Intravenous Edaravone plus Therapeutic Hypothermia Offers Limited Neuroprotection in the Hypoxic-Ischaemic Newborn Piglet.

BACKGROUND: Therapeutic hypothermia (TH) is a standard therapy for neonatal hypoxic-ischaemic encephalopathy. One potential additional therapy is the free radical scavenger edaravone (EV; 3-methyl-1-phenyl-2-pyrazolin-5-one). OBJECTIVES AND METHODS: This study aimed to compare the neuroprotective effects of edaravone plus therapeutic hypothermia (TH + EV) with those of TH alone after a hypoxic-ischaemic insult in the newborn piglet. Anaesthetized piglets were subjected to 40 min of hypoxia (3-5% inspired oxygen), and cerebral ischaemia was assessed using cerebral blood volume. Body temperature was maintained at 39.0 ± 0.5°C in the normothermia group (NT, n = 8) and at 33.5 ± 0.5°C (24 h after the insult) in the TH (n = 7) and TH + EV (3 mg/kg intravenous every 12 h for 3 days after the insult; n = 6) groups under mechanical ventilation. RESULTS: Five days after the insult, the mean (standard deviation) neurological scores were 10.9 (5.7) in the NT group, 17.0 (0.4) in the TH group (p = 0.025 vs. NT), and 15.0 (3.9) in the TH + EV group. The histopathological score of the TH + EV group showed no significant improvement compared with that of the other groups. CONCLUSION: TH + EV had no additive neuroprotective effects after hypoxia-ischaemia in neurological and histopathological assessments.

Green light-emitting diode phototherapy for neonatal hyperbilirubinemia: Randomized controlled trial.

BACKGROUND: The main photochemical pathway in phototherapy for neonatal hyperbilirubinemia is the production and elimination (in bile or urine) of cyclobilirubin, which is a structural photoisomer of bilirubin, and which is most efficiently produced by green light. Green light-emitting diode (LED) phototherapy, however, has not been evaluated in the clinical setting because it is not recommended in American Academy of Pediatrics guidelines. We therefore compared the efficacy of green LED phototherapy and blue LED phototherapy in patients with neonatal hyperbilirubinemia. METHODS: In this prospective randomized controlled trial, neonates with hyperbilirubinemia were randomly allocated to a green LED or blue LED phototherapy group. Both groups underwent 24 h of phototherapy, and blood was sampled before and after 24 h of phototherapy. Total serum bilirubin (TSB) was measured using enzymatic methods and bilirubin photoisomers were measured on high-performance liquid chromatography. RESULTS: Thirty-four infants were randomized (green, n = 16; blue, n = 18). TSB decreased significantly from 15.3 ± 1.5 to 13.9 ± 1.5 mg/dL in the green LED group (P < 0.01) and from 16.2 ± 1.3 to 14.5 ± 1.7 mg/dL in the blue LED group (P < 0.01) after 24 h of phototherapy. No significant difference was found in TSB reduction after phototherapy between the groups. CONCLUSIONS: Both light sources produced a significant reduction in TSB, indicating clinical effectiveness.

Hydrogen ventilation combined with mild hypothermia improves short-term neurological outcomes in a 5-day neonatal hypoxia-ischaemia piglet model.

Despite its poor outcomes, therapeutic hypothermia (TH) is the current standard treatment for neonatal hypoxic-ischaemic encephalopathy (HIE). In this study, due to its antioxidant, anti-inflammatory, and antiapoptotic properties, the effectiveness of molecular hydrogen (H2) combined with TH was evaluated by means of neurological and histological assessments. Piglets were divided into three groups: hypoxic-ischaemic insult with normothermia (NT), insult with hypothermia (TH, 33.5 ± 0.5 °C), and insult with hypothermia with H2 ventilation (TH-H2, 2.1-2.7%). H2 ventilation and TH were administered for 24 h. After ventilator weaning, neurological assessment was performed every 6 h for 5 days. On day 5, the brains of the piglets were harvested for histopathological analysis. Regarding the neurological score, the piglets in the TH-H2 group consistently had the highest score from day 2 to 5 and showed a significantly higher neurological score from day 3 compared with the NT group. Most piglets in the TH-H2 group could walk at day 3 of recovery, whereas walking ability was delayed in the two other groups. The histological results revealed that TH-H2 tended to improve the status of cortical gray matter and subcortical white matter, with a considerable reduction in cell death. In this study, the combination of TH and H2 improved short-term neurological outcomes in neonatal hypoxic-ischaemic piglets.

Relationship between prolonged neural suppression and cerebral hemodynamic dysfunction during hypothermia in asphyxiated piglets.

OBJECTIVES: Hypothermia (HT) improves the outcome of neonatal hypoxic-ischemic encephalopathy. Here, we investigated changes during HT in cortical electrical activity using amplitude-integrated electroencephalography (aEEG) and in cerebral blood volume (CBV) and cerebral hemoglobin oxygen saturation using near-infrared time-resolved spectroscopy (TRS) and compared the results with those obtained during normothermia (NT) after a hypoxic-ischemic (HI) insult in a piglet model of asphyxia. We previously reported that a greater increase in CBV can indicate greater pressure-passive cerebral perfusion due to more severe brain injury and correlates with prolonged neural suppression during NT. We hypothesized that when energy metabolism is suppressed during HT, the cerebral hemodynamics of brains with severe injury would be suppressed to a greater extent, resulting in a greater decrease in CBV during HT that would correlate with prolonged neural suppression after insult. METHODS: Twenty-six piglets were divided into four groups: control with NT (C-NT, n = 3), control with HT (C-HT, n = 3), HI insult with NT (HI-NT, n = 10), and HI insult with HT (HI-HT, n = 10). TRS and aEEG were performed in all groups until 24 h after the insult. Piglets in the HI-HT group were maintained in a hypothermic state for 24 h after the insult. RESULTS: There was a positive linear correlation between changes in CBV at 1, 3, 6, and 12 h after the insult and low-amplitude aEEG (<5 µV) duration after insult in the HI-NT group, but a negative linear correlation between these two parameters at 6 and 12 h after the insult in the HI-HT group. The aEEG background score and low-amplitude EEG duration after the insult did not differ between these two groups. DISCUSSION AND CONCLUSION: A longer low-amplitude EEG duration after insult was associated with a greater CBV decrease during HT in the HI-HT group, suggesting that brains with more severe neural suppression could be more prone to HT-induced suppression of cerebral metabolism and circulation.

Hypoxic-Ischemic Encephalopathy-Associated Liver Fatty Degeneration and the Effects of Therapeutic Hypothermia in Newborn Piglets.

BACKGROUND: Although liver can be injured under the hypoxic-ischemic encephalopathy (HIE) condition, there is currently no histopathological evidence. Therapeutic hypothermia is used to protect the brain; however, the therapeutic potential for concomitant liver injury is unknown. OBJECTIVES: This study aimed to histopathologically prove HIE-associated liver injury and to investigate the influence of therapeutic hypothermia in a newborn piglet HIE model. METHODS: Eighteen newborn piglets were divided into 3 groups: control (n = 4), HIE (n = 8), and therapeutic hypothermia (n = 6) groups. The hypoxic insult was induced by decreasing the fraction of inspiratory oxygen from 21 to 2-4% over 40 min while monitoring cerebral blood volume and cerebral hemoglobin oxygen saturation. For therapeutic hypothermia, whole-body cooling at 33-34°C was administered for 24 h after the hypoxic insult. We hematologically and histopathologically investigated the liver injury in all groups. RESULTS: Alanine transaminase and lactate dehydrogenase levels in the HIE group were significantly elevated compared with those in the control group. Micro-lipid droplet accumulation in the periportal zone, but not in the perivenous zone, was significantly greater in the HIE group than in the control group and significantly smaller in the therapeutic hypothermia group than in the HIE group. CONCLUSIONS: We demonstrated that micro-lipid droplet accumulation in the cytoplasm of hepatocytes in the periportal zone occurs under the HIE condition and that this accumulation is suppressed by therapeutic hypothermia.

Surgery for gastroesophageal reflux disease with Gaucher disease type 2.

Gaucher disease, the most common lysosomal storage disease, is sometimes complicated with gastroesophageal reflux disease (GERD). The present patient was a 136-day-old Japanese boy with Gaucher disease type 2. Enzyme replacement therapy and chemical chaperone therapy were successful for the skin disorders, joint contractures, hepatosplenomegaly and thrombocytopenia, but he also had GERD. Accordingly, a Nissen fundoplication with gastrostomy was performed. There was no vulnerability of organs, easy bleeding or difficulty of maintaining the visual field because of hepatosplenomegaly during operation. In the perioperative period, there was no prolonged wound healing or infection. GERD was improved. In the near future, the number of long-term survivors of Gaucher disease will increase due to improvements in medical therapy. Therefore, it is expected that the number of patients requiring fundoplication will also increase. In patients with successful medical therapy, surgical fundoplication can be safely and effectively performed.

Simultaneous measurement of cerebral hemoglobin oxygen saturation and blood volume in asphyxiated neonates by near-infrared time-resolved spectroscopy.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) usually results in a poor clinical outcome even when treated with hypothermic therapy (HT). Early postnatal changes in cerebral blood oxygenation and hemodynamics may be critical determinants of brain injury and the efficacy of HT. OBJECTIVES: We measured cerebral hemoglobin oxygen saturation (ScO2) and cerebral blood volume (CBV) by near-infrared time-resolved spectroscopy (TRS) in HT-treated and non-HT-treated neonatal HIE patients to assess the influence of these parameters on clinical outcome. METHODS: We retrospectively compared ScO2, CBV, and clinical outcomes of 11 neonates with HIE: 5 were treated by HT (HT-treated; 33.5°C±0.5°C for 72h starting approximately 6h after delivery) and 6 were not (non-HT-treated). Both CBV and ScO2 were measured by TRS at 6, 24, 48, and 72h after birth. Magnetic resonance imaging (MRI) was performed 1-2weeks after birth to assess brain injury. RESULTS: Five neonates had adverse outcomes (3 HT-treated, 2 non-HT-treated). Of these, 1 died within 3days of birth and 4 had abnormal MRI findings, including basal ganglia, white matter, and/or thalamic lesions. The other 6 neonates had normal MRI findings (favorable outcome). At 6h after birth, CBV was significantly higher in neonates with adverse outcomes compared with those with a favorable outcome. At 24h after birth, ScO2 was significantly higher in neonates with adverse outcomes. Furthermore, we found that combined CBV at 24h after birth plus ScO2 had the best predictive ability for neurological outcome: sensitivity, specificity, positive predictive value, and negative predictive value were all 100%. CONCLUSION: Early postnatal CBV and ScO2 elevations were predictive of a poor outcome in HIE. Therefore, measuring combined CBV plus ScO2 at 24h after birth can allow more precise prediction of neurological outcome. Control of postnatal CBV and ScO2 is critical for effective HIE treatment.

Cerebral blood volume measurement using near-infrared time-resolved spectroscopy and histopathological evaluation after hypoxic-ischemic insult in newborn piglets.

The aim of this study was to assess the relationship between the cerebral blood volume (CBV) measured by near-infrared time-resolved spectroscopy (TRS) and pathological change of the brain in a hypoxic-ischemic (HI) piglet model. Twenty-one anesthetized newborn piglets, including three sham controls, were studied. An HI event was induced by low inspired oxygen. CBV was measured using TRS (Hamamatsu TRS-10). Data were collected before, during, and 6h after the insult. CBV was calculated as the change from the end of the insult. The piglets were allowed to recover from anesthesia for 6h after the insult. At the age of 5 days, the brains of the piglets were perfusion-fixed, and histologic evaluations of brain tissue were performed. The extent of histopathological damage was graded in 0.5-unit intervals on a 9-step scale. CBV increments were well correlated with histopathological scores, especially at 1 and 3h after resuscitation. Spearman's rank-correlation coefficients at 1, 3, and 6h after resuscitation in the gray matter were 0.9016, 0.9127, and 0.6907, respectively. We conclude that an increased CBV after HI insult indicates more marked histological brain damage. CBV measurement immediately after resuscitation provides a more precise prediction of the histological outcome.

Relationship between early changes in cerebral blood volume and electrocortical activity after hypoxic-ischemic insult in newborn piglets.

BACKGROUND: Early changes in cerebral hemodynamics and depressed electrocortical activity have been reported after a hypoxic-ischemic (HI) insult. However, the relationship between these two parameters is unclear. This study aimed to examine the relationship between changes in cerebral blood volume (CBV) and cerebral Hb oxygen saturation (ScO2) after a HI insult and the low amplitude-integrated electroencephalography (aEEG) duration concomitantly observed. METHODS: Sixteen newborn piglets obtained within 24h of birth were used (n=3 controls). Thirteen piglets were subjected to a HI insult of 20-min low-amplitude aEEG (<5 µV, LAEEG), after which a low mean arterial blood pressure (<70% of baseline) was maintained for 10 min. We measured changes in CBV and ScO2 using near-infrared time-resolved spectroscopy (TRS) and cerebral electrocortical activities using aEEG until 6h after the insult. RESULTS: A positive correlation was observed between the LAEEG duration and CBV increase, but not ScO2, after the insult. CONCLUSION: These results suggest that a larger increase in CBV reflected a more severe failure in cerebral circulation to maintain cell membrane action potentials, which induced a more extended recovery period of electrocortical activity after the insult. We conclude that an early increase in CBV and longer LAEEG indicate severe brain injury.

Extrauterine environment influences spontaneous low-frequency oscillations in the preterm brain.

Low-frequency oscillations in cerebral blood flow that are suggestive of resting-state brain activity have recently been reported, but no study on the development of resting-state brain activity in preterm infants has been performed. The objective of this study was to measure the cerebral blood flow oscillations, which are assumed to represent brain function in the resting state, in preterm and term infants of the same postconceptional age. The subjects were 9 preterm infants who had reached full term (gestational age (GA): 23-34 weeks, postconceptional age: 37-46 weeks) and 10 term infants (GA: 37-40 weeks, postconceptional age: 37-41 weeks). Their changes in concentration of oxyhemoglobin ([oxyHb]) and deoxyhemoglobin ([deoxyHb]) were measured in the parieto-temporal region during quiet sleep using multi-channel near-infrared spectroscopy, and the power spectral densities (PSD) of the oscillations in the concentrations of these molecules were analyzed and compared. The preterm infants displayed a higher proportion of 0.06-0.10 Hz low frequency oscillations of [oxyHb] and [deoxyHb] than the term infants, and the gestational age and the proportion of low frequency oscillations were inversely correlated. These findings suggest that resting-state cerebral blood flow oscillations differ between preterm and term infants, and that the development of circulatory regulation and nerve activity in preterm infants are influenced by the extrauterine environment.