Troponin T correlates with MRI results in neonatal encephalopathy.

AIM: Troponin is a sensitive marker of asphyxia in term infants mirroring the myocardial injury sustained in global hypoxia-ischaemia. In addition, troponin is a sensitive marker of severity of stroke in adults and neonatal encephalopathy (NE). We aimed to examine the relationship between troponin T in infants with perinatal asphyxia and brain injury on MRI and correlate with neurodevelopmental outcome. METHODS: Serum troponin was sampled in infants requiring resuscitation at birth and/or neonatal encephalopathy in a tertiary referral neonatal centre. Birth history, clinical parameters, neuroimaging and developmental outcome (Bayley Scores of Infant Development [BSID] III) were evaluated. RESULTS: Infants with perinatal asphyxia (n = 54) had serum troponin T measured and 27 required therapeutic hypothermia. Troponin T levels on days 1 and 2 were predictive of need for TH, development of seizures and grade II/III NE (AUC = 0.7; P-values < .001), troponin T levels on days 1, 2 and 3 were highly significant predictors of mortality (AUC = 0.99, P-values .005). The cut-off values of troponin T for best prediction of mortality were 0.84, 0.63 and 0.58 ng/mL on days 1, 2 and 3, respectively. Troponin T on day 3 of life was predictive of injury in the combined area of basal ganglia/watershed on MRI (AUC 0.70; P-value = .045). CONCLUSION: Infants with brain injury on neuroimaging following perinatal asphyxia had significantly elevated serum troponin, and troponin also correlated with developmental scores at 2 years. Further studies combining troponin and MRI may assist in the classification of neonatal brain injury to define aetiology, prognosis and response to treatment.

Neonatal Encephalopathy Is Associated With Altered IL-8 and GM-CSF Which Correlates With Outcomes.

Aim: To investigate the relationship between cytokines associated with innate immune cell activation and brain injury and outcome in infants with NE compared to neonatal controls. Methods: Serum and CSF biomarkers associated with activated neutrophils and monocytes [Interleukin-8 (IL-8) and Granulocyte-Macrophage-Colony-Stimulating-Factor (GM-CSF)] were serially measured using duplex immunoassays on days 1, 3 and 7 in term newborns with NE and controls. Results were compared to grade of encephalopathy, seizures, MRI brain imaging, mortality and Bayley Score of Infant and Toddler Development (Bayley-III) at 2 years of age. Results: Ninety-four infants had serum samples collected with 34 CSF samples. NE Grade II/III was significantly associated with elevated on day 2 serum IL-8. Mortality was best predicted by elevated day 1 IL-8. GM-CSF was initially elevated on day 1 and abnormal MRI imaging was associated with decreased day 2 GM-CSF. Elevated GM-CSF at day of life 6-7 correlated negatively with composite cognitive, language and motor Bayley-III scores at 2 years. Conclusion: Moderate or severe NE and mortality was associated with elevated IL-8. Day 2 GM-CSF could predict abnormal MRI results in NE and Bayley-III. Therefore, these cytokines are altered in NE and may predict early outcomes and further implicate inflammatory processes in NE.

Intrapartum antibiotics for prolonged rupture of membranes at term to prevent Group B Streptococcal sepsis.

The timely administration of intrapartum antibiotic prophylaxis (IAP) to eligible pregnant mothers reduces the risk of early onset Group B Streptococcus (GBS) neonatal sepsis. The incidence of neonatal GBS sepsis is increasing, in spite of national guidelines for its prevention. This retrospective cohort study was undertaken to assess the incidence of culture-proven GBS sepsis before and after a change of practice on intrapartum management of GBS sepsis in babies born at Sunderland Royal Hospital between January 1 2008 and December 31 2017. The data regarding the risk factors, the intrapartum antibiotic prophylaxis and the outcomes of the babies were collected. Twenty-nine cases were identified and presented in two epochs-before and after changing guidelines for intrapartum management. There was a statistically significant reduction in early onset sepsis rates and no difference in late-onset sepsis rates. The prolonged rupture of membranes is a significant risk factor at any gestation. Impact statement What is already known on this subject? Appropriate intrapartum administration of antibiotics in mothers reduces 80% of early-onset GBS infections. In the United Kingdom, IAP is given based on risk factors, which fail to accurately identify and treat the woman who harbours GBS in the birth canal in labour and the incidence of GBS neonatal sepsis is increasing. The national guideline on the prevention of GBS sepsis is not consistent and is open to interpretation. What do the results of this study add? This study highlights prolonged rupture of membranes as a significant risk factor at any gestation and there were missed opportunities to prevent GBS sepsis in term babies with the prolonged rupture of membranes. This study also highlights that it is possible to reduce the neonatal GBS sepsis burden by adhering to guidelines and administering timely intrapartum antibiotics. What are the implications of these findings for clinical practice and/or further research? The timely administration of IAP to all eligible women is possible if the national guidelines are consistent and interpreted correctly. Our national guideline on the prolonged rupture of membranes at term is not clear and is interpreted differently. If IAP is provided in all those with risk factors irrespective of gestation, this would involve additional costs to the NHS; but in the long term, it will benefit as it reduces morbidity.

Perinatal Asphyxia and Erythropoietin and VEGF: Serial Serum and Cerebrospinal Fluid Responses.

BACKGROUND: Infants with neonatal encephalopathy (NE) of hypoxic-ischaemic origin are at risk of oxidative and ischaemia-reperfusion injury, which may induce abnormal inflammatory responses involving excessive cytokine production and release in serum and cerebrospinal fluid (CSF). Systemic inflammation is found in infants with NE, and we therefore were interested in cytokines associated with hypoxia, including vascular endothelial growth factor (VEGF) and erythropoietin (Epo). OBJECTIVE: To investigate the relationship between Epo, VEGF levels, brain injury and outcome in a group of term infants exposed to perinatal asphyxia (PA) compared to controls. METHODS: Serum and CSF biomarkers associated with hypoxia (VEGF, Epo) were serially measured using multiplex immunoassays over days 1-4 in term infants exposed to PA including infants with NE and controls. Results were compared to severity of encephalopathy, MR brain imaging and mortality. RESULTS: Ninety-four infants had 247 serum samples collected (n = 12 controls, 82 exposed to PA with 34 CSF samples), and 4 infants died. Controls had significantly lower serum Epo levels on days 1 and 2 compared to those exposed to PA (p = 0.02). Grade II/III NE was significantly associated with elevated day 2 Epo and decreased day 1 VEGF (p < 0.05; day 2 Epo AUC = 0.74, cut-off 10.05 IU/ml). Elevated serum Epo was associated with severely abnormal MRI. Mortality was associated with elevated day 3 Epo and decreased day 1 VEGF. CSF levels were all after hypothermia and were not significantly associated with outcome. CONCLUSION: Serum Epo and VEGF may be markers of severity of hypoxia-ischaemia and brain injury as they are closely related to hypoxic exposure.

Renal function and novel urinary biomarkers in infants with neonatal encephalopathy.

AIM: Perinatal asphyxia is associated with multi-organ injury including acute kidney injury (AKI). New urinary biomarkers may detect more subtle renal injury. METHODS: Urinary biomarkers (albumin, beta-2 microglobulin, cystatin-C, epidermal growth factor, neutrophil gelatinase-associated lipocalin, osteopontin, uromodulin) were serially measured from days 1 to 7 in term infants with perinatal asphyxia and controls and compared to 'Kidney Disease Improving Global Outcome' scoring of renal injury and to encephalopathy grade. RESULTS: A total of 255 urine samples were taken from infants exposed to perinatal asphyxia (n = 82) and term controls (n = 10). Thirty-nine infants underwent therapeutic hypothermia, four died and 30 infants had acute kidney injury. Infants with acute kidney injury had significantly higher levels of urinary albumin (day 2), cystatin-C (days 1, 2, 3 and 7), neutrophil gelatinase-associated lipocalin (days 2, 3 and 7) and osteopontin (days 2, 3 and 7) and lower epidermal growth factor and uromodulin (day 1) compared to those without AKI. Day 2 cystatin-C predicted AKI with an area under receiver operating characteristic curve of 0.89, p < 0.001, cut-off 9.8 × 104  pg/mL. NE grade II/III infants had significantly elevated levels of urinary cystatin-C, neutrophil gelatinase-associated lipocalin and decreased EGF compared to grade 0/I infants. CONCLUSION: Asphyxiated infants who develop acute kidney injury have significantly altered urinary biomarkers postnatally. Validation of neonatal AKI urinary biomarkers in a large prospective study is required. Long-term follow-up of infants post-asphyxial insult for chronic renal injury is advised.

Vitamin D enhances reactive oxygen intermediates production in phagocytic cells in term and preterm infants.

BACKGROUND: Newborn infants are endotoxin tolerant which may be responsible for their increased susceptibility to bacterial sepsis. Vitamin D has an immunomodulatory effect and newborn infants are at risk of vitamin D deficiency. We examined the in vitro effect of 1, 25-dihydroxyvitamin D (1,25OHD) on whole blood phagocytic toll-like receptor 4 (TLR4), CD11b, and reactive oxygen intermediates (ROIs) in newborn infants during sepsis. METHODS: Whole blood from preterm infants <32-wk gestation, control term neonates, and adults were sampled for phagocytic expression of ROI, TLR4, CD11b in response to lipopolysaccharide (LPS), and 1,25OHD using flow cytometer. RESULTS: ROI production from newborn phagocytes incubated with LPS alone was decreased. Pretreatment with 1,25OHD demonstrated increased (P = 0.001) phagocytic ROI production in newborns but not in adults. 1,25OHD did not have any effect on TLR4 and CD11b in both newborns and adults. Pretreatment with ROI inhibitors (apocynin (APO) and diphenyleneiodonium), phosphoinositide 3-kinase (PI3K) inhibitor, and p38 inhibitor blocked neutrophil ROI production. CONCLUSION: Neonatal phagocytic cells had diminished ROI production in the presence of LPS, however, pretreatment with 1,25OHD reversed this hyporesponsiveness. This action by 1,25OHD was mediated by activation of nicotinamide adenine dinucleotide phosphate oxidase system through PI3K signaling enzymes.

Inadequate vitamin D levels are associated with culture positive sepsis and poor outcomes in paediatric intensive care.

AIM: This study aimed to assess vitamin D status, and its determinants, in paediatric patients with suspected sepsis who were admitted to a paediatric intensive care unit (PICU). We also investigated the association between vitamin D status and clinical outcomes. METHODS: Serum 25-hydroxy vitamin D (25OHD) and clinical determinants were prospectively assessed in children with suspected sepsis (<12 years old) admitted to the PICU. The relationship between 25OHD and clinical outcomes was evaluated. Vitamin D status was also assessed in control children of a similar age. RESULTS: We enrolled 120 children with suspected sepsis admitted to the PICU and 30 paediatric controls. 25OHD was <50 nmol/L in 59% of the children admitted to the PICU and 25OHD was lower than in the controls (47 ± 29 vs 66 ± 26 nmol/L, p < 0.001). After adjusting for potential confounders, 25OHD was strongly associated with culture positive sepsis (p < 0.001), the paediatric index of mortality (p = 0.026) and the duration of mechanical ventilation (p = 0.008). There was a negative correlation between 25OHD and C-reactive protein (CRP): each 0.1% decrease in 25OHD increased CRP (p = 0.04). CONCLUSION: Children admitted to the PICU with suspected sepsis had lower 25OHD than controls and inadequate 25OHD status was associated with confirmed sepsis and poor outcomes.

The Association of Vitamin D Status with Acute Respiratory Morbidity in Preterm Infants.

OBJECTIVE: To assess the association between serum 25-hydroxyvitamin D (25OHD) levels and outcomes in preterm infants (<32 weeks gestation). STUDY DESIGN: Serum 25OHD was measured in mothers and their infants within 24 hours of birth, before the start of enteral vitamin D supplementation, and at discharge from the neonatal intensive care unit. We evaluated the associations between vitamin D status and various early preterm outcomes. RESULTS: Ninety-four preterm infants and their mothers were included; 92% of the infants had a 25OHD level≤50 nmol/L (20 ng/mL), and 64% had a 25OHD level<30 nmol/L (12 ng/mL). A low 25OHD level (<30 nmol/L) in preterm infants at birth was associated with increased oxygen requirement (P=.008), increased duration of intermittent positive-pressure ventilation during resuscitation at delivery (P=.032), and greater need for assisted ventilation (P=.013). CONCLUSION: We observed a high prevalence of low 25OHD (<30 nmol/L), and found an association between vitamin D status and acute respiratory morbidity in preterm infants after birth.

Neutrophil and monocyte toll-like receptor 4, CD11b and reactive oxygen intermediates, and neuroimaging outcomes in preterm infants.

BACKGROUND: Activated leukocytes and infection are implicated in neonatal brain injury. Leukocyte surface receptors are increased in stroke models and may be targets for future adjunctive therapies. METHODS: Serial blood samples were analyzed from preterm infants (n = 51; <32 wk gestation) on days 0, 1, 2, and 7 of life. Monocyte and neutrophil activation were evaluated via flow cytometry at baseline and following endotoxin stimulation ex vivo by measuring CD11b (activation), toll-like receptor 4 (TLR-4; endotoxin recognition) expression, and intracellular reactive oxygen intermediate (ROI) production (function). RESULTS: Control preterm infants with normal neuroimaging had elevated baseline CD11b and TLR-4 expression and ROI production compared with adults as well as a robust immune response following endotoxin stimulation. Preterm infants with abnormal neuroimaging had increased neutrophil TLR-4 and ROI compared with all controls. CONCLUSION: Preterm infants have a robust immune response compared with adults. Increased TLR-4 expression in preterm infants with abnormal neuroimaging is similar to findings in adult stroke. In addition, ROI production may cause tissue injury. The modulation of these responses may be beneficial in preterm inflammatory disorders.

Vitamin D status in Irish children and adolescents: value of fortification and supplementation.

BACKGROUND: Vitamin D has important skeletal and extraskeletal roles but those living at northerly latitudes are at risk of suboptimal levels because of reduced sunlight exposure. AIM: To describe the vitamin D status of Irish children and identify factors predictive of vitamin D status. METHODS: A prospective cross sectional study was undertaken over a 12 month period. Two hundred and fifty two healthy children attending for minor medical or surgical procedures were recruited. All had 25-hydroxyvitamin D (25OHD), parathyroid hormone and bone profiles measured. RESULTS: The mean (standard deviation) for 25OHD was 51(25) nmol/L (20.4 (10) ng/mL). Forty-five percent had levels >50 nmol/L (20 ng/mL). The following variables were significantly associated with 25OHD levels >50 nmol/L (20 ng/mL): sample drawn in April-September, use of vitamin D supplements, consumption of formula milk, and non-African ethnicity. CONCLUSION: More than half of the children in this study had 25OHD levels less than 50 nmol/L (20 ng/mL). Vitamin D status was significantly improved by augmented oral vitamin D intake.