Guidelines when Randomised Trial was Designed

In 2009, when the trial for this PhD study was designed, CHG was the antiseptic agent recommended by National and International guidelines for the prevention and control of intravascular catheter and haemodialysis catheter related-infection (CARI 2000, CDC 2002, NKF K/DOQI 2006a, Pratt et al.

2007, The UK Renal Association 2007, SARI 2009). Although all guidelines were unanimous in recommending a CHG solution, recommendations differed in its strength and formulation. Two guidelines did not specify the strength or formulation of CHG (CARI 2000, The UK Renal Association 2007). The remaining guidelines recommended the use of 2% CHG, with one guideline not stating its formulation (CDC 2002). All others recommended a 2% CHG in 70% isopropyl alcohol solution. The variation in these guideline recommendations reflects the lack of strong evidence on the most effective strength and formulation of CHG antiseptic solutions for the prevention of intravascular catheter-related infections.

5.6 Summary

Following a rigorous search of the literature, 17 RCTs were identified comparing the effectiveness of CHG based solutions versus other antiseptic solutions for the prevention of intravascular catheter-related infection. Those trials that monitored for adverse reactions did not observe any events. The duration of RCTs ranged from three months (Astle & Jensen 2005) to three years. RCTs were primarily undertaken in the ICU (n=10), with one trial, which was assessed as at a high risk for bias, conducted in a haemodialysis centre. Various catheter types were included in the trials, with three RCTs focusing exclusively on CVCs.

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The superiority of CHG versus povidone iodine, as a cutaneous antiseptic solution for the prevention of intravascular catheter-related colonisation was confirmed by six RCTs (Maki et al. 1991, Sheehan et al. 1993, Maki et al.

2001, Kelly et al. 2006, Valles et al. 2008, Bilir et al. 2013). CHG solutions investigated in these studies included 4% CHG, 2% aqueous CHG, 2% CHG in 70% isopropyl alcohol, 1% CHG in 75% alcohol and 0.5% CHG in alcohol (no strength given). This finding was not observed in three RCTs (Humar et al. 2000, Langgartner et al. 2004, Garland et al. 2009), with no significant difference in frequency of catheter colonisation in 0.5% CHG alcohol and 2% CHG alcohol treated participants as compared to participants treated with povidone iodine. There is strong evidence from the three meta-analyses (Chalyakunapruk et al. 2002, Rickard & Ray-Barruel 2010, Maiwald & Chan 2012) that CHG antiseptic solutions (any strength) are more effective at reducing the risk for catheter colonisation than povidone iodine or 70% alcohol solutions.

There is conflicting evidence on the effectiveness of CHG as compared to povidone iodine for the prevention of catheter-related bacteraemia (catheter- related bloodstream infections). In three RCTs (Maki et al. 2001, Kelly et al.

2006, Bilir et al. 2013), the frequency of catheter-related bacteraemia was lower in CHG (1% CHG in 75% alcohol, 2% CHG in 70% alcohol and 4% CHG) than povidone iodine treated participants. This compares to findings from six RCTs (Maki et al. 1991, Sheehan et al. 1993, Legras et al. 1997, Humar et al. 2000, Valles et al. 2008, Garland et al. 2009) that report no significant difference in the frequency of catheter-related bacteraemia between participants assigned to CHG (0.5% CHG alcohol, 0.5% CHG tincture, 2% aqueous CHG & 2% CHG alcohol) and povidone iodine groups.

Of the six trials that found no significant difference in the frequency of catheter-related bacteraemia, four (Legras et al. 1997, Humar et al. 2000, Valles et al. 2008, Garland et al. 2009) lacked information on the alcohol concentration of the CHG solution, raising concerns about the alcohol’s optimal range (60% to 90%) for antimicrobial activity. Five trials (Maki et al.

1991, Sheehan et al. 1993, Legras et al. 1997, Humar et al. 2000, Valles et al.

2008) had a lower CHG in alcohol solution (0.5% versus 1% and 2% CHG) or were in a lower aqueous based solution (2% versus 4%) when compared to those trials that report a significant effect on catheter-related bacteraemia rates (Maki et al. 2001, Kelly et al. 2006, Bilir et al. 2013). Although the sixth

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trial used a 2% CHG in alcohol solution (Garland et al. 2009), its sample size was small (24/24), the alcohol concentration of the CHG was not provided and participants were recruited from neonatal units, a patient population that was particularly vulnerable to infection. All other CHG trials recruited participants over the age of 18 years. Given the difference between trials that had an effect versus those that did not, it could be hypothesised that a higher strength of CHG (4%) or a higher strength of CHG in alcohol (1-2% CHG in 70% isopropyl alcohol) could potentially have a more beneficial effect than 0.5% CHG in alcohol or 2% aqueous CHG.

Differences in trial findings are also mirrored by conflicting findings from the systematic reviews. None of the reviews included all 17 trials that are discussed individually in this chapter. These systematic reviews were guided by specific criteria that potentially limited trials that were identified as eligible for the meta-analysis. It is unclear what impact the exclusion of trials may have on the meta-analysis of trial data. In Chalyakunapruk et al. (2002) meta- analysis, CHG (0.5% & 1% in alcohol, 2% aqueous) solutions, as compared to povidone iodine solution, significantly reduced the risk of intravascular catheter (all types) and CVC catheter-related bloodstream infections. This is somewhat supported by Maiwald & Chan (2012), whereby participants treated with CHG (0.5%, 1% and 2%) in alcohol had a significantly lower risk of catheter-related bloodstream infections than participants treated with aqueous povidone iodine. However, there was no statistically significant difference between participants treated with 2% aqueous CHG and aqueous povidone iodine solution in the frequency of catheter-related bloodstream infections. Based on findings from two RCTs, Rickard & Ray-Barruel (2010) meta- analysis also estimated that there was no statistically significant differences in the frequency of catheter-related bloodstream infections between CHG (any strength) and povidone iodine treated participants. Conclusions made in the Rickard & Ray-Barruel (2010) meta-analysis need to be tempered given the exclusion from their meta-analysis of RCTs published before 2002.

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5.7 Conclusion

There is strong evidence that CHG antiseptics solutions of any strength are more effective than other agents in reducing the risk of intravascular catheter colonisation. However, there is no clear evidence that aqueous and alcohol CHG antiseptic solutions are more effective than other antiseptic solutions in reducing the risk of catheter-related bloodstream infections.

National and international guidelines recommend the use of CHGs for the insertion and maintenance of CVCs, including haemodialysis catheters. However, only one RCT compared the effectiveness of different strengths of CHG for the prevention of catheter-related infections. This three arm trial found no significant difference in the frequency of catheter colonisation and catheter-related bloodstream infection in participants treated with 0.5% CHG in alcohol versus participants treated with a 2% aqueous CHG solution. A number of intravascular-catheter guidelines recommend a 2% CHG in 70% isopropyl alcohol solution, even though no RCTs were found that directly compared this solution to other strength/formulations of CHG. Such RCTs would provide the evidence justifying such a recommendation. A lack of evidence is the cause of continuing uncertainty as to which strength and formulation of CHG is the most effective in reducing the risk of CVC-related infections. This gap in the existing evidence provides further justification for the direction and focus of the randomised trial for this PhD research. The findings in this chapter, and from the Cochrane Review in chapter 4, highlight the need to explore the comparison through a pilot RCT testing the relative effectiveness of 2% CHG in 70% isopropyl alcohol versus other alcohol or aqueous strengths of CHG for the prevention of catheter-related infections in haemodialysis patients. There is also a need to explore the feasibility of undertaking a more powerful study, as a multi-national, multi-centre trial.

The review of CHG RCTs highlights a number of issues that have implications for the design of this randomised trial. Only three trials focused exclusively on CVCs, with one (Astle & Jensen 2005) recruiting participants from an in-centre haemodialysis unit. The type of catheter used in that trial was a dual lumen, tunnelled, permanent cuffed catheter; similar to what is used for haemodialysis patients in Ireland (chapter 3 section 3.5). RCTs focused on CVC, including Astle & Jensen (2005), recruited participants with newly inserted CVCs and trial solutions were used for catheter insertion, exit site and catheter hub care. It is not feasible to confine this pilot trial population to haemodialysis patients

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with newly inserted CVCs, because there are insufficient numbers of such patients in Ireland (chapter 3 sections 3.3 and 3.4). It is important that at each dialysis session and dressing change, trial solutions are used by haemodialysis nursing staff for all aspects of participants’ CVC exit site and catheter hub care. This includes the avoidance of topical antimicrobial ointments, limiting potential confounding variables in this trial.

As most of the RCTs were undertaken in ICUs, their inclusion and exclusion criteria are of relatively little help for planning the design of my trial, other than their decisions to require that patients be over the age of 18, able to give informed consent, have no allergies to the trial solutions, and with a standard CVC site e.g., internal jugular and subclavian vein and the use of CVCs for haemodialysis only. Astle & Jensen (2005) did not report the methods used to randomise haemodialysis patients to their assigned solution, but some of the other RCTs used randomised block allocation sequence that were blinded, with one study using a block size of 8. In general, no detail was provided on the method used to generate the randomisation sequence, except for one RCT that used a computer. For a majority of trials, staff and participants were not blinded to the assigned treatment because of the nature of the solutions being applied, but efforts were made to keep outcome assessors unaware of participant allocation. Drawing on these features of earlier trials, a computer generated randomised block sequence is an appropriate method for ensuring a low risk of selection bias in my trial and allocation concealment bias can be addressed through the use of a central randomisation centre.

Primary outcomes for many of the RCTs included colonisation, exit site infections and bloodstream infections related to the use of a catheter. Various case definitions were used in the trials, which impinges on comparability. The most clinically important primary outcomes for outpatient haemodialysis participants are bloodstream infections related to the use of the CVC and exit site infections (chapter 3, section 3.5.1). These two outcomes were taken into account when designing my trial. It is also important that adverse reactions to the trial solutions are monitored, recorded and reported in the CHG Trial. Another consideration for the design of my trial was the potential impact haemodialysis nursing staff turnover may have on the consistent implementation of the trial protocol, as highlighted by Astle & Jensen (2005). In order to overcome this potential limitation, the trial protocol included the

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provision of in-service education to new haemodialysis nursing staff during the course of the trial.

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