed.
Incomplete outcome data (attrition bias)
Intention to treat analysis
High riskNot reported.
Selective reporting (reporting bias)Unclear riskAll outcomes stated in the methods section of the study were addressed, but study protocol could not be not accessed.
Other potential sources of biasUnclear risk

Trial was stopped after 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

MethodsRCT.
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 with 2 weeks prior to the current surgical procedure.

InterventionsGroup 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 1 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: 3 in the intervention group and 2 in the control group.
Postoperative antibiotics: given to 1 participant in the control group for a deep infection with MRSA.

Other serious infections: 3 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: multicentred, 6 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 IntegSEAL 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Blocked by investigational centre to ensure equal numbers randomised to each group. Computer program 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 riskConfirmed, following contact with the author, that participants were blinded.
Blinding (performance bias and detection bias)
Care provider
High riskAuthor 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 riskQuote: "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 risk29 lost to follow-up, 20 in microbial sealant group and 9 in control group.
Incomplete outcome data (attrition bias)
Intention to treat analysis
High riskITT was not performed.
Selective reporting (reporting bias)Unclear riskAll outcomes stated in the methods section of the study were addressed, but study protocol could not be accessed.
Other potential sources of biasHigh 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).

von Eckardstein 2011

  1. a

    Abbreviations

    ≤ = equal to or less than
    ≥ = equal to or more than
    > = more/greater than
    CABG = coronary artery bypass graft
    FDA = Food and Drugs Administration
    ITT = intention-to-treat analysis
    IV = intravenous
    RCT = randomised controlled trial
    SD = standard deviation
    SSI = surgical site infection

MethodsRCT.
Participants

300 participants undergoing CABG.

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.

InterventionsGroup 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.

4 deaths (1 in intervention and 3 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: Multicentred.

Funding source: study initiated and funded by Kimberly-Clark and 2 authors (Oslund and Kelley) had financial relationships with Kimberly-Clark Corporation.

Risk of bias
BiasAuthors' judgementSupport 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 riskQuote: "open label clinical trial".
Blinding (performance bias and detection bias)
Care provider
High riskQuote: "open label clinical trial".
Blinding (performance bias and detection bias)
Outcome assessor
High riskQuote: "open label clinical trial".
Incomplete outcome data (attrition bias)
Drop out rates
Unclear risk31 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 riskITT data based on 293 participants randomised into the study.
Selective reporting (reporting bias)Unclear riskAll outcomes stated in the methods section of the study were addressed, but study protocol could not be accessed.
Other potential sources of biasHigh risk
  • Early stopping: no.

  • Baseline imbalance: 20 participants were obese in the control group and 40 in the intervention group.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    Abbreviation

    RCT = randomised controlled trial

Dohmen 2007Not an RCT, a review.
Dohmen 2008bNot an RCT, a case-control study.
Dohmen 2008cNot an RCT, a matched case-control study.
Dohmen 2008dUnclear from abstract and contact with author whether an RCT, or not.
Dohmen 2009Not an RCT, a case-control study.
Dohmen 2011Not an RCT, a before/after trial.
Pekar 2009Not an RCT, unmatched case-control study.

Characteristics of studies awaiting assessment [ordered by study ID]

Dohmen 2012

Methods 
Participants 
Interventions 
Outcomes 
Notesawaiting full text retrieval

Doorly 2013

Methods 
Participants 
Interventions 
Outcomes 
Notesawaiting full text retrieval

Dromzee 2012

Methods 
Participants 
Interventions 
Outcomes 
Notesawaiting full text retrieval

Waldow 2012

Methods 
Participants 
Interventions 
Outcomes 
Notesawaiting full text retrieval

Ancillary