Marty O. Visscher, PhD · Topical agents include anything that touches the infant's skin. The skin...

From the SCenter, CinAddress coInstitute, CAvenue, Ci© 2009 El1527-3369doi:10.1053

Update on the Use of Topical Agents in Neonates

Marty O. Visscher, PhD

Topical agents include anything that touches the infant's skin. The skin is crucial to the way the infantperceives and responds to the care environment and, therefore, in neurodevelopment. Psychological stressnegatively affects the barrier. The full-term infant has well-developed epidermal barrier despite spending9 months being submerged in water. Vernix caseosa is a natural topical agent that facilitates stratum corneumbarrier development through protective and adaptive mechanisms. Its properties include hydration, woundhealing, antiinfection, and acid mantle development. The ontogeny of neonatal skin development and vernixbiology provide the basis for assisting barrier maturation in premature infants, treating compromised skin andselecting topical agents. The published research on the effects of topical products on premature and damagedneonatal skin is very limited, especially for adequately sized randomized controlled clinical trials. Health careproviders have keen interest and the skills to identify improved treatments through outcomes-based research.

Keywords: Skin barrier; Neonate, Topical agent; Stratum corneum; Compromised skin

Overview and PerspectiveThe article will review topical products in infants. Conceptually,we define topical products in the broadest sense to includeanything that touches or interacts with infant skin. The skin is aprimary care interface vitally important in any patient-caregiverinteraction.1 The most recent information about skin structure,development, and function will be discussed to generate thecontext of topical treatments and products.

Touch is the first sense to develop in the infant. As a result,the skin is an important element in the process of how the infantperceives and reacts to the environment of care and, therefore,in neonatal neurodevelopment. Examples of skin-based infantinteractions include skin-to-skin contact (kangaroo care), infantmassage, Newborn Individualized Developmental Care andAssessment (NIDCAP), and tactile stimulation. Skin-to-skincontact immediately after birth results in increased temperatureand blood glucose levels compared with swaddling next to themother.2 Skin-to-skin contact for 1 hour shortly after birthimpacted state organization and the time spent sleeping.3

Premature infants cared for with NIDCAP methods hadsignificantly better neurobehavioral function and more matureneuronal fiber structure.4 In a longer-term study, infantsreceiving NIDCAP had significantly better mother-child inter-

kin Sciences Institute, Cincinnati Children's Hospital Medicalcinnati, OH.rrespondence to Marty O. Visscher, PhD, The Skin Sciencesincinnati Children's Hospital Medical Center, 3333 Burnetncinnati, OH 45229. E-mail: [email protected] Inc. All rights reserved./08/0901-0289$36.00/0/j.nainr.2008.12.010

action (cluster communication), better hearing/speech, andlower behavior symptom scores.5 Tactile stimulation viarepeated stroking increased circulating lactate levels by 200%in the neonatal rat model.6 These findings demonstrate thecritical role of simple infant-caregiver skin-based interactions onthe cognitive development of the infant.

Specific skin receptors are sensitive to mechanical stimuliand are critical for survival. The signaling proteins involved inthis transduction are being identified.7 Psychological stress dueto environmental overcrowding is associated with a delay inskin barrier recovery in mice, an effect attributed to increasedproduction of glucocorticoids.8 Psychological stress decreasedepidermal cell proliferation, adversely effected differentiation,and decreased the size and density of corneodesmosomes, all ofwhich negatively impact skin barrier function.9 Stress decreasedantimicrobial peptides in the epidermis (animal model), aneffect that resulted in more severe skin infections.10

Skin Structure and FunctionHuman skin serves multiple functions including barrier (to

water loss, irritant exposure, light, etc), immunosurveillance,infection control, sensation, structural support, and thermalregulation (Table 1). The major skin layers are the epidermis,dermis, and hypodermis (subcutaneous). Fig 1 shows a cross-section and the structures responsible for the functions. Twolayers comprise the dermis. The upper is the papillary layer,contains capillary loops, and is loosely organized. The lower isthe reticular dermis composed of tightly packed collagen andelastin with glycosaminoglycans, which provide mechanicalproperties and elasticity. The epidermis includes the stratumcorneum (SC, outer) and the viable epidermis (Fig 2). Anunderstanding of SC structure and function is essential for being

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Table 1. Skin FunctionsFunction Skin Structure

BarrierPhysical(irritants)

SC and epidermis

Light Melanocytes of the epidermisImmunologic Langerhans cells of the epidermis

Resilientfoundation

Dermis

Sensation Sensory nerves in epidermis anddermis

Tactilediscrimination

SC and sensory nerves

Thermalregulation

Eccrine sweat glands in dermisBlood supply in dermisAdipose fat in subcutaneous layer(hypodermis)

ig 1. Skin structures. A cross-section of the skinhows the structures responsible for the functions.he major skin layers are the epidermis, dermis, andypodermis (subcutaneous). The outermost layer,he SC, is directly exposed to the environment. Theigure was provided by the National Institutes ofealth for use by the public and can be found at

http://media.nih.gov/imagebank/display_search.

able to select topical products. The SC is the main barrier towater loss and penetration by outside agents. The viableepidermis has four layers (top to bottom): clear (stratumlucidum), granular (stratum granulosum), spinous (stratumspinosum, nucleated cells), and basal (stratum basale, nucleatedcells). Two specialized dendritic cells are housed in the viableepidermis. Langerhans cells (antigen-presenting cells) are part ofthe immune system and serve as the line of defense if the SCbarrier is breached (Fig 2). The melanocytes (pigment cells)reside in the basal layer and produce melanin, the pigmentresponsible in part for inherent skin color. When the skin isexposed to UVradiation,melanocytes are activated and transportmelanin to the nuclei of the epidermal cells to shield them andprotect the DNA. Skin tanning is the result of this process. Thepigmentary system is influenced by irritation and inflammationand may respond by producing more pigment (hyperpigmenta-tion) or by deactivation (resulting in hypopigmentation).

The function of the viable epidermis is to continually buildand replenish the SC. The cells “move up” from the basal layerand transition to SC cells through a programmed process.About 28 days is required for a cell to go from the basal layerand be lost from the outer SC. The SC is made up of about 16layers of flattened cells (corneocytes) joined together bymolecular “rivets” (aggregates of large molecules) calleddesmosomes (insert in Fig 2). The SC is about half of thethickness of a sheet of paper but incredibly strong. The processof going from nucleated cells to SC corneocytes begins in theupper spinous and granular cells with formation of the cross-linked cell envelope. Structures, called lamellar bodies, in thespinous layer store lipids. In the upper granular layer (belowthe SC), the lipids (cholesterol, fatty acids, ceramides) aresecreted from the lamellar bodies into the intercellular spacesbetween the corneocytes to form a regular “brick (cells) andmortar (lipids)” structure. The lipids form a regular orderedbilayer structure, alternating with water, between the cells. Bydesign, the SC structure is difficult to penetrate from theoutside. It is the barrier to water loss but allows normal water

32 VOLUME 9, NUMBER 1

vapor from respiration to be released. The integrity of the SC ismeasured in terms of the rate of transepidermal water loss(TEWL). Normal skin has TEWL values of approximately 6 to8 grams per square meter per hour, and higher rates indicate adamaged barrier, poorly developed SC, or SC with fewer layersthan normal. The important goal of topical skin treatments isto maintain or restore the SC barrier. A schematic of showingnormal and compromised SC barriers is shown in Fig 3.Normal skin looses about one SC layer per day through theprocess of desquamation where the connections between SCcells degrade and release the cells to the environment. Anappropriate level of hydration is required for proper desqua-mation. Stratum corneum that is too dry will not desquamateproperly and results in large aggregates of cells, scales or dryskin flakes. The protein filaggrin in the SC corneocytes isconverted to small water-binding amino acids called naturalmoisturizing factor (NMF). Natural moisturizing factor is inpart responsible for maintaining the appropriate level of SChydration, and loss of NMF or disruption of the NMFgeneration will result in low SC moisture. Excess hydration willalso cause barrier damage as will be discussed later.

Neonatal Skin DevelopmentBirth marks are a significant environmental change for the

infant from a warm, sterile, and safe womb to a dry high-oxygenenvironment with multiple organisms (bacteria) and demandsfor self-sufficiency such as air breathing, enteral nutrition, wasteelimination, and maintenance of water balance. Neonatal skinserves many functions at birth, including a barrier to water lossand chemicals, temperature regulation, tactile discrimination,

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Fig 2. Structure of the epidermis. The SC is the main barrier to water loss and penetration by outside agents.The viable epidermis has four layers (top to bottom): clear, granular, spinous (nucleated cells), and basal(nucleated cells). Two specialized dendritic cells are housed in the viable epidermis. Langerhans cells (antigen-presenting cells) are part of the immune system and serve as the line of defense if the SC barrier is breached.

infection control, immunosurveillance, antioxidation, and acidmantle formation.

The Full-Term InfantThe full-term infant has well-developed epidermal barrier at

birth, despite spending 9 months being submerged in water. Inmost cases, overhydration of the skin has a damaging effect, thatis, maceration, barrier disruption, and tissue injury. Transepi-dermal water loss (rate of respiratory water vapor loss, TEWL) isvery low at birth for full-term infant, equal to or lower thanadults, indicating a highly effective skin barrier.11,12 Withinminutes to hours after birth, skin hydration (moisture) varieswith body site (chest, back, forehead), time under the warmer,and retention or removal of vernix caseosa.13,14 Hydrationdecreases rapidly in the first day and then increases during thefirst 2 weeks compared with constant values in the mother. Thischange indicates that significant adaptive changes occur in theupper SC.15 Newborn skin was significantly drier than the skinof older infants (1, 2, and 6 months) and the mothers.16 Water-binding ability increased during the first 14 days, denotingchanges in the water-handling processes within the SC. Toidentify possible causes of low hydration, we measured theNMF levels at birth and found it to be extremely low.17 Theywere higher at 1 month but lower than levels in adults. Naturalmoisturizing factor is water soluble and may be extracted fromthe SC into the amniotic fluid. Alternatively, NMF generationfrom filaggrin may be activited as part of the adaptation to dryconditions. At birth, the full-term skin pH is relatively neutral,

NEWBORN & INFANT NURSIN

decreases significantly during the first 1 to 4 days, andcontinues to drop during the first 3 months.12,15,18 Theantimicrobial protein lysozyme was found in newborn SC atlevels five times higher than adults. Lysozyme activity was notaltered with routine bathing.19

Vernix Caseosa: Natural TopicalTreatment

The question remains: How does the full-term infant developan excellent barrier while in water? During the last trimester,vernix caseosa begins to coat the skin from head to toe and backto front and may facilitate SC barrier development.14 Vernix is acomplex mixture of 80% water, 10% protein, and 10% lipids,with corneocytes embedded in a lipid matrix.20 The remarkablyhigh water is associated with the cells. Vernix formation isbelieved to be under hormonal control during gestation, withlipids generated by the sebaceous gland and cells from the hairfollicle. It is “extruded” onto the interfollicular epidermis tocover the whole surface.21 Presumably, vernix forms a hydro-phobic surface, thereby protecting the epidermis from exposureto water, and creates conditions under which the cornificationand formation of the SC can occur. Vernix contains antimicro-bials; for example, lysozyme, lactoferrin, and the antiinfectiveproperties have been demonstrated by several researchers.22-25

Vernix treatment of adult volar skin increased the SC water-binding capacity.26 Native vernix treatment of SC wounds (tapestripped skin) assisted barrier repair relative to controls and

33G REVIEWS, MARCH 2009

Fig 3. The development of the SC occurs during thelast trimester of gestation and is relatively well formedon average by week 34 to 35. At 23 weeks, the SC isnearly absent and TEWL values are 75 grams persquare meter per hour. By week 26, a few cornifiedlayers have formed (TEWL of approximately 45 gramsper square meter per hour). At 29 weeks, the TEWL is17 grams per square meter per hour and markedlyhigher than values of 5 to 6 grams per square meterper hour observed in the full-term infant.

demonstrated wound healing properties.27 In some settings,vernix is removed immediately after birth. The role of vernix inneonatal skin adaptation was assessed by comparing the effectsof vernix retention vs removal in parallel groups of full-terminfants at delivery. Vernix retention resulted in significantlyhigher skin hydration 24 hours after birth.14 Skin pH valueswere lower in the vernix-retained group, suggesting that vernixfacilitates the development of the acid mantle. Treatment of SCwounds (created by repeatedly tape stripping adult forearm skinto remove SC layers) with vernix assisted barrier repair relative tocontrols.27,28 In model systems, vernix enhanced SC formationwithout increasing epidermal thickness.29 Films of verniximpeded the penetration of the exogenous enzyme chymo-trypsin (found in meconium, similar proteolytic enzymespresent in feces) but maintained the activity of native enzymes(necessary for epidermal development) in vitro.29

Overall, vernix facilitates SC barrier development in thenormal full-term infant through a variety of protective andadaptive mechanisms. The findings provide support for thepractice of vernix retention (rather than removal) at birth. TheWorld Health Organization recommends waiting for at least 6hours before bathing newborn infants in part to facilitate thepositive effects of residual vernix.


Premature Infant Skin DevelopmentUnlike that of the full-term baby, the dermis of the premature

infant is not fully formed and deficient of structural proteins. Asa result, the mechanical properties are poor and the skin is easilytorn. The preterm epidermis is markedly thinner, and the SC ispoorly formed in contrast to the thick fully developed SC of thefull-term neonate. The SC structural integrity is directly relatedto gestational age at birth, and rapid barrier development occursfrom weeks 24 to 34. Very low-birth-weight infants are atgreatest risk for skin damage during the early days of life. At23 weeks, the SC is nearly absent with TEWL of 75 grams persquare meter per hour (Fig 3).30 By week 26, a few cornifiedlayers have formed (TEWL of approximately 45 grams persquare meter per hour). The very premature infant has,essentially, a wounded skin surface.31,32 At 29 weeks, theTEWL is 17 grams per square meter per hour and markedlyhigher than the values of 5 to 6 grams per square meter per hourobserved in the full-term infant. Around weeks 34 to 35, thebarrier is relatively well formed. Infants born prematurely (ie,b28 weeks) do not have the covering of vernix.

Poor SC integrity puts the premature infant at risk for highwater loss, electrolyte imbalance, thermal instability andincreased exposure to environmental irritants and infectiousagents due to increased permeability. After birth, the barriercontinues to develop, but even after 1 month, TEWL issignificantly higher than in normal full-term infants.33 Furtherimpairment of barrier function in premature infants wasindicated by significantly higher values of skin hydration, andinfants less than 30 weeks gestation have significantly highervalues of skin hydration than those older than 30 weeks as aresult of higher rates of water being lost through the skin.34 Byday 5, the skin hydration was significantly lower for infants lessthan 27 weeks' gestational age, indicating rapid barrierdevelopment. The humidity of the environment influences therate and quality of SC barrier maturation. Exposure to lowhumidity (10% relative humidity [RH], animal model) resultedin a decrease in SC hydration and an increase in epidermal DNAsynthesis. This observation suggests that low hydration triggerscell proliferation.35 Clinically, very premature infants frequentlyexhibit an abnormal pattern of desquamation several weeksafter birth, indicative of a hyperproliferative SC. Humidityaffects the degradation of epidermal filaggrin to NMF that bindswater in the SC.36 Without NMF, the SC is dry, does notdesquamate properly, and has poor water-holding capacity. Atbirth (animal model), filaggrin degradation occurred at 80% to95% humidity but not at high (100% RH) or low humidities,suggesting that NMF generation depends upon ambient wateractivity.37 Natural moisturizing factor levels are likely to be verylow under the conditions of rapid SC development such as forpremature infants in low humidity.

Skin OcclusionAppropriate SC hydration is necessary for effective skin

function, for example, to allow sufficient plasticity andflexibility during movement, to prevent cracking, and for

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desquamation.38,39 However, prolonged exposure to watercauses skin maceration, barrier breakdown, and dermatoses,including inflammation, irritation, and urticaria.40-45 Waterexposure caused SC abnormalities, including disruption of theintercellular lipid bilayers, degradation of the desmosomes, andcreation of amorphous regions within the lipids, as illustratedin Fig 3.46

Hydration causes the SC corneocytes to swell, increases thefluidity of the lipids, and enhances molecular transport toincrease permeability to exogenous materials.47,48 Occlusion ofthe skin surface can occur from any material that does not allowsufficient water to pass through it, including diapers, certaintapes, thick layers of topical products, and devices such asbraces, casts, and splints.49 Water builds up under the materialand causes SC hydration to increase and barrier damage tooccur, as shown in Fig 4.

Topical Treatments for InfantsThe biology of infant skin development and maturation

provides the clues for identifying strategies for treatingcompromised skin. Vernix may be the “ideal” topical treatment,as some suggest, for infants and adults.50,51 Infants bornprematurely (ie, b28 weeks) are missing protective covering ofvernix. In the broadest sense of “topical treatments” as anythingthat interacts with the outer skin surface, specific strategies willbe discussed.

Treatments for Barrier Maturation

Environmental conditions Humidified isolettes have been usedto mitigate the high water loss in premature infants. Extremely

Fig 4. Effects of skin occlusion. Occlusive treatments pdamage to the SC barrier, and allow increased penetra


low-birth-weight infants needed lower fluids and had improvedelectrolyte balance.52 Humidity is used routinely with levelsadjusted to manage fluid loss, temperature, and so on toensure that overhumidification does not cause bacterialcontamination.53 A 2006 study among infants of 23 to27 weeks' gestational age showed that the SC barrier developedmore rapidly for the neonates in isolettes at 50% RH comparedwith infants at 75% RH.54

Films Transparent semipermeable dressings (eg, Tegaderm; 3M,St. Paul, MN) have been used to control water loss in prematureinfants. Tegaderm dressing was applied to large body surfaceareas on infants of 24 to 26 weeks' gestational age, and dailyfluid intake, serum sodium levels, and weight loss weresignificantly lower compared with infants who had not beentreated.55 Transepidermal water loss was also reduced, indicat-ing that the film had assisted in barrier maturation. In infantsless than 32 weeks' gestational age, TEWL decreased for a skinsite treated with a semipermeable dressing relative to theuntreated control, and counts of gram-negative bacilli werecomparable.56 Application of nonadhesive semipermeable filmsto infants less than 32 weeks' gestational age significantlyreduced water loss and improved barrier maturation comparedwith the contralateral untreated control site.57 For infants of770 to 1450 grams, those treated with a dressing required lesscurrent for thermal control and had lower TEWL than theuntreated control group.58

Barrier creams The effects of whole-body treatment topicalpetrolatum-based “skin barrier creams” in premature infantshave been reported in various settings. Infants (n = 32, 29–36weeks) received a cream (containing petrolatum, mineral oil,

revent water loss, allow water to build up resulting intion.


Table 2. Skin Protective Active Ingredients Under the FDA Final MonographIngredient Allowed Amounts (%) Other Label Claims

Allantoin 0.5–2 ⁎, #Aluminum hydroxide gel 0.15–5Calamine 1–25Cocoa butter 50–100 ⁎, #Cod liver oil 5–13.56 not to exceed 10 000 USP units of

vitamin A, and 400 USP units cholecalciferol⁎

Colloidal oatmeal 0.007 (minimum) or 0.003 (minimum)combined with mineral oil

Dimethicone 1–30 #Glycerin 20–45 #Hard fat 50–100 ⁎, #Kaolin 4–20Lanolin 12.5–50 ⁎, #

15.5 with other skin protectants for diaper rashMineral oil 50–100 and 30–35 with colloidal oatmeal ⁎, #Petrolatum 30–100 ⁎, #Sodium bicarbonate NaTopical starch 10–98White petrolatum 30–100 ⁎, #Zinc acetate 0.1–2Zinc carbonate 0.2–2Zinc oxide 1–25

Those with asterisk (⁎) may also claim “temporarily protects minor cute, scrapes, and burns,” and those with pound sign (#) can state “helps prevent andtemporarily protects and helps relieve chaffed, chapped, or cracked skin. USP = United States Pharmacopeia.

mineral wax, wool wax alcohol, water) or no treatment twice aday for 12 days. Transepidermal water loss decreased for bothgroups, but skin condition was better for the treatment group vsthe controls whose condition worsened.59 A second studyamong 60 babies (b33 weeks; mean, 29 weeks) who weretreated with a similar formulation twice a day showed lowerTEWL, less dermatitis, lower skin colonization, and fewerpositive blood and cerebrospinal fluid cultures.60 A group ofinvestigators from Association of Women’s Health Obstetric andNeonatal Nurses (AWHONN) and National Association ofNeonatal Nurses (NANN) conducted a major research project toreview the scientific literature and develop an evidence-basedpractice guideline for all aspects of skin care for neonates.61

Based on the available research, the guideline recommended

Fig 5. A, Normal and damaged SC. The SC cells are jlipid bilayer structure can be compromised, for exampenetrate a damaged barrier. Premature infant skin has fB, Effects of the diaper environment. The figure illustrskin barrier structure, function, and response. The hucausing disruption of the lipid bilayer structure. Wmicroorganisms can penetrate and reach the Langerhanintegrity by degrading proteins, providing another mechwith keratinocytes, stimulating them to release cytokiresulting in inflammation.


twice-daily whole-body application of a barrier cream (eg,Aquaphor (Beiersdorf AG, Hamburg, Germany) containingpetrolatum, mineral oil, mineral wax, wool wax alcohol, water).To test the effectiveness of the practices on outcome, that is, skincondition and compliance, they enrolled 51 units across thecountry to participate. The research plan involved education inthe specific practices and evaluation methods.62 A total of 2820infants (mean, 2100 grams; range, 500–5700 grams) wereincluded. The skin condition score decreased, and thefrequency of compliance with the guideline increased as aresult (preguideline vs postguideline comparison).63 The skinscores reflected the combination of practices, and the effect ofthe topical treatment alone could not be determined. Infectionrates were not formally evaluated.

oined by molecular “rivets” called desmosomes. Theple, from water exposure. Irritants can more easilyewer SC layers and, therefore, increased permeability.ates how factors of the “diaper environment” impactmid environment leads to overhydration of the SChen the SC integrity is damaged, irritants ands cells and epidermis. Fecal enzymes disrupt the SCanism for barrier breach. Penetrants/irritants interact

nes. Cytokines act on the vasculature of the dermis,

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37NEWBORN & INFANT NURSING REVIEWS, MARCH 2009

Another multicenter (n = 54 neonatal intensive care units)trial in 1191 younger premature infants (mean, 26.2 weeks)compared twice-daily treatment with an ointment (petrolatum,mineral oil, mineral wax, wool wax alcohol) with no treatmentamong parallel groups to isolate the effects of the ointment.64

The nosocomial infection rates were not different for the totalgroup but were significantly higher for the treatment vs controlamong infants from 501 to 750 grams. The sepsis was causedby coagulase negative in more than 60% of the cases. Thisfinding was not anticipated, given the favorable results ofothers. However, the infants from this multicenter trial had amean estimated gestational age (EGA) of 26 weeks vs the meanof 29 weeks in previous reports. Transepidermal water loss wasnot measured, but TEWL for a 26-week infant would be about45 grams per square meter per hour vs 15 to 17 grams persquare meter per hour for a 29-week infant and represents asubstantial difference in barrier maturation and integrity.30,34

Product doses may have differed between the trials. Levels of0.5 to 2.0 grams per square centimeter can be quite

Fig 6. Diaper skin care. The manageme


occlusive.65 Normal adult volar forearm skin was occludedwith plastic film for 5 days.66 Significant increases in totalaverage microbial counts were seen on day 5, and coagulase-negative staphylococci (well tolerated in healthy adults) werepresent in the greatest amounts (63%). One possible explanationfor the increased incidence of nosocomial infection in the extremelylow-birth-weight infants is that the treatment was sufficientlyocclusive to delay barrier maturation and to allow the growth ofcoagulase-negative Staphylococcus. In another report, an increasein systemic candidiasis was found in extremely low-birth-weight infants (n = 40) treated with topical petrolatum.67 Untilthe cause of the increased infection rates is understood, the useof petrolatum-based low-water ointments in very prematureinfants will remain controversial. A Cochrane review publishedin 2004 recommended that they not be used on prematureinfants because of the risk of infection.68 It is important toremember that a petroleum-based cream is a barrier to stool,but it does not allow the skin to breathe and remove toxinsbecause it blocks the pores.

nt of diaper skin condition is outlined.

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Topical oils Daily infant massage with oils is common practice inmany societies. A study of family attitudes in Bangladesh showedthat massage begins within the first 3 days in premature and full-term infants and is believed to prevent infections and loss ofheat.69 Mustard oil is commonly used, but controlled studiesshowed that it delayed SC barrier maturation and caused skindamage, whereas sunflower seed oil improved the barrier.70 Theapplication of sunflower seed oil to the skin surface of prematureinfants less than 33 weeks' gestational age at birth reduced theincidence of nosocomial blood infections by 41% in developingcountries.71 In the same study, infants less than 1250 grams whowere treated with Aquaphor had a reduced incidence (71%) ofsepsis. A controlled trial among 457 infants with 33 weeks'gestational age or less in the special care nursery of Dhaka ShishuHospital, Bangladesh, evaluated the effects of daily treatmentwith sunflower seed oil (n = 159) or Aquaphor (n = 157) vs a notreatment (n = 181) on mortality rates.72 Rates were significantlyreduced for both treatments (26% sunflower seed oil, 32%Aquaphor), and the results continue to support these treatmentsfor use in developing countries. A controlled trial among 173infants of 25 to 36 weeks' gestational age compared the effect onskin of two topical treatments vs no treatment control for 4weeks of twice-daily application.73 One treatment was a mixtureof olive oil (30%) and lanolin (70%), and the other wasBepanthen (Bayer Health Care, Leverkusen, Germany), a water-in-oil cream containing dexpanthenol and phenoxyethanol. Thecomposition of the cream is not disclosed by the manufacturer.The infants treated with olive oil/lanolin had significantly lessskin dermatitis (dryness, erythema) than either Bepanthen or notreatment, and no difference in infection rates was reportedamong the groups. The mechanism by which these oils enhanceSC barrier formation continues to be investigated, particularly interms of the uptake of certain components into the SC lipidarchitecture and in the optimum mixture of lipids.74–76

Topical Treatment of Skin CompromiseThe presence of minor skin damage increases the likelihood

of further injury in the high-risk neonate, and prevention/earlyintervention has been the focus of health care providers whocare for them. The published research on the effects of topicalproducts on damaged skin in neonates is very limited, especiallyfor adequately sized randomized controlled clinical trials. Thetask becomes selecting one of the appropriate and effectiveproducts. Consideration of the regulatory guidelines for skincare products may be helpful in making those selections.

Regulatory Guidance for Skin Products

Topical interventions include “barrier creams,” “barriers,”“skin pastes,” “skin protectants,” “moisture barriers,” and“moisturizers.” Many are marketed under the Food and DrugAdministration (FDA) Final Monograph entitled Skin ProtectantDrug Products for Over-the-Counter Human Use.77 Skin protec-tants “provide temporary relief from harmful or annoyingstimuli.” The “active ingredients” and their allowed levels are


listed in Table 2. Those with asterisk (⁎) may also claim“temporarily protects minor cute, scrapes, and burns,” andthose with pound sign (#) can state “helps prevent andtemporarily protects and helps relieve chaffed, chapped, orcracked skin.” The label must also state the following: forexternal use only, do not use on (deep puncture wounds,serious burns, animal bites), do not get into eyes, keep awayfrom face and mouth to avoid breathing it, stop use/ask doctor ifcondition worsens or symptoms last more than 7 days or clearand return. Unlike prescription drugs and other categories of OTCdrugs, the FDA does not require randomized controlled clinical trialsbefore approval and to demonstrate effectiveness. Therefore, oneshould be aware that effectiveness has not been shown incontrolled clinical trials. The FDA does not review or approvecosmetic claims, such as “soothes” or “dryness.” The paucity ofdata can be attributed in part to the fact that products can bemarketed without demonstrated efficacy.

Treatment of Diaper Dermatitis

Etiology Skin damage in the diaper area is the result of severalfactors in the “diaper environment.” They include increased skinhydration, contact with skin irritants (urine, feces, enzymes infeces, bile salts, etc), mechanical friction (skin to skin, diaper toskin), skin pH, nutritional status or diet (fecal composition),gestational age (barrier maturation status), use of antibiotictherapy, presence of diarrhea, and medical condition.48,78-83

Diapered skin pH was higher than a nondiapered control site inneonates and older infants, and increased pH was related to theeffects of occlusion and increased skin permeability.18,84,85

Higher skin pH was associated with higher skin hydration(wetness) and diaper rash scores.81 Irritants cause skin damageby disrupting the lipid bilayers of the SC, thereby allowingpenetration into the viable epidermis. Irritants (eg, sodium laurylsulfate (SLS)) increase keratinocyte proliferation and altermetabolism and differentiation.86,87 In response, the epidermisup-regulates SC formation, resulting in a defective structure,aberrant water handling, and inadequate desquamation.88-93

Perineal skin excoriation can occur in conditions wherepancreatic enzymes are not deactivated in the colon.94,95 Whena mixture of pancreatic enzymes and bile salts was applied underocclusion, erythema, blood flow, skin pH, and TEWL allincreased.96 Patients who get supplemental digestive enzymes(eg, for metabolic diseases) are at risk for skin breakdown becausethe unabsorbed enzymes can be excreted in the feces and breakdown the SC proteins.97 Infants with neonatal abstinencesyndrome often have diarrhea and can have severe diaper skinexcoriation.98–100 Figs 5A and B illustrate the processes involvedin diaper skin breakdown.

Strategy The approach for resolving diaper breakdown is basedon minimizing or eliminating the causes and intervening early.Fig 6 shows the aspects of diaper skin care.

When damage is noted, the presence of infection (eg, yeast,bacterial) must first be determined. Rash due to Candida


Fig 8. Skin evaluation. The effects of treatment planscan be monitored by the evaluating the damage (ie,erythema, rash, dryness, etc) in terms of area ofcoverage and severity.

albicans can include bright red color, patchy pattern (areas maybe surrounded by scales), and pustules. Topical antifungalagents are the treatment of choice and include nystatin,miconazole, clotrimazole, and ciclopirox for infants.101 Nysta-tin is prescribed most frequently by pediatricians.102 Combina-tions of antifungals and mid-high potency corticosteroids arenot recommended because they can cause skin atrophy andpenetrate more easily under the occlusive diaper conditions.102

A placebo-controlled trial of subjects with acute rash showedsignificantly lower rash scores for treatment with 0.25%miconazole nitrate in zinc oxide/petrolatum than the controlswith the zinc oxide/petrolatum vehicle, and subjects withmoderate to severe rash had the greatest improvement.103 Aseparate safety study showed low systemic absorption ofmiconazole nitrate in infants.104 Treatment of bacterial infec-tions is based on the organisms involved.

The goal for managing diaper skin breakdown is to somehowallow for healing despite the continuing exposure to the

ig 7. Algorithm for diaper dermatitis. An algorithmor the management and selection of treatments for
Ff diaper dermatitis is shown.

offending agents. Ideally, topical treatments (a) provide asemipermeable “film” or “layer” over the damaged skin to allowSC barrier repair, (b) provide a physical shield between the skinand the irritants, (c) remain in place on the skin (not removedby feces), and (d) allow for ease of skin cleansing (minimizestripping). Complete occlusion of damaged skin can cause delayin healing. Skin repair occurs more quickly when treated withbarriers, creams, or films that are semipermeable to watervapor.105,106 An algorithm for the management and selection oftreatments is shown in Fig 7. Once a plan is in place, it can behelpful to monitor the effects by noting the area of involvement(% area covered) and severity of damage (faint erythema,definite redness, intense redness, rash, bleeding, etc). Forexample, Fig 8 shows a scheme for evaluating erythema.

Topical treatment The diaper rash creams and moisturebarriers usually contain a skin protectant (ie, one of the “activeingredients” covered by the FDA monograph), commonly zincoxide, petrolatum, or dimethicone alone or in combination. Thepublished data on topical protectants are virtually nonexistentfor adequate controlled trials in infants, especially the high-riskpopulation. In vivo studies (usually adults) on treatment irritantdermatitis with barrier creams have shown mixed results, withskin improvement in some and worsening in others.107

Hoggarth et al108 evaluated six commercially available productsfor irritant protection, prevention of maceration, and protectionagainst topical agents. However, the test applied them once aday and then exposed the skin to irritant (sodium lauryl sulfatesurfactant) for 24 hours daily for 4 days. Patches are completelyocclusive and probably caused the irritant to pass through thebarrier cream as well as through the SC.

Common diaper rash creams, moisture barriers, and theiringredients are shown in Table 3. The “skin protectant” is inbold and must be at FDA monograph level to make the claim.The others are considered to be “inactive,” and US regulationsrequire them to be listed in the order of amount, unless they areat 1% or less where they can be in any order. These ingredientsgive the products the features of thickness, ease of application,and so on, but they also function to provide uniformity. As anexample, Table 4 lists the function of each ingredient in two ofthe products.

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Table 3. Diaper Rash and Moisture Barrier Creams and Their IngredientsName Ingredient List

Desitin (Pfizer, Inc., New York, NY) Zinc oxide (40%), BHA, cod liver oil, fragrance, lanolin, methylparaben, petrolatum,talc, and water

Desitin Creamy(Pfizer, Inc.)

Zinc oxide (10%), Aloe barbadensis leaf juice, cyclomethicone, dimethicone, fragrance,methylparaben, microcrystalline wax, mineral oil, propylparaben, purified water,sodium borate, sorbitan sesquioleate, vitamin E, white petrolatum, and white wax

Desitin Clear All Purpose(Pfizer, Inc.)

White petrolatum (60.4%), cholecalciferol, cocoa butter, fragrance, light mineral oil,mineral oil, modified lanolin, paraffin, sodium pyruvate, sunflower seed oil, vitamin Apalmitate, vitamin E (DL-alpha tocopherol and DL-alpha tocopheryl acetate)

A&D Ointment Original (ScheringPlough, Kenilworth, NJ)

Petrolatum (53.4%), lanolin (15.5%), cod liver oil (contains vitamin A andvitamin D), fragrance, light mineral oil, microcrystalline wax, paraffin

A&D Diaper Rash Cream with ZincOxide (Schering Plough)

Dimethicone (1%), zinc oxide (10%), aloe barbadensis extract, benzyl alcohol,coconut oil, cod liver oil (contains vitamin A and vitamin D), fragrance, glyceryl oleate,light mineral oil, ozokerite, paraffin, propylene glycol, sorbitol, synthetic beeswax, water

Triple Paste (Sommers Laboratories,Inc., Collegeville, PA)

Zinc oxide, lanolin, and beeswax. Triple paste is fragrance free and contains noadded preservatives

Boudreaux's Butt Paste (Blairex,Columbus, IN)

Zinc oxide (16%), boric acid, castor oil, mineral oil, paraffin, Peruvian balsam,petrolatum

Canus Li'l Goat's Milk 40% ZincOxide Ointment (Canus,Waitsfield, VT)

Zinc oxide (40%), petrolatum, goats milk (fresh), mineral oil, emulsifying wax NF,fragrance (parfum), beeswax, propylene glycol, diazolidinyl urea, methylparaben,propylparaben

Aquaphor (Beiersdorf) Petrolatum, mineral oil, ceresin, lanolin alcohol, panthenol, glycerin, bisabololBalmex (Chattem, Inc.,Chattanooga, TN)

White petrolatum (51%), cyclomethicone, dimethicone, mineral oil, polyethylene,silica

Mustela Bebe Vitamin BarrierCream (LaboratoriesExpanscience, Paris, France)

Zinc oxide (10%), water, mineral oil, propylene glycol dioctanoate, methyl glucosedioleate, titanium dioxide, PEG 45 docecyl glycol copolymer, glycerin, ceresin, ethyllinoleate, Shea butter, PEG 8, panthenol, potassium sorbate, fragrance, magnesiumsulfate, methylparaben, caprylyl glycol, propylparaben, sodium polyacrylate

Triple paste medicated ointment(Sommers Laboratories, Inc.)

Zinc oxide (12.8%), white petrolatum, corn starch, anhydrous lanolin, stearylalcohol, beeswax, bisabolol, cholesterol, water, glycerin, oat kernel extract (Avenasativa), polysorbate 80

Aveeno baby soothing relief DiaperRash Cream (Johnson &Johnson Consumer Companies,Inc., New Brunswick, NJ)

Zinc oxide (13%), A sativa (oat) kernel extract, beeswax, benzoic acid, dimethicone,Epilobium angustifolium flower/leaf/stem extract, glycerin, methylparaben,microcrystalline wax, mineral oil, Oenothera biennis (evening primrose) seed extract,potassium hydroxide, propylparaben, sorbitan sesquioleate, synthetic beeswax, water

Burt's Bees Baby Bee (Burt's Bees,Durham, NC)

Zinc oxide, sweet almond oil, beeswax, tocopheryl acetate, tocopherol (vitamin E),jojoba oil, lavender oil, retinyl palmitate (vitamin A), extract of rosemary, lavender,calendula, chamomile, rose petal, comfrey root

Mustela Dermo-Pediatrics StelactivDiaper Rash Cream (LaboratoriesExpanscience)

Zinc oxide (10%), water, mineral oil, propylene glycol diethylhexanoate, methylglucose dioleate, titanium dioxide, PEG 45 docecyl glycol copolymer, glycerin, ceresin,panthenol, Lupinus albus seed extract, PEG 8, Butyrospermum parkii fruit (Shea butter),ethyl linoleate, potassium sorbate, caprylyl glycol, methylparaben, magnesium sulfate,propylparaben, sodium polyacrylate

Palmer's Bottom Butter (E.T.Browne Drug Company, Inc.,Edgewood Cliffs, NJ)

Petrolatum (30%), dimethicone (1%), water, mineral oil, aluminum starchoctenylsuccinate, PEG 30 dipolyhydroxystearate, stearyl alcohol, Theobroma cacao(cocoa) seed butter, microcrystalline wax, fragrance, Zea mays (corn) oil, retinylpalmitate, cholecalciferol, panthenol, beta carotene, vegetable oil, isopropyl myristate,propylene glycol, methylparaben, propylparaben, diazolidinyl urea

Jason Natural Cosmetics Earth'sBest Organic Diaper ReliefOintment, Aloe Vera andVitamin E (The Hain CelestialGroup, Inc., Melville, NY)

Zinc Oxide (12%), lavender extract, caprylic/capric triglycerides, C12 15 alkyl benzoate,sorbitan isostearate, sorbitan sesquioleate, water (purified), ethylhexyl palmitate, calciumstarch octenylsuccinate, ethyl macadamiate, stearalkonium hectorite, glyceryl laurate, oatkernel oil, tocopheryl acetate (vitamin E), beta glucan, chamomile flower extract (certifiedorganic), marigold flower extract (certified organic), propylene carbonate, magnesiumsulfate, benzyl alcohol, potassium sorbate, sodium benzoate

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41NEWBORN & INFANT NURSING REVIEWS, MARCH 2009

Table 3 (continued)

Name Ingredient List

Method Squeaky Green DiaperCream, Rice Milk + Mallow(Method Products, Inc.,San Francisco, CA)

Zinc Oxide (10%), Althaea officinalis extract, caprylic/capric triglycerides, cetylalcohol, cetyl hydroxyethylcellulose, decylene glycol, dimethicone, glycerin,Helianthus annuus (sunflower) seed oil, Oryza sativa (Rice) bran extract, O sativa (Rice)germ oil, phenoxyethanol, polysorbate 60, sorbitan stearate, water (agua), xanthangum

Lansinoh Diaper Rash Ointment(Lansinoh Laboratories,Alexandria, VA)

Dimethicone (5.5%) (skin protectant), USP modified lanonin (15.5%) (skinprotectant), zinc oxide (5.5%) (skin protectant), allantoin, beeswax, bisabolol,caprylic/capric triglycerides, esters, glyceryl behenate/eicosadioate, Jojoba Chamomillarecutita flower extract (Martricaria), petrolatum, polydecene, polyethylene,propylparaben, stearyl glycyrrhetinate, tocopheryl acetate (vitamin E), Z mays (corn)starch

Sensi-Care Skin Protectant(ConvaTec, Skillman, NJ)

Petrolatum (49%), zinc oxide (15%), carboxymethylcellulose sodium, water,stearic acid, glycerin, cetyl dimethicone copolyol, polyglyceryl-4-isostearate, hexyllaurate, phenoxyethanol

Aloe Vesta Skin Protectant(ConvaTec)

Petrolatum (43%), water, mineral oil, hydroxylated lanolin, sorbitan sesquioleate,ozokerite, PEG-30 dipolyhydroxystearate, glycerin, steareth-20, magnesium sulfate,DMDM hydantoin, iodopropynyl butylcarbamate, aloe barbadensis leaf juice

Carrington Moisture Barrier Cream(Carrington Laboratories, Irving,TX)

Petrolatum (90%), mineral oil and paraffin, acemannan hydrogel, butylparaben,lecithin, propylparaben, purified water, quaternium 15, sodium chloride

The “skin protectant” is in bold. USP = United States Pharmacopea; BHA = butylated Hydroxy anisole; NF = normal form; PEG = polyethylene glycol.

Most contain zinc oxide, petrolatum, or mixtures andcompositionally appear to be similar. This is, perhaps, notsurprising given the number of ingredients that can be used tomake a “skin protectant claim.” Thicker products (pastes,creams, ointments) usually have low water content. Pastes andpetrolatum barriers can be very occlusive. Some cliniciansrecommend against their use for long periods and only insituations where soils (feces) are high in water and

Table 4. Ingredients in a Common Diaper Rash CIngredient

Zinc oxide (10%)A barbadensis leaf juiceCyclomethiconeDimethiconeFragranceMethylparabenMicrocrystalline waxMineral oilPropylparabenPurified waterSodium borateSorbitan sesquioleateVitamin EWhite petrolatumWhite wax

Desitin Creamy ingredients: Zinc oxide (10%), A barbadensis leaf juice, cyclometoil, propylparaben, purified water, sodium borate, sorbitan sesquioleate, vitamin


irritants.109,110 There are no studies on the use petrolatum-based barriers to prevent diaper dermatitis in normal diaperedskin.109 Products transfer onto the inner diaper sheet and mayinterfere with absorbance of moisture from the skin.111

Some patients have conditions that affect fecal composition(eg, gastrointestinal conditions) and may benefit from topicalagents designed to mitigate the specific irritants. For example,cholestyramine binds with bile acids to make them inactive, and

ream and Their FunctionsFunction

Skin protectant claimed from monographMoisturizer, hydrating agentAssists in spreadingAssists in spreadingProvides pleasant odor and/or covers ingredient odorsPreservativeViscosity controlEmollient, solventPreservativeSolventProduct pH controlMoisturizer, emollientVitamin at low level, effectiveness not establishedViscosity controlViscosity control

hicone, dimethicone, fragrance, methylparaben, microcrystalline wax, mineralE, white petrolatum, and white wax.

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Table 5. Surfactants Found in Skin CareProducts and the Relative Irritancy PotentialRelative Irritancy Surfactants

High Sodium lauryl sulfateSodium dodecyl sulfateSodium alkyl sulfateSodium or potassium cocoateSodium or potassium tallowateSodium palmitateSodium or potassium stearateLinear alkyl benzene sulfateTriethanolamine laurateSodium olefin sulfonateBenzalkonium chlorideDodecyl trimethyl ammoniumbromide

Moderate Sodium ethoxylatesSodium laureth sulfateAmmonium laureth sulfate

Low Sodium cocoyl isethionateSodium alkyl glycerol ether sulfonateSodium cocoyl sulfosuccinateDisodium stearyl sulfosuccinate

preparations have been used successfully for severe perinealskin breakdown.112-114 Cholestyramine ointments can beprepared in hospital pharmacies. Sucralfate (Carafate; MarionMerrell Dow, Kansis City, MO) in the form of an ointment orpowder has been used to treat skin damage from gastricsecretions. If candidiasis is also present, these patients must betreated with an antifungal as well.115,116

Topical creams can be limited by poor substantivity andremoval by stool. Solutions and sprays that form a semiperme-able barrier film upon drying are available. They are intended tobe left in place to protect the skin from direct irritant contact withirritants. They are semipermeable to assist barrier repair. Skinstripping during cleansing is minimized. Sureprep No-StingProtective Barrier Wipe (Sureprep NSPBW; Medline Industries,Inc, Mundelein, IL) comes as a water-based solution, isnonflammable, and has no age restrictions. Another is CavilonNo-Sting Barrier Film (Cavilon NSBF; 3M Corporation, St Paul,MN). The material is in volatile silicone solvent and dries to formthe semipermeable film. It can be used on infants older than 1month (eg, not for use on preterms) and is flammable. SureprepNSPBW was evaluated in a small study in 10 NICU patients withsevere perineal skin breakdown.117 The skin condition, based onassessment of area and severity, improved. Two were dischargedafter 1 day. A trial of suitable size among parallel treatmentgroups is necessary to determine the effectiveness of SureprepNSPBW vs other barrier creams, but it represents a potentialalternative for diaper skin breakdown in high-risk infants.

Skin cleansing Bathing practices vary with the infant's age andmedical condition. Skin cleansing products usually contain


ingredients, surfactants (surface active agents), to emulsify soilsfor removal during rinsing. Cleansers can be no-rinse liquids orcreams, in bar form, or liquids added to water. Because theyemulsify lipids, surfactants can damage the SC barrier andcause skin irritation. Relative skin irritancy has been deter-mined via skin testing, and rankings for common surfactantsare shown in Table 5. After cleaning, residual surfactant canremain on the skin, especially when copious rinsing is notpractical.118 Liquid products containing surfactants with verylow irritancy are recommended for infants. The irritancy canbe determined by checking the ingredient label against the listin Table 5.

Diaper skin can be cleansed with a soft cloth and an oil-in-water lotion to assist in soil removal.119 Wipes composedof a substrate with cleansing agents and/or emollients havebeen developed for use on diaper skin. Wipe treatmentresulted in significantly lower erythema and surface rough-ness vs water plus an implement (cotton washcloth, cottonwool balls) in healthy infants.120,121 Wipes made of a softnonwoven substrate containing water, nonionic cleansers,and emollients resulted in reduced skin irritation (erythema,rash) and TEWL vs cloth and water in critically ill pre-mature and full-term neonates.122,123 Wipes used on diaperskin should be free of alcohol, fragrance, and ingredients ofknown irritancy or cytotoxicity and contain only essentialmaterials.109

Skin pH Reduction in diaper skin pH may be another strategyfor improving skin health. An acidic pH is important for theenzymes involved in SC formation and integrity to be effective.It contributes to the SC's innate immune function byinhibiting colonization of pathogens, for example, Staphylo-coccus aureus.124-126 Application of a pH 5.5 buffer solutionincreased the rate of barrier recovery after damage.127 Wipeswith pH buffers have been developed.128 Routine skincleansing with a new diaper wipe resulted in significantlylower diaper skin pH than the hospital standard of cloth andwater in a trial among high-risk premature and full-terminfants.123 Provision of an acidic skin pH may also help reducethe activity of fecal enzymes.

Other product ingredients and use on infants Published dataon the many products that touch, interact with, adhere to, orinfluence the skin barrier of infants are very limited. Itemsdeveloped for the health and consumer skin care markets aretypically tested on adults and/or rely on marketplace experience(lack of adverse effects) to support use on infants. They maycontain ingredients that should be avoided, if possible, or usedwith caution.129 For example, products containing boric acidare not recommended because of its toxicity.130,131 Benzalk-onium chloride is used in skin products as a disinfectant orpreservative and should be evaluated before use on infants. Ithas been implicated in allergic dermatitis in infants.132 Theingredients are listed on the label and should be checked forpotential negative effects in the neonatal population beforebeing adopted for routine use.


dchakrav

Highlight

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Marty O. Visscher, PhD · Topical agents include anything that touches the infant's skin. The skin...

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