Magnesium Sulfate as an Adjunct to Therapeutic Hypothermia in the Management of Term Infants with Hypoxic-Ischemic Encephalopathy: A Randomized, Parallel-Group, Controlled Trial.

OBJECTIVE: To evaluate whether magnesium sulfate and therapeutic hypothermia in combination decreases mortality and/or major neurodevelopmental disability at 1 y of age among term neonates with hypoxic-ischemic encephalopathy. METHODS: A total of 134 term neonates were randomized to receive intravenous magnesium sulfate at a dose of 250 mg/kg (at 8 mg/kg/min) once daily for 3 d starting within 6 h after birth along with therapeutic hypothermia in the intervention group and therapeutic hypothermia alone in the comparator group. The primary outcome was the composite outcome of mortality and/or major neurodevelopmental disability (Developmental Assessment Scale for Indian Infants score < 70) at 1 y of age. RESULTS: A total of 115 infants were included in the primary analysis. The composite primary outcome occurred in 14 (24%) infants in the intervention group and 19 (33%) infants in the comparator group, and the difference was not statistically significant (p = 0.30; relative risk 0.72; 95% confidence interval 0.40-1.30). The secondary outcomes including neonatal mortality, major neurodevelopmental disability at 1 y of age, neurological status at discharge, level of oxidative stress markers, and adverse effects including hypotension and respiratory depression requiring support were also comparable between the groups. CONCLUSIONS: The combination of magnesium sulfate and therapeutic hypothermia did not improve the composite outcome of neonatal mortality and/or major neurodevelopmental disability at 1 y of age. TRAIL REGISTRATION: Clinical Trials Registry of India (CTRI/2018/06/014594), prospectively registered.

Therapeutic Hypothermia for Perinatal Asphyxia in India-Experience and Evidence.

Therapeutic hypothermia is an established therapy with proven benefit for term neonates with moderate and severe hypoxic-ischemic encephalopathy (HIE). Many centers in India have started therapeutic cooling of asphyxiated infants. There is enough evidence for the beneficial effect of cooling from the randomized trials conducted in India. However, the recently published hypothermia for encephalopathy in low- and middle-income countries (HELIX) trial has contrasting findings. In this context, this review is written summarizing the available experience and evidence for therapeutic hypothermia for perinatal asphyxia in India.

Short Term Outcome and Predictors of Mortality Among Very Low Birth Weight Infants - A Descriptive Study.

OBJECTIVE: To assess the short term outcome and predictors of mortality among very low birth weight (VLBW) neonates. METHODS: This descriptive study from a tertiary care teaching institute in south India included 239 VLBW neonates who were uniformly managed as per unit's protocol and followed up till discharge or death, whichever was earlier. Univariate analysis and logistic regression analysis were done to determine the predictors of mortality. Two logistic regression models were developed and to evaluate their discriminative performance, area under the receiver operating characteristic curves were calculated. RESULTS: Mean gestational age and mean birth weight of neonates were 31.4 ± 3 wk and 1191 ± 245 g respectively. Among the 239 infants, 49 (20.5%) expired and 190 (70.5%) survived. Mortality among extremely low birth weight (ELBW) and extreme preterm infants were 69.3% and 73.3% respectively. Univariate analysis showed multiple perinatal factors and neonatal morbidities were associated with mortality. On adjusted multivariate logistic regression, birth weight < 1000 g (OR 9.27), severe grade of intraventricular hemorrhage (IVH) (OR 29.2), hyperglycemia (OR 7.8) and respiratory distress syndrome (RDS) requiring surfactant therapy (OR 6.2) were the significant predictors of mortality. Both logistic regression models developed showed good prediction of mortality. CONCLUSIONS: VLBW mortality rate is 20% in the population studied. Birth weight < 1000 g, severe grade of IVH, hyperglycemia, and RDS requiring surfactant therapy were the significant predictors of mortality among VLBW neonates. Both prediction models developed showed good prediction of mortality.

Neurodevelopmental Outcome of Preterm Newborns with Abnormal Umbilical Artery Doppler - A Prospective Cohort Study.

OBJECTIVE: To assess the neurodevelopmental outcome of preterm neonates with absent/reversed end diastolic flow (A/REDF) in umbilical artery Doppler at 1 year of corrected age. METHODS: A cohort of 70 preterm newborns with fetal growth restriction (FGR), defined as estimated fetal weight (EFW) <10th centile, confirmed by birthweight <10th centile, along with A/REDF in the umbilical artery Doppler was followed up till 1 year of corrected age (CA). An equal number of gestation and gender matched preterm newborns with birthweight >10th centile [appropriate for gestational age (AGA)] and normal antenatal ultrasound were taken as controls. Primary outcome was a composite of death or major neurodevelopmental disability (NDD) at 1 year of corrected age. Matched analysis was performed. RESULTS: A total of 140 newborns were enrolled, of which, 20 expired and 8 were lost to follow-up. The primary outcome (death/major NDD) occurred in 26.8% of the FGR (A/REDF) newborns as compared to 9.3% of their AGA counterparts (RR-2.83, p = 0.02, 95% CI:1.11-7.18). Mean motor quotient in Development Assessment Scale for Indian Infants (DASII) at 1 year of corrected age was significantly lower in FGR (A/REDF) infants (91 ± 13.6 vs. 96.3 ± 7.1, p < 0.05). Multiple other co-morbidities were also significantly more among these newborns. CONCLUSIONS: Preterm newborns with FGR and A/REDF are at significantly increased risk of death/major NDD at 1 year of corrected age.

Utility of Low Dose Vasopressin for Persistent Pulmonary Hypertension of Newborn with Catecholamine Refractory Shock.

OBJECTIVE: To evaluate the effect of low dose vasopressin on the hemodynamics of neonates with persistent pulmonary hypertension and catecholamine refractory shock. METHODS: This retrospective study was conducted in a level III NICU of a tertiary care teaching hospital, south India. Eighteen neonates with hypoxemic respiratory failure due to persistent pulmonary hypertension of newborn with catecholamine refractory shock were studied. Neonates were managed for hypotension with conventional inotropic support with the additional use of low dose vasopressin (LDV). Effect of vasopressin on oxygenation index (OI), blood pressure, duration of inotropic usage and survival was evaluated. RESULTS: Mean OI was 38.2 ± 4.9, and mean blood pressure was 30.7 ± 5.3 mmHg before the start of vasopressin. Initiation of LDV (0.0003 ± 0.0001 IU/kg/min) for a median duration 36.4 ± 17.9 h was followed by a reduction in OI (p < 0.001), control of hypotension (p < 0.001), reduction in lactic acidosis (p < 0.001) and decline in inotropic support. CONCLUSIONS: In resource-restricted settings, LDV may be useful as a rescue therapy for persistent pulmonary hypertension of newborn with catecholamine refractory shock.

Neuronal Biomarkers in Predicting Neurodevelopmental Outcome in Term Babies with Perinatal Asphyxia.

OBJECTIVE: To assess whether serum levels of neuronal biomarkers (S100 calcium-binding protein B and Neuron specific enolase) correlate with the neurodevelopmental outcome of term neonates at 18 mo who had hypoxic ischemic encephalopathy and underwent therapeutic hypothermia. METHODS: This randomized controlled trial was conducted in a tertiary care teaching hospital, south India. There were 162 term infants with moderate to severe hypoxic ischemic encephalopathy who were randomized into 2 groups (Group A and B). Neonates in Group A and B received normothermia and therapeutic hypothermia respectively. Serum levels of neuronal biomarkers were estimated at 0, 24 (±1) and 72 (±1) h after birth using sandwich ELISA in both groups. All neonates were carefully monitored till discharge. Infants who survived the neonatal period were followed up in the high risk clinic for 18 mo and neurodevelopmental assessment was done using Developmental Assessment Scale for Indian Infants (DASII). Neurodevelopmental outcomes between the two groups were compared using Chi square test and neuronal biomarker levels between the groups were compared using Mann Whitney test. RESULTS: The baseline maternal and neonatal characteristics in both groups were comparable. There was statistically insignificant lesser mortality in therapeutic hypothermia group compared to normothermia group with Risk Ratio (RR): 0.82 (28.2% vs. 34.5%, 95% CI: 0.52-1.29, p = 0.38). Among the survivors, children in therapeutic hypothermia group had better motor and mental scores compared to those in normothermia group at 18 mo. There was no significant correlation between S100B and Neuron specific enolase levels and neurodevelopmental outcome. CONCLUSIONS: Serum levels of neuronal biomarkers (S100B and Neuron specific enolase) do not correlate with the long term neurodevelopmental outcome among these infants.

Two Randomized Trials of the Effect of the Russian Strain of Bacillus Calmette-Guérin Alone or With Oral Polio Vaccine on Neonatal Mortality in Infants Weighing <2000 g in India.

BACKGROUND: In randomized trials in Guinea-Bissau, the Danish strain of Bacillus Calmette-Guérin (BCG) reduces neonatal mortality, primarily by reducing deaths from pneumonia and sepsis. Because World Health Organization-prequalified BCG-Denmark was not available in India, we conducted 2 randomized trials to test whether BCG-Russia alone or with oral polio vaccine (OPV) has similar effects to BCG-Denmark. METHODS: We randomized neonates weighing <2000 g to a control group that was not vaccinated before 28 days of age or to receive either BCG-Russia alone (first trial) or BCG-Russia with OPV (second trial) soon after birth. We performed intention-to-treat analysis using Cox hazards models with age as the underlying time and adjusted for weight, sex and inborn versus outborn status. RESULTS: Administration of BCG-Russia alone had no effect on neonatal mortality (to 28 days of age): 15.6% of 1537 infants died in the BCG-Russia group and 16.1% of 1535 died in the control group; the adjusted hazard ratio was 0.95 [95% confidence interval (CI): 0.80-1.13]. Administration of BCG-Russia with OPV also had no effect on neonatal mortality: 18.0% of 1103 infants died in the BCG-OPV group and 17.6% of 1104 died in the control group; the adjusted hazard ratio was 1.01 (95% CI: 0.83-1.23). The adjusted hazard ratio for the 2 trials combined was 0.98 (95% CI: 0.85-1.11). CONCLUSIONS: BCG-Russia with or without OPV had no effect on neonatal mortality. It is important to determine which strains of BCG have the greatest specific effects (on tuberculosis) and nonspecific effects (on infections other than tuberculosis) in high-mortality regions.

Expression Levels of Candidate Circulating microRNAs in Early-Onset Neonatal Sepsis Compared With Healthy Newborns.

The high mortality rate of neonatal sepsis is directly connected with time-consuming diagnostic methods that have low sensitivity and specificity. The need of the hour is to develop novel diagnostic techniques that are rapid and more specific. In this study, we estimated the expression levels of circulating microRNAs (miRNAs) that are involved in regulating immune response genes and underlying inflammatory responses, which may be used for sepsis diagnosis. The total circulating miRNA was isolated and the candidate miRNAs (miR-132, miR-146a, miR-155, and miR-223) were quantified by real-time polymerase chain reaction technique. Statistical analysis revealed that miR-132 (P < .01) and miR-223 (P < .05) were downregulated in septic newborns compared with healthy babies. The decrease in expression of miR-132 and miR-223 may be associated with increased expression of immune-related genes involved in TLR (Toll-like receptor) signaling pathway. Further case-control studies with large sample size are required to identify the potential of miRNAs in neonatal sepsis diagnosis.

Choroid Osteoma in Schimmelpenning-Feuerstein-Mims Syndrome.

BACKGROUND: Schimmelpenning syndrome is a multisystem disorder. CASE CHARACTERISTICS: A term female neonate with sebaceous nevi of the face had choroid osteoma of the right eye. OBSERVATION: At one month of age, the infant was observed to have choroidal neovascularization that was successfully treated with laser photo-coagulation and anti-VEGF. MESSAGE: Choroid osteoma and neovascularization are rare associations of Schimmelpenning syndrome, and should be screened for and managed early.

p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome is an early-onset severe neurological disorder characterized by intracranial calcification, white matter abnormalities, hepatosplenomegaly, cerebrospinal fluid lymphocytosis, and elevated interferon-α levels, thus mimicking congenital viral infections. It is a genetically heterogeneous condition and autosomal recessive and autosomal dominant forms with variations in seven genes known till date. Variations in RNASEH2C cause an autosomal recessive form of AGS. Here we report three Indian families with variant, c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C gene identified by whole-exome sequencing and targeted molecular testing of the variant. Review of literature and our data suggest this is likely to be a founder variant in Asians and it would be a good initial variant to screen in patients with Aicardi-Goutières syndrome in Indians.

Role of microRNAs in sepsis.

INTRODUCTION: MicroRNAs have been found to be of high significance in the regulation of various genes and processes in the body. Sepsis is a serious clinical problem which arises due to the excessive host inflammatory response to infection. The non-specific clinical features and delayed diagnosis of sepsis has been a matter of concern for long time. FINDINGS: MicroRNAs could enable better diagnosis of sepsis and help in the identification of the various stages of sepsis. Improved diagnosis may enable quicker and more effective treatment measures. The initial acute and transient phase of sepsis involves excessive secretion of pro-inflammatory cytokines which causes severe damage. MicroRNAs negatively regulate the toll-like receptor signaling pathway and regulate the production of inflammatory cytokines during sepsis. Likewise, microRNAs have shown to regulate the vascular barrier and endothelial function in sepsis. They are also involved in the regulation of the apoptosis, immunosuppression, and organ dysfunction in later stages of sepsis. Their importance at various levels of the pathophysiology of sepsis has been discussed along with the challenges and future perspectives. CONCLUSION: MicroRNAs could be key players in the diagnosis and staging of sepsis. Their regulation at various stages of sepsis suggests that they may have an important role in altering the outcome associated with sepsis.

Differential Paradigms in Animal Models of Sepsis.

Sepsis is a serious clinical problem involving complex mechanisms which requires better understanding and insight. Animal models of sepsis have played a major role in providing insight into the complex pathophysiology of sepsis. There have been various animal models of sepsis with different paradigms. Endotoxin, bacterial infusion, cecal ligation and puncture, and colon ascendens stent peritonitis models are the commonly practiced methods at present. Each of these models has their own advantages and also confounding factors. We have discussed the underlying mechanisms regulating each of these models along with possible reasons why each model failed to translate into the clinic. In animal models, the timing of development of the hemodynamic phases and the varied cytokine patterns could not accurately resemble the progression of clinical sepsis. More often, the exuberant and transient pro-inflammatory cytokine response is only focused in most models. Immunosuppression and apoptosis in the later phase of sepsis have been found to cause more damage than the initial acute phase of sepsis. Likewise, better understanding of the existing models of sepsis could help us create a more relevant model which could provide solution to the currently failed clinical trials in sepsis.

Could stem cells be the future therapy for sepsis?

The severity and threat of sepsis is well known, and despite several decades of research, the mortality continues to be high. Stem cells have great potential to be used in various clinical disorders. The innate ability of stem cells such as pluripotency, self-renewal makes them potential agents for therapeutic intervention. The pathophysiology of sepsis is a plethora of complex mechanisms which include the initial microbial infection, followed by "cytokine storm," endothelial dysfunction, coagulation cascade, and the late phase of apoptosis and immune paralysis which ultimately results in multiple organ dysfunction. Stem cells could potentially alter each step of this complex pathophysiology of sepsis. Multiple organ dysfunction associated with sepsis most often leads to death and stem cells have shown their ability to prevent the organ damage and improve the organ function. The possible mechanisms of therapeutic potential of stem cells in sepsis have been discussed in detail. The route of administration, dose level, and timing also play vital role in the overall effect of stem cells in sepsis.