Sumio Fukuda

Hemodynamics of the cerebral arteries of infants with periventricular leukomalacia.

OBJECTIVE. This study investigated the developmental changes in blood flow in each cerebral artery among infants with and without periventricular leukomalacia (PVL), to elucidate the time of onset of PVL. METHODS. Eight of 67 low birth weight infants were diagnosed through ultrasonography as having PVL with cyst formation. The mean cerebral blood flow velocities (CBFVs) in the anterior cerebral artery, middle cerebral arteries (MCAs), posterior cerebral arteries (PCAs), internal carotid arteries (ICAs), and basilar artery were measured with Doppler ultrasonography at postnatal days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, 56, and 70. Four of 8 infants with cyst formation and 1 of 59 infants without cyst formation developed cerebral palsy. RESULTS. The mean CBFVs of infants with PVL were significantly lower in the anterior cerebral artery (days 14–70), the right MCA (days 14–70), the left MCA (days 14–70), the right PCA (days 7–70), the left PCA (days 5–70), the right ICA (days 7–70), the left ICA (days 7–70), and the basilar artery (days 14 and 28–70). The CBFVs in all arteries were also lower among those with PVL than among intact infants on day 0. The CBFVs increased postnatally in the PCAs of infants with intact brains, whereas they remained unchanged after day 14 or 21 among infants with PVL. There was a significant difference in the prevalence of cerebral palsy between the 2 groups. CONCLUSIONS. We suggest that the total cerebral blood supply is decreased in cases of cystic PVL and that this reduction occurs just after birth, in a defined sequence, in the cerebral arteries. We conclude that the insult resulting in PVL might occur close to the time of birth.

Total hydroperoxide and biological antioxidant potentials in a neonatal sepsis model.

Oxidant/antioxidant imbalance plays an important role in septic shock. The present study examined changes in circulating oxidative components in a neonatal sepsis model. Subjects were 14 newborn mixed-strain piglets randomly divided into two groups: a cecal ligation and perforation (CLP) model (n = 7) and sham (n = 7). Blood samples for total hydroperoxide (TH), biological antioxidant potential (BAP), tumor necrosis factor (TNF) α, interleukin (IL)-6, and IL-10 were collected pre-CLP and at 1, 3, and 6 h post-CLP. TH and BAP levels at 1 h post-CLP were significantly higher in the CLP group than in the sham group. In the CLP group, TH decreased gradually and reached baseline levels by 6 h post-CLP, while BAP remained elevated. Linear correlations were identified between serum TH and BAP at 1 h post-CLP, serum TH and TNF-α at 1 h post-CLP, and BAP and IL-6 at 6 h post-CLP. Changes in and correlations between circulating oxidative and inflammatory state components in a neonatal sepsis model were clarified. This is the first study to reveal that the presence of oxidant/antioxidant imbalance in sepsis and septic shock changes during the disease course.

Comparison of venoarterial versus venovenous access in the cerebral circulation of newborns undergoing extracorporeal membrane oxygenation

Abstract This study was designed to compare venoarterial (VA) with venovenous (VV) access in the cerebral circulation of newborn infants during extracorporeal membrane oxygenation (ECMO). Among 14 infants with VA ECMO, 7 had no intracranial complications (group 1), while the others (group 2) developed intracranial hemorrhage (ICH). In contrast, among 19 infants with VV ECMO, only 1 developed ICH. Serial echocardiograms were performed before and after 1, 6, 12, and 24 h and 2 and 3 days of ECMO. The mean cerebral blood flow (CBF) velocities were measured in the anterior cerebral artery (ACA), right and left internal carotid arteries (Rt, Lt-ICA), basilar artery (BA), and right and left middle cerebral arteries (Rt, Lt-MCA). Ejection fraction (EF), cardiac output (CO), and stroke volume (SV) were also measured using standard echography. The velocity levels in the ACA, Rt-MCA, and Lt-MCA in VA ECMO were lower than those in VV ECMO, while those in the Lt-ICA and BA in VA ECMO were higher than those in VV ECMO. The EF, CO, and SV were lower in cases of VA ECMO than in VV ECMO. In cases of VA ECMO, there were no differences between groups 1 and 2 in velocities in the ACA, Rt-ICA, or Lt-ICA. However the velocities in group 2 in the BA, Rt-MCA, and Lt-MCA were lower than those in group 1 before and during ECMO. Similarly, the EF, CO, and SV were lower in group 2 (12.0%–31.0%, 0.10–0.32 l/min, and 0.66–1.55 ml, respectively) than in group 1 (29.5%–49.3%, 0.25–0.63 l/min, and 2.15–3.85 ml) during ECMO. However, in the infants on VV ECMO the CBF was either maintained or gradually increased before and during ECMO. Their cardiac parameters were: EF 46.1%–53.0%, CO 0.43–0.52 l/min, and SV 2.72–3.84 ml during ECMO. It is concluded that in VA ECMO CBF velocities, particularly in infants who developed ICH, decreased after the onset of ECMO in association with poor cardiac function, while in VV ECMO they were stable, probably due to normal systemic hemodynamics and cardiac function.

Effect of hemoperfusion using polymyxin B-immobilized fiber on IL-6, HMGB-1, and IFN gamma in a neonatal sepsis model.

To evaluate effects of polymyxin B direct hemoperfusion (PMX-DHP) on a neonatal sepsis cecal ligation and perforation (CLP) model, in 24 anesthetized and mechanically ventilated 3-d-old piglets, 16 were assigned to CLP and an arteriovenous extracorporeal circuit from 3 h until 6 h post-CLP, with a PMX-column in PMX-DHP–treated group (8 piglets) and 8 as sham. Plasma lipopolysaccharide (LPS) was measured at before CLP and at 3 and 9 h. Changes in mean systemic blood pressure (mSBP), mean pulmonary blood pressure, serum IL-6, tumor necrosis factor alpha, interferon gamma, and highly mobile group-1 box protein were measured before CLP and at 1, 3, 6, and 9 h. LPS was lower in the sham and PMX-DHP groups than in the control at 9 h. The mSBP was higher in the sham and PMX-DHP groups than in the control at both 6 h. IL-6 was lower in the sham and PMX-DHP groups than in the control at 6 h. HMGB-1 was lower in the PMX-DHP group than in the control at 6 h. IFN-γ was only detected in the control group at 9 h. Survival times in the PMX-DHP group were longer than in the control. Thus, PMX-DHP improved septic shock in a neonatal septic model.

Development and characterization of a novel porcine model of neonatal sepsis.

Sepsis and its sequela remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Many models of neonatal sepsis have been developed for investigating the pathophysiology of this disease and application of therapy, and a model with an infectious focus is closer to clinical reality. To establish an animal model that mimics the clinical characteristics of neonatal sepsis, the cecal devascularization and perforation procedure was implemented on 15 mixed-strain newborn piglets, which produced an infectious focus that acted as a continuous source of microorganisms to the peritoneal cavity. The mean survival time in animals with sepsis was 10.4 h (range 5.5-17.9 h), whereas all of the sham-operated control animals survived more than 24 h. Animals with sepsis showed a gradual significant decrease in the mean systemic blood pressure (mSBP; 71 ± 3 mmHg in sepsis vs. 64 ± 3 mmHg in control at 3 h, 38 ± 7 mmHg in sepsis vs. 59 ± 4 mmHg in control at 6 h, mean ± SEM). They also showed an increase of serum levels of endotoxin (5.6 × 105 ± 4.5 × 105 pg/mL in sepsis vs. 6.0 × 102 ± 3.8 × 102 pg/mL in control at 6 h). Serum levels of TNF-α in the animals with sepsis became significantly higher than the control animals at 0 h (96 ± 31 pg/mL in sepsis vs. 12 ± 1 pg/mL in control) and remained significantly higher than all through the experiment. Serum levels of IL-6 in animals with sepsis showed a gradual increase (484 ± 231 pg/mL in sepsis in its peak at 6 h vs. 24 ± 5 pg/mL in control), however, there were no significant differences in serum IL-10 levels between the groups. Microorganisms detected in the blood of animals with sepsis were gram-negative enteric and anaerobic organisms. These results suggested that this model mimics the clinical state of neonatal sepsis and hence may have significant implications for the treatment of sepsis, including its use as a model in further investigations.

High cerebrospinal fluid antioxidants and interleukin 8 are protective of hypoxic brain damage in newborns

Abstract The objective was to explain the discrepancy in the development of hypoxic ischemic brain injury (HIE) in some asphyxiated newborns rather than others. Forty newborns were classified according to their cerebrospinal neuron-specific-enolase (CSF-NSE) levels on their 5th-day of life; group 1 with low-NSE (n = 25). The remaining 15 newborns had high-NSE and were further divided into a group with no HIE (n = 10, group 2) and another with HIE (n = 5, group 3). CSF-NSE, totalhydroperoxide (TH), biological-antioxidant-potentials (BAPs), 12 cytokines and Erythropoietin (EPO) were measured. The TH/BAP gave the oxidative-stress-index (OSI). The BAPs of serial dilutions of three types of EPO were tested. CSF-NSE and TH and mean OSIs were higher in group 3. IL-8 and mean BAPs were higher in group 2 than in group 1. EPO was less detected in group 3. Serial EPO dilutions correlated with their BAPs. Compensatory antioxidants and IL-8 elevation could be protective of perinatal asphyxic brain injury. Antioxidative effect of EPO could be neuroprotective.

High postnatal oxidative stress in neonatal cystic periventricular leukomalacia

Oxidative stress plays an important role in cystic periventricular leukomalacia (PVL). We performed a case-control study of preterm infants delivered at <35 weeks of gestation between January 2003 and December 2006. Patients were stratified into three groups, according to age at which cysts were initially identified: 10 days old (early cystic PVL; n=10), >10 days old (late cystic PVL; n=12); and no cystic PVL (controls; n=22). Serum total hydroperoxide, biological antioxidant potential and oxidative stress index (calculated as total hydroperoxide/biological antioxidant potential) were measured within 3h after birth. Frequencies of preterm rupture of membrane and chorioamnionitis were significant higher in early cystic PVL than in late cystic PVL or controls. Duration of oxygen treatment and mechanical ventilation and frequency of apnea were significantly higher in late cystic PVL than in controls or early cystic PVL. Serum total hydroperoxide levels and oxidative stress index were significantly higher in early cystic PVL than in late cystic PVL or controls (p<0.05, respectively). Postnatal duration until cyst identification displayed a significant negative correlation with oxidative stress index and total hydroperoxide level (r=-0.497, p<0.05; r=-0.50, p<0.05, respectively). These findings suggest that early onset of cystic PVL might be due to either antenatal or intrapartum factors, but late onset might be due to postnatal factors. In the pathophysiology and therapy of cystic PVL, oxidative stress and onset timing appear crucial. This is the first study to reveal that neonates experiencing much more oxidative stress at birth show earlier onset of cystic PVL.

Late-onset circulatory dysfunction of premature infants and late-onset periventricular leukomalacia

Background: The sudden appearance of hypotension and oliguria without obvious cause following stable circulation and respiration in preterm infants is frequent in Japan. Such episodes are referred to as late‐onset circulatory dysfunction of premature infants (LCD). Volume expanders and inotropic agents are often ineffective against this condition, whereas i.v. steroids are significantly effective. A major problem is that cystic periventricular leukomalacia (PVL) often develops a few weeks after an episode. The aim of the present study was to clarify the risk factors, including LCD, related to cystic PVL.

The sex differences of cerebrospinal fluid levels of interleukin 8 and antioxidants in asphyxiated newborns.

Newborn males are more sensitive to brain injury than newborn females are. The aim of the present study was to find an explanation for this. We used the neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) for the classification of 32 newborns (19 males and 13 females) on their fifth postnatal day. The NSE levels were higher than normal (8.4 ± 1.6 ng/mL) in 10 newborn males and 6 females and were, respectively, considered asphyxiated male and female groups. The remaining newborns, 9 males and 7 females, had normal CSF levels of NSE and were considered normal newborn male and female groups. The CSF samples were measured for 12 cytokines, using a cytokine array kit, and for total hydroperoxide and biological antioxidant potentials (BAPs), using the free radical analytic system. Among the 12 cytokines measured, only interleukin 8 (IL-8) was properly detected. The CSF levels of IL-8 were higher in the asphyxiated newborn females than in the other three groups. The mean CSF levels of BAPs in the asphyxiated newborn females were higher compared with the other three groups, but significance was detected only in comparison with the BAP levels in the CSF samples of the normal newborn males. There were no differences in total hydroperoxide levels among the groups. There are sex-related differences in the CSF levels of IL-8 and antioxidants in asphyxiated newborns, with higher levels in newborn females; this might contribute in the sexual dimorphism regarding the fact that females have better protection from brain injury than the males.

Influence of premature rupture of membrane on the cerebral blood flow in low-birth-weight infant after the delivery

Cerebral white matter injury, usually called periventricular leukomalacia (PVL), is the most common form of injury to preterm infants that is associated with adverse motor and cognitive outcomes. Intrauterine infection may be an important etiological factor in PVL, and premature rupture of the membranes (PROM) can be identified antepartum. In order to investigate the pathophysiology of cerebral white matter injury induced by PROM, the cerebral blood flow (CBF) of the internal carotid artery and the vertebral artery was measured by neck ultrasonography. The CBF was determined in 84 low-birth-weight infants with gestational ages ranging from 24 to 35 weeks, including 71 infants without PROM and 13 infants with PROM. The mean blood flow velocity and diameter of each vessel were measured on postnatal days 0-70. The intravascular flow volume was determined by calculating the mean blood flow velocity and the cross-sectional area. The mean blood pressures were recorded, and the ejection fraction was determined. The total cerebral blood flow (CBF) was significantly lower in infants with PROM than in infants without PROM from day 10 to day 70. The ejection fraction was significantly higher in infants with PROM than in infants without PROM on days 0, 5, 10, 21, and 42. There was no difference in the mean blood pressure between infants with PROM and infants without PROM. The results of the present study suggest that PROM may decrease cerebral blood flow after the birth.