Cutaneous antisepsis for prevention of intravascular catheter–associated infection in newborn infants

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the safety and efficacy of different cutaneous antisepsis regimens for prevention of sepsis in newborn infants. Planned subgroup comparisons would include term infants and preterm infants, as well as various types of intravenous access.


Catheter-related bloodstream infection (CRBSI) or central line–associated bloodstream infection (CLABSI) is an all too common occurrence in paediatric and neonatal intensive care units around the world. CRBSIs are estimated to cause up to 70% of all hospital-acquired bloodstream infections in preterm infants (Kaplan 2011), placing a strain on limited resources in terms of staff and cost. A recent study in the USA showed an increase of four to seven days in length of stay associated with nosocomial bacteraemia (Payne 2004). Newborn infants, especially extremely preterm sick infants, are vulnerable to bloodstream infection because of poor skin barriers and invasive catheters in situ. Infection rates of 14 infections per 1000 infant-days of exposure have been reported in Australian and New Zealand neonatal nurseries (Gill 2009). Efforts to reduce infection in the nursery would include optimal infection control practices (hand hygiene), judicious use of invasive devices and appropriate use of antimicrobial agents (Brady 2005). Skin colonisation and catheter hub colonisation remain important determinants of CRBSI (Moro 1994), and methods to decrease its occurrence include appropriate skin antisepsis during vascular access and vigilance during catheter maintenance and access. Reducing bacterial colonisation at central line insertion sites remains an important step in decreasing CRBSIs. Povidone-iodine was used frequently in the past, but preterm infants are now known to be vulnerable to iodine toxicity from skin absorption, especially hypothyroidism (Linder 1997). Cetrimide, a quaternary ammonium compound, was widely used for its sterilising properties and for cutaneous antisepsis. However, chemical burns in the form of cutaneous blisters and erythema have been reported in infants (Gathwala 2006; Mercer 1983). Chlorhexidine gluconate (CHG) has been demonstrated to be superior to povidone-iodine in achieving topical antisepsis and preventing bacterial colonisation of the catheter tip (Garland 2009). CHG has a broad spectrum of antimicrobial activity that is mediated by protein denaturation and disruption of the microbial cell membrane. Chlorhexidine-based antiseptic for skin preparation before central line insertion and dressing changes has been recommended for use in infants over two months of age (Bryant 2010). CHG is available in different concentrations from 0.015% to 4.0%. Concerns have been raised about potential cutaneous toxicity of CHG, and the risk/benefit ratio needs to be weighed when decisions are made about the best cutaneous antisepsis for newborn infants. Adverse effects of CHG in the form of cutaneous erythema, blisters and skin burns, especially in premature infants, have been reported (Shah 2013). Uniformity regarding skin antisepsis in newborn infants is lacking, and its use is currently not approved by the US Food and Drug Administration for infants younger than two months. However, a national US survey of neonatology programme directors revealed that 78% of neonatal intensive care units use CHG, often with some restrictions (Tamma 2010).

Description of the condition

Despite advances in neonatal care, especially with survival of extremely preterm infants, infection remains a major challenge in neonatal intensive care units around the world. The most common infective agent causing infection is coagulase-negative Staphylococcus. Studies of adult and paediatric participants implicate intravascular catheter placement and secondary invasion around the catheter as the sources of bacteraemia (Hall 1991). Direct inoculation of bacteria may occur during insertion of the cannula, especially in the immunocompromised preterm infant. Skin colonisation and hub colonisation are the two major determinants of catheter-related infection (Moro 1994). Skin colonisation due to multiple factors can be strongly affected by factors such as age, duration of catheterisation and type of dressing. Cutaneous disinfection before the vascular device is inserted may reduce the risk of CRBSI.

Description of the intervention

Effective cutaneous disinfection in preterm infants can reduce the incidence of infection, and careful adherence to strict aseptic technique is desirable for reducing catheter site contamination (Malathi 1993). Cutaneous disinfectants widely used in neonatal nurseries include chlorhexidine, isopropyl alcohol, povidone-iodine, hexachlorophane or cetrimide or a combination of these agents at varying concentrations.

Chlorhexidine: Chlorhexidine is a cationic biguanide that has broad-spectrum microbicidal activity mediated by disruption of microbial cell membranes (Kuyyakanond 1992). Use of chlorhexidine in neonatal nurseries is widespread for various invasive procedures such as central/umbilical line insertion, central line maintenance and bathing of newborn infants. Although chlorhexidine acetate is available as well, chlorhexidine gluconate is widely used and is available in aqueous and alcohol-based solutions. However, concerns have arisen regarding the safety of CHG in newborn infants, and reports of cutaneous adverse effects have been published. Garland 2009 reported increased blood levels of CHG in preterm infants after its use for cutaneous antisepsis; however, toxic effects have not been seen.

Isopropyl alcohol: Isopropyl alcohol contains 68% to 99% isopropanol by volume and is very effective in disinfecting by denaturing proteins and dissolving lipids, effectively destroying bacterial and viral cells.

Povidone-iodine: Iodine exhibits rapid, broad-spectrum antimicrobial activity against bacteria, viruses and fungi by penetrating micro-organisms and attacking groups within nucleotides (DNA), fatty acids and thiol groups within proteins. In povidone-iodine solutions, the polyvinylpyrrolidone polymer (PVP) is complexed with iodine, acting as a reservoir for free iodine (Gottardi 2001). Cutaneous absorption of povidone-iodine may compromise thyroid function in preterm infants, with elevated urine iodine levels reflecting abnormally high iodine absorption (Gordon 1995; Linder 1997).

Hexachlorophane: Hexachlorophane has been used in the past as a topical anti-infective agent; however, as the result of adverse effects from cutaneous absorption, its use has been discontinued (Gillespie 1974).

Cetrimide: Cetrimide (alkyltrimethylammonium bromide) is a halogenated quaternary ammonium antiseptic that is not commonly used in newborn infants. It is available in powder and liquid formulations at different concentrations. Concentrations exceeding 1% have been reported to cause irritation and burns to the skin and mucous membranes because of the caustic nature of these compounds (Gathwala 2006; Mercer 1983).

How the intervention might work

The best intervention for reducing CRBSIs would require identifying clinical practices that have the potential for success because they can be implemented by clinicians in a reliable way. Experimental studies such as randomised controlled trials (RCTs) will be useful in exploring the efficacy of these clinical practices to prevent CRBSI. To reduce CRBSI, evidence-based catheter care practices including hand hygiene, maximal barrier precautions, appropriate skin disinfection before catheter insertion and appropriate dressing of the central line need to be instituted. Assessment of the need for catheters and daily assessment of their continued need are important aspects of interventions to reduce infection. Similarly, catheter maintenance practices such as evaluation of the catheter insertion site, asepsis during line changes, use of heparin in infusion and minimisation of catheter access ports need to be established.

Why it is important to do this review

No recent evidence or guidelines have been provided for the use of cutaneous antiseptic solutions in newborn infants for intravenous access. Surveys performed across neonatal nurseries suggest lack of uniformity with regard to type and strength of antiseptic solutions used. Further evidence of adverse events of skin antisepsis would be useful in evaluating best practice. By conducting this review, we would like to evaluate the efficacy and safety of antiseptic solutions for use in newborn infants.


To determine the safety and efficacy of different cutaneous antisepsis regimens for prevention of sepsis in newborn infants. Planned subgroup comparisons would include term infants and preterm infants, as well as various types of intravenous access.


Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised controlled trials, cluster-randomised trials, published and unpublished.

Types of participants

Term and preterm infants admitted to the neonatal intensive care unit requiring intravenous access.

Types of interventions

Chlorhexidine: chlorhexidine versus placebo, chlorhexidine (aqueous) versus chlorhexidine (alcohol) and chlorhexidine versus other agents (isopropyl alcohol, iodine, hexachlorophane, cetrimide).

Isopropyl alcohol: isopropyl alcohol versus placebo and isopropyl alcohol versus other agents (chlorhexidine, iodine, hexachlorophane, cetrimide).

Povidone-iodine: iodine versus placebo and iodine versus other agents (chlorhexidine, isopropyl alcohol, hexachlorophane, cetrimide).

Hexachlorophane: hexachlorophane versus placebo and hexachlorophane versus other agents (chlorhexidine, isopropyl alcohol, iodine, cetrimide).

Cetrimide (cetrimonium compounds): cetrimide versus placebo and cetrimide versus other agents (chlorhexidine, isopropyl alcohol, iodine, hexachlorophane).

Types of outcome measures

Primary outcomes
  1. Death from any cause before hospital discharge.

  2. Neonatal death (death from any cause in the first 28 days of life).

  3. Neonatal sepsis (defined as clinical symptoms of sepsis and isolation of bacteria/fungi from normally sterile body fluids).

  4. Neonatal meningitis (defined as symptoms of meningitis and isolation of bacteria/fungi from cerebrospinal fluid by culture or identification on microscopy in association with increased white cell count in cerebrospinal fluid).

Secondary outcomes
  1. Adverse effects of skin antisepsis solutions (immediate or late), including skin irritation, burns, erythema, blisters and hypothyroidism.

  2. Length of stay in the neonatal nursery (days).

  3. Retinopathy of prematurity (any stage and severe stage 3 or 4, or need for retinal ablation or surgery) (ICROP 2005).

  4. Necrotising enterocolitis (NEC) according to Bell criteria (Bell 1978): stage IA: suspected NEC; stage IB: suspected NEC with blood from rectum; stage IIA: confirmed NEC, mildly ill with pneumatosis intestinalis; stage IIB: confirmed NEC, moderately ill with portal vein gas; stage IIIA: advanced NEC with organ dysfunction; stage IIIB: advanced NEC with pneumoperitoneum.

  5. Long-term neurodevelopmental outcome: neurodevelopmental outcome at approximately two years corrected age (acceptable range 18 months to 28 months) including cerebral palsy, significant mental developmental delay (Bayley Scales of Infant Development Mental Developmental Index < 70), legal blindness (< 20/200 visual acuity) and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" was defined as having any one of the aforementioned deficits.

Search methods for identification of studies

The Cochrane Neonatal Review Group (CNRG) search strategy will be used.

Electronic searches

The following databases will be searched.

  1. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to current), EMBASE (1980 to current) and CINAHL (1982 to current).

The following MeSH terms or text words will be used.

  1. antisepsis, cutaneous OR antisepsis, skin AND

  2. intravenous access OR central lines AND

  3. infant, newborn/OR infant, premature/OR infant, premature, disease OR (neonate: OR prematur*: OR newborn) AND

  4. controlled clinical trial OR randomised controlled trial OR cohort studies

  5. chlorhexidine

  6. iodine

  7. povidone iodine

  8. cetrimonium compounds

  9. alcohols

  10. anti-infective agents

Searching other resources

Abstracts of annual conferences of the Academic Paediatric Society (1996 to current), the Perinatal Society of Australia and New Zealand (PSANZ; 1997 to current) and the European Society for Pediatric Gastroenterology and Hepatology and Nutrition (ESPHGAN; 1987 to current) will be searched.

Unpublished trials from the International Clinical Trials Registry Platform and the Australia and New Zealand Clinical Trial Registry will be searched as well.

Data collection and analysis

Selection of studies

Each review author will independently assess the eligibility of studies for inclusion. The criteria and methods of the CNRG (CNRG 2011) will be used to assess the methodological quality of included trials.

Data extraction and management

The review authors will use data extraction forms to independently assess selected studies for data quality on issues of blinding of allocation, blinding of intervention, completeness of follow-up and blinding of outcome ascertainment. Data extraction will be done independently by two review authors.

Assessment of risk of bias in included studies

In addition, the following issues will be evaluated and entered into the 'Risk of bias' table.

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated? For each included study, the method used to generate the allocation sequence will be categorised as:

    1. adequate (any truly random process, e.g. random number table, computer random number generator);

    2. inadequate (any non-random process, e.g. odd or even date of birth, hospital or clinic record number); or

    3. unclear.

  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed? For each included study, the method used to conceal the allocation sequence will be categorised as:

    1. adequate (e.g. telephone or central randomisation, consecutively numbered sealed opaque envelopes);

    2. inadequate (open random allocation, unsealed or non-opaque envelopes, alternation, date of birth); or

    3. unclear.

  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment? For each included study, the methods used to blind study participants and personnel from knowledge of which intervention a participant received will be categorised. Blinding will be assessed separately for different outcomes or classes of outcomes. The methods will be categorised as:

    1. adequate, inadequate or unclear for participants;

    2. adequate, inadequate or unclear for personnel; and

    3. adequate, inadequate or unclear for outcome assessors.

  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed? For each included study and for each outcome, the completeness of data including attrition and exclusions from the analysis will be described. Whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total number of randomly assigned participants), reasons for attrition or exclusion when reported and whether missing data were balanced across groups or were related to outcomes will be noted. When sufficient information was reported or supplied by the trial authors, missing data in the analyses will be re-included. The methods will be categorised as:

    1. adequate (< 20% missing data);

    2. inadequate (≥ 20% missing data); or

    3. unclear.

  5. Selective reporting bias. Were reports of the study free of the suggestion of selective outcome reporting? For each included study, the possibility of selective outcome reporting bias and what will be found will be reported. The methods will be assessed as:

    1. adequate (when it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

    2. inadequate (when not all of the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported); or

    3. unclear.

  6. Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias? For each included study, any important concerns about other possible sources of bias (e.g. whether a potential source of bias was related to the specific study design, whether the trial was stopped early because of some data-dependent process) will be described. Whether each study was free of other problems that could put it at risk of bias will be assessed as:

    1. yes;

    2. no; or

    3. unclear.

If needed, review authors will explore the impact of the level of bias by undertaking sensitivity analyses.

Measures of treatment effect

For dichotomous outcomes, risk ratio (RR) and risk difference (RD) and their confidence intervals will be used. Number needed to treat for an additional beneficial outcome (NNTB) and number needed to treat for an additional harmful outcome (NNTH) if the RD is statistically significant will be calculated. Differences between means and standard deviations will be used for continuous outcomes. Meta-analysis of pooled data, if suitable, will be performed and a fixed-effect model assumed. Review Manager software (RevMan 5.2) will be used for statistical analysis.

Unit of analysis issues

If a cluster-randomised trial is included in the meta-analysis, the standard error derived from the confidence interval of the effect estimate will be multiplied by the square root of the design effect.

The unit of analysis will be infection per line inserted or infection per infant.

Dealing with missing data

For all included studies with missing data, the review authors will contact the authors of the published papers to request further information.

Assessment of heterogeneity

The proportion of total statistical heterogeneity not explained by chance will be estimated using the I2 statistic. I2 (calculated as I2 = 100% × (Q-df)/Q; where Q is Cochrane's heterogeneity statistic and df is degrees of freedom) lies between 0% and 100%. The following cutoffs will be used.

  1. < 25%: no heterogeneity.

  2. 25% to 49%: low heterogeneity.

  3. 50% to 74%: moderate heterogeneity.

  4. ≥ 75%: high heterogeneity.

If statistical heterogeneity is detected, possible causes will be explored. A fixed-effect model will be used for the meta-analyses. Publication bias will be examined using a funnel plot, and a regression approach will be used to assess funnel plot asymmetry (Egger 1997).

Assessment of reporting biases

The standard methods of the CNRG (CNRG 2011) will be used for reporting biases. The methodological quality of the studies will be assessed by using the following key criteria: allocation concealment (blinding of randomisation), blinding of intervention, completeness of follow-up and blinding of outcome measurement/assessment. The review authors will assess each study separately, and disagreements will be resolved by discussion.

Data synthesis

Review Manager (RevMan 2012) will be used to perform the meta-analysis of studies included in the review. Strategies from the Cochrane Handbook for Systematic Reviews of Interventions will be followed (Higgins 2011).

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be performed on the basis of:

  1. gestational age (≤ 37 weeks or > 37 weeks);

  2. type of intravenous access (central line vs peripheral line vs umbilical line); and

  3. single versus multiple line placements.

Sensitivity analysis

A sensitivity analysis will be performed on all studies definitively known to be eligible.


None identified.

Contributions of authors

Both review authors will perform literature searches and will assess methodological quality. Dharmesh Shah (DS) will enter the data into Review Manager and will write the discussion. Mark Tracy (MT) will check the data entered, correspond with authors of the studies and revise and edit the draft of the review.

Declarations of interest

None identified.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C