Objective The skin disinfectant ‘0.5% chlorhexidine gluconate in 70% alcohol’ (0.5% CHG-70% alc) may cause skin lesions in extremely preterm infants (gestational age <26 weeks). In April 2013, 0.2% chlorhexidine gluconate solution in acetate (0.2% CHG-acetate) was introduced as skin disinfectant for extremely preterm infants in our neonatal intensive care units. We aimed to compare the incidence of skin lesions and central line-associated bloodstream infection (CLABSI) among extremely preterm infants when using 0.5% CHG-70% alc and 0.2% CHG-acetate.
Design Retrospective pre-post comparison cohort study.
Patients All electronic patient records of extremely preterm infants born between January 2011–March 2013 (‘0.5% CHG-70% alc’ cohort) and April 2013–October 2015 (‘0.2% CHG-acetate’ cohort) were reviewed.
Main outcome measures The incidence of skin lesions and CLABSI. Skin lesions were defined as the presence of erythema, blisters, excoriation, oedema or induration. CLABSI was defined according to the definition of the US Centers for Disease Control and Prevention.
Results The incidence of skin lesions was 22% (95% CI 11% to 37%) in the ‘0.5% CHG-70% alc’ cohort (n=41) and 5% (95% CI 1% to 15%; p=0.02) in the ‘0.2% CHG-acetate’ cohort (n=41). The incidence of CLABSI was the same in both groups (28%; 95% CI 14% to 46% in ‘0.5% CHG-70% alc’ vs 27%; 95% CI 14% to 44% in ‘0.2% CHG-acetate’; p=0.98).
Conclusions Using 0.2% CHG-acetate as skin disinfectant in extremely preterm infants resulted in statistically significant reduction of skin lesions, without increasing the risk of CLABSI as compared with 0.5% CHG-70% alc.
- chlorhexidine gluconate
- central line associated bloodstream infection
- skin lesions
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What is already known on this topic?
The 2011 guidelines for prevention of intravascular catheter-related infections recommend the use of at least 0.5% chlorhexidine solution with alcohol for skin disinfection.
No recommendations can be made for the safety or efficacy of chlorhexidine in infants aged <2 months.
Chlorhexidine skin disinfectants are widely used in neonates, but this solution may cause skin lesions in extremely preterm infants (gestational age <26 weeks).
What this study adds?
This work provides the first data of the efficacy and safety of the use of 0.2% chlorhexidine gluconate in acetate as skin disinfectant in extremely preterm infants.
0.2% chlorhexidine gluconate in acetate as skin disinfectant is associated with fewer skin lesions in extremely preterm infants compared with 0.5% chlorhexidine gluconate in 70% alcohol.
Lower concentration of chlorhexidine gluconate in acetate did not result in more central-line associated bloodstream infections.
A commonly used and very effective topical antiseptic at neonatal intensive care units (NICU) is 0.5% chlorhexidine gluconate solution in 70% alcohol (0.5% CHG-70% alc). It is used prior to invasive procedures, such as insertion of umbilical catheters and peripherally inserted central catheters (PICC).1–3 The 2011 ‘guidelines for the prevention of intravascular catheter-related infections’ recommend the use of at least 0.5% CHG with alcohol for skin disinfection before insertion of intravascular catheters in paediatric and adult patients.2
In extremely preterm infants with gestational age (GA) <26 weeks this solution may cause skin lesions, usually described as chemical burns. CHG as well as alcohol might be the cause of these skin lesions.3–12 Skin damage in this population may result in significant morbidity due to dehydration, thermal instability, skin scarring, opportunistic infections and absorption of topically applied agents. There is also the possible impact of skin damage (pain and stress) on neuronal migration and hence long-term outcomes.5 13 In 2012, the Food and Drug Administration authorised a labelling change to chlorhexidine-based products to ‘use with care in premature infants or infants under 2 months of age.’
A possible solution to reduce the risk on skin lesions may be using a lower concentration of CHG dissolved in a non-alcoholic antiseptic solution.14 Therefore, in April 2013 we implemented the use of 0.2% chlorhexidine gluconate solution in acetate (0.2% CHG-acetate) instead of 0.5% CHG-70% alc for extremely preterm infants (GA <26 weeks). Lower concentration of chlorhexidine might be less toxic and acetate is a non-toxic antiseptic agent, which is considered to be safe.15 The use of a lower concentration of chlorhexidine could lead to reduced effectiveness for disinfection, subsequently increasing the risk for central line-associated bloodstream infections (CLABSI). No previous studies have explored the effect of this skin antiseptic combination on the incidence of CLABSI or skin lesions. For this reason, we conducted a retrospective study to determine the effect of using 0.2% CHG-acetate instead of 0.5% CHG-70% alc as skin disinfectant on the incidence of skin lesions and CLABSI among extremely preterm infants.
Subjects and methods
We conducted a retrospective pre-post comparison study and reviewed all electronic patient records of extremely preterm infants with GA <26 weeks. This study was conducted at a tertiary level 15-bed NICU at the Amalia Children’s Hospital, Radboud University Medical Centre (Nijmegen, The Netherlands), which has on average 500 admissions per year.
Two patient cohorts were defined by type of antiseptic used in the NICU: (1) all extremely preterm infants (GA <26 weeks) who were admitted at our NICU between 1 January 2011 and 1 April 2013, and (2) all extremely preterm infants (GA <26 weeks) admitted between 1 April 2013 and 1 September 2015. From 2011 to 2013, the only skin disinfectant used at our NICU was 0.5% CHG-70% alc (Orphi Farma, Lage Zwaluwe, The Netherlands), and from 2013 to 2015, 0.2% CHG-acetate (Fresenius Kabi, Uppsala, Sweden) was the only skin disinfectant used. The skin disinfectant was used prior to insertion of umbilical venous and arterial catheters (Argyle Umbilical Vessel Catheter, 3.5 or 5 Fr; Covidien, Mansfield, Massachusetts, USA), PICCs (Leaderflex, 22 G; Vygon, Aachen, Germany), peripheral arterial catheters (Neoflon, 24 or 26 G; Becton Dickinson, Helsingborg, Sweden), peripheral venous catheters (Neoflon, 24 or 26 G; Becton Dickinson) and heel sticks.
The exclusion criteria were: (1) extremely preterm infants born in another NICU, because of the use of other skin disinfectants, (2) extremely preterm infants who died before a central catheter was inserted, and (3) extremely preterm infants with other causative mechanisms for the skin lesions, such as electrode jelly, temperature probe and adhesive tape removal.13
From each patient, we obtained the following data: demographic information, skin lesions that were observed within 3 days after application of the skin disinfectant and that were consistent with the area of application of the disinfectant, catheter type and location, days of catheterisation, microbiological blood culture results, and laboratory and clinical findings to assess the incidence of CLABSI. Data were collected from all central catheters that were inserted before the age of 26 weeks only, because once infants reached the age of 26 weeks or more, we switched to the standard skin disinfectant (0.5% CHG-70% alc).
Definitions and outcomes
The two primary outcome measures were skin lesions, categorised according to ‘the dermatitis severity score,’16 and CLABSI, defined according to the most recent definition of the US Centers for Disease Control and Prevention.2
Skin lesions were defined as: the presence of erythema, blisters, excoriation, oedema and/or induration. The severity of the skin lesion was classified in four categories on the basis of ‘the dermatitis severity score’: (1) erythema without oedema, (2) erythema with oedema and/or induration, (3) erythema with onset of blisters, oedematous and/or indurated, and (4) erythema with blisters or excoriation.16 All skin lesions with a dermatitis score of ≥2 were defined as ‘severe.’ To minimise the risk of misclassification, all skin lesions were classified independently by two different researchers (LMAJ and KDL). In case of a different scoring, the lesion was judged again by the two researchers together until consensus was reached.
Statistical analysis was performed with SPSS V.20.0. The incidence of skin lesions was calculated by dividing the number of neonates with skin lesions by the total number of neonates per group. The incidence of CLABSI was measured as CLABSI episodes per 1000 catheter days and was calculated by dividing the number of neonates with CLABSI by the number of neonates eligible for analysis. This means that newborn infants who had died within 3 days after birth were excluded for analysis for incidence of CLABSI, because if there is an infection at that time, these usually result from maternal transmission and are unlikely to be influenced substantially by disinfectant use.
Continuous variables were described as mean (SD) or median (with IQR) depending on the distribution, and compared between two groups using a t-test or a non-parametric test (Mann-Whitney U test). The incidence of skin lesions and CLABSI was compared between the groups with a Pearson’s χ2 test. The effects were considered statistically significant at a 0.05 threshold.
A total of 82 infants were included in the study, 40 in 2011–2013 (0.5% CHG-70% alc) and 42 in 2013–2015 (0.2% CHG-acetate). In one infant in the period of 2013–2015, 0.5% CHG-70% alc was used instead of 0.2% CHG-acetate. Therefore, for the analysis this infant was included in the group of 0.5% CHG-70% alc. There were no statistical significant differences in the baseline characteristics between the two groups, such as GA and birth weight (table 1).
The number and types of skin lesions are described in table 2. The incidence of skin lesions in the ‘0.2% CHG-acetate’ cohort (2/41; 5%; 95% CI 0.8% to 15.2%) was much lower compared with the ‘0.5% CHG-70% alc’ cohort (9/41; 22%; 95% CI 11.3% to 36.5%; p=0.02). This reduction was similar when focusing on ‘severe skin lesions’ only, with seven severe lesions in the ‘0.5% CHG-70% alc’ cohort (17%; 95% CI 7.8% to 30.9%) and one severe skin lesion in the ‘0.2% CHG-acetate’ cohort (2%; 95% CI 0.1% to 11.4%; p=0.03). Almost all skin lesions were localised on the skin above or beneath the umbilicus or on the lateral side of the abdomen. The skin lesions in all neonates fully re-epithelialised and none of the observed skin lesions resulted in death of the newborn infant.
Central line-associated bloodstream infections
In the ‘0.5% CHG-70% alc’ cohort, 12 preterm infants died within 3 days after birth and in the ‘0.2% CHG-acetate’ cohort, eight preterm infants died within 3 days after birth, allowing respectively 29 vs 33 preterm infants to be included for analysis for the incidence of CLABSI (table 2). The incidence of laboratory-confirmed CLABSI was the same in both study periods (15.5/1000 catheter days in the ‘0.5% CHG-70% alc’ cohort vs 15.3/1000 catheter days in the ‘0.2% CHG-acetate’ cohort; p=0.98).
In the ‘0.5% CHG-70% alc’ cohort, 73 central catheters (UVC and PICC) were inserted when the newborn infants were younger than 26 weeks with a total catheter duration time of 516 days and in the ‘0.2% CHG-acetate’ cohort, 77 central catheters (UVC and PICC) were inserted with a total catheter duration time of 587 days. There was no significant difference in mean indwelling time of the umbilical artery catheters between the two groups (6.9 days (SD 4.0) vs 8.1 days (SD 4.7), p=0.31). Also, the mean indwelling time of the umbilical venous catheter was similar between the two groups (6.1 days (SD 3.8) vs 6.2 days (SD 2.8), p=0.98). There were no differences in the types of dressing, type of central catheter or the protocol for hygiene used between the two periods. The empirical antibiotic treatment protocol for CLABSI included vancomycin with ceftazidime and remained unchanged during the study periods.
This work provides the first data of the efficacy and safety of the use of 0.2% CHG-acetate as skin disinfectant in extremely preterm infants. The main finding of this study is that the introduction of a skin disinfectant with a lower percentage of CHG in a non-alcoholic solution in a group of extremely preterm infants resulted in a reduced incidence of skin lesions as compared with alcohol-based skin disinfectants, but without increasing the risk for infection (CLABSI). Until now, a considerable proportion of the evidence for the potential of CHG and alcohol to cause skin lesions in extremely preterm infants was in the form of case reports.
The most likely reasons for the decline in skin lesions are probably the removal of the alcohol component and the use of a lower concentration of chlorhexidine. The evidence that both alcoholic and aqueous CHG 0.5% can cause skin damage supports this hypothesis.10 12 Almost all skin lesions emerged after the insertion of umbilical catheters and were localised on the skin around the umbilicus or on the lateral side of the abdomen, suggesting that this skin is most vulnerable immediately post partum. Also, the abdomen is much more frequently exposed to the disinfectant, as PICCs were only inserted when UVC insertion had failed.
Explanations for the occurrence of skin lesions from chlorhexidine and alcohol are the irritant effects and its interference with the skin’s lipid barrier and microcirculatory function.17 18 In addition, the extremely preterm infant has an increased risk of skin damage due to a poor epidermal barrier, as the epidermis matures during the last quarter of gestation.19 The dermis is deficient in structural proteins and the skin is easily torn.8 20 21
The literature on skin lesions caused by CHG in extremely preterm infants is scarce. A 2014–2015 survey of 59 NICUs in USA reported adverse effects of CHG by just over half of respondents (53%), all of which were dermatologic. Concerns of CHG use regarding potential skin effects, systemic absorption and potential neurotoxicity were reported by 60%.22 A large multicentre randomised controlled trial has reported on skin lesions after different antiseptic regimens used before central catheter insertion.11 Neonates were randomised to topical antisepsis using either povidone-iodine or 70% alcohol followed by application of a CHG-impregnated dressing. It was found that localised skin lesions from the CHG-impregnated dressing occurred in 15 (15.3%) of 98 exposed neonates weighing ≤1000 g. A 2011 Australia-New Zealand survey of various neonatal nurseries found that skin damage caused by CHG was reported by 12 units. Six out of 10 units who reported the adverse effects were using CHG concentrations of more than 0.5%.23
Our results show that using a lower concentration of chlorhexidine is associated with fewer skin lesions, but information on the toxicity profile of 0.2% CHG-acetate in extremely preterm infants is beyond the scope of this article. As extremely preterm infants have thin and porous skin the absorption of a topical agent may have systemic effects.16 The study of Chapman et al could not define any neurotoxic effects of chlorhexidine in term neonates.24 Using a lower concentration of CHG dissolved in acetate might increase the safety profile of this skin disinfectant, since alcohol increases the risk for systemic chlorhexidine absorption and acetate is not toxic as it is naturally broken down in the body.11 15
Central line-associated bloodstream infections
The finding that the use of a skin disinfectant with a lower percentage of CHG in a non-alcoholic solution did not increase the risk for CLABSI suggests that there is no difference in the antiseptic effect between 0.2% CHG-acetate and 0.5% CHG-70% alc. This is supported by a clinical study in adult patients, which showed similar effectiveness of alcoholic and aqueous solution of CHG on the incidence of CLABSI.25 This raises the possibility that the alcohol component might be superfluous, unnecessary exposing neonates to adverse morbidity.
The safety of the use of a more diluted solution of chlorhexidine is supported by the epic guidelines, which update the evidence-based guidelines for preventing healthcare-associated infections in England.26 This guideline has reported that both (0.5% and 1%) CHG in alcohol and (0.5% and 2%) CHG in aqueous skin antiseptics provide concentrations of CHG that are higher than the minimal inhibitory concentration for most nosocomial bacteria and yeasts (0.05 mg/ml). Even a concentration of 0.2% (2 mg/ml) is still higher than this minimal inhibitory concentration. Although we cannot apply adult data to our population, these results imply that a lower concentration of CHG can be used to achieve the same antiseptic effect.
The most important limitation of this study is the fact that it was a descriptive retrospective study comparing two different time periods. Possibly, under-reporting and possible environmental changes between the two time periods could have played a role. It is conceivable that increased awareness regarding the dangers of chemical injury among all staff may have caused more adequate management in recent years, like turning away the procedure lamp from shining the skin after disinfection and preventing pressure effects on the skin. This could have contributed to a reduction in skin lesions in the 2013–2015 period (the ‘0.2% CHG-acetate’ cohort). However, the protocol for the insertion of central catheters and hand hygiene did not differ between the two periods of time, which meant that the procedure lamp was rotated away from shining the skin as soon as possible after disinfection from 2011 onwards.
0.2% CHG-acetate is associated with fewer skin lesions in extremely preterm infants compared with 0.5% CHG-70% alc. Despite the use of a lower concentration of chlorhexidine, the numbers of CLABSI were similar when using 0.2% CHG-acetate or 0.5% CHG-70% alc. The use of 0.2% CHG-acetate could be considered as a preferred option for skin disinfection in extremely preterm infants. A randomised clinical trial comparing the safety and efficacy of the two disinfectants is recommended for improving the evidence.
Contributors LMAJ conceptualised and designed the study, acquired data, carried out the initial analyses and drafted the initial manuscript.
AT reviewed and revised the manuscript, carried out statistical analyses and approved the final manuscript as submitted.
JH designed the study, critically reviewed the manuscript and approved the final manuscript as submitted.
KDL conceptualised and designed the study, coordinated and supervised all data
collection, critically reviewed and revised the manuscript, and approved the final manuscript as submitted.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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