PEDIATRICS Vol. 107 No. 6 June 2001, pp. 1431-1436

EXPERIENCE AND REASON:
A Randomized Trial Comparing Povidone-Iodine to a Chlorhexidine Gluconate-Impregnated Dressing for Prevention of Central Venous Catheter Infections in Neonates

	ABSTRACT

Top Abstract Introduction Methods Results Discussion Conclusion References

Neonates who require a central venous catheter (CVC) for prolonged vascular access experience high rates of catheter-related bloodstream infection (CRBSI).

Purpose.  A multicenter randomized clinical trial was undertaken to ascertain the efficacy of a novel chlorhexidine-impregnated dressing (Biopatch Antimicrobial Dressing) on the CVC sites of neonates for the prevention of catheter tip colonization, CRBSI, and bloodstream infection (BSI) without a source.

Setting.  Six level III neonatal intensive care units.

Patients Studied.  Neonates admitted to study units who would require a CVC for at least 48 hours.

Methods.  Eligible infants were randomized before catheter placement to 1 of the 2 catheter site antisepsis regimens: 1) 10% povidone-iodine (PI) skin scrub, or 2) a 70% alcohol scrub followed by placement of a chlorhexidine-impregnated disk over the catheter insertion site. A transparent polyurethane dressing (Bioclusive Transparent Dressing) was used to cover the insertion site in both study groups. Primary study outcomes evaluated were catheter tip colonization, CRBSI, and BSI without an identified source.

Results.  Seven hundred five neonates were enrolled in the trial, 335 randomized to receive the chlorhexidine dressing and 370 to skin disinfection with PI (controls). Neonates randomized to the antimicrobial dressing group were less likely to have colonized CVC tips than control neonates (15.0% vs 24.0%, relative risk [RR]: 0.6 95% confidence interval [CI]: 0.5-0.9). Rates of CRBSI (3.8% vs 3.2%, RR: 1.2, CI: 0.5-2.7) and BSI without a source (15.2% vs 14.3%, RR: 1.1, CI: 0.8-1.5) did not differ between the 2 groups. Localized contact dermatitis from the antimicrobial dressing, requiring crossover into the PI treatment group, occurred in 15 (15.3%) of 98 exposed neonates weighing 1000 g. No neonates in the PI group developed contact dermatitis.

Conclusion.  The novel chlorhexidine-impregnated dressing, replaced weekly, was as effective as cutaneous disinfection with 10% PI and redressing the site every 3 to 7 days for preventing CRBSI and BSI without a source in critically ill neonates requiring prolonged central venous access. The risk of local contact dermatitis under the chlorhexidine dressing limits its use in low birth weight infants who require prolonged central access during the first 2 weeks of life.

Critically ill neonates have a high incidence of nosocomial bloodstream infection (BSI), which most often derives from central venous cathethers (CVCs) needed for prolonged central access.^1-7 CVC-related BSIs increase exposure of neonates to potentially toxic antibiotics and greatly increase length of stay and hospital costs.^8,9 Many of these infections derive from invasion of the transcutaneous catheter tract by microorganisms from the cutaneous flora, particularly during the first 2 weeks of catheterization.^10-15 Suppressing catheter site colonization with local antisepsis is an effective means of reducing the risk of catheter-related bloodstream infection (CRBSI).^16,17

Although 10% povidone-iodine (PI) is widely used for skin antisepsis before placement of CVCs in neonates, systemic absorption of iodine by premature neonates after iodophor scrubs with development of laboratory findings of hypothyroidism, has been reported.^18-20 Recent trials in adults suggest that chlorhexidine gluconate is a more effective cutaneous antiseptic than PI for the prevention of CVC-related BSI in adults^16,17 and peripheral intravenous catheter tip colonization in neonates.²¹ We report the results of a multicenter prospective, randomized trial undertaken to ascertain the efficacy of a novel chlorhexidine-impregnated dressing for the prevention of catheter colonization and CRBSI in critically ill neonates.

	METHODS

Top Abstract Introduction Methods Results Discussion Conclusion References

Subjects

This study was conducted in 6 level III neonatal intensive care units, 4 in university teaching hospitals (Children's Hospital of Wisconsin, Children's Hospital of Philadelphia, Boston Children's Hospital, and University of Massachusetts Memorial Medical Center) and in 2 community hospitals (St Joseph's Hospital and Sinai-Samaritan Medical Center). The study protocol was approved by the investigational review board at each site and informed consent was obtained from the parents of each participating neonate. Study units ranged from 16 to 50 beds. Neonates admitted to units who would likely require a CVC for at least 48 hours were eligible for the study.

Treatment

After obtaining parental consent, neonates were block randomized to 1 of 2 treatment groups. Computer-generated randomization codes developed by the study statistician were maintained by center pharmacists. Neonates randomized to the control skin care regimen had the catheter insertion site cleansed for at least 30 seconds with PI (Purdue Frederick, Norwalk, CT); after the PI was allowed to dry, the CVC was inserted and then dressed with a polyurethane dressing (Bioclusive Transparent Dressing, Johnson and Johnson Medical, Division of Ethicon, Inc, Arlington, TX). Neonates randomized to the novel chlorhexidine dressing (Biopatch Antimicrobial Dressing, Johnson and Johnson Medical) had the insertion site cleansed for at least 30 seconds with 70% isopropyl alcohol; after the alcohol dried, the catheter was inserted, and the insertion site was covered with the chlorhexidine dressing (1.9-cm diameter for infants 1500 g, 2.5 cm for infants >1500 g). The site was then dressed with the same type of polyurethane dressing used in the control group.

The chlorhexidine antiseptic dressing used in the trial is a hydrophilic polyurethane absorptive foam impregnated with 250 µg/mg of chlorhexidine gluconate. Chlorhexidine gluconate is released continuously onto the underlying skin surface over a 10-day period,²² with the greatest concentrations released onto the skin during the first 3 days. At steady-state release, approximating zero-order kinetics, occurs from day 4 through day 10.

At 5 centers, percutaneously placed CVCs were placed by neonatologists or nurse practitioners. A dedicated group of staff nurses inserted catheters at the sixth center. Broviac (Evermed, Inc, Cranston, RI) catheters were used when surgically placed CVCs were required. All catheters were placed by personnel wearing a mask, hat, sterile gloves, and gown. Sterile drapes were used to protect the field during catheter insertion.

Percutaneously placed CVC dressings were changed every 7 days. Surgically placed Broviac catheter dressings were changed every 7 days in the chlorhexidine dressing group and twice weekly in the control group. At each dressing change in both treatment groups, the site was recleansed using the same antiseptic used at catheter placement. A new chlorhexidine-impregnated dressing was placed at the time of dressing changes in the antiseptic dressing group. Decisions to remove catheters were made independently by primary nurses and attending physicians. Blood cultures were obtained in neonates with signs of sepsis. Blood cultures were obtained at the discretion of the attending neonatologist.

Culture Techniques

At the time the catheter was removed, a 1 × 1-cm area of skin surrounding the catheter was swabbed with a sterile cotton swab saturated with Stuart's media (Becton Dickinson Microbiology Systems, Sparks, MD). The skin swab was cultured semiquantitatively.²³ Heavy skin colonization was defined as 50 colony-forming units (CFUs).²¹ CVCs were removed aseptically and the last 5 cm of the catheter tip was cultured using the semiquantitative method of Maki et al.²⁴ Catheter hubs were also cultured quantitatively.²⁵ Skin and hub cultures were performed to help determine route of CRBSI or BSI. Specimens not immediately cultured were refrigerated at 4°C. All cultures were inoculated within 8 hours of catheter removal. Standard laboratory methods were used to identify microorganisms colonizing the skin, hub, and CVC tips.²⁶ Species of coagulase-negative Staphylococcus (CNS) grown from the blood, skin, catheter tip, and catheter hub of patients with CRBSI were identified using standard laboratory biochemical analyses and antibiotic susceptibility profiles.²⁷ In addition, restriction-fragment subtyping^28,29 of isolates of CNS was performed to confirm concordance between strains of CNS grown from the blood cultures and catheter tips or hubs in neonates with CNS BSIs.

Primary Outcomes

Catheter tip colonization was defined by a semiquantitative catheter colony count 15 CFUs.²⁴ Catheter colonization was considered a primary outcome because of its strong association with CRBSI and BSI without a source.^24,30,31

BSI without a source was defined as: a positive blood culture during the time the catheter was in situ or within 24 hours of removal; clinical signs or symptoms of a BSI within 6 hours of the positive culture; antibiotic therapy for 7 days, and no other documented primary site of infection; catheter tip and hub cultures were either not colonized or colonized with organisms different from those grown from the blood.

Signs and symptoms of BSI, defined before initiation of the trial included: an increase or decrease in the white blood cell count by 3 × 10³ per mm² or 0.15 immature neutrophils ratio on a complete blood count, new-onset apnea, glucose intolerance or hypoglycemia, metabolic acidosis, tachycardia or hypotension, mottled or ashen appearance with a normal hematocrit, new onset of feeding intolerance, lethargy, or fever. A BSI without a source was considered a primary outcome because CVCs are often left in place if the episode of BSI can be cleared with antibiotic therapy given through the CVC and, thus, concomitant catheter tip and catheter hub cultures cannot be obtained.

CRBSI was defined as a clinically relevant BSI without an identifiable primary source other than a CVC colonized by the same strain grown from blood cultures. Hub cultures, if obtained, were negative for the organism grown from the blood.

Data Collection and Analysis

Data were extracted prospectively from maternal and neonatal charts of neonates enrolled in the study by a study nurse at each study center and sent to the primary center (St Joseph's Hospital, Milwaukee, WI). Data collectors at each center were trained by the principal investigator (J.S.G.) before initiation of the trial. Data obtained on each patient included maternal and neonatal demographics, 24-hour and 7-day Score for Neonatal Acute Physiology scores,³² day of life of catheterization, catheter type, medications, invasive therapies, other sites of infection while the catheter was in situ, anatomic location of the catheter, number of attempts to insert the catheter, person placing the catheter, and laboratory and clinical findings used to assess infection.

A primary study nurse (C.P.A.) communicated monthly with each center to deal with study questions, ensure study compliance, and timely data collection. After study center data collection sheets were checked for potential errors and missing items by the primary study nurse, data were double entered into a data set for analysis using Statistical Analysis System 6.1 for the PC (SAS Institute, Cary, NC).

All findings were based on intention-to-treat analyses. To preserve statistical independence, only 1 catheter per patient was enrolled in the trial. Baseline differences between treatment groups were analyzed using ² analysis for dichotomous variables and Student's t test for continuous variables. Where appropriate, Wilcoxon rank sum test was used for nonparametric analyses. Differences in primary outcomes stratified by catheter type (percutaneous or Broviac) were compared using Mantel-Haenszel stratified analysis. Mantel-Haenszel common relative risk (RR) ratios and 95% confidence intervals (CIs) were determined for all primary outcomes using the PI treatment group as the control group. The log-rank test was used to compare length of time until the first episode of a BSI among treatment groups.

Sample size was calculated for a power of 80% and an  error of 0.05. It was estimated that to detect a 50% reduction in CRBSI risk, from 9%^33,34 in the PI group to 4.5% in the antimicrobial dressing group, would require approximately 490 neonates in each treatment group. To detect a 50% reduction in catheter colonization from approximately 20%^6,34 in PI patients to 10% in chlorhexidine dressing neonates would require approximately 200 neonates in each treatment group.

	RESULTS

Top Abstract Introduction Methods Results Discussion Conclusion References

During the study period (June 1994 to August 1997), 919 neonates in study nurseries required CVC. Two hundred fourteen of these eligible infants were not enrolled in the trial because their parents refused consent, study members were not available for patient enrollment, or the primary physician did not permit study enrollment. Enrollment was halted after 705 neonates were enrolled in the trial (335 chlorhexidine dressing and 370 PI).

The 2 groups were very similar with respect to baseline demographic characteristics, measures of illness severity, patient characteristics at the time of catheter placement, and patient characteristics and treatment during the time CVCs were in situ (Table 1). A comparable small proportion of study patients' catheters were not cultured at removal because of accidental extrusion, contamination, or deviation from the study protocol (control 8%, chlorhexidine dressing 6%, P = .40). Among neonates whose CVCs were not cultured there was no difference between treatment groups with respect to baseline characteristics shown in Table 1 (data not shown).

Catheter Tip Colonization

A comparison of primary outcomes is shown in Table 2. Three hundred fourteen (94%) of neonates randomized to the chlorhexidine dressing group had CVC tips cultured compared with 341 (92%) of 370 control neonates. Catheter tip colonization occurred in 129 (19.7%) of 655 neonates whose catheter tips were cultured. Neonates with Broviac catheters were more likely to have colonized catheter tips, 11 (31%) of 35, than neonates with percutaneously placed CVCs, 118 (19.0%) of 620, although the difference did not reach statistical significance (P = .08). After stratifying by catheter type, among neonates with cultured catheters, catheter tip colonization was significantly less frequent in chlorhexidine dressing neonates when compared with control neonates (15.0% vs 24.0%, RR: 0.6, CI: 0.5-0.9, Table 2). Among neonates with cultured catheters, incidence density of catheter tip colonization was also lower in antimicrobial dressing treatment group (8.5 vs 14.1 episodes per 1000 catheter-days, P = .005).

In subcohort analyses, differences in catheter tip colonization rates between the treatment groups were most evident for neonates whose catheters were in situ 14 days (11% vs 25%, P = .0007). There was no difference detected between treatment groups' colonization rates in neonates whose catheters were in situ >14 days (23% vs 20%, P = .53).

Heavy cutaneous colonization of the insertion site was more common with colonized catheter tips than with noncolonized catheter tips (62% vs 15%; P = .001) and in PI-treated neonates than in neonates in the chlorhexidine dressing group (28% vs 20%; P = .02). CNS was the most common organism cultured from colonized catheter tips (Table 3).

Catheter Tip-Related BSIs

CRBSI occurred in 23 (3.5%) of 655 of neonates whose catheters were cultured. No difference in CRBSI rates was detected between the treatment groups (Table 2). Incidence density of CRBSI per 1000 catheter days in the 2 groups was also similar (1.9 vs 2.2 episodes per 1000 catheter-days, P = .60). There was no difference in rates of CRBSI in subcohort analyses based on length of catheterization time (data not shown).

Organisms causing CRBSI are shown in Table 3. Distribution of organism responsible for CRBSI among treatment groups was similar. CNS was the most common organism responsible for CRBSI in each treatment group. Subtyping by pulsed field gel electrophoresis (PFGE) was done on CNS isolates from eight of 15 neonates who had a CNS CRBSI. Restriction-fragment DNA subtyping showed concordance in isolates from catheter tips and blood cultures in 3 of the 5 presumed CRBSI in the control group and 2 of 3 in the chlorhexidine dressing group.

BSI Without a Source

The first episode of cryptogenic BSI without an identifiable source was also evaluated on the premise that most primary BSIs in patients with CVCs originate from the intravascular device.³⁵ There was no detectable difference between BSI without a source between the 2 treatment groups (15.2% vs 14.3%, RR: 1.1, CI: 0.8-1.5; Table 2). Incidence density of BSI without a source was also similar (2.5 vs 2.6 episodes per 1000 catheter-days; P = .70).

Most of the episodes of BSI without a source were caused by CNS (Table 3). Distribution of organisms responsible for episodes of BSIs among treatment groups was similar.

There was also no difference between the treatment groups with respect to days to the first episode of BSI without a source (log-rank test; P = .70). There was no difference in rates of BSI without a source in subcohort analyses based on length of catheterization time (data not shown).

Thirteen episodes (5 chlorhexidine dressings) of BSI without a source occurred in neonates whose catheter tip and catheter hub were not cultured when the CVC was removed. Six of the 13 episodes occurred at least 10 days before removal of the catheter.

Adverse Reactions

During the first 15 months of the study, 7 (5.9%) of 118 of neonates randomized to the antimicrobial dressing developed a severe localized contact dermatitis under the chlorhexidine dressing; 2 additional neonates developed an area of pressure necrosis under the chlorhexidine dressing. Two reactions, which led to scar formation at the site, have been reported previously.³⁶ Mean gestational age of neonates with contact dermatitis was 24.5 weeks (range: 22.5-26.5 weeks) and mean birth weight was 720 g (range: 560-880 g). All CVCs had been placed on or before the eighth day of life.

After these reactions, criteria for study enrollment were changed. Infants <26 weeks gestational age were enrolled only if the CVC was inserted after the first week of life. After the change in the protocol, there were 12 more episodes of contact dermatitis from the chlorhexidine dressing among 217 neonates randomized to the antiseptic dressing group. During the entire study period, 15 (15%) of 98 neonates <1000 g and 4 (1.5%) of 237 neonates 1000 g randomized to the antiseptic dressing group developed a contact dermatitis under the dressing (P < .0001). Contact dermatitis did not occur in any control neonates.

	DISCUSSION

Top Abstract Introduction Methods Results Discussion Conclusion References

Ill neonates often require prolonged access with a CVC. In this trial, disinfection of the insertion site with 70% alcohol before catheter placement followed by application of a novel chlorhexidine-impregnated dressing to the site reduced CVC tip colonization when compared with the use of 10% PI cutaneous antisepsis. There were no differences between the 2 site care regimens in rates of CRBSI and BSI without a source.

Chlorhexidine gluconate is a cationic biquanide that provides rapid antisepsis because of its broad spectrum germicidal activity against most neonatal pathogens.^37,38 Microbial resistance to chlorhexidine gluconate is rare.³⁹ Although chlorhexidine gluconate can be absorbed through the skin of neonates, minimal absorption has been detected in prospective trials.^40-43 Toxic effects have not been seen, and the agent has been well-tolerated as a skin antiseptic in term and preterm infants.^2140-45 The novel chlorhexidine-impregnated dressing reduces heavy cutaneous colonization at the insertion site and, as a consequence, reduces catheter tip colonization. Cutaneous antisepsis with chlorhexidine gluconate has been proven to be more efficacious than antisepsis with PI in preventing peripheral intravenous catheter tip colonization in neonates,²¹ and CVC tip colonization and CRBSI in adults.^16,17

Differences in catheter tip colonization were most evident in neonates whose catheters were in situ 14 days. In adult patients, the risk of catheter tip colonization and CRBSI increases with catheterization time.^12,13,46 Adults with percutaneously placed CVCs that are in place >7 days are more likely to have CRBSI than those whose catheters remain in place <7 days.^{12,13,15,2447-49} Infection control strategies aimed at reducing catheter tract colonization may be less effective in preventing CRBSI in adults who require prolonged catheterization because the intraluminal route of infectionthe catheter hubbecomes a more important portal of entry for microorganisms as catheterization time increases.^14,46,50

Although the antiseptic dressing reduced catheter tip colonization when compared with PI antisepsis, there were no differences in CRBSI or BSI without a source between the 2 treatment groups. Study power may have precluded finding a difference in rates of CRBSI and BSI. The study was halted after 705 neonates were enrolled because of funding constraints and the low rate of CRBSI in the study population. Given the low rate of CRBSI in both groups, it is unlikely that significant differences between the 2 treatment groups would have been detected even if enrollment had continued to the initial goal of 980 neonates.

Hub contamination causing BSI is an important mechanism of CRBSI in neonates,⁵ and likely is the most important mechanism of BSI in adult patients whose percutaneously placed CVCs remain in situ >7 days.^14,46,50 Because mean length of time CVCs were in situ exceeded 17 days in each treatment group, hub contamination not detected by the investigators and not preventable by cutaneous antisepsis, may have been responsible for a large proportion of the cases of BSI without a source.

As in other CVC studies,^{6,11,12,16,51} CNS was the most common organism responsible for CVC tip colonization, CRBSI, and BSI without a source. CNS isolates grown from catheter tips and the blood of neonates with CRBSI were compared using biotypes and antibiotic sensitivity profiles. A more reliable means of determining isolate concordance using DNA restriction-fragment subtyping by PFGE was performed.²⁸ Eight of 15 episodes of CRBSI attributable to CNS could be evaluated with PFGE, 5 of 8 showed concordance between isolates grown from the catheter tip and blood cultures. Peripheral and CVCs are often colonized with multiple CNS species.^15,21,52 If multiple CNS isolates from catheter or hub cultures are not subjected to DNA typing, potential matches can be missed.^15,21 This may have been the case in the 3 catheter-associated CNS BSIs that did not show DNA concordance.

The chlorhexidine-impregnated dressing can reduce the potential risk of hypothyroxemia in low birth weight infants by reducing exposure to iodine-based antiseptics.^18-20 However, local reactions at the site of the chlorhexidine dressing occurred in 5.7% of the antiseptic dressing-treated neonates. Most reactions occurred in neonates 28 weeks gestational age and 1000 g. Local contact dermatitis from the chlorhexidine dressing may limit its use in acutely ill low birth weight neonates.

In a recent randomized trial of adult patients with CVCs or arterial catheters, patients randomized to the novel chlorhexidine-impregnated dressing group had a significantly lower incidence of CRBSI than controls.⁵³ We believe that the chlorhexidine dressing was more effective in preventing CRBSI in this trial than in our trial because adult patients studied by Maki et al⁵³ had catheters in place for an average of 6 days, far less than the 17 days in our patients. The largest proportion of CRBSIs in the trial of Maki et al⁵³ derived from skin colonization rather than hub colonization and the antiseptic dressing was most effective for preventing CRBSIs by this route.

	CONCLUSION

Top Abstract Introduction Methods Results Discussion Conclusion References

The use of alcohol for cutaneous antisepsis followed by the placement of a chlorhexidine-impregnated dressing over the insertion site of CVCs, left on for up to 7 days between dressing changes, provides protection against catheter tip colonization. CRBSI and BSI without a source rates were similar amount treatment groups. However, a substantial risk of contact dermatitis at the dressing site may limit its use in low birth weight infants in the first 2 weeks of life.

	ACKNOWLEDGMENTS

Funding was provided in part by a grant from Johnson and Johnson Medical; Children's Foundation, Children's Hospital, Milwaukee, Wisconsin; and NIH Grant No. MO 1 RR00240. None of the authors hold personal financial interest or have served as consultants for Johnson and Johnson Medical.

We thank the physician, laboratory, and nursing staff at each study center for their generous cooperation with the study protocol and Dorothy Bauer for secretarial support.

Jeffery S. Garland, MD, SM^*
Colleen P. Alex, BSN^*
Chris D. Mueller, RNC
Dewey Otten, MSN^§
Chandra Shivpuri, MD
^* St Joseph's Hospital
 Sinai-Samaritan Medical Center
^§ Children's Hospital of Wisconsin
Milwaukee, WI 53210

Mary C. Harris, MD
Department of Neonatology
University of Pennsylvania
School of Medicine
Philadelphia, PA 19104

Mary Naples, BSN
James Pellegrini, MD
University of Massachusetts Memorial Medical Center
Worcester, MA 01605

Rosanne K. Buck, MSN
Children's Hospital and Department of Neonatology
Beth Israel-Deaconess Medical Center
Boston, MA 02115

Timothy L. McAuliffe, PhD
Department of Biostatistics
Medical College of Wisconsin
Milwaukee, WI 53226

Donald A. Goldmann, MD
Division of Infectious Diseases
Hospital Epidemiology Program
Children's Hospital and Department of Pediatrics
Harvard Medical School
Boston, MA 02115

Dennis G. Maki, MD
Section of Infectious Diseases
Department of Medicine
University of Wisconsin
Madison, WI 53705

	FOOTNOTES

Received for publication May 22, 2000; accepted Sep 14, 2000.

Presented in part at the annual meeting of the Society of Pediatric Research; May 4, 1998; New Orleans, LA.

Address correspondence to Jeffery S. Garland, MD, SM, 5000 W Chambers St, Milwaukee, WI 53210. E-mail: jsgarland{at}hotmail.com

	ABBREVIATIONS

BSI, bloodstream infection; CVC, central venous catheter; CRBSI, catheter-related bloodstream infection; PI, povidone-iodine; CFU, colony-forming unit; CNS, coagulase-negative Staphylococcus; RR, relative risk; CI, 95% confidence interval; PFGE, pulsed field gel electrophoresis.

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Top Abstract Introduction Methods Results Discussion Conclusion References

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