The global mortality in children younger than 5 years of age has declined substantially in recent decades; however, neonatal mortality has remained relatively unchanged and has emerged as a major public health priority. Approximately two-thirds of global infant mortality and one-third of deaths in children younger than 5 years old occur in the first month of life. 1–6 Infections and complications of prematurity cause an estimated 50–75% of these deaths. 1,2 Among the estimated 4 million annual neonatal deaths in developing countries, most occur among low birth weight (LBW) infants, 3 and of these, approximately one-fourth occur in preterm very LBW infants weighing <1500 g. 7,8
Preterm infants are particularly susceptible to infections, because their skin barrier lacks the naturally protective cutaneous biofilm, vernix, 9 and is developmentally immature, easily injured and functionally compromised. 10 Skin barrier function may be further compromised in infants in developing countries as a result of malnutrition. 11 The first week of life, when epithelial barrier function is most highly compromised, is the neonate’s most vulnerable period when 50–70% of fatal and life-threatening neonatal illnesses occur, 2,7 the most important of which are serious bacterial infections. 2,7,12
In light of the limited options for management of serious neonatal bacterial infections in developing countries and global threats to the effectiveness of antibiotic therapy because of rising rates of antibiotic resistance, there is an urgent need to develop more effective measures to prevent neonatal infections.
Organisms that normally inhabit the skin are the major agents of sepsis in very LBW infants. 13 Topical therapy may be an effective strategy for enhancing epidermal barrier function, preventing infections and improving neonatal outcomes in developing countries, particularly among preterm infants weighing <1500 g whose skin barrier is temporarily but critically compromised. In experimental conditions, perturbed epidermal barrier function and dermatitis in essential fatty acid (EFA)-deficient rodents was reversed by topical application of either purified EFAs or EFA-rich vegetable oils, particularly sunflower seed oil (SSO). 14–20 Cutaneous absorption and metabolism of linoleic acid appeared to be largely responsible for the beneficial effects of SSO. 16,18,19 Topical therapy with SSO also corrected cutaneous signs of EFA deficiency [ie, normalization of transepidermal water loss, resolution of dermatitis] in several patients, including premature infants. 21–24
Besides the ability of standard emollients to act as a mechanical and semipermeable barrier, highly active lipid metabolism in the epidermis and the presence of a fatty acid transporter on keratinocytes make it possible for even the immature epidermis to metabolize lipids derived from topically applied emollients and to use them as nutritional building blocks for the formation of a healthy, functional epidermal barrier. 25,26 Thus epidermal barrier-enhancing emollients have been shown to decrease transepidermal water loss, 27,28 which is a principal measure of skin barrier integrity; improve skin condition; and minimize skin injury in extremely preterm infants in U.S.-based trials. 27–30 In developing counties, topical therapy with natural oils improved thermoregulation and growth of newborns. 31–33 Topical therapy, however, has had variable impact on risk of infection in developed country studies, and no studies have been reported from developing countries. 27,30,34,35
This trial was conducted in Egypt to determine whether SSO would improve skin condition and reduce the incidence of invasive bacterial infections when applied to premature infants <34 weeks gestation.
Study Site and Population.
Evaluation of the impact of topical therapy with SSO on prevention of systemic infections in preterm infants was conducted at Kasr El-Aini neonatal intensive care unit (NICU) at Cairo University. The Kasr El-Aini unit is a free, government-subsidized unit that admits 600 neonates annually, approximately one-half of whom are < 34 weeks gestational age.
All infants admitted to the unit who were <34 weeks gestational age and <72 h old were considered eligible for the study. Gestational age was determined with an average of gestational age values by last menstrual period, per the criteria of Ballard et al 36 and Dubowitz et al. 37 Infants were excluded if they met any of the following criteria: (1) the admitting physician anticipated that the infant might die within 48 h of admission, for any reason; (2) presence of a major congenital anomaly; (3) major surgical procedure required; or (4) the infant or mother had known immunodeficiency.
Patients were stratified for gestational age and randomly assigned to the intervention or control group. Patients in the intervention arm received applications of SSO 3 times daily for the first 14 days and then twice daily until 28 days of life or until discharge from the NICU, according to a dosing schedule that provided 4 g of oil per kg of body weight per treatment. Daily supplies for each patient were distributed from a refrigerated stock container, which was replaced once weekly. Daily dispensing of oil, strict adherence to sterile procedures during dispensing and application and regular replacement of the oil stock obviated the potential for contamination of the oil.
Infants in the control group received the standard of the unit for skin care, which was minimal to no use of topical emollients, and otherwise received the same general care as the infants in the SSO group.
Baseline blood cultures were drawn routinely during the first 48 h of admission on all patients, with which subsequent cultures of blood and cerebrospinal fluid (CSF) drawn for episodes of suspected sepsis were compared. Cultures drawn for suspected sepsis that grew the same organism as present during the baseline were considered as persistent congenital infections and were excluded from analysis for nosocomial infection. The primary outcome measure was a noncontaminated (cultures positive for diphtheroids or Micrococcus spp. were excluded) positive blood or CSF culture for suspected sepsis after the first 48 h of hospitalization, where the culture did not grow the same organism as the most recent previous culture in the same infant, not on the same day (ie, cultures that were positive on the basis of persistent infection were excluded) (Fig. 1). If an infant had both a positive CSF and a positive blood culture drawn on the same day, only one nosocomial infection on that day was counted. Secondary outcome measures were determined by the study physicians and included: (1) skin condition score (Table 1) at birth and days 3, 7, 14, 21 and 28 days of life, as long as the patient remained in the NICU; and (2) mortality attributed primarily to sepsis. The ability of the study physicians to monitor skin condition was verified by an investigating physician (P.A.L.).
Data Analysis and Management.
All analyses were conducted using STATA 7.0 statistical software (Stata Corp., College Station, TX). The Poisson regression method was used to estimate the differentials in nosocomial infection rates by intervention arms. 38 Because the development of nosocomial infection was treated as an incident and multiple spells of nosocomial infection possible, robust variance estimation methods were used to address intracluster correlation and overdispersion in the Poisson model. Cox’s proportional hazards model was used for the mortality analysis, and a repeated measures analysis of variance model was used to compare skin condition scores.
Baseline Characteristics of Patients.
Baseline characteristics of patients enrolled in the control (n = 52) and SSO (n = 51) groups were comparable in all aspects evaluated, with the exception of mean birth weight, which was lower in treatment group 2; P = 0.04) (Table 2), and was adjusted for during analysis.
Skin Condition Score.
Both groups started with the same mean skin condition score of 1.0, but the score increased more rapidly with time and to a higher degree at all time points in the first 28 days of life in the control than in the SSO group (Fig. 2) (P = 0.037).
None of the cultures drawn for detection of nosocomial infection was contaminated (Fig. 1). Fifty-nine nosocomial infections were diagnosed (Fig. 1;Table 3). Incidence of nosocomial infections was significantly reduced in the treated compared with the control infants [crude incidence ratio (IR), 0.61; 95% confidence interval (CI). 0.39–0.94; P = 0.024; adjusted IR (for weight on admission, gestational age, gender), 0.46; 95% CI 0.26–0.81; P = 0.007]. The median time of nosocomial infection was day of life 7 in both treatment groups. There was no difference in the agents of nosocomial infections in the SSO and control groups (data not shown), and reduction in incidence of infection was of a similar magnitude when analysis was restricted to nosocomial infections with Klebsiella pneumoniae (adjusted IR, 0.40; 95% CI 0.18–0.90; P = 0.028), the principal agent of infection.
Death beyond the first 2 days of life due to sepsis, as determined by the study physicians, was not significantly different in the treated compared with the control infants (adjusted odds ratio, 0.72; 95% CI 0.39–1.34; P = 0.30).
Overall morbidity in the study was high but similar to prior experience in the unit. There were no reported adverse events related to use of SSO.
In this study, we evaluated the impact of topical emollient therapy as a strategy to enhance skin barrier function and prevent nosocomial infections in preterm infants in a developing country setting whose skin barrier was compromised because of prematurity and likely also by malnutrition (~40% of Egyptian children younger than 2 years are moderately to severely malnourished). Emollient therapy is inexpensive (~$.20 for a course of therapy in a preterm infant weighing 1.5 kg, the average weight of the infants enrolled in this trial), is technologically simple, can be readily delivered by health care workers and by caregivers and has a number of demonstrated and potential benefits. 10,20 Moreover preliminary research suggested that the practice of applying products to the skin of newborns is commonplace in Egyptian homes and acceptable as a medical therapy to the majority (79%) of mothers, as also reported previously for Bangladesh. 39
We found that topical therapy with SSO was safe and highly efficacious in improving skin condition and reducing the incidence of nosocomial infections. These positive results were found despite limitation in the power of the study resulting from the high mortality rate. More than 60% of the patients died (64 of 103), curtailing the number of surveillance days available for observing an effect of the emollient.
Our results compare favorably with a pilot study at Stanford University that showed an improvement in skin condition, presumably reflecting enhancement of skin barrier integrity, and a reduction in episodes of culture-proved sepsis in premature infants <33 weeks gestational age who received twice daily application of the ointment Aquaphor for the first 2 weeks of life compared with control infants. 27,29 Similarly Aquaphor therapy in neonates weighing <1500 g decreased the nosocomial bloodstream infection rate to 5.4/1000 patient-days, compared with 12.7/1000 patient-days during the preceding 16 months. 34 In contrast, unlike our study in which no increase in fungal infections was seen in emollient-treated infants, a recent case-control study suggested that extremely preterm infants weighing <1000 g who were treated with topical petrolatum ointment were at increased risk for Candida infections. 40 However, the study was small (n = 10), risk factors for infection (eg, skin condition) were inadequately controlled and the patient population described (<1000 g; only 3 patients weighed >700 g) bears little relevance to developing country medicine where survival of such extremely preterm infants is unlikely. Another report suggested that topical applications of Aquaphor might serve as a source for nosocomial infections with coagulase-negative staphylococci and Gram-negative organisms, 41 and a recently completed multicenter U.S.-based trial showed that Aquaphor therapy increased relative risk (odds ratio, 1.43) for sepsis with coagulase-negative staphylococci among neonates weighing 501–749 g; no effects were seen in neonates weighing 750–1000 g. 30 A Cochrane review of developed country studies concluded that prophylactic topical ointment therapy increases the risk of coagulase negative staphylococcal infection and any nosocomial infection. 35 This does not appear to apply to the developing world, however, where Gram-negative organisms are more prominent among skin flora, 42 and invasive infections are caused by more virulent Gram-negative (eg, K. pneumoniae, Escherichia coli) and Gram-positive (eg, Staphylococcus aureus) organisms (AKM Zaidi, SA Ali, GL Darmstadt, S Qozi, ZA Bhutta. Serious bacterial infections among neonates and young infants in developing countries: evaluation of etiology and therapeutic management strategies in community settings, submitted for publication). 43 Moreover the mechanism of transcutaneous sepsis may be different in developing country settings. Because the predominant cutaneous portals of entry for low virulence strains of coagulase-negative staphylococci in neonates in developed countries are sites of instrumentation (ie, indwelling catheters), 44,45 it may not be possible for topical therapy to prevent such infections. Conversely increased handling of extremely fragile skin during application of topical therapy in preterm infants, particularly those weighing <750 g, could conceivably cause further barrier injury and introduce additional infectious risks. In developing countries, however, where indwelling intravascular devices are used less frequently and levels of environmental contamination are much higher, 42 it is plausible that infections occur more often via sites amenable to topical therapy, such as microscopic sites of skin barrier compromise resulting from injury or maturational or nutritional underdevelopment. 11 The fact that adherence to, entry into and in some cases transcytosis through epithelial cells has been demonstrated for several of the virulent Gram-negative and Gram-positive bacteria that are principal agents of septicemia in neonates in developing countries further supports this contention. 46–49
Emollients containing a physiologic balance of epidermal lipids (3:1:1:1 molar ratio of cholesterol, ceramide, palmitate and linoleate) are optimal for barrier repair, 26,50,51 and tests of impact on neonatal outcomes appear to be warranted for the use of topical products with optimized effects on skin barrier function. Yet vegetable oils are readily available worldwide and may provide a technologically simple, inexpensive and clinically effective albeit less than optimal, yet feasible, alternative. It is possible, but unproved, that vegetable oils enhance epidermal barrier function in neonates by: (1) forming a physical barrier; (2) providing the fatty acid building blocks of stratum corneum lipid membranes and the fatty acid ligands of the nuclear hormone receptor, peroxisome proliferator-activated receptor-α, which are known to accelerate skin barrier ontogenesis; and (3) providing γ-linolenic acid, which decreases cutaneous inflammation. 20,26,50–52
In summary, this trial showed a highly significant, 54% reduction in incidence of nosocomial infections in infants treated with SSO as compared with control infants. Reduction of infection seemed to be a general phenomenon, in that the infections caused by K. pneumoniae, the predominant nosocomial pathogen, were reduced to a magnitude similar to that of all pathogens combined. Although a significant reduction in mortality due to sepsis was not demonstrated, a larger trial with greater statistical power is warranted in a developing country to further evaluate this as a possible outcome. It may be advisable to first perform additional background investigations into the local acceptability and biochemical profile and clinical effects of locally available emollients on skin barrier function in the mouse model to identify an acceptable product with demonstrated benefit for skin barrier function, because the effects of different oils are variable. 20 Alternatively a follow-up trial could evaluate the impact of a product with optimized barrier-enhancing properties as a test-of-principal of topical therapy as a strategy to reduce infections and save newborn lives in developing countries.
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