Koravangattu Sankaran

Vitamin D deficiency in young children with severe acute lower respiratory infection.

Acute lower respiratory infection (ALRI) is one of the most common reasons for hospitalization and intensive care unit admission among children. Season related decreases in the immunomodulatory molecule, vitamin D, remain an unexplored factor that might contribute to the increased occurrence of ALRI in children.

Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units.

Objectives: Necrotizing enterocolitis (NEC) is the most common acquired intestinal disease of neonates. Previous reports on incidence have generally examined small cohorts of extremely low–birth-weight infants and have not examined risk-adjusted variations among neonatal intensive care units (NICUs). The authors examined risk-adjusted variations in the incidence of NEC in a large group of Canadian NICUs and explored possible therapy-related risks. Methods: The authors obtained data on 18,234 infants admitted to 17 tertiary level Canadian NICUs from January 1996 to October 1997. They used multivariate logistic regression analysis to examine the inter-NICU variation in incidence of NEC, with adjustment for population risk factors and admission illness severity, and explored therapy-related variables. Results: The incidence of NEC was 6.6% (n = 238) among 3,628 infants with birth weight ≤1,500 g (VLBW), and 0.7% (n = 98) among 14,606 infants with birth weight >1,500 g (HBW). Multivariate logistic regression analysis showed that for VLBW infants, NEC was associated with lower gestational age and treatment for hypotension and patent ductus arteriosus. Among HBW infants, NEC was associated with lower gestational age, presence of congenital anomalies (cardiovascular, digestive, musculoskeletal, multiple systems) and need for assisted ventilation. There was no significant variation in the risk-adjusted incidence of NEC among NICUs, with the exception of one NICU reporting no cases of NEC. Conclusions: Risk factors for NEC were different in VLBW and HBW infants. There was no significant variation in the risk-adjusted incidence of NEC among Canadian NICUs, with one possible exception.

Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: a cause for concern?

Objective:To compare risk-adjusted changes in outcomes of preterm infants <29 weeks gestation born in 1996 to 1997 with those born in 2006 to 2007.Study Design:Observational retrospective comparison of data from 15 units that participated in the Canadian Neonatal Network during 1996 to 1997 and 2006 to 2007 was performed. Rates of mortality and common neonatal morbidities were compared after adjustment for confounders.Result:Data on 1897 infants in 1996 to 1997 and 1866 infants in 2006 to 2007 were analyzed. A higher proportion of patients in the later cohort received antenatal steroids and had lower acuity of illness on admission. Unadjusted analyses revealed reduction in mortality (unadjusted odds ratio (UAOR): 0.83, 95% confidence interval (CI): 0.63, 0.98), severe retinopathy (UAOR: 0.68, 95% CI: 0.50 to 0.92), but increase in bronchopulmonary dysplasia (UAOR: 1.61, 95% CI: 1.39 to 1.86) and patent ductus arteriosus (UAOR: 1.22, 95% CI: 1.07 to 1.39). Adjusted analyses revealed increases in the later cohort for bronchopulmonary dysplasia (adjusted odds ratio (AOR): 1.88, 95% CI: 1.60 to 2.20) and severe neurological injury (AOR: 1.49, 95% CI: 1.22 to 1.80). However, the ascertainment methods for neurological findings and ductus arteriosus differed between the two time periods.Conclusion:Improvements in prenatal care has resulted in improvement in the quality of care, as reflected by reduced severity of illness and mortality. However, after adjustment of prenatal factors, no improvement in any of the outcomes was observed and on the contrary bronchopulmonary dysplasia increased. There is need for identification and application of postnatal strategies to improve outcomes of extreme preterm infants.

Improving the quality of care for infants: a cluster randomized controlled trial.

Background: We developed and tested a new method, called the Evidence-based Practice for Improving Quality method, for continuous quality improvement. Methods: We used cluster randomization to assign 6 neonatal intensive care units (ICUs) to reduce nosocomial infection (infection group) and 6 ICUs to reduce bronchopulmonary dysplasia (pulmonary group). We included all infants born at 32 or fewer weeks gestation. We collected baseline data for 1 year. Practice change interventions were implemented using rapid-change cycles for 2 years. Results: The difference in incidence trends (slopes of trend lines) between the ICUs in the infection and pulmonary groups was − 0.0020 (95% confidence interval [CI] − 0.0007 to 0.0004) for nosocomial infection and − 0.0006 (95% CI − 0.0011 to − 0.0001) for bronchopulmonary dysplasia. Interpretation: The results suggest that the Evidence-based Practice for Improving Quality method reduced bronchopulmonary dysplasia in the neonatal ICU and that it may reduce nosocomial infection.

The Age of Red Blood Cells in Premature Infants (ARIPI) Randomized Controlled Trial: Study Design

Despite recent trends in decreasing transfusion thresholds and the development of technologies designed to avoid allogeneic exposure, allogeneic red blood cell (RBC) transfusions remain an important supportive and life-saving measure for neonatal intensive care patients experiencing illness and anemia. Reluctantly, a number of laboratory and observational studies have indicated that the amount of time RBCs are stored can affect oxygen delivery to tissues. Consequently, older RBCs may result in higher rates of organ dysfunction, nosocomial infection, and lengths of stay. Because of such harmful effects, an evaluation of the association between age of blood and nosocomial infection and organ dysfunction is warranted. The aim of the study was to determine if RBCs stored for 7 days or less (fresh RBCs) compared to current standard transfusion practice decreases major nosocomial infection and organ dysfunction in neonates admitted to the neonatal intensive care unit and requiring at least one RBC transfusion. This study is a double-blind, multicenter, randomized controlled trial design. The trial will be an effectiveness study evaluating the effectiveness of stored vs fresh RBCs in neonates requiring transfusion. Neonatal patients requiring at least one unit of RBCs will be randomized to receive either (1) RBCs stored no longer than 7 days or (2) standard practice. The study was conducted in Canadian university-affiliated level III (tertiary) neonatal intensive care units. The primary outcome for this study will be a composite measure of major neonatal morbidities (necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, and mortality). Secondary outcomes include individual items of the composite measure and nosocomial infection (bacteremia, septic shock, and pneumonia). The sample size calculations have been estimated based on the formula for 2 independent proportions using an alpha of .05, a (1-beta) of .80, and a 10% noncompliance factor. The baseline rate for our composite measure is estimated to be 65% as indicated by the literature. Assuming a 15% absolute risk reduction with the use of RBCs stored 7 days or less, our estimated total sample size required will be 450 (225 patients per treatment arm). The Age of Red Blood Cells in Premature Infants (ARIPI) trial is registered at the US National Institutes of Health (ClinicalTrials.gov) no. NCT00326924 and current controlled trials ISRCTN65939658.

Treatment of Patent Ductus Arteriosus and Neonatal Mortality/Morbidities: Adjustment for Treatment Selection Bias

OBJECTIVE To examine the association between treatment for patent ductus arteriosus (PDA) and neonatal outcomes in preterm infants, after adjustment for treatment selection bias. STUDY DESIGN Secondary analyses were conducted using data collected by the Canadian Neonatal Network for neonates born at a gestational age ≤ 32 weeks and admitted to neonatal intensive care units in Canada between 2004 and 2008. Infants who had PDA and survived beyond 72 hours were included in multivariable logistic regression analyses that compared mortality or any severe neonatal morbidity (intraventricular hemorrhage grades ≥ 3, retinopathy of prematurity stages ≥ 3, bronchopulmonary dysplasia, or necrotizing enterocolitis stages ≥ 2) between treatment groups (conservative management, indomethacin only, surgical ligation only, or both indomethacin and ligation). Propensity scores (PS) were estimated for each pair of treatment comparisons, and used in PS-adjusted and PS-matched analyses. RESULTS Among 3556 eligible infants with a diagnosis of PDA, 577 (16%) were conservatively managed, 2026 (57%) received indomethacin only, 327 (9%) underwent ligation only, and 626 (18%) were treated with both indomethacin and ligation. All multivariable and PS-based analyses detected significantly higher mortality/morbidities for surgically ligated infants, irrespective of prior indomethacin treatment (OR ranged from 1.25-2.35) compared with infants managed conservatively or those who received only indomethacin. No significant differences were detected between infants treated with only indomethacin and those managed conservatively. CONCLUSIONS Surgical ligation of PDA in preterm neonates was associated with increased neonatal mortality/morbidity in all analyses adjusted for measured confounders that attempt to account for treatment selection bias.

Serum Cytokines in a Clinical Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

Inflammatory cytokines may mediate hypoxic-ischemic (HI) injury and offer insights into the severity of injury and the timing of recovery. In our randomized, multicenter trial of hypothermia, we analyzed the temporal relationship of serum cytokine levels in neonates with hypoxic-ischemic encephalopathy (HIE) with neurodevelopmental outcome at 12 months. Serum cytokines were measured every 12 hours for 4 days in 28 hypothermic (H) and 22 normothermic (N) neonates with HIE. Monocyte chemotactic protein-1 (MCP-1) and interleukins (IL)-6, IL-8, and IL-10 were significantly higher in the H group. Elevated IL-6 and MCP-1 within 9 hours after birth and low macrophage inflammatory protein 1a (MIP-1a) at 60 to 70 hours of age were associated with death or severely abnormal neurodevelopment at 12 months of age. However, IL-6, IL-8, and MCP-1 showed a biphasic pattern in the H group, with early and delayed peaks. In H neonates with better outcomes, uniform down modulation of IL-6, IL-8, and IL-10 from their peak levels at 24 hours to their nadir at 36 hours was observed. Modulation of serum cytokines after HI injury may be another mechanism of improved outcomes in neonates treated with induced hypothermia.

Cue-based feeding for preterm infants: a prospective trial.

We set out to test whether premature infants were able to be fed orally on feeding cues and be discharged home earlier than infants fed by traditional feeding regimens. Attainment of adequate growth, adverse events, and nursing time to provide care were also assessed. After screening, the recruited premature infants (< 36 wks post-conceptual age [PCA]) were divided into two feeding regimens. A control group of 40 infants was fed using an initial combination of scheduled gavage and bottle feeding and then graduating to demand feeds. The intervention group comprised 39 neonates who had gavage feeds discontinued at study entrance and fed orally on cues. Outcomes measured were: weight gain in grams/kg/day, length of stay (in days) after enrollment, PCA on entrance and at discharge, adverse events during feeding, number of cues per feed in the intervention group, and resource utilization using nurse/patient ratios. Differences between groups were evaluated using Mann-Whitney U test, Fishers exact test, and regression analysis. Two-tailed P values of < 0.05 were considered significant. There was no difference between groups in the mean weight gain; in the control group mean weight gain was 12.5 gm/kg/day and in the intervention group 12.1 gm/kg/day ( P = 0.83). The average length of stay in the control group of 14.5 days was significantly longer than the 10.0 days in the intervention group ( P = 0.009). This difference remained significant after adjusting for gestational age at birth in regression analysis. The average total number of adverse events in the control group (12.5 events) was significantly greater than in the intervention group (3.5 events; P = 0.007). The mean PCA on study entry was 34.4 wks in both groups and on exit 36.5 wks in the control group and 35.8 wks in the intervention group, a significant difference ( P = 0.02), The intervention group elicited 2.8 cues/feed. The nurse to patient ratios was equal in both groups throughout the study period. Cue-based feeding was possible for premature infants with similar weight gain as traditional feeding without affecting workload. Hospitalization and adverse events were decreased.

Immediate and late ventillatory response to high and low O2 in preterm infants and adult subjects.

Summary: The differences in the immediate (30 sec or l min) and late (5 min) ventilatory response to high and low O2 have not been quantitated in preterm infants and adult subjects using the same methods. It was thought that these differences might explain the paradoxical ventilatory response to CO2 at various O2 concentrations in preterm infants (12). Thus, 9 preterm infants and 10 adult subjects were given 21% O2 to breathe and then 100 or 15% O2 for 5 min each. Adults also breathed 15% O2 before 100% O2 or 12% O2 in order to make their resting arterial PO2 more comparable to those of infants breathing 21% O2. The ventilatory response to 100% O2 was the same in preterm infants and adult subjects, but the late response to 15% O2 remained paradoxical, ventilation decreasing at 5 min by 18% in infants and increasing by 19% in adults. The authors conclude: 1) the traditional concept of the ventilatory response to 100% O2 being different in infants and adult subjects is false; 2) the notion that the response to low O2 is paradoxical in infants is correct; and 3) the data do not explain why the response to CO2 under various background concentrations of O2 in infants is the reverse of that in adult subjects, but the depressed ventilatory response to hypoxia in infants may justify, at least in part, their flatter response to CO2 during low O2 breathing.Speculation: The findings suggest that the response of preterm infants to high and low O2 per se is not the cause of the paradoxical response to CO2 under various background concentrations of O2. If it were, it would be expected that the response to low and high O2 would differ in infants and adults. This was true for hypoxia only, the response to hyperoxia being the same in infants and adults. The speculation, therefore, is that differences in cerebral blood flow caused by CO2 and O2 interaction may be responsible for the paradoxical response to CO2.

Neonatal Outcomes of Small for Gestational Age Preterm Infants in Canada

To compare the effect of small for gestational age (SGA) on mortality, major morbidity and resource utilization among singleton very preterm infants (<33 weeks gestation) admitted to neonatal intensive care units (NICUs) across Canada. Infants admitted to participating NICUs from 2003 to 2008 were divided into SGA (defined as birth weight <10th percentile for gestational age and sex) and non-small gestational age (non-SGA) groups. The risk-adjusted effects of SGA on neonatal outcomes and resource utilization were examined using multivariable analyses. SGA infants (n = 1249 from a cohort of 11,909) had a higher odds of mortality (adjusted odds ratio [AOR] 2.46; 95% confidence interval [CI], 1.93-3.14), necrotizing enterocolitis (AOR 1.57; 95% CI, 1.22-2.03), bronchopulmonary dysplasia (AOR 1.78; 95% CI, 1.48-2.13), and severe retinopathy of prematurity (AOR 2.34; 95% CI, 1.71-3.19). These infants also had lower odds of survival free of major morbidity (AOR 0.50; 95% CI, 0.43-0.58) and respiratory distress syndrome (AOR 0.79; 95% CI, 0.68-0.93). In addition, SGA infants had a more prolonged stay in the NICU, and longer use of ventilation continuous positive airway pressure, and supplemental oxygen (p < 0.01 for all). SGA infants had a higher risk of mortality, major morbidities, and higher resource utilization compared with non-SGA infants.