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Figure 1.
Recruitment, Randomization, and Patient Flow of Chlorhexidine Bathing Study
Recruitment, Randomization, and Patient Flow of Chlorhexidine Bathing Study

A total of 10 783 patients were admitted to the participating intensive care units (ICUs) during the study period. Each ICU was randomized to an initial bathing treatment for a 10-week period followed by a 2-week washout prior to crossover into the alternate bathing treatment. Each unit crossed between treatments 3 times during the study period. Therefore, each unit received 2 nonsequential 10-week periods of chlorhexidine bathing alternating with 2 nonsequential 10-week periods of control bathing. The 1443 patients admitted during washout periods were excluded from the analysis per protocol. The number of patients admitted to each ICU is shown.

Figure 2.
Effect of Chlorhexidine Bathing on Primary and Secondary Outcomes
Effect of Chlorhexidine Bathing on Primary and Secondary Outcomes

The chlorhexidine effect on intention-to-treat, as-treated, and adjusted analyses of the primary outcome of the composite rate of central line-associated bloodstream infection (CLABSI), catheter-associated urinary tract infection (CAUTI), probable and possible VAP (ventilator-associated pneumonia), and Clostridium difficile infection (CDI) are shown. Intention-to-treat analyses of secondary outcomes, which are components of the primary outcomes, are shown. HA-BSI indicates health care–associated bloodstream infection; MDRO, multidrug-resistant organisms. For crude data, see Table 2.

Figure 3.
Effect of Chlorhexidine Bathing on the Primary Outcome by Intensive Care Unit
Effect of Chlorhexidine Bathing on the Primary Outcome by Intensive Care Unit

The chlorhexidine effect on the primary outcome of the composite rate of central line–associated bloodstream infection, catheter-associated urinary tract infection, probable and possible ventilator-associated pneumonia, and Clostridium difficile infection in a prespecified subgroup of the intention-to-treat analysis by intensive care unit (ICU) is shown. The vertical line depicts a risk ratio of 1. For crude data, see Table 3 and Table 4.

Table 1.  
Baseline Demographics and Clinical Characteristics
Baseline Demographics and Clinical Characteristics
Table 2.  
Primary and Secondary Outcomes
Primary and Secondary Outcomes
Table 3.  
Primary and Secondary Outcomes for Cardiovascular and Medical Intensive Care Unitsa
Primary and Secondary Outcomes for Cardiovascular and Medical Intensive Care Unitsa
Table 4.  
Primary and Secondary Outcomes for Neurological, Surgical, and Trauma Intensive Care Unitsa
Primary and Secondary Outcomes for Neurological, Surgical, and Trauma Intensive Care Unitsa
1.
Kaye  KS, Marchaim  D, Chen  TY,  et al.  Effect of nosocomial bloodstream infections on mortality, length of stay, and hospital costs in older adults. J Am Geriatr Soc. 2014;62(2):306-311.
PubMedArticle
2.
Warren  DK, Quadir  WW, Hollenbeak  CS, Elward  AM, Cox  MJ, Fraser  VJ.  Attributable cost of catheter-associated bloodstream infections among intensive care patients in a nonteaching hospital. Crit Care Med. 2006;34(8):2084-2089.
PubMedArticle
3.
Roberts  RR, Scott  RD  II, Hota  B,  et al.  Costs attributable to healthcare-acquired infection in hospitalized adults and a comparison of economic methods. Med Care. 2010;48(11):1026-1035.
PubMedArticle
4.
Siegel  JD, Rhinehart  E, Jackson  M, Chiarello  L; Health Care Infection Control Practices Advisory Committee.  2007 Guideline for Isolation Precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control. 2007;35(10)(suppl 2):S65-S164.
PubMedArticle
5.
Boyce  JM, Pittet  D; Healthcare Infection Control Practices Advisory Committee. Society for Healthcare Epidemiology of America. Association for Professionals in Infection Control. Infectious Diseases Society of America. Hand Hygiene Task Force.  Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Infect Control Hosp Epidemiol. 2002;23(12)(suppl):S3-S40.
PubMedArticle
6.
O’Grady  NP, Alexander  M, Burns  LA,  et al; Healthcare Infection Control Practices Advisory Committee (HICPAC).  Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52(9):e162-e193.
PubMedArticle
7.
Karki  S, Cheng  AC.  Impact of non-rinse skin cleansing with chlorhexidine gluconate on prevention of healthcare-associated infections and colonization with multi-resistant organisms: a systematic review. J Hosp Infect. 2012;82(2):71-84.
PubMedArticle
8.
Climo  MW, Yokoe  DS, Warren  DK,  et al.  Effect of daily chlorhexidine bathing on hospital-acquired infection. N Engl J Med. 2013;368(6):533-542.
PubMedArticle
9.
Calfee  DP, Salgado  CD, Milstone  AM,  et al.  Strategies to prevent methicillin-resistant Staphylococcus aureus transmission and infection in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(7):772-796.
PubMedArticle
10.
Suwantarat  N, Carroll  KC, Tekle  T,  et al.  High prevalence of reduced chlorhexidine susceptibility in organisms causing central line-associated bloodstream infections. Infect Control Hosp Epidemiol. 2014;35(9):1183-1186.
PubMedArticle
11.
Wang  JT, Sheng  WH, Wang  JL,  et al.  Longitudinal analysis of chlorhexidine susceptibilities of nosocomial methicillin-resistant Staphylococcus aureus isolates at a teaching hospital in Taiwan. J Antimicrob Chemother. 2008;62(3):514-517.
PubMedArticle
12.
Centers for Disease Control and Prevention. CDC/NHSN surveillance definitions for specific types of infections; http://www.cdc.gov/nhsn. Accessed October 16, 2014.
13.
University HealthSystem Consortium. About UHC. http://www.uhc.edu/about. Accessed December 10, 2014.
14.
Huang  SS, Septimus  E, Kleinman  K,  et al; CDC Prevention Epicenters Program; AHRQ DECIDE Network and Healthcare-Associated Infections Program.  Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 2013;368(24):2255-2265.
PubMedArticle
15.
Rupp  ME, Cavalieri  RJ, Lyden  E,  et al.  Effect of hospital-wide chlorhexidine patient bathing on healthcare-associated infections. Infect Control Hosp Epidemiol. 2012;33(11):1094-1100.
PubMedArticle
16.
Climo  MW, Sepkowitz  KA, Zuccotti  G,  et al.  The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial. Crit Care Med. 2009;37(6):1858-1865.
PubMedArticle
17.
Kassakian  SZ, Mermel  LA, Jefferson  JA, Parenteau  SL, Machan  JT.  Impact of chlorhexidine bathing on hospital-acquired infections among general medical patients. Infect Control Hosp Epidemiol. 2011;32(3):238-243.
PubMedArticle
18.
Vernon  MO, Hayden  MK, Trick  WE, Hayes  RA, Blom  DW, Weinstein  RA; Chicago Antimicrobial Resistance Project (CARP).  Chlorhexidine gluconate to cleanse patients in a medical intensive care unit: the effectiveness of source control to reduce the bioburden of vancomycin-resistant enterococci. Arch Intern Med. 2006;166(3):306-312.
PubMedArticle
19.
Viray  MA, Morley  JC, Coopersmith  CM, Kollef  MH, Fraser  VJ, Warren  DK.  Daily bathing with chlorhexidine-based soap and the prevention of Staphylococcus aureus transmission and infection. Infect Control Hosp Epidemiol. 2014;35(3):243-250.
PubMedArticle
Original Investigation
Caring for the Critically Ill Patient
January 27, 2015

Chlorhexidine Bathing and Health Care–Associated InfectionsA Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine, Vanderbilt University, Nashville, Tennessee
  • 2Department of Biostatistics, Vanderbilt University, Nashville, Tennessee
JAMA. 2015;313(4):369-378. doi:10.1001/jama.2014.18400
Abstract

Importance  Daily bathing of critically ill patients with the broad-spectrum, topical antimicrobial agent chlorhexidine is widely performed and may reduce health care–associated infections.

Objective  To determine if daily bathing of critically ill patients with chlorhexidine decreases the incidence of health care–associated infections.

Design, Setting, and Participants  A pragmatic cluster randomized, crossover study of 9340 patients admitted to 5 adult intensive care units of a tertiary medical center in Nashville, Tennessee, from July 2012 through July 2013.

Interventions  Units performed once-daily bathing of all patients with disposable cloths impregnated with 2% chlorhexidine or nonantimicrobial cloths as a control. Bathing treatments were performed for a 10-week period followed by a 2-week washout period during which patients were bathed with nonantimicrobial disposable cloths, before crossover to the alternate bathing treatment for 10 weeks. Each unit crossed over between bathing assignments 3 times during the study.

Main Outcomes and Measures  The primary prespecified outcome was a composite of central line–associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), ventilator-associated pneumonia (VAP), and Clostridium difficile infections. Secondary outcomes included rates of clinical cultures that tested positive for multidrug-resistant organisms, blood culture contamination, health care–associated bloodstream infections, and rates of the primary outcome by ICU.

Results  During the chlorhexidine bathing period, 55 infections occurred: 4 CLABSI, 21 CAUTI, 17 VAP, and 13 C difficile. During the control bathing period, 60 infections occurred: 4 CLABSI, 32 CAUTI, 8 VAP, and 16 C difficile. The primary outcome rate was 2.86 per 1000 patient-days during the chlorhexidine and 2.90 per 1000 patient-days during the control bathing periods (rate difference, −0.04; 95% CI, −1.10 to 1.01; P = .95). After adjusting for baseline variables, no difference between groups in the rate of the primary outcome was detected. Chlorhexidine bathing did not change rates of infection-related secondary outcomes including hospital-acquired bloodstream infections, blood culture contamination, or clinical cultures yielding multidrug-resistant organisms. In a prespecified subgroup analysis, no difference in the primary outcome was detected in any individual intensive care unit.

Conclusion and Relevance  In this pragmatic trial, daily bathing with chlorhexidine did not reduce the incidence of health care–associated infections including CLABSIs, CAUTIs, VAP, or C difficile. These findings do not support daily bathing of critically ill patients with chlorhexidine.

Trial Registration  clinicaltrials.gov Identifier: NCT02033187

Introduction

Infections acquired during hospitalization (health care–associated infections) are associated with increased hospital length of stay, rates of death, and increased costs.13 Substantial effort is devoted to preventing infections through practices designed to reduce the transmission of nosocomial pathogens, such as hand hygiene, bundles for insertion and care of devices, and isolation of patients with multidrug-resistant organisms.4,5

The skin of hospitalized patients is a reservoir for pathogens. Invasion by skin flora is thought to be a mechanism contributing to health care–associated infections.6 Chlorhexidine is a broad-spectrum topical antimicrobial agent that, when used to bathe the skin, may decrease the bacterial burden thereby reducing infections. Several observational and quasi-experimental studies have found that daily bathing with chlorhexidine results in decreased skin colonization with multi-drug resistant organisms, decreased rates of bloodstream infections, and reduced Clostridium difficile infections.7 A recent multicenter cluster-randomized trial demonstrated that bathing patients with chlorhexidine reduced multidrug-resistant organism acquisition and hospital-acquired bloodstream infections,8 and chlorhexidine bathing is incorporated into some expert guidelines.9 These results, however, have not been replicated and the effect of chlorhexidine bathing on other infections is unclear. Furthermore, chlorhexidine increases costs. Unnecessary exposure may result in the development of chlorhexidine resistance.10,11 Therefore, we conducted a cluster-randomized trial to evaluate the effect of chlorhexidine bathing on the rates of multiple health care-associated infections among critically ill adults.

Methods
Study Design

We performed a pragmatic cluster randomized, crossover, controlled study involving patients admitted to 5 adult intensive care units (ICUs) at a tertiary care medical center between July 2012 and July 2013. The neurological unit had 34, the surgical unit 34, and the trauma unit 31 ICU and step-down beds. The cardiovascular unit had 27 and the medical unit had 34 ICU beds. Each unit is staffed by critical care nurses and nurse practitioners with 24-hour physician coverage. Units performed once-daily bathing of all patients with cloths impregnated with 2% chlorhexidine (2% Chlorhexidine Gluconate Cloths, Sage Products) or with disposable nonantimicrobial cloths (Comfort Bath, Sage Products) as a control. Due to differences in the scent and appearance of the cloths, blinding of patients, treating physicians, nurses, and unit staff was not possible. Infection control personnel responsible for adjudicating infection outcomes according to standardized definitions were blinded to the treatment assignments. Each unit was randomized to a bathing sequence by generating 5 numbers from 1 to 2 at random using software available at http://www.randomizer.org. Each number in the sequence corresponded to 1 of the 5 ICUs. Those assigned a 1 began with chlorhexidine bathing and those assigned a 2 began with control bathing. Bathing assignment alternated thereafter. Bathing treatments were performed for a 10-week period followed by a 2-week washout period during which patients were bathed with nonantimicrobial disposable cloths, before crossover to the alternate bathing treatment for 10 weeks. Each unit crossed over between bathing assignments 3 times during the study (Figure 1).

Bathing was performed once daily according to the manufacturer’s instructions with sequential cloths used to rinse all body surfaces. Patients who became soiled after the initial daily bath were allowed to be bathed a second time in that day with bathing cloths maintaining the randomization. The face was not bathed to avoid exposure of the mucous membranes to chlorhexidine. The cardiovascular ICU used chlorhexidine cloths for a single, preoperative bathing of patients undergoing cardiac surgery regardless of the unit treatment assignment at the time. However, routine daily bathing of patients was performed according to the study bathing assignment. All other units were supplied only with the assigned cloths and the alternate cloths were not available during each bathing period. Prior to the study, 2 units were using daily chlorhexidine bathing in routine care and 3 were not. Before the study began, nurses on each unit were instructed to use only the available cloths and were reminded of proper bathing technique. All other infection control and cleaning procedures, including the use of contact precautions for patients colonized or infected with multidrug-resistant organisms, were performed according to the usual practice of each unit throughout the study period. Active surveillance for multidrug-resistant organism colonization was not done.

All patients admitted to the cardiovascular, medical, neurological, surgical, and trauma ICUs during the study period were included. Patients were excluded if they were known to have an allergy to chlorhexidine, were admitted with burns or toxic epidermal necrolysis or Stevens-Johnson syndrome, or the treating physician thought bathing would be unsafe. Patients admitted during a washout period were excluded from the primary analysis.

The study was approved by the Vanderbilt University Institutional Review Board with waiver of consent.

This study was conceived as an institutional quality improvement project and underwent institutional review board review as is our practice, with approval of the study design, end points, and analysis plan on May 7, 2012 (study protocol is available in Supplement 1). Patient enrollment began July 19, 2013. After patient enrollment was completed, the researchers realized the novel design and size of this study might be of interest to others and registered the study at clinicaltrials.gov on January 8, 2014; this occurred before any data analyses were conducted. The study end points are concordant with the protocol approved by the institutional review board, a detailed statistical analysis plan dated November 26, 2013, those specified in the trial registration, and the results reported in this article. Health care–associated bloodstream infections were added as a secondary end point because these data became available electronically during the course of the study. The complete data set was available to investigators for analysis on February 4, 2014. No data analyses were conducted during the study or prior to trial registration.

Study Outcomes and Definitions

Because individual health care–associated infections are rare events, the analysis plan specified a composite primary outcome including central line–associated bloodstream infection (CLABSI), catheter-associated urinary tract infection (CAUTI), possible or probable ventilator-associated pneumonia (VAP), or C difficile infection. Infections were determined using Centers for Disease Control and Prevention National Healthcare Safety Network definitions by trained infection control personnel, who were blinded to the bathing assignment.12 Secondary outcomes included the rates of each individual infection included in the primary outcome, in-hospital mortality, hospital and ICU length of stay, rates of clinical cultures positive for multidrug-resistant organisms (number of positive cultures per 1000 patient-days), blood culture contamination (number of contaminants per 1000 patient-days), health care–associated bloodstream infections, and rates of the primary outcome by ICU. Additional definitions of infection-related outcomes are available in the online eAppendix in Supplement 2.

Statistical Analysis

The study was conducted over 1 year. The approximately 10 000 patients expected to be admitted to the participating ICUs based on the previous year’s admissions would provide at least 95% power to detect a change in the primary outcome of 0.1 infections per 1000 patient-days. Using an intention-to-treat-design, each patient was analyzed according to the bathing assignment of the unit at the time of admission regardless of length of stay or the number of days he/she was bathed. Patients whose hospital stay bridged a crossover event, and therefore changed bathing treatment, were analyzed according to their initial bathing assignment. The primary analysis was a comparison of the infection rate (number of infections per 1000 patient-days) between groups using a Poisson regression model. All events meeting an outcome definition were included. Therefore, repeated infections from an individual patient were included as events in the analysis. Several patients contributed to multiple events: 5 to the primary outcome, 24 with clinical cultures that tested positive for multidrug-resistant organisms, 23 for health care–associated bloodstream infections, and 34 for blood culture contamination.

Prespecified secondary analyses included tests for a chlorhexidine effect for each individual infection comprising the primary outcome, differences in hospital and ICU length of stay as well as rates of health care–associated bloodstream infections, blood culture contamination, and cultures positive for multidrug-resistant organisms using a Mann-Whitney U test or Poisson model where appropriate. Adjusted estimates of chlorhexidine effect were obtained using a logistic and Poisson model. Covariates included age, sex, race (white, nonwhite, or unknown), admission ICU, study time, University HealthSystem Consortium–expected mortality,13 comorbid conditions, and admission white blood cell count, along with bathing assignment. Race was collected from an administrative database based on patient self-reporting. Effectiveness of chlorhexidine was also assessed by comparing the primary outcome occurrence rate within each ICU using Poisson regression. Sensitivity analyses were performed including an analysis in which patients receiving both bathing treatments were excluded, an as-treated analysis to account for a study protocol violation, and a group-level analysis performed on the unit clusters as opposed to analyses of individual patients. A logistic regression model with the same covariates and primary predictors of treatment assignment described above including an interaction term for treatment assignment and infection status was used to estimate the effect of chlorhexidine on the outcome of in-hospital mortality as well as its interaction with our primary outcome. All tests were 2-tailed with a significance threshold of P < .05. The statistical analysis was performed with R (version 2.10.1, http://www.r-project.org, the R Foundation for Statistical Computing) and IBM SPSS Statistics (version 22).

Results
Enrollment and Patient Characteristics

A total of 10 783 patients were admitted to the 5 participating ICUs during the study period (Figure 1). None met exclusion criteria. The 1443 patients admitted during washout periods were excluded from the analysis per protocol. Therefore, 9340 patients were included in the primary analysis with 4488 patients in the chlorhexidine bathing periods and 4852 patients in the control bathing periods. Baseline patient characteristics were balanced between the control and intervention periods with regard to age, sex, race/ethnicity, comorbid conditions, and baseline laboratory data (Table 1).

Primary Outcome

A total of 55 infections occurred during the chlorhexidine bathing period (4 CLABSI, 21 CAUTI, 17 VAP, and 13 C difficile) and 60 infections during the control bathing periods (4 CLABSI, 32 CAUTI, 8 VAP, and 16 C difficile infections). The rate of the primary outcome was 2.86 per 1000 patient-days during chlorhexidine bathing and 2.90 per 1000 patient-days during control bathing (rate difference, −0.04; 95% CI, −1.10 to 1.01; P = .95). After adjusting for age, sex, race/ethnicity, unit of admission, time, comorbid conditions, and admission white blood cell count, no significant difference between groups in the rate of the primary outcome was detected (adjusted risk ratio in treatment group, 0.94; 95% CI, 0.65 to 1.37; P = .83) (Table 2, Figure 2). Five patients who developed more than 1 infection were included in the primary outcome during the study (3 during chlorhexidine and 2 during control bathing).

Secondary Outcomes

No significant difference in the rate of health care–associated bloodstream infections was seen between the chlorhexidine and control periods (5.00 and 5.45, respectively; rate difference, −0.45; 95% CI, −1.87 to 0.97; P = .53; Table 2, Figure 2). In addition, no significant differences in the rates of blood culture contamination (4.84 per 1000 patient-days and 5.45 per 1000 patient-days; rate difference, −0.61; 95% CI, −2.02 to 0.80; P = .40) or clinical cultures positive for multidrug-resistant organisms (4.84 and 5.41 per 1000 patient-days; rate difference, −0.57; 95% CI, −1.97 to 0.83; P = .43) were found between the chlorhexidine and control periods (Table 2 and eTable 3 in Supplement 2, Figure 2). When analyzed independently, the individual infections comprising the primary outcome were not significantly different between intervention and control bathing periods and no difference in ICU or hospital length of stay was observed (Table 2). In-hospital mortality was 8.18% in the chlorhexidine bathing periods and 9.25% in the control periods (difference in percent, −1.07%; 95% CI, −2.22% to 0.07%; P = .07).

In a prespecified subgroup analysis by ICU, no difference in the rate of the primary outcome was detected in any individual ICU in the chlorhexidine bathing and control periods (Table 3 and Table 4 and Figure 3). A significant reduction in blood culture contamination (2.37 and 8.25 per 1000 patient-days during chlorhexidine and control periods, respectively; rate difference, −5.88; 95% CI, −9.41 to −2.35; P = .003) was detected in the cardiovascular ICU during periods of chlorhexidine bathing without a significant reduction in health care–associated bloodstream infections (2.71 and 4.42 per 1000 patient-days during chlorhexidine and control periods, respectively; rate difference, −1.71; 95% CI, −4.63 to 1.21; P = .26). The rates of health care–associated bloodstream infections, blood culture contamination, or clinical cultures positive for multidrug-resistant organisms did not differ between intervention and control periods in any other unit. Although infection-related outcomes did not differ, the trauma ICU had a significant reduction in in-hospital mortality during periods of chlorhexidine bathing (6.17% vs 8.58%; difference in percent, −2.41%; 95% CI, −4.64% to −0.19%; P = .03). After adjusting for the University HealthSystem Consortium–expected mortality rate, the adjusted odds ratio was 0.85 (95% CI, 0.51-1.39; P = .51).

Three post hoc analyses were performed: (1) an as-treated analysis to address a protocol violation in the cardiovascular ICU where 235 patients bathed with the incorrect cloths were analyzed according to the bathing treatment they received rather than the bathing treatment they were assigned (Table 2), (2) an analysis in which the 658 patients whose hospital stay spanned a crossover event were excluded and therefore received both bathing treatments (eTable 1 in Supplement 2), and (3) a group-level analysis performed on the unit clusters as opposed to the analyses of individual patients (eTable 2 in Supplement 2). In each of these analyses, no difference between groups was detected for the primary outcome, health care–associated bloodstream infections, blood culture contamination, or clinical cultures testing positive for multidrug-resistant organisms. When the infections comprising the primary outcome were analyzed individually, a statistically significant increase in possible or probable VAP was detected during periods of chlorhexidine bathing in all post hoc analyses (as-treated: 0.37 and 0.92 per 1000 patient-days in chlorhexidine and control bathing periods, respectively, rate difference, 0.55; 95% CI, 0.05-1.05; P = .04; analysis excluding patients who received both bathing treatments: 0.24 and 0.84 per 1000 patient-days in chlorhexidine and control bathing periods, respectively, rate difference, 0.6; 95% CI, 0.09-1.11; P = .03; and group-level analysis performed on the unit clusters: 0.41 and 0.95 per 1000-patient days in chlorhexidine and control bathing periods, respectively, rate difference, 0.54; 95% CI, 0.02-1.06; P = .047; Table 2 and eTables 1 and 2 in Supplement 2).

A nonsignificant reduction in-hospital mortality was present during chlorhexidine bathing periods in the primary intention-to-treat analysis (9.25% vs 8.18% during control and chlorhexidine bathing periods, respectively, rate difference, −1.07; 95% CI, −2.2 to 0.07; P = .07). In-hospital mortality was significantly reduced during chlorhexidine bathing periods in 2 post hoc analyses (as-treated analysis, 8.14% and 9.31% in chlorhexidine and control periods, respectively, rate difference, −1.17; 95% CI −2.3 to −0.03; P = .046; analysis excluding patients who received both bathing treatments, 7.99% and 9.24% in the chlorhexidine and control periods, respectively, 95% CI, −1.25; −.02 to .001; P = .04, Table 2 and eTable 1 in Supplement 2). This reduction in in-hospital mortality was not present after adjusting for baseline variables (as-treated analysis adjusted P = .051, analysis excluding patients who received both bathing treatments adjusted P = .31; eTables 4, 5, and 6 in Supplement 2).

Discussion

In this single-center, multi-ICU, cluster randomized, crossover study, once daily bathing with chlorhexidine did not reduce the rate of the composite primary outcome of infections including CLABSI, CAUTI, possible or probable VAP, or infection with C difficile. Other infection-related secondary outcomes, including health care-associated bloodstream infections, blood culture contamination, and clinical cultures positive for multi-drug resistant organisms were also not improved by chlorhexidine. Chlorhexidine bathing is widely practiced in an effort to reduce health care–associated infections and has been incorporated into some expert guidelines.9 Yet chlorhexidine use incurs a cost and exposure to chlorhexidine may increase microbial resistance.10,11 Therefore, the finding that chlorhexidine bathing did not reduce infections in this study suggests that such bathing may not be necessary, resulting in cost saving and avoidance of unnecessary exposure without adversely affecting clinical outcome.

In contrast to the findings of the current study, Climo et al8 performed a multicenter, cluster randomized, crossover trial of daily chlorhexidine bathing of 7727 patients admitted to 9 ICUs or bone marrow units and reported a significant reduction in methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) acquisition, health care–associated bloodstream infections, and CLABSI with chlorhexidine bathing. These studies differ in several ways. The duration of the chlorhexidine bathing intervention in the Climo study was 24 weeks compared with 10 weeks in the current study. It is possible that a longer intervention may have ecological consequences that reduce infectious outcomes. Climo et al performed active surveillance for MRSA and VRE colonization, and included bone marrow transplant units, neither of which were done in this study. Because bone marrow transplant places patients at high risk of infection, this may have altered outcomes. In addition, some of the infection rates were low in this study, and a lower limit to the rates of infection may exist beyond which chlorhexidine bathing no longer provides detectable benefit. The reduction in health care–associated bloodstream infections in the Climo study was driven primarily by a reduction in positive blood culture results caused by the skin commensal coagulase-negative staphylococci, and it is not clear if this observation was a result of blood culture contamination or true infection. Another recent study included chlorhexidine bathing as one of many interventions shown to reduce MRSA clinical isolates in a large cluster randomized trial of targeted vs universal decolonization of ICU patients.14 The individual benefit from chlorhexidine bathing cannot be ascertained from this study, however.

In post hoc unadjusted analyses, in-hospital mortality was significantly reduced during periods of chlorhexidine bathing but not after adjustment for baseline variables (Table 2 and eTable 1 in Supplement 2). This finding also does not account for multiple comparisons. Furthermore, this in-hospital mortality difference is partially explained by differences in the University HealthSystem Consortium–expected mortality, which differ between bathing periods. Although it is possible that chlorhexidine bathing reduced the incidence of unmeasured infections, such as viral or surgical site infections, no clear mechanism for improved survival from chlorhexidine bathing exists in the absence of reduced infections.

This study has several strengths. The multiple crossover events allowed for assessment of 2 temporally separated intervention and control periods within each unit, which better accounts for intercluster variability while also controlling for seasonal variation in outcomes. The individual infections included in the primary outcome are rare events and a composite primary outcome was chosen to maximize the chance of detecting a difference between groups. Additionally, this study focused on patient-centered outcomes and tested the effect of chlorhexidine bathing on several infections other than bloodstream infection, CLABSI, and clinical cultures that tested positive for multidrug-resistant organisms, including C difficile infection, which has been impacted by chlorhexidine in a previous quasi-experimental study.15 The limitations to this study include the inability to blind staff administering baths to the treatment group; however, personnel responsible for adjudicating infections were blinded to the treatment. Additionally, this is a single-center study that included multiple ICUs encompassing a diverse patient population and a large sample size. Of the infections included in the Medicare Hospital Compare website (http://www.medicare.gov/hospitalcompare), Vanderbilt University Medical Center is similar to national benchmarks, suggesting these findings are generalizable to other medical centers. This trial was designed as an effectiveness rather than an efficacy trial whereby the interventions were performed as a component of routine patient care rather than by dedicated study personnel. Therefore, bathing adherence was not assessed, and it is unclear if this may have affected outcomes. Active surveillance for multidrug-resistant organism acquisition is not routinely performed in our ICUs and was not a component of this study but has been included as an outcome in previous studies.8,1519

Conclusions

In this pragmatic trial, daily bathing with chlorhexidine did not reduce the incidence of health care–associated infections including CLABSI, CAUTI, VAP, or C difficile. These findings do not support daily bathing of critically ill patients with chlorhexidine.

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Article Information
Section Editor: Derek C. Angus, MD, MPH, Associate Editor, JAMA (angusdc@upmc.edu).

Corresponding Author: Michael J. Noto, MD, PhD, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Ave S, T-1223, MCN, Nashville, TN 37232-2650 (michael.j.noto@vanderbilt.edu).

Published Online: January 20, 2015. doi:10.1001/jama.2014.18400.

Author Contributions: Dr Noto and Mr Domenico had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Noto, Domenico, Rice, Bernard, Wheeler.

Acquisition, analysis, or interpretation of data: Noto, Domenico, Byrne, Talbot, Rice, Wheeler.

Drafting of the manuscript: Noto, Domenico, Byrne, Rice.

Critical revision of the manuscript for important intellectual content: Noto, Domenico, Byrne, Talbot, Rice, Bernard, Wheeler.

Statistical analysis: Domenico, Byrne, Rice.

Obtained funding: Noto.

Administrative, technical, or material support: Noto, Rice, Wheeler.

Study supervision: Byrne, Rice, Bernard, Wheeler.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Talbot reported that his spouse has received research funding from SanofiPasteur, Gilead, and MedImmune and serves on the advisory board for Teva Pharmaceuticals. No other disclosures were reported.

Funding/Support: Research reported in this publication was supported by grants UL1 TR000445 and 2T32HL087738-06 from the National Institutes of Health and through the Vanderbilt Institute for Clinical and Translational Research. The chlorhexidine impregnated and nonantimicrobial cloths were purchased from Sage Products.

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Sage Products had no input into study design, implementation, or data analysis.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: We thank the following persons at Vanderbilt University for their assistance, none of whom received compensation for their role in this study: Amber Goldston, BS; JeNelle Rivers, Addison May, MD; Chad Wagner, MD; Joseph Fredi, MD; John Barwise, MB, ChB; Oscar Guillamondegui, MD; Marcella Woods, PhD; Lixin Chen, MS; Li Wang, MS; John Newman, MD, and C. Buddy Creech, MD, as well as the Vanderbilt University Department of Infection Prevention.

References
1.
Kaye  KS, Marchaim  D, Chen  TY,  et al.  Effect of nosocomial bloodstream infections on mortality, length of stay, and hospital costs in older adults. J Am Geriatr Soc. 2014;62(2):306-311.
PubMedArticle
2.
Warren  DK, Quadir  WW, Hollenbeak  CS, Elward  AM, Cox  MJ, Fraser  VJ.  Attributable cost of catheter-associated bloodstream infections among intensive care patients in a nonteaching hospital. Crit Care Med. 2006;34(8):2084-2089.
PubMedArticle
3.
Roberts  RR, Scott  RD  II, Hota  B,  et al.  Costs attributable to healthcare-acquired infection in hospitalized adults and a comparison of economic methods. Med Care. 2010;48(11):1026-1035.
PubMedArticle
4.
Siegel  JD, Rhinehart  E, Jackson  M, Chiarello  L; Health Care Infection Control Practices Advisory Committee.  2007 Guideline for Isolation Precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control. 2007;35(10)(suppl 2):S65-S164.
PubMedArticle
5.
Boyce  JM, Pittet  D; Healthcare Infection Control Practices Advisory Committee. Society for Healthcare Epidemiology of America. Association for Professionals in Infection Control. Infectious Diseases Society of America. Hand Hygiene Task Force.  Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Infect Control Hosp Epidemiol. 2002;23(12)(suppl):S3-S40.
PubMedArticle
6.
O’Grady  NP, Alexander  M, Burns  LA,  et al; Healthcare Infection Control Practices Advisory Committee (HICPAC).  Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52(9):e162-e193.
PubMedArticle
7.
Karki  S, Cheng  AC.  Impact of non-rinse skin cleansing with chlorhexidine gluconate on prevention of healthcare-associated infections and colonization with multi-resistant organisms: a systematic review. J Hosp Infect. 2012;82(2):71-84.
PubMedArticle
8.
Climo  MW, Yokoe  DS, Warren  DK,  et al.  Effect of daily chlorhexidine bathing on hospital-acquired infection. N Engl J Med. 2013;368(6):533-542.
PubMedArticle
9.
Calfee  DP, Salgado  CD, Milstone  AM,  et al.  Strategies to prevent methicillin-resistant Staphylococcus aureus transmission and infection in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(7):772-796.
PubMedArticle
10.
Suwantarat  N, Carroll  KC, Tekle  T,  et al.  High prevalence of reduced chlorhexidine susceptibility in organisms causing central line-associated bloodstream infections. Infect Control Hosp Epidemiol. 2014;35(9):1183-1186.
PubMedArticle
11.
Wang  JT, Sheng  WH, Wang  JL,  et al.  Longitudinal analysis of chlorhexidine susceptibilities of nosocomial methicillin-resistant Staphylococcus aureus isolates at a teaching hospital in Taiwan. J Antimicrob Chemother. 2008;62(3):514-517.
PubMedArticle
12.
Centers for Disease Control and Prevention. CDC/NHSN surveillance definitions for specific types of infections; http://www.cdc.gov/nhsn. Accessed October 16, 2014.
13.
University HealthSystem Consortium. About UHC. http://www.uhc.edu/about. Accessed December 10, 2014.
14.
Huang  SS, Septimus  E, Kleinman  K,  et al; CDC Prevention Epicenters Program; AHRQ DECIDE Network and Healthcare-Associated Infections Program.  Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 2013;368(24):2255-2265.
PubMedArticle
15.
Rupp  ME, Cavalieri  RJ, Lyden  E,  et al.  Effect of hospital-wide chlorhexidine patient bathing on healthcare-associated infections. Infect Control Hosp Epidemiol. 2012;33(11):1094-1100.
PubMedArticle
16.
Climo  MW, Sepkowitz  KA, Zuccotti  G,  et al.  The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial. Crit Care Med. 2009;37(6):1858-1865.
PubMedArticle
17.
Kassakian  SZ, Mermel  LA, Jefferson  JA, Parenteau  SL, Machan  JT.  Impact of chlorhexidine bathing on hospital-acquired infections among general medical patients. Infect Control Hosp Epidemiol. 2011;32(3):238-243.
PubMedArticle
18.
Vernon  MO, Hayden  MK, Trick  WE, Hayes  RA, Blom  DW, Weinstein  RA; Chicago Antimicrobial Resistance Project (CARP).  Chlorhexidine gluconate to cleanse patients in a medical intensive care unit: the effectiveness of source control to reduce the bioburden of vancomycin-resistant enterococci. Arch Intern Med. 2006;166(3):306-312.
PubMedArticle
19.
Viray  MA, Morley  JC, Coopersmith  CM, Kollef  MH, Fraser  VJ, Warren  DK.  Daily bathing with chlorhexidine-based soap and the prevention of Staphylococcus aureus transmission and infection. Infect Control Hosp Epidemiol. 2014;35(3):243-250.
PubMedArticle
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