Objective:

The purpose of this pilot trial was to determine whether rates of contact dermatitis following cutaneous antisepsis for central catheter placement were similar among neonates treated with chlorhexidine gluconate and povidone-iodine. Chlorhexidine gluconate absorption was also evaluated.

Study Design:

Infants weighing 1500 g and 7 days of age were randomized to a 10% povidone-iodine or 2% chlorhexidine gluconate site scrub before catheter placement. Primary outcomes evaluated included dermatitis, catheter colonization and chlorhexidine gluconate absorption.

Result:

A total of 48 neonates were enrolled. Colonization rates were similar among treatment groups (P<0.6). Dermatitis did not occur at chlorhexidine gluconate (central catheters, n=24; peripheral catheters, n=29) sites. Seven neonates had measurable chlorhexidine gluconate concentrations (range 13 to 100 ng ml^-1) during catheterization.

Conclusion:

In this small trial chlorhexidine gluconate antisepsis was tolerated by study neonates. Chlorhexidine gluconate was cutaneously absorbed. Larger trials are needed to determine efficacy and tolerance of chlorhexidine gluconate in neonates.

Introduction

Percutaneously inserted central catheters (PICCs) can cause significant neonatal morbidity.^{1, 2, 3, 4} Catheter-related bloodstream infection (CRBSI), one of the most common complications of central venous catheterization in neonates, increases length of hospital stay, hospital costs, potential for antibiotic toxicity² and neurologic morbidity.⁵

Ten percent povidone-iodine (PI) has been widely used for antisepsis before PICC placement in neonates. However, laboratory findings consistent with transient hypothyroidism from systemic absorption of iodine after iodophor scrubs have been reported by several authors.^{6, 7} Transient hypothyroidism has not been widely reported in North America.^{8, 9} Recent trials in adults and neonates suggest that a cutaneous chlorhexidine gluconate (CHG) scrub before central venous catheter (CVC) or peripheral catheter insertion may be more effective than PI for prevention of CRBSI in adults and catheter colonization in neonates.^{10, 11, 12, 13} No current CHG-based antiseptic has been approved by the Federal Drug Administration (FDA) for use in neonates for intravenous catheter placement.

In this pilot randomized trial of critically ill neonates <2 months of age who required a PICC, we set out to determine if cutaneous antisepsis before PICC insertion with 2% CHG in an alcohol-based solution was as well-tolerated as 10% PI.

Methods

Subjects

This pilot trial was carried out at five Level III neonatal intensive care units; two community hospitals (Wheaton Franciscan Healthcare, St Joseph and Aurora Sinai Medical Center) and three university teaching hospitals (Children's Hospital of Wisconsin, Children's Hospital of Philadelphia and Boston Children's Hospital). Study units ranged from 24 beds to 50 beds. Institutional review boards at each center approved the protocol and informed consent was obtained from the parents of participating neonates.

The FDA limited study enrollment to neonates who were at least 7 days old and weighed more than 1500 g because of concerns for the development of contact dermatitis in low-birth-weight neonates exposed to topical CHG. Exclusion criteria included 60 days of age at enrollment, catheterization 48 h, prior discharge home and conditions of altered skin integrity.

Treatment arms

Neonates were block randomized to one of two treatment groups: 10% PI or 2% CHG. After randomization insertion sites were cleansed with appropriate antiseptic before catheter placement. In the CHG group, ampoules containing 3 ml of 2% CHG (Enturia Inc., Leawood, KS, USA) were used to cleanse PICC sites. The site was dressed with a polyurethane dressing that was changed weekly while the catheter remained in situ. The same antiseptic was used to re-cleanse the site with each dressing change. All peripheral intravenous catheter sites were also cleansed with the same antiseptic used for PICC insertion. CHG ampoules containing 0.67 ml of 2% CHG were used to cleanse peripheral intravenous sites in CHG-treated neonates.

All catheters were placed using standard sterile techniques with wide barriers. Decisions to remove catheters were made independently by the primary care team. Peripheral blood cultures were performed at the discretion of the primary care team in neonates with signs of sepsis.

Culture techniques

Catheters were aseptically removed and the last 5 cm of the tip was cultured using the semiquantitative method of Maki et al.¹⁴ Standard laboratory methods were used to identify organisms colonizing the catheter tip.¹⁵

Dermatitis assessment

Catheter sites (PICC and peripheral) were inspected daily for the presence and severity of contact dermatitis by a study nurse using a dermatitis severity scale (Table 1).

Table 1 - Contact dermatitis scoring.

Full table

Serum chlorhexidine gluconate concentrations

Blood CHG concentrations were determined at single center using liquid chromatography with tandem mass spectrometry (National Medical Service, Willow Grove, PA, USA) following catheter placement, just before the first dressing change and immediately after the first dressing change. The lower limit for quantitation of CHG was 10 to 20 ng ml^-1 using a 0.5 ml sample of whole blood.

Primary outcome

Catheter tip colonization was defined by a semiquantitative catheter colony count of 15 colony-forming units.¹⁴ Colonization was selected as a primary outcome because of its association with CRBSI and bloodstream infection (BSI) without a source.^{14, 16, 17} BSI without a source was defined by all of the following: a positive peripheral blood culture during the time of catheterization or within 24 h of catheter removal, clinical signs and symptoms of a BSI, antibiotic therapy for 7 days and no other documented primary site of infection.¹⁸ The catheter tip was not colonized or was colonized with organisms other than that grown from the blood. A CRBSI was defined as a BSI in which there was concordance between organisms grown from the blood and catheter tip.

Severe contact dermatitis was defined by a dermatitis score of 2 (Table 1).

Data collection and analysis

Data obtained on each patient included demographic information, 24 h Score for Neonatal Acute Physiology (SNAP) score,¹⁹ catheter type, medications, catheter location, attempts to place catheter, number of CHG ampoules used for PICC and peripheral intravenous catheter placement, sites of infection during catheterization, days of catheterization, reason for catheter removal, invasive treatments, and laboratory and clinical findings to assess infection. After data collection, sheets were checked for errors and missing data, the data were double entered into a data set for analysis using Statistical Analysis System 9.0 for the PC (SAS Institute, Cary, NC, USA).

All results were based on intention to treat. Baseline differences between treatment groups were compared using Student's t-test or Wilcoxon rank-sum analysis for continuous variables and ²-analysis for categorical variables. Differences in primary outcome (catheter colonization, BSI without a source and CRBSI) rates (per 100 catheters) and incidence (per 1000 catheter days) were compared. Relative risk ratios and 95% confidence intervals were determined using the PI treatment group as the reference group. The rate of severe contact dermatitis (dermatitis score 2) and distribution of contact dermatitis scores were compared using ²-analysis. Median differences in contact dermatitis scores were compared using Wilcoxon rank-sum analysis.

As a pilot trial with a goal of enrolling 150 neonates, the study was not powered to evaluate differences in CRBSI, BSI or catheter tip colonization. The trial was designed primarily to evaluate the tolerance and absorption of 2% CHG in an alcohol base and provide preliminary data to support a larger trial including smaller (<1500 g), younger (<7 days of age) neonates. The trial would have 80% power at an error of 0.05 to show a 0.5 point difference in mean contact dermatitis score among treatment groups assuming 400 catheter sites (150 PICC and 250 peripheral intravenous catheter sites) were included in the trial.

Results

Because of the entry criteria stipulated by the FDA, one center, which enrolled a single neonate, withdrew from the trial after the first year. Just 47 neonates were enrolled at other centers during the first 2 years (2005 to 2007) of study enrollment. After 2 years of slow enrollment the sponsor chose to terminate the study. A total of 65 eligible infants were not enrolled in the trial because of parental refusal or lack of availability of a study member for enrollment. The groups were similar for baseline demographic characteristics, severity of illness measures, patient characteristics at time of catheter placement and treatments during catheterization (Table 2).

Table 2 - Comparison of clinical characteristics among treatment groups.

Full table

Outcomes

Catheter tip colonization occurred in 3 of 24 (13%) of CHG-treated neonates and 1 of 24 (4%) PI-treated neonates (P=0.61). Similarly, there was no detectable difference between BSI rates among treatment groups (Table 3, P=0.99). The incidence of BSI was similar among treatment groups (2.8 vs 3.0 per 1000 catheter days among CHG- vs PI-treated neonates, P=0.96). CRBSIs did not occur in either treatment group. Four neonates in each treatment group were treated for at least 7 days of antibiotics for a presumed BSI (that is, signs and symptoms of sepsis with a negative blood culture). Septicemia evaluations were similar among treatment groups (7 of 24 CHG vs 9 of 24 PI, P=0.54). Rates of other infections such as pneumonia (8 vs 4%), cellulitis (0 vs 4%) and urinary tract infections (8 vs 0%) were similar between CHG- and PI-treated neonates (P0.49). Severe contact dermatitis (dermatitis score2) did not occur (upper 95% confidence limit (95% UCL) 5.7%) in CHG- (PICC, n=24; PIV, n=29) or PI (95% UCL 6.4%) -treated catheter sites (PICC, n=24; PIV, n=23). Only one PI catheter site had any signs of dermatitis (dermatitis score=1), which resolved without treatment.

Table 3 - Outcomes among treatment groups.

Full table

Serum chlorhexidine gluconate concentration

Measurements of serum chlorhexidine concentration determinations were planned for the first 20 neonates enrolled at the primary center (Wheaton Franciscan Healthcare, St Joseph Hospital). Because the study was terminated early only 10 neonates had concentrations measured (Table 4). Five of ten had measurable serum concentrations (>10 ng ml^-1) after the first cutaneous application of antisepsis; seven of ten had measurable serum concentrations (range 13 to 100 ng ml^-1) sometime during catheterization. The maximum serum concentration (100 ng ml^-1, Table 4) occurred after the third dressing change in a 27-day-old neonate who was born at 28 weeks' gestation. Serum concentrations increased following the first or second dressing change in six of seven neonates with measurable concentrations on at least two separate occasions.

Table 4 - Serum concentration of 10 neonates randomized to CHG antisepsis.

Full table

Discussion

In this small pilot trial, cutaneous disinfection with 2% CHG in an alcohol base was not associated with an increased risk of contact dermatitis when compared to a cutaneous scrub with PI. The FDA limited enrollment of this trial to larger and older neonates because approximately 6% of neonates in our previous work¹⁸ experienced a serious episode of contact dermatitis at the site of a novel CHG-impregnated dressing. Strict entry criteria limited subject accrual and the trial was discontinued before enrolling sufficient neonates to adequately power the trial to evaluate differences in dermatitis rates. Chlorhexidine was detectable in the blood of over two-thirds of neonates who had concentrations measured.

Chlorhexidine gluconate, a cationic biguanide, rapidly and effectively kills most skin pathogens.^{20, 21} It has residual effects on the skin to provide antisepsis for up to 24 h. CHG antisepsis is well tolerated in pediatric and adult patients with few toxic side effects. We previously reported severe contact dermatitis with the use of a novel CHG-impregnated dressing that was placed over catheter sites after insertion.¹⁸ Most episodes occurred in neonates who were less than a week old and 28 weeks' gestation at birth. Occlusiveness, pressure created by the dressing, CHG or a combination of all three factors may have been responsible for episodes of severe contact dermatitis at the dressing sites. In a time sequence trial to evaluate a multifactorial approach to reduce CRBSI, Andersen et al.²² noted that 4 of 36 (11%) neonates <1000 g developed contact dermatitis after a 2% aqueous chlorhexidine scrub. There were no episodes of contact dermatitis in 49 study neonates who were 1000 g. In our trial there were no episodes of dermatitis at the 53 catheter sites of relatively mature (32.412.9 weeks), heavy (2085846 g) neonates. In a cohort of neonates whose mean gestational age and birth weight were 355.1 weeks and 2.451.07 kg, respectively, cutaneous antisepsis with a 0.5% CHG solution in an alcohol base for peripheral catheter insertions did not cause dermatitis at insertion sites that necessitated catheter removal or local treatment.¹² These results suggest that CHG-induced contact dermatitis is uncommon in heavier, mature neonates.

Anaphylactic reactions have occurred in adults following application of CHG to mucosal membranes or with the use of CHG-impregnated catheters.^{23, 24} Impregnated catheters are not approved for use in neonates and there have not been reports of neonatal anaphylactic reactions to CHG. During this study no anaphylactic reactions occurred.

Cutaneous antisepsis with CHG before CVC insertion effectively reduces risk for CRBSI infections in adults who require CVCs.¹¹ To date there have been no randomized trials showing CHG to be more efficacious than PI in preventing CRBSI in neonates. Because most adult CVC are in place less than 7 days, adequate cutaneous antisepsis before catheter placement will effectively prevent most CRBSI. Neonatal PICCs are often in situ greater than 10 days when hub contamination becomes a more likely source for CRBSI.²⁵ In a cohort trial²⁵ nested in a randomized trial¹⁸ to assess the efficacy of an antibiotic lock solution in neonates, Garland et al. showed that at least 60% of CRBSI could be traced to catheter hub contamination before the BSI. Just 20% of CRBSI were acquired through contamination of the cutaneous catheter tract. Cutaneous antisepsis before PICC placement prevents CRBSI by reducing catheter tract contamination and subsequent catheter tip colonization. A novel CHG-impregnated gauze at the catheter insertion site reduced CVC tip colonization risk when compared to PI cutaneous antisepsis, but did not reduce CRBSI rates in a randomized trial of over 700 neonates whose catheters were in situ an average of 170.9 days.²⁶ The low CRBSI rate following catheter tract contamination in neonates will require a very large randomized trial to show that cutaneous CHG antisepsis is more efficacious than PI for the prevention CRBSI.

Cutaneous absorption of PI may compromise thyroid function in preterm infants, but does not appear to be a common cause of transient neonatal hypothyroidism in neonates in North America.^{8, 9} Concern over iodine absorption in neonates is one reason given for exploring the use of CHG as an antiseptic in neonates. In this trial CHG was absorbed from the intact skin of neonates enrolled in the trial. Others have also shown cutaneous absorption of CHG in neonates.^{27, 28, 29} The concentration of CHG found in the blood of enrolled neonates was similar to what others report.²⁹ Although the study was not designed to evaluate the pharmacokinetics of cutaneously absorbed CHG, at least two infant appeared to have increasing concentrations following each application suggesting accumulation through increased absorption or reduced metabolism and excretion of CHG. Although cutaneously applied CHG is absorbed through neonatal skin, there have been few reported side effects. Animal trials have shown no significant toxicity from CHG.³⁰ There were no significant systemic side effects in this trial or previous trials that evaluated CHG as a cutaneous antiseptic for neonates.^{12, 24}

This small pilot trial failed to detect contact dermatitis (95% UCL 5.7%) following cutaneous antisepsis with a 2% CHG before PICC insertion in neonates who were >1500 g and at least a week old. Neonates absorbed CHG. Before the widespread use of CHG for prevention of CRBSI in neonates, larger trials will be necessary to determine if CHG is more effective and as well-tolerated as PI.

Conflict of interest

Study funded by Enturia (formerly Medi-Flex).

References

1. Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996; 129: 63–71. | Article | PubMed | ISI | ChemPort |
2. Gray JE, Richardson DK, McCormick MC, Goldmann DA. Coagulase-negative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome. Pediatrics 1995; 95: 225–230. | PubMed | ChemPort |
3. Fanaroff AA, Korones SB, Wright LL, Verter J, Poland RL, Bauer CR et al. Incidence, presenting features, risk factors, and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J 1998; 17: 593–598. | Article | PubMed | ISI | ChemPort |
4. Sohn AG, Garrett DO, Sinkowitz-Cochran RL, Grohskopf LA, Levine GL, Stover BH et al. Prevalence of nosocomial infections in neonatal intensive care unit patients: results from the first national point-prevalence survey. J Pediatr 2001; 139: 821–827. | Article | PubMed | ChemPort |
5. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292: 2357–2365. | Article | PubMed | ChemPort |
6. Smerdely P, Lim A, Boyages SC, Waite K, Wu D, Roberts V et al. Topical iodine-containing antiseptics and neonatal hypothyroidism in very-low-birthweight infants. Lancet 1989; 2(8664): 661–664. | Article | PubMed | ChemPort |
7. Parravicini E, Fontana C, Paterlini G, Tagliabue P, Rovelli F, Leung K et al. Iodine, thyroid function, and very low birth weight infants. Pediatrics 1996; 98: 730–734. | PubMed | ChemPort |
8. Gordan CM, Rowitch DH, Mitchell ML, Kohane IS. Topical iodine and neonatal hypothyroidism. Arch Pediatr Adolesc Med 1995; 149: 1336–1339. | PubMed |
9. Brown RS, Bloomfield S, Bednarek FJ, Mitchell ML, Braverman L. Routine skin cleansing with povidone-iodine is not a common cause of transient neonatal hypothyroidism in North America: a prospective controlled study. Thyroid 1997; 7: 395–400. | Article | PubMed | ChemPort |
10. Mimoz O, Pieroni L, Lawrence C, Edouard A, Costa Y, Samii K et al. Prospective, randomized trial of two antiseptic solutions for prevention of central venous or arterial catheter colonization and infection in intensive care unit patients. Crit Care Med 1996; 24: 1818–1823. | Article | PubMed | ChemPort |
11. Maki DG, Ringer M, Alvarado CJ. Prospective randomized trial of povidone-iodine, alcohol and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet 1991; 338: 339–343. | Article | PubMed | ChemPort |
12. Garland JS, Buck RK, Maloney P, Durkin BM, Toth-Lloyd S, Duffy M et al. A comparison of 10% povidone-iodine and 0.5% chlorhexidine gluconate for the prevention of peripheral intravenous catheter colonization in neonates: a prospective trial. Pediatr Infect Dis J 1995; 14: 510–516. | PubMed | ChemPort |
13. Chaiyakunapruk N, Veenstra DL, Lipsky B, Saint S. Chlorhexidine compared with povidone-iodine solution for vascular catheter-site care: a meta-analysis. Ann Intern Med 2002; 136: 792–801. | PubMed | ChemPort |
14. Maki DG, Weise CE, Sarafin HW. A semiquantitative culture method for identifying intravenous catheter-related infection. N Engl J Med 1997; 296: 1305–1309.
15. Brun-Buisson C, Abrouk F, Legrand P, Huet Y, Larabi S, Rapin M. Diagnosis of central venous catheter-related sepsis. Critical level of quantitative tip cultures. Arch Intern Med 1987; 147: 873–877. | Article | PubMed | ChemPort |
16. Collignon PJ, Soni N, Pearson IY. Is semiquantitative culture of central vein catheter tips useful in the diagnosis of catheter-associated bacteremia? J Clin Microbiol 1986; 24: 532–535. | PubMed | ChemPort |
17. Cooper GL, Hopkins CC. Rapid diagnosis of intravascular catheter-associated infection by direct Gram staining of catheter segments. N Engl J Med 1985; 18: 1142–1147.
18. Garland JS, Alex C, Mueller CP, Cisler-Kahill LA. Local reactions to a chlorhexidine gluconate-impregnated antimicrobial dressing in very low birth weight infants. Pediatr Infect Dis J 1996; 15: 912–914. | Article | PubMed | ChemPort |
19. Richardson DK, Gray JE, McCormick MC, Workman K, Goldmann DA. Score for Neonatal Acute Physiology: a physiologic severity index for neonatal intensive care. Pediatrics 1993; 91: 617–623. | PubMed | ISI | ChemPort |
20. Aly R, Mailbach HI. Effect of antimicrobial soap containing chlorhexidine on the microbial flora of skin. Appl Environ Microbiol 1976; 31: 931–935. | PubMed | ChemPort |
21. Shelton DM. A comparison of the effects of two antiseptic agents on staphylococcus epidermis colony forming units at the peritoneal dialysis catheter exit site. Adv Perit Dial 1991; 7: 120–124. | PubMed | ChemPort |
22. Andersen C, Hart J, Vemgal P, Harrison C. Prospective evaluation of a multi-factorial prevention strategy on the impact of nosocomial infection in very-low-birthweight infants. J Hosp Infect 2005; 61: 162–167. | Article | PubMed | ChemPort |
23. Okano M, Nomura M, Hata S, Okada N, Sato K, Kitano Y et al. Anaphylactic symptoms due to chlorhexidine gluconate. Arch Dermatol 1989; 125: 50–52. | Article | PubMed | ChemPort |
24. Oda T, Hamasaki J, Kanda N, Mikami K. Anaphylactic shock induced by an antiseptic-coated central venous catheter. Anesthesiology 1997; 87: 1242–1244. | Article | PubMed | ChemPort |
25. Garland JS, Alex CP, Sevallius JM, Murphy DM, Good MJ, Volberding AM et al. Cohort study of the pathogenesis and molecular epidemiology of catheter-related bloodstream infection in neonates with peripherally inserted central venous catheters. Infect Control Hosp Epidemiol 2008; 29: 243–249. | Article | PubMed
26. Garland JS, Alex CP, Mueller CD, Otten D, Shivpuri C, Harris MC et al. A randomized trial comparing povidone-iodine to a chlorhexidine gluconate-impregnated dressing for prevention of central venous catheter infections in neonates. Pediatrics 2001; 107: 1431–1437. | Article | PubMed | ChemPort |
27. Obrien CA, Blummer JL, Speck WT, Carr H. Effect of bathing with a 4% chlorhexidine gluconate solution on neonatal bacterial colonization. J Hosp Infect 1984; 5(Suppl A): 141.
28. Cowen J, Ellis SH, McAinsh J. Absorption of chlorhexidine from intact skin of newborn infants. Arch Dis Child 1979; 54: 379–383. | Article | PubMed | ChemPort |
29. Agget PJ, Copper LV, Ellis SH, McAinsh J. Percutaneous absorption of chlorhexidine in neonatal cord care. Arch Dis Child 1981; 56: 878–891. | Article | PubMed | ChemPort |
30. Case DE, McAinsh J, Rushton A, Winrow MJ. Chlorhexidine: attempts to detect percutaneous absorption in man. Chemotherapy 1976; 3: 367–374. | ChemPort |

Acknowledgments

We acknowledge the research coordinator assistance received from the various centers—Wheaton Franciscan Healthcare, St Joseph: Elizabeth Bongert, Melinda P Bushong, Leslie L Hofer, Mary Koehnke, Heidi May, Lori A McLain, Dawn M Murphy, Tiffany N Perine, Jackie M Sevallius, Rae Toman, Amy WernerWoida. Aurora Sinai Medical Center: Joan Becker; Children's Hospital of Wisconsin: Laura Lane; Children's Hospital of Philadelphia: Linda Corcoran, Jane Fricko, Sharon Zirin; Children's Hospital (Boston): Hannah Pawlzendo. Financial support was provided by Enturia (formerly Medi-Flex). The sponsor reviewed the study design developed by the primary investigator. It was not involved with the data collection, implementation, analysis or interpretation of data. They had an opportunity to review the paper before publication. The project described was supported by Grant Number UL1-RR-024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.