Cleansing Solutions in

ELBWArticle Review

IntroductionSkin functions:• Modulation of transepidermal water fluxes,

protection from dehydration and excessive water influx, and maintenance of electrolyte homeostasis

• Thermoregulation and minimisation of caloric losses

• Antimicrobial defense• Protection from environmental toxins, trauma and

UV radiation• Tactile sensation

Introduction• Competent epidermal barrier necessary at birth

to maintain fluid homeostasis in extrauterine environment

• Barrier located in stratum corneum (outermost)o mediated by lamellar bilayers of hydrophobic lipids (principally fatty

acids), cholesterol and ceramideso located in extracellular spaces of multiple layers of tightly knit,

anucleate corneocytes, surrounded with protein and keratin-rich cornified cell envelope

Premature infants’ skin

Epidermal permeability barrier forms during 3rd trimester; developmentally immature in preterm infants:• Structural immaturity – stratum corneum and epidermis

thinner • Anchoring fibrils and anchoring filaments fewer and smaller

↓ anchoring of epidermis and ↑ susceptibility to shear forces• Increased TEWL, heat loss, higher caloric demands, increased

potential for absorption of environmental toxins, and compromised antimicrobial defense

• Antibacterial acid mantle forms more slowly in ELBWo Skin pH > 6.0 at birth, declines to 5.5 over 1st few weeks, then 5.0 over 1st month (4.95

in term infants within 1st week)

• Formation of protective layer of vernix underdeveloped (starts 17-20W, well formed 36-38W)

• Fat and zinc accumulate in 3rd trimestero Low subcutaneous fat supply limits thermoregulationo Zinc deficiency causes skin disruption, dermatitis

Premature infants’ skin

• Barrier maturation in prems requires 2-4/52 (up to 8/52 in extreme prems) • Interfollicular cornification and stratum corneum maturation 22-24W

Premature infants’ skin

Developmental immaturity and large surface area-to-body mass ratio (10-15x greater in 25W compared to FT) causes TEWL fluid losses up to 30% total BW in 24H (40-130 ml/kg/day)This may be associated with: • Significant morbidity due to dehydration and hypotension,

increased risk off IVH and NEC• Electrolyte imbalance, esp hyperosmolar hypernatremia

(thus increased risk for IVH)• Thermal instability• Increased caloric demands as skin evaporative losses may

comprise up to 20% of total energy expenditure in < 30WRehydration of prems may exacerbate or induce PDA, heart failure, pulmonary oedema, NEC

Safety and efficacy of cleansing solutions

• Infections leading cause of death in NICU, especially in 1st 2/52 of life as epidermal barrier immature and functionally compromised

• Premature infants suffer significant morbidity and mortality, esp during 1st week of life (~2/3 NND)

• Guidelines for the Prevention of Intravascular Catheter-Related Infections (CDC, 2011)o Numerous studies demonstrated less CRBSI using chlorhexidine skin

prep compared to povidone-iodine.o No recommendation can be made for the safety or efficacy of

chlorhexidine in infants aged <2 months due to limited safety data

CDC Guidelines for the Prevention of Intravascular Catheter-Related

Infections• 0.5% tincture of chlorhexidine vs 10% povidone

iodine – no differences in CVC colonisation or CRBSI

• Three-armed study (2% aqueous chlorhexidine gluconate vs 10% povidone-iodine vs 70% alcohol): 2% aqueous chlorhexidine gluconate decreased CRBSI compared with 10% povidone iodine or 70% alcohol

• Meta-analysis of 4,143 catheters: chlorhexidine preparation reduced risk of catheter related infection by 49% (95% CI .28 to .88) relative to povidone iodine

• RCT (n = 705) reported substantial decrease in colonised catheters in neonates in chlorhexidine impregnated sponge dressing group vs standard dressings (15% vs 24%; RR = .6; 95% CI 5 0.5–.9), but no difference in CRBSI rates or BSI of unknown source

• Chlorhexidine impregnated sponge dressings associated with localised contact dermatitis in VLBW infants o 15 (15%) of 98 VLBW developed localised contact dermatitis; four (1.5%)

of 237 neonates >1,000 g developed this reaction (P < .0001)o Infants <26 weeks GA with CVCs placed at age <8 days were at

increased risk for having localised contact dermatitis, whereas no infants in the control group developed this local reaction

CDC Guidelines for the Prevention of Intravascular Catheter-Related

Infections

Absorption and tolerability of aqueous chlorhexidine gluconate used for skin

antisepsis prior to catheter insertion in preterm neonates

• CHG absorption into blood of preterm infants after topical exposure

• 20 infants, <32W GA, >48HOL but < 14DOL• 2% aqueous CHG impregnated cloth before PICC insertion• Blood samples 1-2H and 6-12H after CHG exposure from

extremity not exposed to CHG• 10/20 infants had detectable CHG concentration, highest

concentration 48-72H after exposure• No correlation of serum concentration to GA, BW or CGA• No increase in AST/ALT after exposure, no increase in

creatinine (except 1 infant with sepsis)• No CRBSI• No CHG-related skin toxicity

Absorption and tolerability of aqueous chlorhexidine gluconate used for skin

antisepsis prior to catheter insertion in preterm neonates

• No data on clinical relevance of trace CHG absorption

• No safety data on tolerable blood CHG concentration and what level there may be adverse consequences

• Several studies in term infants and adults showing safety and tolerance after CHG exposure, no reports of adverse consequences; but preterm infants have developing neurologic systems and immature drug clearance this possible higher risk of adverse outcome

Does skin cleansing with chlorhexidine affect skin condition, temperature and colonization in hospitalized preterm low birth weight infants?

A RCT• Chlorhexidine is shown to reduce skin flora and incidence of

sepsis, although predominantly term neonates• Study on LBW prem 28-36W; 0.25% free• chlorhexidine (= 0.44% chlorhexidine digluconate)• Skin condition at 24H, D3, D7; skin temperature at 30 min,

1H, 6H; colonisation rate of axilla and groin at 24H and 72H after intervention – chlorhexidine vs NS vs no cleansing

• 62% risk reduction in skin colonisation at 24H compared to no cleansing (RR: 0.38; 95% CI: 0.15, 0.98), but no significant reduction when compared to NS cleansing (RR: 0.42; 95% CI: 0.16, 1.10); no significant difference at 72H (?small sample size)

• No significant difference in skin condition

Safety and Impact of Chlorhexidine Antisepsis Interventions for Improving

Neonatal Health in Developing Countries

• Contact dermatitis was reported in 5% of ELBW infants after long-term (> 7 days) placement of chlorhexidine-impregnated dressings for CVC – may have been caused by occlusive dressing instead of chlorhexidine

• No infants receiving skin prep with 0.5% chlorhexidine developed dermatitis, nor those receiving full-body wiping, bathing, or umbilical cord cleansing with chlorhexidine

• 32 consecutive daily bathing of hospitalised newborns (n = 34; 29 preterm) with 4.0% chlorhexidine (Hibiscrub)o 10/23 heel prick samples positive for chlorhexidine samples probably contaminated from

residual chlorhexidine on skin o 5/24 venous blood samples had detectable chlorhexidine – all < 36W GA thus increased epidermal

permeability due to immature skin development

• Potential for absorption appears to be reduced when chlorhexidine is applied in aqueous or other nonethanol-based formulations

• No indication that low levels of chlorhexidine detected in the blood samples resulted in any harmful effects clinically

Safety of chlorhexidine gluconate used for skin antisepsis in the

preterm infant• Chlorhexidine: phenol derivatives, chlorinated

cationic biguanide; bacteriocidal, increasing cell• membrane permeability with more rapid onset of

action; effective against Gram-positive and Gram-negative bacteria

• Leaves a residue on the skin• Binds more strongly to protein in outermost layer

of skin, withstanding removal by alcohol and immediately decreasing organisms on sskin after one application

• Garland et al reported severe contact dermatitis with CHG-impregnated dressing over catheter sites

• 15 (15%) of 98 infants <1000 g and 4 (1.5%) of 237 infants >1000 g developed related contact dermatitis under dressing – most occurred in neonates < 28W and < 1/52 olf

• ?secondary to CHG or external pressure from occlusive adhesive dressing restricting capillary perfusion to skin causing local skin breakdown

• No contact dermatitis reported in infants receiving full-body CHG skin cleansing when occlusive dressings were not necessary, even for severe prem/VLBW

• Alcohol alone can cause skin burns in preterm infants, therefore impact of CHG as trigger of skin breakdown in alcohol-based CHG preparations is unknown

Safety of chlorhexidine gluconate used for skin antisepsis in the

preterm infant

• Literature review of 11 studies demonstrated adverse effects in 4 studies, ranging from self-limited rash to severe skin irritation (4/36 < 1000g and <48H of age)

• From three studies reporting CHG absorption in preterm infants, there were no reports of severe adverse reactions in the patients, including no neurological complications or skin toxicity.

This 644 g baby sustained extensive burns after cleansing with chlorhexidine 0.5% with 70% methanol during umbilical catheterisation. He became hypothermic (32.6˚C), hypernatraemic, then developed systemic fungal sepsis with extensive skin breakdown. After 2/52, skin healed

without apparent cosmetic damage,but he died from renal failure 25/7 later.

Aquaeous chlorhexidine gluconate 2% used to before umbilical catheter insertion soon after birth in a DCDA 25 weeker. 2H later, skin in RIF, right flank, periumbilical area, perineum and groin turned

erythematous. After 6H, the skin became pale. Epithelium was lost in affected areas – diagnosed mixed-depth, partial-thickness

burns.These injuries completely healed with conservative management over 4 weeks with no residual

scarring.

Use with CautionComplications of severe burns:• Hypothermia, excessive water loss, sepsis, and

renal failure. • Pain and stress can adversely affect neuronal

maturation in the brain, and skin scarring and depigmentation

If CHG is going to be used frequently in preterm infants, it is important to identify which component, the CHG or the ethanol, causes skin irritation in this population and to develop formulations of CHG products that can be more safely administered to these infants.

Use with Caution• Wiping off excess chlorhexidine with normal

saline may help reduce skin irritation, but there are reports of skin burns even after cleansing skin with NS

• Dry immediately and avoid prolonged contact, avoid pooling of cleanser under infant

• Higher risks of skin irritation in 1st 48HOL• Alcohol based skin cleansers associated with

higher risk of skin irritation – reported to cause extensive burns in prems, where skin vulnerability accentuated by hypoxia and hypothermia

Additional measures for skin care

• Avoid alkali bathing soap (pH up to 9) alter skin’s pH, takes up to 1H for term skin to regain acidic property, takes even longer for prems (inteferes with acid mantle) proliferation of bacterial growth and increases permeability of skin surface

• Barrier products e.g. emollients (white soft paraffin) adds lipid layer to surface of the skin, and/or provides lipids which can penetrate stratum corneum, simulating effects of naturally occurring lipids protect skin from irritants and microorganisms and prevent increased TEWL through damaged areas

• Humidified environment 85-90% in 1st week, gradually reducing by 40% over 2-3/52 – prevents excessive TEWL

References• O’Grady NP, Alexander M, Dellinger EP, Gerberding JL, Heard SO, Maki DG et al. Guidelines

for the prevention of intravascular catheter-related infections, 2011. The Hospital Infection Control Practices Advisory Committee, Center for Disese Control and Prevention.

• Mullany LC, Darmstadt GL, Tielsch JM. Safety and impact of chlorhexidine antisepsis interventions for improving neonatal health in developing countries. Pediatr Infect Dis J 2006; 25(8): 665–675.

• Chapman AK, Aucott SW, Milstone AM. Safety of chlorhexidine gluconate used for skin antisepsis in the preterm infant. J Perinatol 2012; 32(1): 4–9.

• Reynolds PR, Banerjee S, Meek JH. Alcohol burns in extremely low birthweight infants: still occurring. Arch Dis Child Fetal Neonatal Ed 2005; 90(1): F10.

• Sankar MJ, Paul, VK, Kapil A, Kalaivani M, Agarwal R, Darmstadt GL, Deorari AK. Does skin cleansing with chlorhexidine affect skin condition, temperature and colonization in hospitalized preterm low birth weight infants?: a randomized clinical trial. J Perinatol 2009; 29: 795-801.

• Chapman AK, Aucott SW, Gilmore MM, Advani S, Clarke W, Milstone AM. Absorption and tolerability of aqueous chlorhexidine gluconate used for skin antisepsis prior to catheter insertion in preterm neonates. J Perinatol 2013; 33: 768-771.

• Upadhyayula S, Kambalapalli M, Harrison CJ. Safety of anti-infective agents for skin preparation in premature infants. Arch Dis Child 2007;92:646–7.

• Lashkari HP, Chow P, Godambe S. Aqueous 2% chlorhexidine-induced chemical burns in an extremely premature infant. Arch Dis Child Fetal Neonatal Ed 2011.

• Lund C, Kuller J, Lane A, Lott JW, Raines DA. Neonatal Skin Care: The Scientific Basis for Practice. Neonatal Network 1999; 18 (4): 15-26.