Relationships between cerebral autoregulation and markers of kidney and liver injury in neonatal encephalopathy and therapeutic hypothermia.

OBJECTIVE: We studied whether cerebral blood pressure autoregulation and kidney and liver injuries are associated in neonatal encephalopathy (NE). STUDY DESIGN: We monitored autoregulation of 75 newborns who received hypothermia for NE in the neonatal intensive care unit to identify the mean arterial blood pressure with optimized autoregulation (MAPOPT). Autoregulation parameters and creatinine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were analyzed using adjusted regression models. RESULTS: Greater time with blood pressure within MAPOPT during hypothermia was associated with lower creatinine in girls. Blood pressure below MAPOPT related to higher ALT and AST during normothermia in all neonates and boys. The opposite occurred in rewarming when more time with blood pressure above MAPOPT related to higher AST. CONCLUSIONS: Blood pressures that optimize cerebral autoregulation may support the kidneys. Blood pressures below MAPOPT and liver injury during normothermia are associated. The relationship between MAPOPT and AST during rewarming requires further study.

Acute paraplegia in a preterm infant with cerebral sinovenous thrombosis.

We report the case of a 1-month old, 28-week gestational age infant who presented with acute paraplegia after cardiopulmonary arrest. Later imaging confirms cerebral sinovenous thrombosis (CSVT) and a suspected infarction in the conus medullaris of the spinal cord. A prothrombotic state may explain the numerous areas of infarction visualized on neuroimaging. To our knowledge this is the first case report of acute and persistent paraplegia in an infant with CSVT and conus medullaris injury, which may be due to venous infarction of the spinal cord.

Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1.

Brain injury due to neonatal hypoxia-ischemia (HI) is more homogenously severe in male than in female mice. Because, necrostatin-1 (nec-1) prevents injury progression only in male mice, we hypothesized that changes in brain-derived neurotrophic factor (BDNF) signaling after HI and nec-1 are also sex-specific providing differential conditions to promote recovery of those more severely injured. The increased aromatization of testosterone in male mice during early development and the link between 17-ß-estradiol (E2) levels and BDNF transcription substantiate this hypothesis. Hence, we aimed to investigate if sexual differences in BDNF signaling existed in forebrain and diencephalon after HI and HI/nec-1 and their correlation with estrogen receptors (ER). C57B6 mice (p7) received nec-1 (0.1µl [8µM]) or vehicle (veh) intracerebroventricularly after HI. At 24h after HI, BDNF levels increased in both sexes in forebrain without evidence of tropomyosin-receptor-kinase B (TrkB) activation. At 96h after HI, BDNF levels in forebrain decreased below those seen in control mice of both sexes. Additionally, only in female mice, truncated TrkB (Tc.TrkB) and p75 neurotrophic receptor (p75ntr) levels increased in forebrain and diencephalon. In both, forebrain and diencephalon, nec-1 treatment increased BDNF levels and TrkB activation in male mice while, nec-1 prevented Tc.TrkB and p75ntr increases in female mice. While E2 levels were unchanged by HI or HI/nec-1 in either sex or treatment, ERα:ERß ratios were increased in diencephalon of nec-1-treated male mice and directly correlated with BDNF levels. Neonatal HI produces sex-specific signaling changes in the BDNF system, that are differentially modulated by nec-1. The regional differences in BDNF levels may be a consequence of injury severity after HI, but sexual differences in response to nec-1 after HI may represent a differential thalamo-cortical preservation or alternatively off-target regional effect of nec-1. The biological significance of ERα predominance and its correlation with BDNF levels is still unclear.

Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells.

OBJECTIVE: Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors (OPRs) expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants. STUDY DESIGN: Using blood from preterm (≤ 30 weeks gestational age (GA), n=7) and full-term ( ≥ 37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNF-α), cyclic adenosine monophosphate (cAMP) levels and µ-, δ- and κ- opioid receptor (OPR) gene and protein expression, following in-vitro exposure to morphine, methadone, fentanyl or clonidine at increasing concentrations ranging from 0 to 1 mM. RESULT: Following lipopolysaccharide activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10(-5) M decreased all tested cytokines except IL-8. In contrast, clonidine at <10(-9) M increased IL-6, while at >10(-5) M increased IL-1ß and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three µ-, δ- and κ-OPR genes were expressed in mononuclear cells (MNC) from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10(-5)M decreased the expression of µ-OPR, but not δ- or κ-OPRs. CONCLUSION: Generalized cytokine suppression along with downregulation of µ-OPR expression observed in neonatal MNC exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.

Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia.

Receptor interacting protein (RIP)-1 kinase activity mediates a novel pathway that signals for regulated necrosis, a form of cell death prominent in traumatic and ischemic brain injury. Recently, we showed that an allosteric inhibitor of RIP-1 kinase activity, necrostatin-1 (Nec-1), provides neuroprotection in the forebrain following neonatal hypoxia-ischemia (HI). Because Nec-1 also prevents early oxidative injury, we hypothesized that mechanisms involved in this neuroprotection may involve preservation of mitochondrial function and prevention of secondary energy failure. Therefore, our objective was to determine if Nec-1 treatment following neonatal HI attenuates oxidative stress and mitochondrial injury. Postnatal day (p) 7 mice exposed to HI were injected intracerebroventricularly with 0.1 µL (80 µmol) of Nec-1 or vehicle. Nec-1 treatment prevented nitric oxide (NO•), inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine increase, and attenuated glutathione oxidation that was found in vehicle-treated mice at 3h following HI. Similarly, Nec-1 following HI prevented: (i) up-regulation of hypoxia inducible factor-1 alpha (HIF-1α) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) expression, (ii) decline in mitochondrial complex-I activity, (iii) decrease in ATP levels, and (iv) mitochondrial structural pathology in astrocytes and in neurons. Up-regulation of glial fibrillary acidic protein (GFAP) following HI was also prevented by Nec-1 treatment. No differences by gender were observed. We conclude that Nec-1 immediately after HI, is strongly mitoprotective and prevents secondary energy failure by blocking early NO• accumulation, glutathione oxidation and attenuating mitochondrial dysfunction.

Contribution of early glycemic status in the development of severe retinopathy of prematurity in a cohort of ELBW infants.

OBJECTIVE: The objective of this study is to investigate the relationship between glycemic status and severe retinopathy of prematurity (ROP). STUDY DESIGN: This is a retrospective cohort study of 114 infants <1000 g admitted to a level IV neonatal intensive care unit within 48 h of life. A cumulative, time-weighted glucose level (TWGL) derived from plotting glucose values over time was included in logistic regression analysis to identify predictors for severe ROP. RESULT: Infants had 26.6 ± 2 weeks gestational age and had a birth weight of 782 ± 136 g. TWGL during first 10 and 30 days of life were greater in the severe ROP group (P<0.01). Unlike single events of glucose levels ≥ 150 mg dl(-1), 10 days TWGL ≥ 100 mg dl(-1) (odds ratio (OR) 5.2, P<0.02) and 30 days TWGL ≥ 118 mg dl(-1) (OR 5.7, P<0.02) were predictors for severe ROP (univariate). Multivariate regression confirmed 30 days TWGL ≥ 118 mg dl(-1) (OR 9.4 to 10) and gram-positive sepsis (OR 4.1 to 5) as predictors for severe ROP (P<0.05). CONCLUSION: High overall glycemic status is associated with the development of severe ROP.