Macronutrient Digestion and Absorption in the Preterm Infant.

The human fetus receives oral nutrition through swallowed amniotic fluid and this makes a significant nutritional contribution to the fetus. Postnatally, macronutrient absorption and digestion appear to function well in the preterm infant. Although pancreatic function is relatively poor, the newborn infant has several mechanisms to overcome this. These include a range of digestive enzymes in human milk, novel digestive enzymes involved in fat and protein digestion that do not appear to be present in the older child or adult, and the presence of a Bifidobacterium-rich colonic microbiome that may "scavenge" unabsorbed macronutrients and make them available to the infant.

Animal models of neonatal stroke and response to erythropoietin and cardiotrophin-1.

Neonatal stroke is increasingly recognized in preterm and term infants, and the rate of arterial ischemic infarction occurring around the time of birth is as high as the annual incidence of large-vessel ischemic stroke in adults. Thus, neonatal stroke is a major contributor to perinatal morbidity and mortality, and a considerable number of these children will develop long-term neurodevelopmental disabilities. Our ability to investigate this situation has been limited by the technical challenges in developing suitable animal models. Our objective is to describe recent evidence in relation to animal models of neonatal stroke. In addition, we review and report potential neuroprotective strategies specific to neonatal stroke, with a focus on erythropoietin and cardiotrophin-1 because of their potential role in protection as well as repair.

An evident view of evidence-based practice in perinatal medicine: absence of evidence is not evidence of absence.

OBJECTIVE: To provide valuable elements and some humor in this so-called era of "evidence-based practice" with the aim of helping clinicians make better choices in the care they deliver based on evidence, not simply or exclusively based on a randomized clinical trial (RCT) or meta-analysis (which may not be evidence). SOURCES: Books and peer-reviewed articles are quoted and listed in the bibliography. Evidence of life, learning from our own mistakes and many other evident facts that support this review are not quoted. SUMMARY OF THE FINDINGS: 1) "Absence of evidence is not evidence of absence" and "lack of evidence of effect does not mean evidence of no effect." 2) RCTs with "negative" results and those with "positive" results, but without outcomes that matter, often cannot conclude what they conclude. 3) Non-randomized clinical trials and practical trials may be important. 4) Research to prove is different than research to improve. 5) Clinical choice must assess effects on outcomes that matter to patients and their parents. 6) Quantifying adverse outcomes, number needed to damage and to treat is not that simple. CONCLUSIONS: Significant challenges inherent to health service research must be correlated to possible clinical applications using tools to have a more "evident view of evidence-based practice" in perinatal medicine, recalling that absence of evidence is not evidence of absence.

The impact of vaginal delivery in premature infants weighing less than 1,251 grams.

OBJECTIVE: To evaluate whether mode of delivery is a predictor of poor short-term outcome at different birth weight categories in very low birth weight infants. METHODS: This study examined a cohort of infants weighing less than 1,251 g born at 2 perinatal centers from January 1, 2000, to December 31, 2003. Outborn infants or those with major anomalies were excluded from the study. Outcome variables included death, severe intraventricular hemorrhage, periventricular leukomalacia (PVL), and combined poor short-term outcomes (death, severe intraventricular hemorrhage, and PVL). RESULTS: Of the 397 infants who met enrollment criteria, 44% were born vaginally and 56% by cesarean delivery. The proportion of multiparous, breech presentation and prolonged rupture of membranes was significantly different between groups. For infants weighing less than 751 g, the risks of severe intraventricular hemorrhage (41% versus 22%; odds ratio [OR] 2.79, 95% confidence interval [CI] 1.08-7.72) and combined poor short-term outcome (67% versus 41%; OR 2.95, 95% CI 1.25-6.95) were significantly higher if delivered vaginally. Among survivors weighing less than 751 g, the risk of severe intraventricular hemorrhage was higher among those delivered vaginally (24% versus 9%; OR 8.18, 95% CI 1.58-42.20). In infants less 1,251 g who survived, vaginal delivery had a strong association with PVL (5% versus 1%; OR 11.53, 95% CI 1.66-125). CONCLUSION: In infants less than 1,251 g who survived to discharge, vaginal delivery is associated with higher risk for PVL. Furthermore, in infants less than 751 g, vaginal delivery is a predictor for severe intraventricular hemorrhage and combined poor short-term outcome. The negative impact of vaginal delivery mode decreases as birth weight category increases.

Cardiotrophin-1 protects cortical neuronal cells against free radical-induced injuries in vitro.

Cardiotrophin-1 (CT-1) was initially defined as a mediator of cardiomyocyte hypertrophy. Additional studies have showed that CT-1 enhanced survival of differentiated cardiac muscle cells and inhibited cardiac myocyte apoptosis after serum deprivation or cytokine stimulation. Moreover, CT-1 has recently been shown to act as a neuroregulatory cytokine in the peripheral nervous system. However, its effects in the central nervous system have not been determined. In the present study, we evaluated whether CT-1 protects cultured cortical neurons against oxidative injuries caused by the hydroxyl radical-producing agent FeSO4 and by the peroxynitrite-producing agent 3-morpholinosydnonimine (SIN-1). CT-1 reduced neuronal cell death caused by FeSO4 and also attenuated the neurotoxic effect of SIN-1 in a dose-dependent manner. These results indicate that CT-1 is neuroprotective in an in vitro model of cerebral ischemia. This study indicates that further evaluation of CT-1 in acute brain injury should be investigated in vivo.

Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain.

The excitotoxic cascade may represent an important pathway leading to brain damage and cerebral palsy. Brain lesions induced in newborn mice by ibotenate (acting on N-methyl-D-aspartate receptors) and by S-bromowillardiine (acting on alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid and kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Fructose 1,6-biphosphate (FBP) is a high-energy glycolytic pathway intermediate which, in therapeutic doses, is non-toxic and neuroprotective in hypoxic-ischemic models of brain injury. Mechanisms of action include modulation of intracellular calcium through phospholipase C (PLC) activation. The goal of this study was to determine the neuroprotective effects of FBP in a mouse model of neonatal excitotoxic brain injury. Mice that received intraperitoneal FBP had a significant reduction in size of ibotenate-induced (80% reduction) or S-bromowillardiine-induced (40% reduction) cortical plate lesions when compared with control animals. Studies of fragmented DNA and cleaved caspase 3 confirmed the survival promoting effects of FBP. FBP had no detectable effect on excitotoxic white matter lesions. The effects of FBP were antagonized by co-administration of PLC, protein kinase C or mitogen-associated protein kinase inhibitors but not by protein kinase A inhibitor. A moderate, transient cooling of pups immediately after the insult extended the therapeutic window for FBP, as FBP administered 24 h after ibotenate was still significantly neuroprotective in these pups. This data extends the neuroprotective profile of FBP in neonatal brain injury and identifies gray matter lesions involving N-methyl-D-aspartate receptors as a major target for this promising drug.

Permanent focal cerebral ischemia activates erythropoietin receptor in the neonatal rat brain.

Erythropoietin (Epo) has been shown to act as a neurotrophic and neuroprotective factor via binding to its receptor (EpoR) which is activated in adult brains following hypoxia and ischemia. However, no evidence suggests that cerebral ischemia can activate EpoR in the neonatal brain. In the present study, the changes in EpoR expression were investigated using a modified model of permanent focal cerebral ischemia (FCI) in 7-day-old rat pups. Western blot analysis with an anti-rabbit EpoR antibody revealed a significant increase in the EpoR protein in the ischemic areas, starting from 6 to 12 h after FCI. Moreover, many EpoR-positive cells were detected in the ischemic areas from 12 h after FCI, and the positive cells were identified as neurons and microglia/macrophage but not astrocytes 24 h after FCI. Additionally, double staining with a red in situ apoptosis detection kit and the EpoR antibody indicated that EpoR-positive cells were in apoptotic cell death in the ischemic area. Therefore, these results suggest that EpoR is activated in the ischemic areas of neonatal rats and plays an important role in brain injury during development.

A reproducible experimental model of focal cerebral ischemia in the neonatal rat.

Recent data suggest that the incidence of focal cerebral ischemia (FCI) and stroke is higher than previously recognized and could account for a large proportion of brain lesions in the preterm and full term neonate. Therefore, it is critically important to develop an appropriate model of FCI in neonatal animals. We describe here a modified model of permanent FCI in rat pups at postnatal day-7 (P7). To produce permanent FCI, a suture embolus with different diameters (180-220 microm) was inserted into the left common carotid artery (CCA) of the pups with different weight (14-19 g). Then the suture embolus was advanced to the middle cerebral artery (MCA) to produce its occlusion. The success of vascular occlusion was evaluated by imaging the ischemic territory on serial brain sections with carbon black staining immediately after permanent FCI. The consistent cerebral infarction was confirmed by 2,3,5-triphenyltetrazolium chloride (TTC) staining 24 h after permanent FCI. Terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphospate-biotin nick end labeling (TUNEL) staining showed cell death with TUNEL labeling in the ischemic areas, which is one of the features of apoptosis. The present model opens the way for advanced pathophysiological studies of FCI in neonates.

Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 2: Management of posthemorrhagic hydrocephalus in premature infants.

OBJECT: The objective of this systematic review and analysis was to answer the following question: What are the optimal treatment strategies for posthemorrhagic hydrocephalus (PHH) in premature infants? METHODS: Both the US National Library of Medicine and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words relevant to PHH. Two hundred thirteen abstracts were reviewed, after which 98 full-text publications that met inclusion criteria that had been determined a priori were selected and reviewed. RESULTS: Following a review process and an evidentiary analysis, 68 full-text articles were accepted for the evidentiary table and 30 publications were rejected. The evidentiary table was assembled linking recommendations to strength of evidence (Classes I-III). CONCLUSIONS: There are 7 recommendations for the management of PHH in infants. Three recommendations reached Level I strength, which represents the highest degree of clinical certainty. There were two Level II and two Level III recommendations for the management of PHH. Recommendation Concerning Surgical Temporizing Measures: I. Ventricular access devices (VADs), external ventricular drains (EVDs), ventriculosubgaleal (VSG) shunts, or lumbar punctures (LPs) are treatment options in the management of PHH. Clinical judgment is required. STRENGTH OF RECOMMENDATION: Level II, moderate degree of clinical certainty. Recommendation Concerning Surgical Temporizing Measures: II. The evidence demonstrates that VSG shunts reduce the need for daily CSF aspiration compared with VADs. STRENGTH OF RECOMMENDATION: Level II, moderate degree of clinical certainty. Recommendation Concerning Routine Use of Serial Lumbar Puncture: The routine use of serial lumbar puncture is not recommended to reduce the need for shunt placement or to avoid the progression of hydrocephalus in premature infants. STRENGTH OF RECOMMENDATION: Level I, high clinical certainty. Recommendation Concerning Nonsurgical Temporizing Agents: I. Intraventricular thrombolytic agents including tissue plasminogen activator (tPA), urokinase, or streptokinase are not recommended as methods to reduce the need for shunt placement in premature infants with PHH. STRENGTH OF RECOMMENDATION: Level I, high clinical certainty. Recommendation Concerning Nonsurgical Temporizing Agents. II. Acetazolamide and furosemide are not recommended as methods to reduce the need for shunt placement in premature infants with PHH. STRENGTH OF RECOMMENDATION: Level I, high clinical certainty. Recommendation Concerning Timing of Shunt Placement: There is insufficient evidence to recommend a specific weight or CSF parameter to direct the timing of shunt placement in premature infants with PHH. Clinical judgment is required. STRENGTH OF RECOMMENDATION: Level III, unclear clinical certainty. Recommendation Concerning Endoscopic Third Ventriculostomy: There is insufficient evidence to recommend the use of endoscopic third ventriculostomy (ETV) in premature infants with posthemorrhagic hydrocephalus. STRENGTH OF RECOMMENDATION: Level III, unclear clinical certainty.

Oxygen as a neonatal health hazard: call for détente in clinical practice.

UNLABELLED: Education in oxygenation and in how oxygen is given to newborns needs to increase. Treatment with oxygen should no longer be considered proverbial and customary, regardless of our 'past experience' or consensus recommendations in clinical guidelines, since oxygen may lead to acute or chronic health effects. CONCLUSION: Inappropriate oxygen use is a neonatal health hazard associated with aging, DNA damage and cancer, retinopathy of prematurity, injury to the developing brain, infection and others. Neonatal exposure to pure O2, even if brief, or to pulse oximetry >95% when breathing supplemental O2 must be avoided as much as possible.

Glucocorticoid receptor expression in the cortex of the neonatal rat brain with and without focal cerebral ischemia.

BACKGROUND/AIMS: Glucocorticoid receptors (GR) mediate cellular processes which may be neuroprotective and/or neurotoxic to the neonatal rat brain. Our aim was to describe GR ontogeny in the developing rat brain cortex and changes in GR expression after permanent neonatal focal cerebral ischemia (FCI). METHODS: GR Western blots and immunohistochemical stains were performed on neonatal rat cortices on P1, P3, P7, P10, P15, and P30 and on P7 at 1 h, 3 h, 6 h, 12 h, 24 h, and 72 h after FCI or sham-operation (S-O), 8 per group. Nissl staining was performed on FCI or S-O P7 cortical samples. RESULTS: Cortical GR expression was increased by 65.2% at P7, 110.1% at P15, and 87.0% at P30, compared to P1. On P7, GR expression decreased in the ischemic cortex after 6 h and in the non-ischemic cortex after 24 h of FCI (p < 0.05). Cortical GR expression was not altered in S-O P7 rats. Immunohistochemistry supported Western blot findings. Nissl staining revealed no gross decrease in neuronal number in non-ischemic cortices after 24 h of FCI, compared to baseline. CONCLUSIONS: Neonatal rat cortical GR expression increases during P1 to P30, peaking at P15. At P7, cortical GR expression appears downregulated in the ischemic cortex after 6 h and in the non-ischemic cortex after 24 h of FCI. Thus, cortical GR may play important roles in normal brain development and neonatal brain injury responses.

Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats.

Erythropoietin (Epo) plays a central role in erythropoiesis but also has neuroprotective properties. Recently, Epo-related neuroprotective studies used a hypoxic-ischemic neonatal model, which is different from focal stroke, a frequent cause of neonatal brain injury. We report on the effects of Epo treatment given after focal stroke and its potential neuroprotective mechanisms in postnatal day 7 rats with focal cerebral ischemia (FCI) achieved by occlusion of the middle cerebral artery. The experimental groups included sham operation, FCI plus vehicle, and FCI plus Epo. In the Epo-treated group, pups received a single intraperitoneal injection of 1000 U/kg 15 min after FCI or three injections of 100, 1000, or 5000 U/kg, starting at 15 min and repeated at 1 and 2 d after FCI. Epo treatment produced significant reductions in the mean infarct area and volume at 1 and 3 d after FCI, demonstrated by 2,3,5-triphenyltetrazolium chloride staining. Terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining showed a markedly reduced number of TUNEL-positive cells in the Epo-treated group when compared with the vehicle control 3 d after FCI (p<0.01). The most effective dose after FCI was 1000 U/kg for 3 d. Immunoanalyses showed that Epo induced a significant increase in phosphorylated Janus kinase 2 and signal transducer and activator of transcription-5 expressions at 1 and 3 d and up-regulated Bcl-xL expression by 24 h after FCI but did not affect Epo receptor or NF-kappaB expression. In conclusion, Epo given after FCI in neonatal rats provides significant neuroprotection, mediated possibly by activation of the Janus kinase-signal transducer and activator of transcription-Bcl-xL signaling pathways.

Uma visão evidente da prática baseada em evidências na medicina perinatal: ausência de evidência não é evidência de ausência / An evident view of evidence-based pratice in perinatal medicine: absence of evidence is not evidence of absence

OBJETIVO: Proporcionar elementos valiosos e um pouco de humor nesta chamada era da "prática baseada em evidências" com o objetivo de ajudar os clínicos a fazer escolhas melhores no cuidado que eles provêem com base em evidências, e não simples ou exclusivamente com base em um ensaio clínico randomizado (ECR) ou meta-análise (o que pode não ser evidência). FONTE DOS DADOS: Livros e artigos com revisão por pares são citados e listados na bibliografia. Evidências de vida, aprendizado através de nossos próprios erros e muitos outros fatos evidentes que sustentam esta revisão não são citados. SÍNTESE DOS DADOS: 1) "Ausência de evidência não é evidência de ausência" e "falta de evidência de efeito não significa evidência de nenhum efeito". 2) Os ECR com resultado "negativo" e aqueles com resultado "positivo", mas sem os resultados importantes, muitas vezes não podem concluir o que concluem. 3) Os ensaios clínicos não-randomizados e os estudos práticos podem ser importantes. 4) A pesquisa em busca de provas é diferente da pesquisa em busca de aperfeiçoamento. 5) A escolha clínica deve avaliar os efeitos nos desfechos importantes para os pacientes e seus pais. 6) A quantificação de desfechos adversos, do número necessário para causar dano e do número necessário para tratamento não é assim tão simples. CONCLUSÕES: Desafios importantes inerentes à pesquisa em serviços de saúde devem ser correlacionados a possíveis aplicações clínicas usando ferramentas que permitam uma "visão mais clara da prática baseada em evidências" na medicina perinatal, lembrando que a ausência de evidência não é evidência de ausência.

OBJECTIVE: To provide valuable elements and some humor in this so-called era of "evidence-based practice" with the aim of helping clinicians make better choices in the care they deliver based on evidence, not simply or exclusively based on a randomized clinical trial (RCT) or meta-analysis (which may not be evidence). SOURCES: Books and peer-reviewed articles are quoted and listed in the bibliography. Evidence of life, learning from our own mistakes and many other evident facts that support this review are not quoted. SUMMARY OF THE FINDINGS: 1) "Absence of evidence is not evidence of absence" and "lack of evidence of effect does not mean evidence of no effect". 2) RCTs with "negative" results and those with "positive" results, but without outcomes that matter, often cannot conclude what they conclude. 3) Non-randomized clinical trials and practical trials may be important. 4) Research to prove is different than research to improve. 5) Clinical choice must assess effects on outcomes that matter to patients and their parents. 6) Quantifying adverse outcomes, number needed to damage and to treat is not that simple. CONCLUSIONS: Significant challenges inherent to health service research must be correlated to possible clinical applications using tools to have a more "evident view of evidence-based practice" in perinatal medicine, recalling that absence of evidence is not evidence of absence.