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 infant perceives and responds to the care environment and, therefore, in neurodevelopment. Psychological stress negatively affects the barrier. The full-term infant has well-developed epidermal barrier despite spending 9 months being submerged in water. Vernix caseosa is a natural topical agent that facilitates stratum corneum barrier development through protective and adaptive mechanisms. Its properties include hydration, wound healing, antiinfection, and acid mantle development. The ontogeny of neonatal skin development and vernix biology provide the basis for assisting barrier maturation in premature infants, treating compromised skin and selecting topical agents. The published research on the effects of topical products on premature and damaged neonatal skin is very limited, especially for adequately sized randomized controlled clinical trials. Health care providers 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 Perspective action (cluster communication), better hearing/speech, and lower behavior symptom scores.5 Tactile stimulation via The article will review topical products in infants. Conceptually, repeated stroking increased circulating lactate levels by 200% we define topical products in the broadest sense to include in the neonatal rat model.6 These findings demonstrate the anything that touches or interacts with infant skin. The skin is a critical role of simple infant-caregiver skin-based interactions on primary care interface vitally important in any patient-caregiver the cognitive development of the infant. 1 interaction. The most recent information about skin structure, Specific skin receptors are sensitive to mechanical stimuli development, and function will be discussed to generate the and are critical for survival. The signaling proteins involved in context of topical treatments and products. this transduction are being identified.7 Psychological stress due Touch is the first sense to develop in the infant. As a result, to environmental overcrowding is associated with a delay in the skin is an important element in the process of how the infant skin barrier recovery in mice, an effect attributed to increased perceives and reacts to the environment of care and, therefore, production of glucocorticoids.8 Psychological stress decreased in neonatal neurodevelopment. Examples of skin-based infant epidermal cell proliferation, adversely effected differentiation, interactions include skin-to-skin contact (kangaroo care), infant and decreased the size and density of corneodesmosomes, all of massage, Newborn Individualized Developmental Care and which negatively impact skin barrier function.9 Stress decreased Assessment (NIDCAP), and tactile stimulation. Skin-to-skin antimicrobial peptides in the epidermis (animal model), an contact immediately after birth results in increased temperature effect that resulted in more severe skin infections.10 and blood glucose levels compared with swaddling next to the mother.2 Skin-to-skin contact for 1 hour shortly after birth impacted state organization and the time spent sleeping.3 Skin Structure and Function Premature infants cared for with NIDCAP methods had Human skin serves multiple functions including barrier (to significantly better neurobehavioral function and more mature water loss, irritant exposure, light, etc), immunosurveillance, neuronal fiber structure.4 In a longer-term study, infants infection control, sensation, structural support, and thermal receiving NIDCAP had significantly better mother-child inter- regulation (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. Two From the Skin Sciences Institute, Cincinnati Children's Hospital Medical layers comprise the dermis. The upper is the papillary layer, Center, Cincinnati, OH. contains capillary loops, and is loosely organized. The lower is Address correspondence to Marty O. Visscher, PhD, The Skin Sciences Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet the reticular dermis composed of tightly packed collagen and Avenue, Cincinnati, OH 45229. E-mail: [email protected]. elastin with glycosaminoglycans, which provide mechanical © 2009 Elsevier Inc. All rights reserved. properties and elasticity. The epidermis includes the stratum 1527-3369/08/0901-0289$36.00/0 corneum (SC, outer) and the viable epidermis (Fig 2). An doi:10.1053/j.nainr.2008.12.010 understanding of SC structure and function is essential for being Table 1. Skin Functions vapor from respiration to be released. The integrity of the SC is measured in terms of the rate of transepidermal water loss Function Skin Structure (TEWL). Normal skin has TEWL values of approximately 6 to Barrier 8 grams per square meter per hour, and higher rates indicate a Physical SC and epidermis damaged barrier, poorly developed SC, or SC with fewer layers (irritants) than normal. The important goal of topical skin treatments is Light Melanocytes of the epidermis to maintain or restore the SC barrier. A schematic of showing Immunologic Langerhans cells of the epidermis normal and compromised SC barriers is shown in Fig 3. Resilient Dermis Normal skin looses about one SC layer per day through the foundation process of desquamation where the connections between SC Sensation Sensory nerves in epidermis and cells degrade and release the cells to the environment. An dermis appropriate level of hydration is required for proper desqua- Tactile SC and sensory nerves mation. Stratum corneum that is too dry will not desquamate discrimination properly and results in large aggregates of cells, scales or dry Thermal Eccrine sweat glands in dermis skin flakes. The protein filaggrin in the SC corneocytes is regulation Blood supply in dermis converted to small water-binding amino acids called natural Adipose fat in subcutaneous layer moisturizing factor (NMF). Natural moisturizing factor is in (hypodermis) part responsible for maintaining the appropriate level of SC hydration, and loss of NMF or disruption of the NMF generation will result in low SC moisture. Excess hydration will able to select topical products. The SC is the main barrier to also cause barrier damage as will be discussed later. water loss and penetration by outside agents. The viable epidermis has four layers (top to bottom): clear (stratum lucidum), granular (stratum granulosum), spinous (stratum Neonatal Skin Development spinosum, nucleated cells), and basal (stratum basale, nucleated Birth marks are a significant environmental change for the cells). Two specialized dendritic cells are housed in the viable infant from a warm, sterile, and safe womb to a dry high- epidermis. Langerhans cells (antigen-presenting cells) are part of environment with multiple organisms (bacteria) and demands the immune system and serve as the line of defense if the SC for self-sufficiency such as air breathing, enteral nutrition, waste barrier is breached (Fig 2). The melanocytes (pigment cells) elimination, and maintenance of water balance. Neonatal skin reside in the basal layer and produce melanin, the pigment serves many functions at birth, including a barrier to water loss responsible in part for inherent skin color. When the skin is and chemicals, temperature regulation, tactile discrimination, exposed to UVradiation, melanocytes are activated and transport melanin to the nuclei of the epidermal cells to shield them and protect the DNA. Skin tanning is the result of this process. The pigmentary system is influenced by irritation and inflammation and may respond by producing more pigment (hyperpigmenta- tion) or by deactivation (resulting in hypopigmentation). The function of the viable epidermis is to continually build and replenish the SC. The cells “move up” from the basal layer and transition to SC cells through a programmed process. About 28 days is required for a cell to go from the basal layer and be lost from the outer SC. The SC is made up of about 16 layers of flattened cells (corneocytes) joined together by molecular “rivets” (aggregates of large molecules) called desmosomes (insert in Fig 2). The SC is about half of the thickness of a sheet of paper but incredibly strong. The process of going from nucleated cells to SC corneocytes begins in the upper spinous and granular cells with formation of the cross- Fig 1. Skin structures. A cross-section of the skin linked cell envelope. Structures, called lamellar bodies, in the spinous layer store lipids. In the upper granular layer (below shows the structures responsible for the functions. the SC), the lipids (cholesterol, fatty acids, ceramides) are The major skin layers are the epidermis, dermis, and secreted from the lamellar bodies into the intercellular spaces hypodermis (subcutaneous). The outermost layer, between the corneocytes to form a regular “brick (cells) and the SC, is directly exposed to the environment. The mortar (lipids)” structure. The lipids form a regular ordered figure was provided by the National Institutes of bilayer structure, alternating with water, between the cells. By Health for use by the public and can be found at design, the SC structure is difficult to penetrate from the outside. It is the barrier to water loss but allows normal water http://media.nih.gov/imagebank/display_search.

32 VOLUME 9, NUMBER 1, www.nainr.com 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 acid decreases significantly during the first 1 to 4 days, and mantle formation. continues to drop during the first 3 months.12,15,18 The antimicrobial protein lysozyme was found in newborn SC at levels five times higher than adults. Lysozyme activity was not The Full-Term Infant 19 altered with routine bathing. The full-term infant has well-developed epidermal barrier at birth, despite spending 9 months being submerged in water. In most cases, overhydration of the skin has a damaging effect, that Vernix Caseosa: Natural Topical is, maceration, barrier disruption, and tissue injury. Transepi- dermal water loss (rate of respiratory water vapor loss, TEWL) is Treatment very low at birth for full-term infant, equal to or lower than The question remains: How does the full-term infant develop adults, indicating a highly effective skin barrier.11,12 Within an excellent barrier while in water? During the last trimester, minutes to hours after birth, skin hydration (moisture) varies vernix caseosa begins to coat the skin from head to toe and back with body site (chest, back, forehead), time under the warmer, to front and may facilitate SC barrier development.14 Vernix is a and retention or removal of vernix caseosa.13,14 Hydration complex mixture of 80% water, 10% protein, and 10% lipids, decreases rapidly in the first day and then increases during the with corneocytes embedded in a lipid matrix.20 The remarkably first 2 weeks compared with constant values in the mother. This high water is associated with the cells. Vernix formation is change indicates that significant adaptive changes occur in the believed to be under hormonal control during gestation, with upper SC.15 Newborn skin was significantly drier than the skin lipids generated by the sebaceous gland and cells from the hair of older infants (1, 2, and 6 months) and the mothers.16 Water- follicle. It is “extruded” onto the interfollicular epidermis to binding ability increased during the first 14 days, denoting cover the whole surface.21 Presumably, vernix forms a hydro- changes in the water-handling processes within the SC. To phobic surface, thereby protecting the epidermis from exposure identify possible causes of low hydration, we measured the to water, and creates conditions under which the cornification NMF levels at birth and found it to be extremely low.17 They and formation of the SC can occur. Vernix contains antimicro- were higher at 1 month but lower than levels in adults. Natural bials; for example, lysozyme, lactoferrin, and the antiinfective moisturizing factor is water soluble and may be extracted from properties have been demonstrated by several researchers.22-25 the SC into the amniotic fluid. Alternatively, NMF generation Vernix treatment of adult volar skin increased the SC water- from filaggrin may be activited as part of the adaptation to dry binding capacity.26 Native vernix treatment of SC wounds (tape conditions. At birth, the full-term skin pH is relatively neutral, stripped skin) assisted barrier repair relative to controls and

NEWBORN & INFANT NURSING REVIEWS,MARCH 2009 33 Premature Infant Skin Development Unlike that of the full-term baby, the dermis of the premature infant is not fully formed and deficient of structural proteins. As a result, the mechanical properties are poor and the skin is easily torn. The preterm epidermis is markedly thinner, and the SC is poorly formed in contrast to the thick fully developed SC of the full-term neonate. The SC structural integrity is directly related to gestational age at birth, and rapid barrier development occurs from weeks 24 to 34. Very low-birth-weight infants are at greatest risk for skin damage during the early days of life. At 23 weeks, the SC is nearly absent with TEWL of 75 grams per square meter per hour (Fig 3).30 By week 26, a few cornified layers have formed (TEWL of approximately 45 grams per square meter per hour). The very premature infant has, essentially, a wounded skin surface.31,32 At 29 weeks, the TEWL is 17 grams per square meter per hour and markedly higher than the values of 5 to 6 grams per square meter per hour observed in the full-term infant. Around weeks 34 to 35, the barrier is relatively well formed. Infants born prematurely (ie, b28 weeks) do not have the covering of vernix. Fig 3. The development of the SC occurs during the Poor SC integrity puts the premature infant at risk for high last trimester of gestation and is relatively well formed water loss, electrolyte imbalance, thermal instability and on average by week 34 to 35. At 23 weeks, the SC is increased exposure to environmental irritants and infectious nearly absent and TEWL values are 75 grams per agents due to increased permeability. After birth, the barrier continues to develop, but even after 1 month, TEWL is square meter per hour. By week 26, a few cornified significantly higher than in normal full-term infants.33 Further layers have formed (TEWL of approximately 45 grams impairment of barrier function in premature infants was per square meter per hour). At 29 weeks, the TEWL is indicated by significantly higher values of skin hydration, and 17 grams per square meter per hour and markedly infants less than 30 weeks gestation have significantly higher higher than values of 5 to 6 grams per square meter values of skin hydration than those older than 30 weeks as a 34 per hour observed in the full-term infant. result of higher rates of water being lost through the skin. By day 5, the skin hydration was significantly lower for infants less than 27 weeks' gestational age, indicating rapid barrier demonstrated wound healing properties.27 In some settings, development. The humidity of the environment influences the vernix is removed immediately after birth. The role of vernix in rate and quality of SC barrier maturation. Exposure to low neonatal skin adaptation was assessed by comparing the effects humidity (10% relative humidity [RH], animal model) resulted of vernix retention vs removal in parallel groups of full-term in a decrease in SC hydration and an increase in epidermal DNA infants at delivery. Vernix retention resulted in significantly synthesis. This observation suggests that low hydration triggers 35 higher skin hydration 24 hours after birth.14 Skin pH values cell proliferation. Clinically, very premature infants frequently were lower in the vernix-retained group, suggesting that vernix exhibit an abnormal pattern of desquamation several weeks facilitates the development of the acid mantle. Treatment of SC after birth, indicative of a hyperproliferative SC. Humidity wounds (created by repeatedly tape stripping adult forearm skin affects the degradation of epidermal filaggrin to NMF that binds 36 to remove SC layers) with vernix assisted barrier repair relative to water in the SC. Without NMF, the SC is dry, does not controls.27,28 In model systems, vernix enhanced SC formation desquamate properly, and has poor water-holding capacity. At without increasing epidermal thickness.29 Films of vernix birth (animal model), filaggrin degradation occurred at 80% to impeded the penetration of the exogenous enzyme chymo- 95% humidity but not at high (100% RH) or low humidities, trypsin (found in meconium, similar proteolytic enzymes suggesting that NMF generation depends upon ambient water 37 present in feces) but maintained the activity of native enzymes activity. Natural moisturizing factor levels are likely to be very (necessary for epidermal development) in vitro.29 low under the conditions of rapid SC development such as for Overall, vernix facilitates SC barrier development in the premature infants in low humidity. normal full-term infant through a variety of protective and adaptive mechanisms. The findings provide support for the practice of vernix retention (rather than removal) at birth. The Skin Occlusion World Health Organization recommends waiting for at least 6 Appropriate SC hydration is necessary for effective skin hours before bathing newborn infants in part to facilitate the function, for example, to allow sufficient plasticity and positive effects of residual vernix. flexibility during movement, to prevent cracking, and for

34 VOLUME 9, NUMBER 1, www.nainr.com desquamation.38,39 However, prolonged exposure to water low-birth-weight infants needed lower fluids and had improved causes skin maceration, barrier breakdown, and dermatoses, electrolyte balance.52 Humidity is used routinely with levels including inflammation, irritation, and urticaria.40-45 Water adjusted to manage fluid loss, temperature, and so on to exposure caused SC abnormalities, including disruption of the ensure that overhumidification does not cause bacterial intercellular lipid bilayers, degradation of the desmosomes, and contamination.53 A 2006 study among infants of 23 to creation of amorphous regions within the lipids, as illustrated 27 weeks' gestational age showed that the SC barrier developed in Fig 3.46 more rapidly for the neonates in isolettes at 50% RH compared Hydration causes the SC corneocytes to swell, increases the with infants at 75% RH.54 fluidity of the lipids, and enhances molecular transport to increase permeability to exogenous materials.47,48 Occlusion of the skin surface can occur from any material that does not allow Films Transparent semipermeable dressings (eg, Tegaderm; 3M, sufficient water to pass through it, including diapers, certain St. Paul, MN) have been used to control water loss in premature tapes, thick layers of topical products, and devices such as infants. Tegaderm dressing was applied to large body surface braces, casts, and splints.49 Water builds up under the material areas on infants of 24 to 26 weeks' gestational age, and daily and causes SC hydration to increase and barrier damage to fluid intake, serum sodium levels, and weight loss were occur, as shown in Fig 4. significantly lower compared with infants who had not been treated.55 Transepidermal water loss was also reduced, indicat- ing that the film had assisted in barrier maturation. In infants Topical Treatments for Infants less than 32 weeks' gestational age, TEWL decreased for a skin site treated with a semipermeable dressing relative to the The biology of infant skin development and maturation untreated control, and counts of gram-negative bacilli were provides the clues for identifying strategies for treating comparable.56 Application of nonadhesive semipermeable films compromised skin. Vernix may be the “ideal” topical treatment, to infants less than 32 weeks' gestational age significantly as some suggest, for infants and adults.50,51 Infants born reduced water loss and improved barrier maturation compared prematurely (ie, b28 weeks) are missing protective covering of with the contralateral untreated control site.57 For infants of vernix. In the broadest sense of “topical treatments” as anything 770 to 1450 grams, those treated with a dressing required less that interacts with the outer skin surface, specific strategies will current for thermal control and had lower TEWL than the be discussed. untreated control group.58

Treatments for Barrier Maturation Barrier creams The effects of whole-body treatment topical petrolatum-based “skin barrier creams” in premature infants Environmental conditions Humidified isolettes have been used have been reported in various settings. Infants (n = 32, 29–36 to mitigate the high water loss in premature infants. Extremely weeks) received a cream (containing petrolatum, oil,

Fig 4. Effects of skin occlusion. Occlusive treatments prevent water loss, allow water to build up resulting in damage to the SC barrier, and allow increased penetration.

NEWBORN & INFANT NURSING REVIEWS,MARCH 2009 35 Table 2. Skin Protective Active Ingredients Under the FDA Final Monograph Ingredient Allowed Amounts (%) Other Label Claims Allantoin 0.5–2 ⁎,# Aluminum hydroxide gel 0.15–5 Calamine 1–25 Cocoa 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 4–20 Lanolin 12.5–50 ⁎,# 15.5 with other skin protectants for diaper rash Mineral oil 50–100 and 30–35 with colloidal oatmeal ⁎,# Petrolatum 30–100 ⁎,# Sodium bicarbonate Na Topical starch 10–98 White petrolatum 30–100 ⁎,# acetate 0.1–2 Zinc carbonate 0.2–2 1–25 Those with asterisk (⁎) may also claim “temporarily protects minor cute, scrapes, and burns,” and those with pound sign (#) can state “helps prevent and temporarily protects and helps relieve chaffed, chapped, or cracked skin. USP = United States Pharmacopeia. mineral wax, wool wax alcohol, water) or no treatment twice a twice-daily whole-body application of a barrier cream (eg, day for 12 days. Transepidermal water loss decreased for both Aquaphor (Beiersdorf AG, Hamburg, Germany) containing groups, but skin condition was better for the treatment group vs petrolatum, mineral oil, mineral wax, wool wax alcohol, water). the controls whose condition worsened.59 A second study To test the effectiveness of the practices on outcome, that is, skin among 60 babies (b33 weeks; mean, 29 weeks) who were condition and compliance, they enrolled 51 units across the treated with a similar formulation twice a day showed lower country to participate. The research plan involved education in TEWL, less , lower skin colonization, and fewer the specific practices and evaluation methods.62 A total of 2820 positive blood and cerebrospinal fluid cultures.60 A group of infants (mean, 2100 grams; range, 500–5700 grams) were investigators from Association of Women’s Health Obstetric and included. The skin condition score decreased, and the Neonatal Nurses (AWHONN) and National Association of frequency of compliance with the guideline increased as a Neonatal Nurses (NANN) conducted a major research project to result (preguideline vs postguideline comparison).63 The skin review the scientific literature and develop an evidence-based scores reflected the combination of practices, and the effect of practice guideline for all aspects of skin care for neonates.61 the topical treatment alone could not be determined. Infection Based on the available research, the guideline recommended rates were not formally evaluated.

Fig 5. A, Normal and damaged SC. The SC cells are joined by molecular “rivets” called desmosomes. The lipid bilayer structure can be compromised, for example, from water exposure. Irritants can more easily penetrate a damaged barrier. Premature infant skin has fewer SC layers and, therefore, increased permeability. B, Effects of the diaper environment. The figure illustrates how factors of the “diaper environment” impact skin barrier structure, function, and response. The humid environment leads to overhydration of the SC causing disruption of the lipid bilayer structure. When the SC integrity is damaged, irritants and microorganisms can penetrate and reach the Langerhans cells and epidermis. Fecal enzymes disrupt the SC integrity by degrading proteins, providing another mechanism for barrier breach. Penetrants/irritants interact with keratinocytes, stimulating them to release cytokines. Cytokines act on the vasculature of the dermis, resulting in inflammation.

36 VOLUME 9, NUMBER 1, www.nainr.com NEWBORN & INFANT NURSING REVIEWS,MARCH 2009 37 Another multicenter (n = 54 neonatal intensive care units) occlusive.65 Normal adult volar forearm skin was occluded trial in 1191 younger premature infants (mean, 26.2 weeks) with plastic film for 5 days.66 Significant increases in total compared twice-daily treatment with an ointment (petrolatum, average microbial counts were seen on day 5, and coagulase- mineral oil, mineral wax, wool wax alcohol) with no treatment negative staphylococci (well tolerated in healthy adults) were among parallel groups to isolate the effects of the ointment.64 present in the greatest amounts (63%). One possible explanation The nosocomial infection rates were not different for the total for the increased incidence of nosocomial infection in the extremely group but were significantly higher for the treatment vs control low-birth-weight infants is that the treatment was sufficiently among infants from 501 to 750 grams. The sepsis was caused occlusive to delay barrier maturation and to allow the growth of by coagulase negative in more than 60% of the cases. This coagulase-negative Staphylococcus. In another report, an increase finding was not anticipated, given the favorable results of in systemic candidiasis was found in extremely low-birth- others. However, the infants from this multicenter trial had a weight infants (n = 40) treated with topical petrolatum.67 Until mean estimated gestational age (EGA) of 26 weeks vs the mean the cause of the increased infection rates is understood, the use of 29 weeks in previous reports. Transepidermal water loss was of petrolatum-based low-water ointments in very premature not measured, but TEWL for a 26-week infant would be about infants will remain controversial. A Cochrane review published 45 grams per square meter per hour vs 15 to 17 grams per in 2004 recommended that they not be used on premature square meter per hour for a 29-week infant and represents a infants because of the risk of infection.68 It is important to substantial difference in barrier maturation and integrity.30,34 remember that a petroleum-based cream is a barrier to stool, Product doses may have differed between the trials. Levels of but it does not allow the skin to breathe and remove toxins 0.5 to 2.0 grams per square centimeter can be quite because it blocks the pores.

Fig 6. Diaper skin care. The management of diaper skin condition is outlined.

38 VOLUME 9, NUMBER 1, www.nainr.com Topical oils Daily infant massage with oils is common practice in listed in Table 2. Those with asterisk (⁎) may also claim many societies. A study of family attitudes in Bangladesh showed “temporarily protects minor cute, scrapes, and burns,” and that massage begins within the first 3 days in premature and full- those with pound sign (#) can state “helps prevent and term infants and is believed to prevent infections and loss of temporarily protects and helps relieve chaffed, chapped, or heat.69 Mustard oil is commonly used, but controlled studies cracked skin.” The label must also state the following: for showed that it delayed SC barrier maturation and caused skin external use only, do not use on (deep puncture wounds, damage, whereas sunflower seed oil improved the barrier.70 The serious burns, animal bites), do not get into eyes, keep away application of sunflower seed oil to the skin surface of premature from face and mouth to avoid breathing it, stop use/ask doctor if infants less than 33 weeks' gestational age at birth reduced the condition worsens or symptoms last more than 7 days or clear incidence of nosocomial blood infections by 41% in developing and return. Unlike prescription drugs and other categories of OTC countries.71 In the same study, infants less than 1250 grams who drugs, the FDA does not require randomized controlled clinical trials were treated with Aquaphor had a reduced incidence (71%) of before approval and to demonstrate effectiveness. Therefore, one sepsis. A controlled trial among 457 infants with 33 weeks' should be aware that effectiveness has not been shown in gestational age or less in the special care nursery of Dhaka Shishu controlled clinical trials. The FDA does not review or approve Hospital, Bangladesh, evaluated the effects of daily treatment cosmetic claims, such as “soothes” or “dryness.” The paucity of with sunflower seed oil (n = 159) or Aquaphor (n = 157) vs a no data can be attributed in part to the fact that products can be treatment (n = 181) on mortality rates.72 Rates were significantly marketed without demonstrated efficacy. reduced for both treatments (26% sunflower seed oil, 32% Aquaphor), and the results continue to support these treatments for use in developing countries. A controlled trial among 173 Treatment of Diaper Dermatitis infants of 25 to 36 weeks' gestational age compared the effect on skin of two topical treatments vs no treatment control for 4 Etiology Skin damage in the diaper area is the result of several 73 One treatment was a mixture weeks of twice-daily application. factors in the “diaper environment.” They include increased skin of olive oil (30%) and lanolin (70%), and the other was hydration, contact with skin irritants (urine, feces, enzymes in Bepanthen (Bayer Health Care, Leverkusen, Germany), a water- feces, bile salts, etc), mechanical friction (skin to skin, diaper to in-oil cream containing dexpanthenol and phenoxyethanol. The skin), skin pH, nutritional status or diet (fecal composition), composition of the cream is not disclosed by the manufacturer. gestational age (barrier maturation status), use of antibiotic The infants treated with olive oil/lanolin had significantly less 48,78-83 therapy, presence of diarrhea, and medical condition. skin dermatitis (dryness, erythema) than either Bepanthen or no Diapered skin pH was higher than a nondiapered control site in treatment, and no difference in infection rates was reported neonates and older infants, and increased pH was related to the among the groups. The mechanism by which these oils enhance effects of occlusion and increased skin permeability.18,84,85 SC barrier formation continues to be investigated, particularly in Higher skin pH was associated with higher skin hydration terms of the uptake of certain components into the SC lipid 81 74–76 (wetness) and diaper rash scores. Irritants cause skin damage architecture and in the optimum mixture of lipids. by disrupting the lipid bilayers of the SC, thereby allowing penetration into the viable epidermis. Irritants (eg, sodium lauryl sulfate (SLS)) increase keratinocyte proliferation and alter Topical Treatment of Skin Compromise metabolism and differentiation.86,87 In response, the epidermis The presence of minor skin damage increases the likelihood up-regulates SC formation, resulting in a defective structure, of further injury in the high-risk neonate, and prevention/early aberrant water handling, and inadequate desquamation.88-93 intervention has been the focus of health care providers who Perineal skin excoriation can occur in conditions where care for them. The published research on the effects of topical pancreatic enzymes are not deactivated in the colon.94,95 When products on damaged skin in neonates is very limited, especially a mixture of pancreatic enzymes and bile salts was applied under for adequately sized randomized controlled clinical trials. The occlusion, erythema, blood flow, skin pH, and TEWL all task becomes selecting one of the appropriate and effective increased.96 Patients who get supplemental digestive enzymes products. Consideration of the regulatory guidelines for skin (eg, for metabolic diseases) are at risk for skin breakdown because care products may be helpful in making those selections. the unabsorbed enzymes can be excreted in the feces and break down the SC proteins.97 Infants with neonatal abstinence syndrome often have diarrhea and can have severe diaper skin – Regulatory Guidance for Skin Products excoriation.98 100 Figs 5A and B illustrate the processes involved in diaper skin breakdown. Topical interventions include “barrier creams,”“barriers,” “skin pastes,”“skin protectants,”“moisture barriers,” and “.” Many are marketed under the Food and Drug Strategy The approach for resolving diaper breakdown is based Administration (FDA) Final Monograph entitled Skin Protectant on minimizing or eliminating the causes and intervening early. Drug Products for Over-the-Counter Human Use.77 Skin protec- Fig 6 shows the aspects of diaper skin care. tants “provide temporary relief from harmful or annoying When damage is noted, the presence of infection (eg, yeast, stimuli.” The “active ingredients” and their allowed levels are bacterial) must first be determined. Rash due to Candida

NEWBORN & INFANT NURSING REVIEWS,MARCH 2009 39 albicans can include bright red color, patchy pattern (areas may be surrounded by scales), and pustules. Topical antifungal agents 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 are not recommended because they can cause skin atrophy and penetrate more easily under the occlusive diaper conditions.102 A placebo-controlled trial of subjects with acute rash showed significantly lower rash scores for treatment with 0.25% Fig 8. Skin evaluation. The effects of treatment plans miconazole nitrate in zinc oxide/petrolatum than the controls with the zinc oxide/petrolatum vehicle, and subjects with can be monitored by the evaluating the damage (ie, moderate to severe rash had the greatest improvement.103 A erythema, rash, dryness, etc) in terms of area of separate safety study showed low systemic absorption of coverage and severity. miconazole nitrate in infants.104 Treatment of bacterial infec- tions is based on the organisms involved. offending agents. Ideally, topical treatments (a) provide a The goal for managing diaper skin breakdown is to somehow semipermeable “film” or “layer” over the damaged skin to allow allow for healing despite the continuing exposure to the SC barrier repair, (b) provide a physical shield between the skin and the irritants, (c) remain in place on the skin (not removed by feces), and (d) allow for ease of skin cleansing (minimize stripping). Complete occlusion of damaged skin can cause delay in healing. Skin repair occurs more quickly when treated with barriers, creams, or films that are semipermeable to water vapor.105,106 An algorithm for the management and selection of treatments is shown in Fig 7. Once a plan is in place, it can be helpful 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). For example, Fig 8 shows a scheme for evaluating erythema.

Topical treatment The diaper rash creams and moisture barriers usually contain a skin protectant (ie, one of the “active ingredients” covered by the FDA monograph), commonly zinc oxide, petrolatum, or dimethicone alone or in combination. The published data on topical protectants are virtually nonexistent for adequate controlled trials in infants, especially the high-risk population. In vivo studies (usually adults) on treatment irritant dermatitis with barrier creams have shown mixed results, with skin improvement in some and worsening in others.107 Hoggarth et al108 evaluated six commercially available products for irritant protection, prevention of maceration, and protection against topical agents. However, the test applied them once a day and then exposed the skin to irritant (sodium lauryl sulfate surfactant) for 24 hours daily for 4 days. Patches are completely occlusive and probably caused the irritant to pass through the barrier cream as well as through the SC. Common diaper rash creams, moisture barriers, and their ingredients are shown in Table 3. The “skin protectant” is in bold and must be at FDA monograph level to make the claim. The others are considered to be “inactive,” and US regulations require them to be listed in the order of amount, unless they are at 1% or less where they can be in any order. These ingredients give the products the features of thickness, ease of application, Fig 7. Algorithm for diaper dermatitis. An algorithm and so on, but they also function to provide uniformity. As an for the management and selection of treatments for example, Table 4 lists the function of each ingredient in two of the products. diaper dermatitis is shown.

40 VOLUME 9, NUMBER 1, www.nainr.com Table 3. Diaper Rash and Moisture Barrier Creams and Their Ingredients Name Ingredient List Desitin (Pfizer, Inc., New York, NY) Zinc oxide (40%), BHA, cod liver oil, fragrance, lanolin, methylparaben, petrolatum, talc, and water Desitin Creamy Zinc oxide (10%), Aloe barbadensis leaf juice, cyclomethicone, dimethicone, fragrance, (Pfizer, Inc.) methylparaben, microcrystalline wax, mineral oil, propylparaben, purified water, sodium borate, sorbitan sesquioleate, vitamin E, white petrolatum, and white wax Desitin Clear All Purpose White petrolatum (60.4%), cholecalciferol, cocoa butter, fragrance, light mineral oil, (Pfizer, Inc.) mineral oil, modified lanolin, paraffin, sodium pyruvate, sunflower seed oil, vitamin A palmitate, vitamin E (DL-alpha tocopherol and DL-alpha tocopheryl acetate) A&D Ointment Original (Schering Petrolatum (53.4%), lanolin (15.5%), cod liver oil (contains vitamin A and Plough, Kenilworth, NJ) vitamin D), fragrance, light mineral oil, microcrystalline wax, paraffin A&D Diaper Rash Cream with Zinc Dimethicone (1%), zinc oxide (10%), aloe barbadensis extract, benzyl alcohol, Oxide (Schering Plough) 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, Zinc oxide, lanolin, and beeswax. Triple paste is fragrance free and contains no Inc., Collegeville, PA) added preservatives Boudreaux's Butt Paste (Blairex, Zinc oxide (16%), boric acid, castor oil, mineral oil, paraffin, Peruvian balsam, Columbus, IN) petrolatum Canus Li'l Goat's Milk 40% Zinc Zinc oxide (40%), petrolatum, goats milk (fresh), mineral oil, emulsifying wax NF, Oxide Ointment (Canus, fragrance (parfum), beeswax, propylene glycol, diazolidinyl urea, methylparaben, Waitsfield, VT) propylparaben Aquaphor (Beiersdorf) Petrolatum, mineral oil, ceresin, lanolin alcohol, panthenol, glycerin, bisabolol Balmex (Chattem, Inc., White petrolatum (51%), cyclomethicone, dimethicone, mineral oil, polyethylene, Chattanooga, TN) silica Mustela Bebe Vitamin Barrier Zinc oxide (10%), water, mineral oil, propylene glycol dioctanoate, methyl glucose Cream (Laboratories dioleate, titanium dioxide, PEG 45 docecyl glycol copolymer, glycerin, ceresin, ethyl Expanscience, Paris, France) linoleate, Shea butter, PEG 8, panthenol, potassium sorbate, fragrance, magnesium sulfate, methylparaben, caprylyl glycol, propylparaben, sodium polyacrylate Triple paste medicated ointment Zinc oxide (12.8%), white petrolatum, corn starch, anhydrous lanolin, stearyl (Sommers Laboratories, Inc.) alcohol, beeswax, bisabolol, cholesterol, water, glycerin, oat kernel extract (Avena sativa), polysorbate 80 Aveeno baby soothing relief Diaper Zinc oxide (13%), A sativa (oat) kernel extract, beeswax, benzoic acid, dimethicone, Rash Cream (Johnson & Epilobium angustifolium flower/leaf/stem extract, glycerin, methylparaben, Johnson Consumer Companies, microcrystalline wax, mineral oil, Oenothera biennis (evening primrose) seed extract, Inc., New Brunswick, NJ) potassium hydroxide, propylparaben, sorbitan sesquioleate, synthetic beeswax, water Burt's Bees Baby Bee (Burt's Bees, Zinc oxide, sweet almond oil, beeswax, tocopheryl acetate, tocopherol (vitamin E), Durham, NC) jojoba oil, lavender oil, retinyl palmitate (vitamin A), extract of rosemary, lavender, calendula, chamomile, rose petal, comfrey root Mustela Dermo-Pediatrics Stelactiv Zinc oxide (10%), water, mineral oil, propylene glycol diethylhexanoate, methyl Diaper Rash Cream (Laboratories glucose dioleate, titanium dioxide, PEG 45 docecyl glycol copolymer, glycerin, ceresin, Expanscience) 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. Petrolatum (30%), dimethicone (1%), water, mineral oil, aluminum starch Browne Drug Company, Inc., octenylsuccinate, PEG 30 dipolyhydroxystearate, stearyl alcohol, Theobroma cacao Edgewood Cliffs, NJ) (cocoa) seed butter, microcrystalline wax, fragrance, Zea mays (corn) oil, retinyl palmitate, cholecalciferol, panthenol, beta carotene, vegetable oil, isopropyl myristate, propylene glycol, methylparaben, propylparaben, diazolidinyl urea Jason Natural Cosmetics Earth's Zinc Oxide (12%), lavender extract, caprylic/capric triglycerides, C12 15 alkyl benzoate, Best Organic Diaper Relief sorbitan isostearate, sorbitan sesquioleate, water (purified), ethylhexyl palmitate, calcium Ointment, Aloe Vera and starch octenylsuccinate, ethyl macadamiate, stearalkonium hectorite, glyceryl laurate, oat Vitamin E (The Hain Celestial kernel oil, tocopheryl acetate (vitamin E), beta glucan, chamomile flower extract (certified Group, Inc., Melville, NY) organic), marigold flower extract (certified organic), propylene carbonate, magnesium sulfate, benzyl alcohol, potassium sorbate, sodium benzoate (continued on next page)

NEWBORN & INFANT NURSING REVIEWS,MARCH 2009 41 Table 3 (continued) Name Ingredient List Method Squeaky Green Diaper Zinc Oxide (10%), Althaea officinalis extract, caprylic/capric triglycerides, cetyl Cream, Rice Milk + Mallow alcohol, cetyl hydroxyethylcellulose, decylene glycol, dimethicone, glycerin, (Method Products, Inc., Helianthus annuus (sunflower) seed oil, Oryza sativa (Rice) bran extract, O sativa (Rice) San Francisco, CA) germ oil, phenoxyethanol, polysorbate 60, sorbitan stearate, water (agua), xanthan gum Lansinoh Diaper Rash Ointment Dimethicone (5.5%) (skin protectant), USP modified lanonin (15.5%) (skin (Lansinoh Laboratories, protectant), zinc oxide (5.5%) (skin protectant), allantoin, beeswax, bisabolol, Alexandria, VA) caprylic/capric triglycerides, esters, glyceryl behenate/eicosadioate, Jojoba Chamomilla recutita flower extract (Martricaria), petrolatum, polydecene, polyethylene, propylparaben, stearyl glycyrrhetinate, tocopheryl acetate (vitamin E), Z mays (corn) starch Sensi-Care Skin Protectant Petrolatum (49%), zinc oxide (15%), carboxymethylcellulose sodium, water, (ConvaTec, Skillman, NJ) stearic acid, glycerin, cetyl dimethicone copolyol, polyglyceryl-4-isostearate, hexyl laurate, phenoxyethanol Aloe Vesta Skin Protectant Petrolatum (43%), water, mineral oil, hydroxylated lanolin, sorbitan sesquioleate, (ConvaTec) ozokerite, PEG-30 dipolyhydroxystearate, glycerin, steareth-20, magnesium sulfate, DMDM hydantoin, iodopropynyl butylcarbamate, aloe barbadensis leaf juice Carrington Moisture Barrier Cream Petrolatum (90%), mineral oil and paraffin, acemannan hydrogel, butylparaben, (Carrington Laboratories, Irving, lecithin, propylparaben, purified water, quaternium 15, sodium chloride TX) 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 and irritants.109,110 There are no studies on the use petrolatum- compositionally appear to be similar. This is, perhaps, not based barriers to prevent diaper dermatitis in normal diapered surprising given the number of ingredients that can be used to skin.109 Products transfer onto the inner diaper sheet and may make a “skin protectant claim.” Thicker products (pastes, interfere with absorbance of moisture from the skin.111 creams, ointments) usually have low water content. Pastes and Some patients have conditions that affect fecal composition petrolatum barriers can be very occlusive. Some clinicians (eg, gastrointestinal conditions) and may benefit from topical recommend against their use for long periods and only in agents designed to mitigate the specific irritants. For example, situations where soils (feces) are high in water and cholestyramine binds with bile acids to make them inactive, and

Table 4. Ingredients in a Common Diaper Rash Cream and Their Functions Ingredient Function Zinc oxide (10%) Skin protectant claimed from monograph A barbadensis leaf juice , hydrating agent Cyclomethicone Assists in spreading Dimethicone Assists in spreading Fragrance Provides pleasant odor and/or covers ingredient odors Methylparaben Preservative Microcrystalline wax Viscosity control Mineral oil Emollient, solvent Propylparaben Preservative Purified water Solvent Sodium borate Product pH control Sorbitan sesquioleate Moisturizer, emollient Vitamin E Vitamin at low level, effectiveness not established White petrolatum Viscosity control White wax Viscosity control Desitin Creamy ingredients: Zinc oxide (10%), A 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.

42 VOLUME 9, NUMBER 1, www.nainr.com Table 5. Surfactants Found in Skin Care ingredients, surfactants (surface active agents), to emulsify soils Products and the Relative Irritancy Potential for removal during rinsing. Cleansers can be no-rinse liquids or creams, in bar form, or liquids added to water. Because they Relative Irritancy Surfactants emulsify lipids, surfactants can damage the SC barrier and High Sodium lauryl sulfate cause skin irritation. Relative skin irritancy has been deter- Sodium dodecyl sulfate mined via skin testing, and rankings for common surfactants Sodium alkyl sulfate are shown in Table 5. After cleaning, residual surfactant can Sodium or potassium cocoate remain on the skin, especially when copious rinsing is not 118 Sodium or potassium tallowate practical. Liquid products containing surfactants with very Sodium palmitate low irritancy are recommended for infants. The irritancy can Sodium or potassium stearate be determined by checking the ingredient label against the list Linear alkyl benzene sulfate in Table 5. Triethanolamine laurate Diaper skin can be cleansed with a soft cloth and an oil- 119 Sodium olefin sulfonate in-water to assist in soil removal. Wipes composed Benzalkonium chloride of a substrate with cleansing agents and/or emollients have Dodecyl trimethyl ammonium been developed for use on diaper skin. Wipe treatment bromide resulted in significantly lower erythema and surface rough- Moderate Sodium ethoxylates ness vs water plus an implement (cotton washcloth, cotton 120,121 Sodium laureth sulfate wool balls) in healthy infants. Wipes made of a soft Ammonium laureth sulfate nonwoven substrate containing water, nonionic cleansers, Low Sodium cocoyl isethionate and emollients resulted in reduced skin irritation (erythema, Sodium alkyl glycerol ether sulfonate rash) and TEWL vs cloth and water in critically ill pre- 122,123 Sodium cocoyl sulfosuccinate mature and full-term neonates. Wipes used on diaper Disodium stearyl sulfosuccinate skin should be free of alcohol, fragrance, and ingredients of known irritancy or cytotoxicity and contain only essential materials.109 preparations have been used successfully for severe perineal skin breakdown.112-114 Cholestyramine ointments can be Skin pH Reduction in diaper skin pH may be another strategy prepared in hospital pharmacies. Sucralfate (Carafate; Marion for improving skin health. An acidic pH is important for the Merrell Dow, Kansis City, MO) in the form of an ointment or enzymes involved in SC formation and integrity to be effective. powder has been used to treat skin damage from gastric It contributes to the SC's innate immune function by secretions. If candidiasis is also present, these patients must be inhibiting colonization of pathogens, for example, Staphylo- treated with an antifungal as well.115,116 coccus aureus.124-126 Application of a pH 5.5 buffer solution Topical creams can be limited by poor substantivity and increased the rate of barrier recovery after damage.127 Wipes removal by stool. Solutions and sprays that form a semiperme- with pH buffers have been developed.128 Routine skin able barrier film upon drying are available. They are intended to cleansing with a new diaper wipe resulted in significantly be left in place to protect the skin from direct irritant contact with lower diaper skin pH than the hospital standard of cloth and irritants. They are semipermeable to assist barrier repair. Skin water in a trial among high-risk premature and full-term stripping during cleansing is minimized. Sureprep No-Sting infants.123 Provision of an acidic skin pH may also help reduce Protective Barrier Wipe (Sureprep NSPBW; Medline Industries, the activity of fecal enzymes. Inc, Mundelein, IL) comes as a water-based solution, is nonflammable, and has no age restrictions. Another is Cavilon Other product ingredients and use on infants Published data No-Sting Barrier Film (Cavilon NSBF; 3M Corporation, St Paul, on the many products that touch, interact with, adhere to, or MN). The material is in volatile silicone solvent and dries to form influence the skin barrier of infants are very limited. Items the semipermeable film. It can be used on infants older than 1 developed for the health and consumer skin care markets are month (eg, not for use on preterms) and is flammable. Sureprep typically tested on adults and/or rely on marketplace experience NSPBW was evaluated in a small study in 10 NICU patients with (lack of adverse effects) to support use on infants. They may severe perineal skin breakdown.117 The skin condition, based on contain ingredients that should be avoided, if possible, or used assessment of area and severity, improved. Two were discharged with caution.129 For example, products containing boric acid after 1 day. A trial of suitable size among parallel treatment are not recommended because of its toxicity.130,131 Benzalk- groups is necessary to determine the effectiveness of Sureprep onium chloride is used in skin products as a disinfectant or NSPBW vs other barrier creams, but it represents a potential preservative and should be evaluated before use on infants. It alternative for diaper skin breakdown in high-risk infants. has been implicated in allergic dermatitis in infants.132 The ingredients are listed on the label and should be checked for Skin cleansing Bathing practices vary with the infant's age and potential negative effects in the neonatal population before medical condition. Skin cleansing products usually contain being adopted for routine use.

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