Strategies for minimizing fluid and evaporative energy losses

A humidified incubator (Fig. 4.2) can provide a thermally neutral environment with low rates of evaporative water loss, because at a relative humidity of 80% or more, skin surface evaporation effectively ceases.^16,34,35 Scrupulous antisepsis, however, is required to prevent bacterial colonization of this environment, particularly with water-loving organisms such as Pseudomonas spp. Moreover, these devices obstruct access to extremely ill or unstable infants. Therefore, these infants are commonly cared for on an open bed, where a radiant warmer provides a thermally neutral environment at the expense of greatly increased rates of TEWL.^34,36,37 Infants requiring care under radiant warmers are typically the youngest and most premature; that is, the population with the poorest skin barriers. Newer hybrid beds with a radiant warmer and humidifier allow for easy access to and observation of infants.³⁵ Use of a plastic cover or plastic bubble blanket may increase the humidity and mitigate to some extent, the adverse effects of the radiant heating on TEWL.^38–42 Although these plastic shields are widely employed, standards for thermal stability and transmission have not been established.⁴³

Other strategies to reduce TEWL in the preterm infant include the use of protective skin dressings or ointments. Semipermeable dressings (e.g., Bioclusive®, Omniderm®, Opsite®, Tegaderm®) that permit some passage of water vapor and other gases, but are impervious to water and microorganisms, can reduce TEWL rates and also are protective against the trauma caused by adhesives from monitors.^40,44–47 Moreover, barrier maturation is not inhibited by these dressings, and neither have increased rates of infection nor colonization by microorganisms been observed. Nonetheless, increased bacterial colonization under such dressings is observed in other clinical settings⁴⁸ and remains a serious consideration with their use on preterm infants. In addition, many of these dressings contain adhesive materials, and even those without adhesives can cling to the moist skin surface of the preterm newborn and injure the epidermis, unless they are either removed carefully or allowed to detach spontaneously. Furthermore, partial body applications (i.e. trunk and abdomen) to very immature infants (<1000 g), may not be sufficient to reduce total fluid requirements.⁴⁴ These limitations hinder the widespread adoption of artificial dressings in routine skin care. Because the benefits of these agents have only been shown in studies with small numbers of subjects, confirmation in larger cohorts is required before their routine use can be generally recommended.⁴²

Topical ointments, such as petrolatum⁴⁹ or Aquaphor®^50,51 reduce TEWL, although the effect from a single application lasts only 4–8 h.^50–52 Less frequent applications do not decrease fluid requirements, but they appear to improve the overall condition of the skin and protect against skin trauma.⁵⁰ Although largely composed of nonphysiologic lipids (e.g., long-chain hydrocarbons and wax esters), these emollients have a long history of dermatologic use without associated toxicity or evidence of significant percutaneous absorption. Nonetheless, internal hydrocarbon accumulations (paraffinomas) are reported, albeit rarely.^53,54 Hence, the possibility remains that these lipids may not be entirely innocuous when applied to the skin of very premature infants (see also Chapter 5). A systematic review of randomized controlled trials comparing prophylactic application of topical ointment in preterm infants to routine skin care⁵⁵ reported that daily application of topical ointment increases the risk for coagulase-negative staphylococcal and nosocomial infections in these patients. Therefore, routine application of topical ointments is no longer recommended for premature infants. However, this should not necessarily be extrapolated to developing countries. Circumstances may be very different in these settings: survival of preterm infants is much lower, care practices differ, and the morbid risks divergent. Indeed, sunflower seed oil and Aquaphor® have been shown to reduce the incidence of nosocomial infections in Bangladesh and Egypt.^56–58 An alternative approach to barrier fortification in these infants would be use of mixtures of lipids physiologic to the skin. The extracellular membranes of the stratum corneum that provide the barrier to TEWL comprise an approximately equimolar mixture of ceramides, long-chain free fatty acids, and cholesterol.⁵⁹ The effect of various mixtures of these physiologic lipids on permeability barrier function has been examined in mature skin in experimental systems, as well as in aged skin and in some skin disorders.^59–61 Recent studies in animal and adult human models suggest that in addition to improving epidermal hydration, vernix-based creams may improve the rate of barrier recovery from injury.^3,62 Yet, despite the theoretic advantages of employing either physiologic lipid mixtures, or vernix-based creams, these formulations have not been examined for efficacy in treating the barrier immaturity of the preterm infant.

Increased percutaneous absorption of xenobiotics

Another direct consequence of skin barrier immaturity is the increased absorption of topically applied substances (Table 4.4), sometimes with tragic consequences (see Chapter 5).^43,63–65 This vulnerability was first recognized historically when preterm infants developed methemoglobinemia through the absorption of aniline dyes in the laundry marks placed on diapers.⁶⁶ Subsequently, the demonstration of neurotoxicity due to percutaneous absorption of hexachlorophene, a commonly used antibacterial cleanser,⁶⁶ led to wider recognition of the vulnerability of the preterm infant to toxicity from topically applied agents.

The same factors that determine the movement of water from inside out also regulate the movement of low molecular weight substances from outside in.⁶⁵ In mature skin, small (<800 Da) hydrophilic molecules are effectively excluded by the extracellular membrane system from penetration across a mature stratum corneum, whereas small hydrophobic molecules or those with amphipathic properties (containing both hydrophilic and hydrophobic parts) are able to penetrate.^1,67 In the preterm infant, the thinner stratum corneum results in a reduction in the length (tortuosity) of the intercellular pathway, which would enhance percutaneous absorption of hydrophilic molecules. It is likely that there are also qualitative changes in the lipid composition and/or structural integrity of the lipid bilayers of immature stratum corneum that may further alter its permeability function.

In addition to immaturity of the permeability barrier, several other factors in premature infants may contribute to toxicity from topical xenobiotics.^64,66 First, the surface area/volume ratio is increased in all infants, but even more so in premature infants; this effectively increases the absorptive surface while reducing the volume of distribution for the absorbed drug. Once absorbed, reduced levels of serum-binding proteins, such as albumin, may increase the proportion of free drug. Similarly, the relative lack of an adipose reservoir to buffer against the redistribution of fat-soluble drugs, such as lindane, to lipid-enriched neural tissues, may make the premature infant particularly vulnerable to central nervous system (CNS) toxicity from such agents. Immaturity of detoxification mechanisms, such as hepatic conjugation and renal function, also alters drug pharmacodynamics and can increase toxicity.

The increased permeability of premature skin to small hydrophilic molecules has also been exploited to enhance the percutaneous delivery of medications such as theophylline.^64,88 A confounding factor in developing transdermal delivery systems for the premature infant is their variability of barrier competence, particularly during postnatal maturation.

Impact of permeability barrier immaturity on other organ systems

Excluding congenital malformations and genetic diseases, the major causes of morbidity and mortality in premature infants are: respiratory distress syndrome leading to bronchopulmonary dysplasia (BPD); patent ductus arteriosus (PDA); necrotizing enterocolitis (NEC); periventricular/intraventricular hemorrhage (IVH); and overwhelming infection. Maintenance of normal blood pressure and ‘optimal’ blood volume protects against these major causes of morbidity and mortality in the preterm infant, and cutaneous fluid losses are perhaps the most important destabilizing factor in fluid homeostasis of the premature infant. For example, overhydration contributes to the development of symptomatic PDA,⁹² as larger blood volumes increase shunting through the ductus arteriosus. Conversely, systemic hypotension may increase the likelihood of an intracranial hemorrhage. Alterations in cerebral blood pressure induce hemorrhage into the periventricular germinal matrix, a gelatinous and highly vascular fetal structure, which is present up to 34 weeks’ gestational age.⁹³ The period of greatest risk for IVH is in the first week of life, particularly the first 2 days, which coincides not only with the time of greatest permeability barrier incompetence but also with the time when tissue fluids undergo redistribution with contraction of the extracellular fluid compartment.⁹⁴ Similarly, bronchopulmonary dysplasia is associated with increased total fluid intake in the first few days of postnatal life and increased time of ventilator use.⁹⁵ Kim and colleagues recently found that extremely low birthweight infants cared for in humidified incubators had decreased fluid intake, improved electrolyte imbalance and a lower rate of severe bronchopulmonary dysplasia.³⁵ Thus, to the extent that BPD, IVH, and PDA are precipitated by fluctuations in systemic blood pressure, overcompensated or uncompensated cutaneous water losses may be an exacerbating factor.

The pathogenesis of NEC is attributed to a triad of ischemia, oral feeding, and infection;^96,97 each of these pathogenic factors may be exacerbated by skin immaturity. As in PDA, IVH, and BPD, fluid imbalance resulting from skin immaturity could be a cofactor, as both overcorrection of fluids⁹⁸ and hypotensive ischemia–reperfusion injury⁹⁹ are implicated in NEC. Early initiation of oral feeds¹⁰⁰ is undertaken to reverse a negative energy balance in the preterm infant. Caloric losses caused by increased evaporative water loss from the skin surface in all likelihood contribute to this caloric drain.

It seems likely, therefore, that efforts to closely monitor cutaneous losses through direct measurements of TEWL, with the goal of tight control of replacement fluids, would decrease the incidence and severity of these major complications of prematurity and improve the outcome of these infants.¹⁰¹

Cutaneous barrier to infection

Although mature skin is colonized by a variety of bacteria and other microorganisms, these organisms are effectively excluded from the interior. The basis for the barrier to transcutaneous infection includes both provision of a mechanical shield against invading microorganisms and specific components, such as certain lipids^107,108 and antimicrobial peptides (defensins and cathelicidins) in the stratum corneum, that inhibit the growth of microorganisms and modulate immune responses.¹⁰⁹ The thinner, easily abraded stratum corneum of the preterm infant constitutes an impaired mechanical shield against the ingress of microorganisms. In addition, specific biochemical components of the cutaneous barrier to infection may also be immature in preterm infants. Extremely preterm infants also lack the initial protection of antimicrobial peptides in vernix caseosa.^3,110 The contribution of the vernix to the antimicrobial barrier is unknown.

Preterm infants’ skin is colonized soon after birth with coagulase-negative staphylococci, predominantly S. epidermidis. Colonization with Malassezia and Propionibacterium occurs later, after 3 weeks,¹¹¹ coincident with the maturation of the permeability barrier. S. epidermidis has become the most frequent cause of postnatally acquired systemic infections in these infants.^112–115 Malassezia, as well as the opportunistic fungi Aspergillus, Candida, and Rhizopus, are also systemic pathogens in this group.^116–119 Direct invasion across the immature epidermis by fungi of low pathogenicity in very preterm infants has been documented,¹²⁰ although exploitation of a portal of entry, such as site of skin injury or along transcutaneous catheter lines, is probably a more common means of entry. Regardless of the route of transcutaneous entry, the immaturity of the immune system, particularly opsonic mechanisms, then permits organisms of low pathogenic potential to mature hosts to establish disease in the preterm infant.¹²¹ The use of intravenous lipid supplements also favors the establishment of a nidus of infection once entry into the circulation has been obtained.¹¹³

Cutaneous barrier to light injury

Energy absorbed from ultraviolet (UV) light passing through the skin may damage critical cellular functions through the generation of free radicals, principally singlet oxygen, as well as through inflammatory responses initiated by cytokine release and the generation of eicosanoids.

For example, free radical damage to deoxyribonucleic acid (DNA) may either result in cell death or initiate carcinogenic mutations. Although shorter wavelengths are more energetic and hence more damaging, they do not penetrate as deeply. In mature skin, ultraviolet B (UVB) (290–320 nm) does not penetrate into the dermis, but ultraviolet A (UVA) (320–400 nm) does, and visible wavelengths (400–800 nm) reach even deeper levels.¹²² Hence, in considering the effects of light on the skin, one must consider not only the cumulative energy of the light absorbed but also the depth of penetration. Cutaneous defenses against UV light injury include:

Rules about depth of penetration of different wavelengths based on studies of mature skin may not hold for premature skin. For example, the stratum corneum is the first-line of defense, filtering out approximately 80% of incident UVB light.¹²² Therefore, the much thinner stratum corneum of the premature infant is one factor that would likely result in increased vulnerability to UV penetration. In addition, although melanocytes are present in the basal epidermis by the end of the first trimester, melanin granule formation is not fully mature, even at term (Table 4.1).¹⁰² Thus, inherent skin color is lighter in neonates. Moreover, the ability of melanocytes in the skin of preterm infants to increase melanin synthesis in response to UV stress is unknown. Other antioxidant defenses may be immature in the epidermis as they are in the lungs of preterm infants.¹²³ Taken together, it is apparent that the premature infant is particularly vulnerable to UV injury.

UVB is filtered out by window glass, but UVA is not. Thus, the preterm infant in the nursery may be exposed to solar UVA, as well as longer wavelengths from artificial light sources. UVA is implicated in certain phototoxic and photoallergic responses.¹²⁴ Chronic UVA exposure is linked to photoaging and is potentially carcinogenic.¹²⁵ Additionally, visible light in the near infrared range (760 nm – 1 mm) is now recognized to contribute to skin photoaging.¹²⁶

Portions of the visible light spectrum (420–500 nm) induce isomerization of bilirubin to compounds that can be excreted without hepatic conjugation. Hence, phototherapy with a variety of light sources is standard therapy for neonatal unconjugated hyperbilirubinemia. Because the commonly used fluorescent daylight bulbs emit UVA, the interposition of a Plexiglas® shield is essential to avoid burns in preterm infants.¹²⁷ Although long considered without risk of long-term complications, recent evidence points to increased numbers of melanocytic nevi (an important independent phenotypic risk factor for melanoma) in children who were exposed to neonatal phototherapy.^128,129 However, several retrospective studies have not found an association with neonatal phototherapy in patients with non-melanoma skin cancer and melanoma, although these studies may not have sufficient follow-up time to capture this association, nor were these sequelae specifically studied in preterm infants. Severe phototoxicity is reported in a preterm infant following use of intravenous fluorescein with prolonged dye retention due to renal immaturity.¹³⁰ Moreover, even internal organs are potentially affected by phototherapy, because light may penetrate more deeply through the skin of the preterm infant. For example, phototherapy has been linked to an increased incidence of symptomatic PDA in preterm infants.^131,132 One study found that shielding the chest wall overlying the heart can mitigate this complication, suggesting a direct photo-effect on ductal tissue; however a follow-up study did not confirm this finding.^132,133

In summary, it should be assumed that the cutaneous barrier to the penetration of light is immature in the preterm infant, hence preterm infants should be physically shielded from exposure to sunlight from exterior windows and other sources of ultraviolet light. Limitation on the intensity of ambient nursery lighting is also recommended out of concern for a contribution to the retinopathy of prematurity.¹³⁴ It would seem prudent also to consider the potential deleterious cutaneous and transcutaneous effects of nursery lighting.

Cutaneous contribution to immaturity of thermal homeostasis

Body heat may escape through a number of mechanisms, as listed below:

Maintenance of a thermally neutral environment, minimizing unwanted heat loss or heat gain, is a major challenge to those who care for premature infants. The survival of very low birthweight infants has been shown to be affected by alterations in thermoregulation, particularly in the ‘golden-hour’ immediately after birth.¹³⁵ The evaporation of amniotic fluid from the skin surface following birth constitutes a major thermal stressor to these infants. Interventions such as plastic wraps or bags, skin-to-skin care and transwarmer mattresses used immediately after delivery keep preterm infants warmer, leading to higher temperatures on admission to neonatal units and less hypothermia.⁴²

The skin participates in thermal homeostasis through several mechanisms. Water loss occurs both through passage of water across the stratum corneum as a function of barrier competency (see above) and from secreted water delivered to the skin surface by ducts (eccrine sweating) in response to neural and other stimuli.²³ Caloric losses caused by an immature skin barrier are a major contributor to the preterm infant’s heat loss, particularly in the first week of life.^135,136

Conversely, because eccrine function is immature, the premature infant is unable to compensate for heat stress by sweating.¹³⁷ Even in term infants, sweating is not functionally mature because the term infant’s set-point is higher than in mature individuals. Sweating in preterm infants matures rapidly following birth; however, the efficiency remains poor, with fewer body sites sweating in response to thermal stimuli and maintenance of a high set-point.¹³⁷ Vasomotor control of cutaneous blood flow is a third component of the skin’s contribution to thermal homeostasis. Both vasoconstriction and vasodilation in response to thermal stimuli are attenuated in the skin of preterm infants, although these responses appear to mature within 2–3 weeks.^23,138 Finally, the subcutaneous adipose reservoir is deficient in preterm infants, reducing both their insulation against heat loss and their energy reserves for thermal conversion.

Neurocutaneous development in the premature infant

Responsiveness to touch is present at a very early age: that is, by the end of the first trimester, the fetus withdraws in response to skin stroking.¹³⁹ In the preterm infant, neurocutaneous responses may be immature and ‘globalized’. Thus, in the unstable premature infant, handling is minimized to avoid adverse effects of skin stimulation, such as changes in heart rate, hypoxia, and apneic episodes.^140,141 However, older and more stable preterm infants may benefit from skin contact in the form of skin-to-skin contact and massage.¹⁴²

Originally, skin-to-skin contact was explored as a mechanism to facilitate maternal bonding with the term infant. A modification of this principle, designated ‘kangaroo care,’ has been advocated for preterm infants in developing countries as a safe and effective mode of care for stable premature infants^143,144 in which the infant is continually housed against the mother’s skin and permitted ad libitum breast-feeding. In low-income countries, kangaroo care can reduce both morbidity and mortality from inadequate thermal protection and infections associated with overcrowding in nurseries and formula-feedings.¹⁴³ Briefer periods of maternal skin-to-skin contact have also been advocated in the care of the preterm infant in high-income countries as a means to enhance maternal confidence and to humanize the nursery experience.^143–146 When preterm infants as early as 22 weeks’ gestational age are carefully selected to avoid the inclusion of unstable ones, the practice does not appear to be deleterious, and may be beneficial (e.g., reduce periods of ‘purposeless’ activity).^147,148 Recent studies suggest that autonomic and psychomotor pain responses are improved in preterm infants who have skin-to-skin contact during heel-sticks, compared with those receiving conventional incubator care.^149,150 Long-term benefits to mother and child of skin-to-skin contact are difficult to distinguish from the benefits of more conventional mother–child contact, but may include prolonged maternal lactation and less infant crying.¹⁴³

Infant massage has been advocated by some as a way to decrease stress and promote growth and development of preterm infants. The mechanisms by which massage improves weight gain are not completely understood, but may involve increased vagal tone, which leads to increased gastric motility, and levels of insulin and insulin-like growth factor-1.¹⁵¹ If larger studies confirm its utility, this relatively simple intervention has the potential to significantly improve weight gain and developmental outcomes, thus decreasing length of hospital stay.¹⁵²

Although it may seem intuitively obvious that both parents and infants would benefit psychologically from the humanizing effects of skin-to-skin contact, the neurocutaneous pathways that are likely to underlie these responses are only beginning to be delineated in mature skin.¹⁵³ It will be important, as this work proceeds, to examine the maturation of these pathways in the preterm infant, so as to both better understand the capacity of the maturing infant to respond to these external stimuli and to develop systems of care that are both rational and ‘humanistic’.

Scars of prematurity

A number of nursery procedures may lead to scars; the number of scars nursery graduates bear is correlated with their degree of prematurity and the duration of intensive care (see also Chapter 8).¹⁶⁰ Although most of these scars are not of great concern, more severe scarring sequelae can occur, particularly those resulting from wounds from chest tubes, skin stripping from adhesive tapes, and extravasated intravenous fluids. In addition, very premature infants (<29 weeks) may develop atrophic scars or so-called ‘anetoderma of prematurity’.¹⁶¹ Although the term ‘anetoderma’ implies a loss of elastic tissue and clinically manifests as an ‘outpouching’ of the skin, scars of prematurity can also be flat. These scars often only become evident at a few weeks to months of life. They often develop at sites of previous application of monitors and adhesives, but may also develop in areas that do not correspond to known areas of injury (Fig. 4.3).

Hemangiomas

Infantile hemangiomas are more common in preterm infants and their frequency is related to the degree of prematurity.¹⁶² In contrast to term infants, there is no significant female predominance in preterm infants with hemangiomas. Premature infants also have higher risk of having multiple hemangiomas, but the exact basis for this increase is not known.¹⁶² Hypotheses include the possibility that preterm infants have higher numbers of endothelial progenitor cells than term infants, and/or are more frequently exposed to medications that may predispose them to hemangiomas such as beta-2-sympathomimetic medications for tocolysis in preterm labor, or erythropoietin (see Chapter 21).^162–165