Zinc as an adjunct treatment for reducing case fatality due to clinical severe infection in young infants: study protocol for a randomized controlled trial.

BACKGROUND: An estimated 2.7 of the 5.9 million deaths in children under 5 years of age occur in the neonatal period. Severe infections contribute to almost a quarter of these deaths. Mortality due to severe infections in developing country settings is substantial despite antibiotic therapy. Effective interventions that can be added to standard therapy for severe infections are required to reduce case fatality. METHODS/DESIGN: This is a double-blind randomized placebo-controlled parallel group superiority trial to investigate the effect of zinc administered orally as an adjunct to standard therapy to infants aged 3 days up to 2 months (59 days) hospitalized with clinical severe infection, that will be undertaken in seven hospitals in Delhi, India and Kathmandu, Nepal. In a 1:1 ratio, we will randomly assign young infants to receive 10 mg of elemental zinc or placebo orally in addition to the standard therapy for a total of 14 days. The primary outcomes hospital case fatality, which is death due to any cause and at any time after enrolment while hospitalized for the illness episode, and extended case fatality, which encompasses the period until 12 weeks after enrolment. DISCUSSION: A previous study showed a beneficial effect of zinc in reducing the risk of treatment failure, as well as a non-significant effect on case fatality. This study was not powered to detect an effect on case fatality, which this current study is. If the results are consistent with this earlier trial, we would have provided strong evidence for recommending zinc as an adjunct to standard therapy for clinical severe infection in young infants. TRIAL REGISTRATION: Universal Trial Number: U1111-1187-6479, Clinical Trials Registry - India: CTRI/2017/02/007966 : Registered on February 27, 2017.

Assessment of Adequacy of Supplementation of Vitamin D in Very Low Birth Weight Preterm Neonates: A Randomized Controlled Trial.

OBJECTIVES: To compare the effect of 400 IU and 1000 IU vitamin D for 6 weeks in very low birth weight preterm neonates. DESIGN: Randomized, double-blinded controlled trial in a teaching hospital. PARTICIPANTS: Fifty very low birth weight preterm neonates. INTERVENTION: Vitamin D 400 IU/day (Group 1) or 1000 IU/day (Group 2). OUTCOME MEASURES: Change in serum calcium, phosphate, alkaline phosphatase (ALP), 25-hydroxy vitamin D (25-OHD), parathormone, incidence of skeletal hypomineralization and growth. RESULTS: After 6 weeks of supplementation, the mean serum calcium and 25-OHD levels were significantly higher (p < 0.001 each), while ALP and parathormone levels significantly lower (p < 0.001 each) in group 2. Skeletal hypomineralization was lesser and growth better in group 2. CONCLUSION: Vitamin D supplementation in a dose of 1000 IU/day is more effective in maintaining serum calcium, phosphate, ALP, 25-OHD and parathormone levels with lower incidence of skeletal hypomineralization and better growth.

Zinc Supplementation in Preterm Neonates and Neurological Development, A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of zinc supplementation on neuro-development and growth of preterm neonates. SETTING: Referral neonatal unit of a teaching hospital. DESIGN: Open-labeled Randomized controlled trial. PARTICIPANTS: 100 preterm neonates. INTERVENTION: Participants randomized to receive oral zinc (study group) or not (controls). MAIN OUTCOME MEASURES: Primary: Neuro-development status at 40 weeks post conceptional age and at 3 month corrected age using Amiel-Tison neurologic assessment. Secondary: anthropometry and serum alkaline phosphatase at 3 months corrected age. RESULTS: At 40 weeks post-conceptional age, greater number of zinc supplemented infants demonstrated alertness and attention pattern normal for their age (P=0.02). Higher number of controls showed signs of hyper-excitability at 40 week post-conceptional age (P=0.001) and 3 months corrected age (P=0.003). At 3 month corrected age, mean serum alkaline phosphatase level was significantly higher in the study group compared to controls. CONCLUSION: Zinc supplementation till 3 month corrected age in preterm breastfed infants improves alertness and attention pattern; and decreases signs of hyperexcitability, and proportion with abnormal reflexes.

Vitamin E supplementation in exclusively breastfed VLBW infants.

We conducted this study to evaluate the adequacy of breastmilk as a source of vitamin E in exclusively breastfed VLBW infants. Such infants (n=44) were randomly allotted to receive vitamin E supplementation (n = 23); the rest (n = 21) did not receive vitamin E. After 21 days, the vitamin E level in the supplemented group was 0.78 + 0.26 mg/dL as compared to 0.77+ 0.25 mg/dL in the unsupplemented group (P=0.69). The ratio of Vitamin E to lipids was also comparable in the two groups, (P=0.65). We concluded that vitamin E supplementation is not routinely needed in VLBW infants.

Systemic inflammatory response syndrome in home delivered neonates: a prospective observational study.

OBJECTIVE: To determine the severity of systemic inflammatory response syndrome (SIRS) at admission, bacteriological profile, antibiotic sensitivity of pathogens and factors associated with fatality in home delivered neonates with sepsis. METHODS: This was a prospective observational study conducted in the referral neonatal unit of a teaching hospital admitting extramural neonates. The subjects comprised of 80 home delivered neonates presenting with systemic inflammatory response syndrome at admission. Skin temperature, oxygen saturation, capillary refill time and blood sugar were recorded in all the neonates at admission. For Blood culture, blood collected by venipuncture was placed in a tryptic soy broth culture bottle. Serum TNF-α was measured by ELISA kit. RESULTS: Early onset sepsis was seen in 27.5%. The commonest clinical feature in the study population was decreased oral acceptance (53.8%). The mean distance traveled to reach the hospital was 19 ± 3 km. At admission, acute physiological derangement in the form of abnormal skin temperature, oxygen saturation, perfusion and blood sugar was present in 53 neonates and 44% had more than one parameter deranged. Only 11% cases had early sepsis while the SIRS was well established in the rest. Klebsiella pneumoniae was the predominant bacteria isolated in 14 cases. Resistance of Klebsiella isolates to Ampicillin was 90% and to Gentamicin 57%. The fatality was higher in presence of advanced stages of SIRS at admission. CONCLUSION: SIRS was well established in 89% cases at admission. Klebsiella resistant to antibiotics was the predominant etiological organism. Fatality was higher in culture positive sepsis and in those associated with meningitis and pneumonia.

A comparative study of cells and anti-microbial proteins in colostrum of mothers delivering pre- and full-term babies.

The different anti-infective factors in the colostrum of 25 mothers delivering pre-term (33.04 +/- 2.18 weeks gestation) and 10 mothers full delivering term (39.1 +/- 0.87 weeks gestation) babies were measured. The mothers of both the groups were comparable with respect to age, parity, nutrition, and haemoglobulin levels. Although the mean volume of colostrum (12 hours) was significantly lower in pre-term (32.28 +/- 7.92 ml) than in full term (44 +/- 4.83 ml) colostrum (P less than 0.05), the concentrations of total protein, sIgA, lysozyme, and lactoferrin were significantly higher in preterm than in full-term colostrum. IgG and IgM levels were similar in both the groups of colostrum. In both the groups, s-IgA was the predominant immunoglobulin. Moreover, the absolute counts of total cells, macrophages, lymphocytes, and neutrophils were significantly higher in pre-term compared to full-term colostrum. Macrophage were the predominant cells. Degree of prematurity has been found to have profound influence on the volume, protein concentration, and cell and macrophage counts of colostrum. Thus, more pre-term the newborn was, the mother produced less amount of colostrum. Total protein concentration and absolute cell count were significantly higher in the colostrum samples of mothers delivering between 28 and 32 weeks as compared to those delivering between 33 and 36 weeks. It is concluded that the colostrum of mothers delivering pre-term, though less in amount, is rich in soluble anti-infective agents and cells. The higher concentration of protective factors compensates for the limited capacity of milk intake in the pre-term infant.

Cellular composition including lymphocyte subsets in preterm and full term human colostrum and milk.

The cellular composition of colostrum (within 72 hours post partum) and mature milk samples (5th-7th day post partum) from 20 mothers delivering preterm babies and 20 mothers delivering full term babies was examined. Lymphocyte subsets including T cells, B cells, T4 and T8 cells were quantitated by indirect immunoperoxidase staining using specific monoclonal antibodies. The mean total cell count in preterm colostrum (9,338/mm3) was significantly higher than in full term colostrum (5,594/mm3). Similarly, counts for macrophages, neutrophils and lymphocytes were significantly higher in preterm colostrum and milk as compared to full term colostrum and milk. B and T lymphocytes including T4 and T8 cells were identified in both preterm and full term breast milk. The absolute count of T, B, T4 and T8 cells was significantly higher in preterm colostrum compared to term colostrum, though the relative percentage distribution of lymphocyte subsets showed no significant difference between the two groups. T and B cells constituted about 74% and 26% of total lymphocytes, respectively in preterm as well as full term colostrum and about 69% and 31% in preterm and full term milk. The mean T4/T8 ratio was higher in preterm colostrum than term colostrum, being 1.82 and 1.60 respectively. However, this difference was not significant statistically and did not change statistically in the milk sample.

Anti-infective factors in preterm human colostrum.

Feeding of the infection prone preterm neonate with concentrated immunologically active ingredients in the form of colostrum may have even more significant clinical implications than in the full term infants. The scarcity of knowledge on anti-infective factors in colostrum of mothers delivering prematurely prompted us to carry out this study. Colostrum was collected and analysed from 25 mothers delivering prematurely (Study group) and 10 delivering at term (Control group). Major anti-infective factors namely IgA, IgG, IgM, lactoferrin and lysozyme were quantitated and total cell, macrophage, lymphocyte and neutrophil counts were performed. The mean concentrations of IgA, lysozyme and lactoferrin of preterm colostrum were significantly higher than in full term colostrum (p less than 0.001). IgG and IgM were found to be similar in both groups. The absolute counts of total cells, macrophages, lymphocytes and neutrophils were found to be significantly higher in the preterm colostrum as compared to the full term colostrum (p less than 0.001). Though in both the groups IgA was the predominant immunoglobulin, the mean percentage of IgA in the study group was significantly higher as compared to the control group. Degree of prematurity did not have any influence on the anti-infective protein levels in colostrum. However total cells and macrophages were significantly higher in colostrum of mothers delivering severely preterm babies.