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Development of Skin Barrier Function in Premature Infants Development of Skin Barrier Function in Premature InfantsTop of pageAbstractHistologic analysis suggests that epidermal development is complete in utero at wk gestational age. Infants born more prematurely have elevated rates of both transepidermal water loss and transcutaneous heat loss, and have difficulty maintaining homeostasis. The underdeveloped integument is also a portal of entry for infection and the percutaneous uptake of toxins. Previous measurements of transepidermal water loss have suggested that, regardless of gestational age, competent barrier function is attained within 2 wk postnatal age. In this study we have utilized another noninvasive biophysical technique, low frequency impedance spectroscopy, to complement transepidermal water loss measurements. We present longitudinal data from infants ranging from 23 to 32 wk gestational age. The results suggest that, for ultra low birth weight infants (23 wk gestational age), the complete development of a fully functional stratum corneum can require significantly longer than 4 wk. Histologic assessment of abdominal skin samples from infants of different gestational ages (24 wk) (Evans Rutter 1986) indicated that, in utero, barrier development increased with gestational age but that neither the stratum corneum nor the dermo undulations were visible until 34 wk gestational age, and that only then was barrier maturation deemed to be complete. Thus, full term infants (40 wk gestational age) are born with a competent barrier, comparable with that found in adults. In contrast, premature infants of lower gestational age have a far less developed dermis at birth and consequently are ill equipped to cope with ex utero conditions. Barrier dysfunction is manifest by an inability to maintain homeostasis owing to excessive fluid loss (resulting in dehydration and electrolyte imbalance) and poor thermoregulation (Hammarlund Sedin 1979;Rutter Hull 1979;Wilson Maibach 1980;Hammarlund et al. 1982;Harpin Rutter 1983). These infants are at further risk because the poorly developed stratum corneum serves as a portal of entry for infection (Leyden 1982;Patrick 1990;Askin 1995), and potential toxicity from topically applied substances (Nachman Esterley 1971;Wester Maibach 1982). In infants of less than 34 wk gestational age, but with a range of postnatal ages, rapid epidermal cell differentiation occurs in the first few weeks of life and, structurally, the skin of the most immature infants resembles that of full term infants by 2 wk of age (Evans Rutter 1986). The stimulus for this burst of epidermal cell differentiation has been suggested to be the transition from a fluid (intrauterine) to a terrestrial environment (Evans Rutter 1986). A variety of techniques have been deployed to correlate skin barrier maturation with gestational and postnatal age (Emery et al. 1991;Lynn et al. 1993;Okah et al. 1995). Transepidermal water loss (TEWL) has identified the significance of both gestational and postnatal age (Hammarlund Sedin 1979;Rutter Hull 1979;Wilson Maibach 1980;Hammarlund et al. 1982;Harpin Rutter 1983;Sedin et al. 1985), the role of humidity (Hammarlund et al. 1996;Lund et al. 1997). Histologic data and TEWL measurements have been cited as evidence that 2 wk of postnatal existence are sufficient to attain functional and structural integrity of the stratum corneum regardless of gestational age (Harpin Rutter 1983;Evans Rutter 1986). The majority of the literature presents of data from different subjects at different gestational and postnatal ages and then attempts to deduce by interpolation and extrapolation a model for neonatal skin development. There is essentially no longitudinal data with which to track the day to day changes in barrier function in a specific infant as stratum corneum (and implicitly, epidermal) development proceeds. We present detailed case histories documenting the progressive evolution of barrier function. We have combined precise TEWL data (Lund et al. 1997) with those from a second, noninvasive and independent technique, namely impedance spectroscopy (IS) (Kalia Guy 1995;Kalia et al. 1996a,b). The longitudinal results have documented the maturation process in a cohort of low birth weight infants, ranging from 23 to 32 wk gestational age. Top of pageMATERIALS AND METHODSElectrodesThe alternating current, required for the impedance measurements, was applied using Tendertrace gel adhesive Ag electrodes (NDM, Dayton, OH). The area of the gel was 4 cm2, of which the electrode surface occupied 0.79 cm2. Experimental apparatus A Macintosh Quadra 800 (Apple, Cupertino, CA) equipped with LabVIEW 3.0.1 (National Instruments, Austin, TX) was used to control a signal generator (HP8116 A Pulse Generator, Hewlett Packard, North Hollywood, CA). At an applied voltage of 1.0 V (peak to peak), this produced a sinusoidal alternating current whose frequency was raised from 1 Hz to 1 kHz incrementally with 10 frequency points sampled per decade. The electrical circuit used for making the impedance measurements included a 2 M resistor in series with the skin. value of The potential difference across the skin was measured using a lock in amplifier (SR850 DSP, Stanford Research Instruments, Sunnyvale, CA). An isolation transformer (Professional Design and Development Services, Berkeley, CA) protected the human subject by ensuring complete isolation of the subject from the mains power supply. TEWL measurements were made using a Servo Med Evaporimeter EP1 (Servomed AB, Stockholm, Sweden) (Nilsson 1977). Subjects Ten neonates admitted to the Intensive Care Nursery of Children Hospital, Oakland, were enrolled in the study after informed parental consent was obtained. All neonates appropriate for gestational age were eligible for the study. Exclusion criteria included dermatologic disease or major congenital anomalies. Gestational age was determined by maternal dates and corroborated by physical examination of the infant. The research protocol was approved by the Institutional Review Board of Children Hospital (Oakland, CA). Experimental procedure The site of both TEWL and impedance measurements was the subject calf (usually) or thigh. The leg was chosen because it was easily accessible regardless of the infant position and of the manifold therapeutic interventions occurring elsewhere on the body surface. (i) TEWL: The sensing probe was held gently against the infant skin for a period of 90 s. Data points were taken every 1.5 s and stored on an IBM compatible PC equipped with an analog digital conversion card (DT 2811, Data Translation, Marlboro, MA) using custom software (Measurement Technologies, Cincinnati, OH). A mean TEWL value was determined by averaging the data recorded from t 30 to t 90 s. (ii) Impedance: After recording the TEWL measurement, two gel adhesive electrode pads were placed on the subject calf (or thigh), mm apart (corresponding to a separation between the active electrodes of 1.5 cm) and an impedance spectrum recorded. The measurement required min. Top of pageRESULTSCase 1: Infant F (see Table 1) Figure 1(a) and (b)display, respectively, the changes in TEWL and skin impedance as functions of postnatal age (PNA, lower abscissa) and postconceptional age (PCA, upper abscissa). Comparison of Figure 1(a) and (b) reveals clearly that changes in low frequency impedance (1.6 Hz) are much more sensitive to barrier maturation than the higher frequency parameter (note the difference in the scales of the right ordinates in Figure 1a,b). Therefore, although data were collected over a wide frequency range, only those at 1.6 Hz were used to compare TEWL and IS as probes of stratum corneum maturation and barrier function. Development of skin barrier function as assessed by increase of skin impedance (Z) and decrease of transepidermal water loss (TEWL). Both (a) and (b) display the change in TEWL (y axis) and the change in Z (x axis) at a specific frequency, either (a) 1.6 Hz or (b) 489 Hz, as functions of PNA (lower abscissa) and PCA (upper abscissa). The solid arrow is a threshold impedance (Znorm) at 1.6 Hz for competent barrier function. The shaded region indicates the range of basal TEWL values (TEWLnorm) typically found in resting human subjects (5 per gm2 per h). The impedance values are given per unit area (cm2) and correspond to double the actual skin impedance value because the current path traverses the stratum corneum twice. Full figure and legend (52K) Table 1 Table 1. The baby was placed in a tent to maintain elevated ambient humidity levels. The first measurements were made at 15 h PNA. Indeed, in adults, for example, such impedance values are diagnostic of a completely deranged barrier with essentially complete removal of the stratum corneum (Yamamoto Yamamoto 1976;Kalia et al. 1996b). Visual observation revealed a very thin skin, with the cutaneous vascular structure clearly visible. Barrier development in this infant was very slow and it was evident, even at 5 wk PNA, that this infant had not developed a useful cutaneous barrier. It was only during the ninth week of measurement that the skin impedance climbed above 250 k and the TEWL decreased to 10 g per m2 per h. Case 2: Infant G Infant G was enrolled in the study at 1 wk PNA and the initial measurements (day 7) were made while the infant was in an incubator at elevated humidity ( (Figure 2) (Hammarlund et al. 1977;Harpin Rutter 1985). TEWL rose sharply once the subject was removed from this environment, increasing from 15 to g per m2 per h. Skin impedance was initially very low, k (7 d PNA). During the first week of measurement, the infant back developed bright erythematous macular patches with evidence of desquamation over approximately one third of the affected area and cultured positive for both Candida albicans and Coagulase negative Staphylococcus, the latter also being found in the bloodstream. There were no generalized or localized areas of papules or pustules. Although the site of measurement was the calf, which was free from skin lesions, it is conceivable that there may have been systemic effects (Baley Silverman 1988;Faix et al. 1989;Rowen et al. 1995) that influenced skin impedance and TEWL measurements. During the seventh week of life, impedance rose steeply and reached the mature value; TEWL decreased, approaching 10 g per m2 per h. Although TEWL and low frequency impedance had changed rapidly during the initial days of the study, both parameters then remained somewhat invariant for several weeks before resolving quickly at the end of the measurement period. Full figure (30K) Case 3: Infants E1 and E2 Infants E1 and E2 were twins maintained on ventilator support in an incubator for most of the study. The increase in Infant E1 skin impedance during the maturation process is shown in Figure 3(a). The initial TEWL value was g per m2 per h, which was artificially low due to the subject being maintained in an environment of higher than ambient humidity. This effect was apparent when TEWL rose to g per m2 per h on the second day of measurement (PNA 8 d) when the increased humidity had been removed. The difference illustrates that elevated humidity can be useful in reducing excessive fluid loss (Hammarlund et al. 1977;Harpin Rutter 1985). Generally, TEWL followed a downward trend over the measurement period and approached the upper limit ( g per m2 per h) of the adult infant range at wk PNA (although day to day variations that resulted in higher TEWL were sometimes observed). Skin impedance increased steadily from the first day of measurement and attained values typical of adult skin at PNA 17 d. Full figure (64K) In the case of the sibling, Infant E2, measurements were made on the right calf and the left thigh (Figure 3b). Although the trends were the same, skin impedance did not reach mature values until PNA 23 d. Furthermore, TEWL values did not fall below g per m2 per h until PNA 30 d. Thus, there was an d differential in barrier development of these twins. This may have been due to inherent intersubject variability, E2 was considerably smaller than E1 (700 g, cf. 880 g at birth). There is not enough evidence, however, to assume that intrauterine growth retardation was responsible for the difference in development shown by twin E2, because it has been found that the period of elevated TEWL is shorter in pre term small for gestational age infants than in pre term appropriate for gestational age infants (Hammarlund et al. 1983). Twin E2 also went through major surgery, and was receiving parenteral nutrition, rather than formula or breastmilk feedings. This may also have contributed to delayed development of many organs, including the skin; however, a drug treatment related effect is also possible, although both twins were given dexamethasone, indomethacin, and dopamine, Infant E2 received dexamethasone for a much longer period ( wk) than her sibling (4 d). The measurements on the left thigh at PNA 47 d were particularly interesting. By this stage of maturation, both TEWL and skin impedance had attained reasonably stable values, g per m2 per h and k respectively; however, the skin impedance at PNA 47 d was only of that on the previous day. TEWL was also elevated to g per m2 per h. Investigation of the cause of the observation revealed that the temperature of the incubator had increased to 36.6 (cf. 30.5 on the previous day) because the servo controlled skin temperature probe had become dislodged; this resulted in E2 axillary temperature climbing to 37.8 Therefore, the anomalously low impedance and elevated TEWL were probably due to a temperature related perturbation of the barrier function. Case 4: Infants J1, J2, and J3 These triplets were in incubators throughout the study (Figure 4a For measurements on days 4 the humidity was elevated and this suppressed TEWL to g per m2 per h; however, when the humidity was removed, TEWL increased to 20 g per m2 per h for Infants J1 and J3. There was a smaller effect on TEWL in Infant J2 suggesting that this infant possessed more efficient barrier function (note also that, during this period, Infant J2 also had higher impedance values than his siblings). All three infants were almost 5 wk PNA before TEWL attained the range, J1 and J3 again taking slightly longer than their sibling. Dexamethasone was administered to each triplet, but with different dosage regimens. Infant J1 received an initial dose of 0.05 mg every 12 h for 20 d, which was then gradually tapered to 0.07 mg every 48 h over the next 3 wk. Infant J2 began at 0.07 mg every 12 h for 12 d, tapering to 0.04 mg per day over the subsequent 10 d. Infant J3 was started at 0.14 mg every 12 h for 10 d, gradually falling to 0.05 mg every 48 h over the following 3 wk.