Comparison of the efficacy of three topical antiseptic solutions for the prevention of catheter colonization: a multicenter randomized controlled study

This multicenter, open-label, parallel randomized controlled study was conducted in 16 ICUs (1 December 2012 to 31 March 2014) including four university hospitals and 12 general hospitals in Japan. Nine intensive care units were medical ICUs only and seven were combined medical-surgical ICUs. The review boards of all participating institutions approved the study protocol, and patients/close relatives provided written informed consent. This study was registered with the Japanese Clinical Research Registration System of the University Hospital Medical Information Network (UMIN) (registration number UMIN000008725).

All consecutive CVCs and ACs placed in patients ≥18 years old after admission to the ICU for the intravenous administration of medications, hemodynamic monitoring and frequent blood sampling were eligible for inclusion. Exclusion criteria included: catheters inserted before ICU admission, catheters inserted for long-term total parenteral nutrition or chemotherapy for seven or more days, patients with a history of drug allergy to the study antiseptic solutions, patients with systemic adverse events or skin reactions at the catheter insertion site, and catheters changed using a guidewire.

The enrolled catheters were randomly allocated to the following three groups according to the antiseptic solution used for initial and subsequent cutaneous antisepsis: 0.5% alcohol/CHG solution with 79% ethanol (Maskin Wethanol Solution 0.5% w/v; Maruishi Pharmaceutical Company, Osaka, Japan), 1.0% alcohol/CHG solution with 79% ethanol (Hexizac AL Solution 1%; Yoshida Pharmaceutical Company, Tokyo, Japan), and 10% aqueous PVI solution (10% PVI; Isodine Solution 10%; Meiji Seika Pharma Co., Tokyo, Japan). Until the randomized catheter was removed, a subsequently placed catheter in the same patient was not included the study. The same antiseptic solution was used during dressing changes and before catheter removal. Randomization was stratified by the hospital and catheter type (CVCs or ACs) using the sealed opaque envelope method with computer-generated randomized blocks of nine which was generated at the central institution and not revealed to the participating patients/physicians/nurses. Although patients/physicians/nurses were not blinded to the antiseptic solution group, the microbiologists performing the catheter-tip cultures and data analyst were blinded to this information.

The type of catheters and insertion sites in this study were selected at the discretion of individual physicians. At the time of conducting the study, silver antiseptic or antimicrobial-impregnated catheters were unavailable in Japan.

Before catheter insertion, the site was prepared using the allocated antiseptic solution for 30 s and allowed to dry according to standardized protocols (i.e., CHG 30s; PVI 2 min). Physicians used maximal barrier precautions (i.e., sterile gloves, gowns, masks, and large drapes covering the chest), as per CDC guidelines [5]. After catheter insertion, sterile polyurethane or gauze dressings (if an exudate was observed) were placed at the insertion site. The dressings were changed every 7 days for polyurethane dressings, every 72 h for gauze dressings, or sooner if soiled or wet. No antiseptic-containing dressings were used. Physicians/nurses inspected the insertion site at ≤24-h intervals for any evidence of infection (e.g., erythema, pain, swelling, or purulent discharge).

Catheters were removed if their use was not required or if a CRBSI was suspected [e.g., fever (temperature of ≥38.5 °C); leukocytosis (leukocyte count ≥14,000 cells/mm³) without any apparent cause; and/or pus, extensive erythema, or tenderness at the insertion site]. Before catheter removal, the same antiseptic solution was used at the site in an identical manner.

After catheter removal, 5 cm and 1–2 cm of the distal CVC and AC tips, respectively, were immediately sent for semi-quantitative culture analysis. The catheter tip is rolled 5–7 times across a 5% sheep blood agar plate and then aerobically cultured at 35 °C–37 °C for 24 h to 7 days [17]. All isolated bacteria were identified using standard methods. When the Maki method was unavailable, the sonication technique was used. Antimicrobial susceptibility testing was performed according to the recommendations of the Clinical and Laboratory Standards Institute.

The procedures including skin site preparation and barrier precautions during catheter insertion and removal, site preparation and dressing method during the dressing change, and the catheter culture method were standardized and explained to physicians in all ICUs before the study began. Video lectures of the standardized procedures were also distributed to the study ICUs. Definitions of study parameters (e.g., acute kidney injury and diabetes) were standardized in all ICUs before the study began.

The primary outcome of this study is catheter colonization incidence per 1000 catheter-days at the time of catheter removal. Secondary outcomes are CRBSI incidence, ICU length of stay, hospital mortality, and antiseptic solution-related adverse events.

Catheter colonization was defined as ≥15 colony-forming units (CFUs) in a semi-quantitative catheter tip culture using the roll-plate technique (i.e., by rolling the catheter segment across 5% sheep blood agar plate) after 24 h [17]. In the sonication technique, the definition of catheter colonization was at the discretion of the microbiological laboratory at each study institution. In the absence of colonization at 24 h, the culture was allowed to grow for up to 7 days. CRBSI was defined according to the CDC [18] and IDSA [19] guidelines, and the definition included three major criteria (Additional file 1: Table S1).

In a previous study, the incidence of catheter colonization with 10% PVI and 0.5% CHG was 24.8% and 15.1%, respectively, whereas another study reported an incidence of 10.2% with 1.0% CHG [12, 13]. Based on these findings, we hypothesized that the incidence of catheter colonization will be 40% lower with CHG (0.5% or 1.0%) than with 10% PVI. We assumed that the incidence of catheter colonization in the PVI group would be 25%. The sample-size estimation showed that 245 catheters are required in each of the three arms of this study to ensure 80% power and a two-sided α error of 5%.

The data is presented as the mean with standard deviation (SD) or median with interquartile range (IQR) for continuous variables and percentages for categorical variables. One-way analysis of variance (ANOVA) and the Kruskal–Wallis test or χ² test and Fisher’s exact test, as appropriate, were used for comparison. The incidence of catheter colonization and CRBSI were compared among the three groups using the log-rank test. Pairwise comparisons of the antiseptic solutions were conducted using a marginal Cox proportional hazards model with a closed testing procedure, and hazard ratios (HR) and 95% confidence intervals (CIs) were calculated. In the closed testing procedure, 0.5% CHG vs. 10% PVI was tested only if 1.0% CHG vs. 10% PVI was significant and 0.5% CHG vs. 1.0% CHG was tested if both were significant. For repeated catheter insertions in a single patient, the correlation between patient factors and catheter factors should be considered. Therefore, we applied a marginal Cox regression hazard model to compare the efficacy of the antiseptic solutions despite low proportion of repeated catheter insertions (13.4%) and a minimal intra-class correlation (r = 0.02) as shown in a previous study [5]. Subgroup analyses by catheter type (CVCs or ACs) and catheter duration (≥72 h or <72 h) were planned before commencement of the study and written in the protocol.

The primary population analyzed in this study is the full analysis set (FAS), while patients without catheter colonization data were excluded from the intention-to-treat (ITT) population (Fig. 1). The groups were compared for differences in catheter site and patient characteristics missing primary outcomes, to evaluate the degree of randomization. As a sensitivity analysis to evaluate the impact of the exclusion of patients with missing data in the primary FAS analysis, multiple imputation (MI) was performed for the imputed missing data [20]. Multiple imputation (MI) is a principled method if the mechanism of missing data is missing at random. The MI by chained equations, applicable for imputations of continuous and categorical variables with a non-monotone missing pattern, was used as an imputation algorithm. The number of imputations in MI was 100, and the number of burn-ins between each imputation was 200. The incomplete response variables were catheter colonization (binary) and the duration of catheterization (continuous; log transformed). The observed covariates in the imputation were the antiseptic solution (categorical) and type of catheter (binary). In MI by chained equations, each incomplete variable was sequentially imputed, given all other variables. Analysis was performed using PROC MI and PROC MIANALYZE in SAS (SAS Inc, Cary, NC, USA). Planned interim analysis was conducted to recalculate the sample size after registration of 50 catheters in each group. The significance level for all tests was two-sided at 5%. All statistical analyses were performed using SAS, version 9.4 (SAS Inc, Cary, NC, USA).