Toshihiko Nakamura

Brain Hypothermic Therapy Dramatically Decreases Elevated Blood Concentrations of High Mobility Group Box 1 in Neonates with Hypoxic-Ischemic Encephalopathy

Background. According to the Consensus 2010 of the International Liaison Committee on Resuscitation (ILCOR), children with moderate to severe hypoxic-ischemic encephalopathy (HIE) should receive brain hypothermic therapy (BHT) after successful resuscitation. Elevated high mobility group box 1 (HMGB1) in the blood at the early stage of brain ischemia-reperfusion injury has been suggested to be involved in the release of various inflammatory cytokines. Methods. In total, 21 neonates plasma HMGB1 concentration was measured. These neonates included 8 with HIE in whom BHT was indicated, 5 controls diagnosed as having HIE but who were not suitable candidates for BHT, and 8 normal controls. Results. The umbilical artery HMGB1 (UA-HMGB1) level before undergoing BHT significantly exceeded reference values. The UA-HMGB1 level in the BHT (−) group did not differ significantly from reference values, but was significantly increased 24 hours after birth. Repeated measure ANOVA showed a significant difference in time course changes between the BHT (+) and BHT (−) groups (P = 0.0002). Conclusions. This study demonstrated hypothermic therapy to significantly decrease HMGB1. Furthermore, HMGB1 is a useful index of the inhibition of early stage inflammation.

Prophylactic effects of recombinant human superoxide dismutase in neonatal lung injury induced by the intratracheal instillation of endotoxin in piglets

The efficacy of prophylactic endotracheal administration of superoxide dismutase (SOD) was assessed in an animal model of acute lung injury induced by intratracheal endotoxin in neonatal piglets. Twenty-one anesthetized piglets were studied and underwent mechanical ventilation. The animals received recombinant human SOD (5 or 20 mg/kg intratracheally) 10 min before induction of acute lung injury with intratracheal endotoxin (20 mg/kg). The PaO2 values of the SOD-treated group remained higher than that of the control group until the end of the experiment. In contrast, the PaCO2 values remained lower. Lung compliance remained higher. Thiobarbituric acid-reactive substances and albumin levels in the broncho-alveolar lavage fluid were more significantly increased in controls. Histologic examination showed that the degrees of atelectasis and edema in the SOD treatment group were milder than those of the control group. Thus, the present findings suggest that prophylactic treatment with SOD may be, at least in part, effective for alleviating acute lung injury caused by endotoxins.

Measurement of plasma concentration of high mobility group box1 (HMGB1) in early neonates and evaluation of its usefulness

BACKGROUND High mobility group box 1 (HMGB1), intensively studied in adult patients by several investigators, is suggested to cause potentially fatal conditions such as systemic inflammatory response syndrome (SIRS) and disseminated intravascular coagulation (DIC). However, little is known about the role of this protein in neonates. METHODS In total, 173 full-term neonates were divided into 4 groups according to mode of delivery: scheduled cesarean section (group E, n=67), unscheduled cesarean section (group ER, n=10), normal delivery (group N, n=64) and other modes of vaginal delivery (group CN, n=32). HMGB1 concentration in umbilical cord blood and plasma samples collected 5 days after birth were compared among these 4 groups. We also attempted to determine a reference value for HMGB1 concentrations in neonates. RESULTS The HMGB1 reference value in neonates was 2.0-35.3 ng/ml in groups E and N (n=131). The concentration was significantly higher in group ER than in group E (P=0.00022), and was also higher in group CN than in group N (P=0.00721). CONCLUSIONS To our knowledge, this study is the first to determine a reference value for HMGB1 concentrations in neonates. We also revealed significantly elevated HMGB1 concentrations in association with ischemic reperfusion injury caused by certain delivery modes.

Inflammatory changes in the lungs of premature infants with symptomatic patent ductus arteriosus

Background : The aim of the study was to observe the inflammatory changes during the therapy for symptomatic patentductus arteriosus (sPDA).

Leukemoid reaction and chronic lung disease in infants with very low birth weight

Objectives: To analyze the relationship between the leukemoid reaction and chronic lung disease in very-low-birth-weight (VLBW) infants. Methods: Neonates born weighing less than 1500 g without evidence of congenital anomalies and admitted to our hospital from October 1985 to December 1999 comprised our study. Leukemoid reaction was defined as a peripheral white blood cell (WBC) count of ≥ 50 × 103/μl. The infants who demonstrated a leukemoid reaction formed the study group, while the remainder formed the control group. The relationship between neonatal variables and WBC counts was studied. Results: Fourteen of the 486 infants demonstrated WBC counts of ≥ 50 × 103/μl, with an incidence of 2.9%. Univariate analysis demonstrated a significant association between a leukemoid reaction and chronic lung disease following intrauterine infection. Conclusion: A leukemoid reaction was observed in 2.9% of VLBW infants in our neonatal intensive care unit. A significant association was demonstrated between the leukemoid reaction and chronic lung disease following intrauterine infection.

Multicenter study for brain/body hypothermia for hypoxic-ischemic encephalopathy: Changes in HMGB-1

We measured changes in the blood level of high‐mobility group box‐1 (HMGB‐1) at 24 h intervals in neonates treated with brain/body hypothermia (body hypothermia therapy: BHT) for hypoxic–ischemic encephalopathy (HIE), to evaluate the usefulness of HMGB‐1 level for determining outcomes.

Neonatal subcutaneous emphysema and pneumomediastinum soon after birth.

Amale infant was born at 41 weeks of gestation by normal vaginal delivery. Apgar scores were 8 and 9 at 1 and 5 min, respectively. Birthweight was 3154 g ( 0.18 SD; appropriate for gestational age). There was no meconium-stained amniotic fluid. The mother was a 36-year-old gravida 0, para 0 who was followed up regularly throughout this pregnancy at hospital and had a normal, uncomplicated pregnancy. Soon after birth, the right supraclavicular area of the baby was observed to be swollen. He had no respiratory distress. There was no clinical evidence of fractured clavicle on examination. Softtissue swelling with snowball crepitation was identified in the right supraclavicular area, indicative of subcutaneous emphysema (Fig. 1a,b). Transillumination with LED suggested air accumulation in the mass (Fig. 1c). Chest radiograph showed subcutaneous emphysema on the right side of the neck and a right-sided pneumomediastinum (Fig. 2). Infection was excluded. The patient was monitored closely and given 25% oxygen to enhance the resolution of air leaks. There was good clinical response to oxygen therapy, with no need for ventilatory support. He received supplemental oxygen for 2 days. After being observed for clinical and radiographic improvement, he was discharged home at 8 days of age. Neonatal spontaneous pneumomediastinum occurs in approximately 2.5 per 1000 live births. Although the incidence of neonatal subcutaneous emphysema is not mentioned clearly, this condition is thought to be rare. When newborns present with neck mass, it must be differentiated from tumor, lymphangioma, cervical cyst, and so on. In the present case, diagnosis was made from the characteristic tactile sensation of subcutaneous air and the transillumination test. Neonatal pneumomediastinum is usually associated with mechanical ventilation, pneumonia, meconium aspiration, or

Remarkably delayed occurrence of normal surfactant composition in an extremely preterm infant

Reported herein is the first case of a remarkably delayed occurrence of normal surfactant composition in an extremely preterm infant who required a total of 15 doses of artificial pulmonary surfactant (Surfacten®). A male infant, born at 26 weeks gestation, developed respiratory distress at birth. Chest radiography was consistent with respiratory distress syndrome. The infant required repeated doses of surfactant, each resulting in transient periods of decreased ventilator requirement and improved blood gas values. Surfactant proteins (SP)‐A, SP‐B, SP‐C, and SP‐D from tracheal aspirate samples were analyzed on the 13th day (deterioration period) and 36th day (recovery period) after birth. On the 13th day sufficient SP‐A and SP‐D but no SP‐B no SP‐C were detected on western blot analysis. SP‐B and SP‐C were eventually detected on the 36th day. This infant therefore required almost 3 months to achieve normal surfactant function.

Neonatal Leukemoid Reaction with Fetal Inflammatory Response Syndrome Is Associated with Elevated Serum Granulocyte Colony Stimulating Factor and Interleukin-6

Leukemoid reaction (LR) is a reactive disease that exhibits abnormal blood values similar to leukemia, but not due to leukemia. One report showed that neonatal LR (NLR) was associated with elevated serum granulocyte colony stimulating factor (G-CSF) in only 30% of the study neonates. NLR is not always associated with the elevation of serum G-CSF. NLR was defined as a white blood cell count of ≥ 40 × 103/μL and/or blast cell concentration of > 2%. We have focused on NLR with fetal inflammatory response syndrome (FIRS), defined as a fetal systemic inflammatory reaction triggered by intrauterine infection. FIRS was diagnosed based on a cord serum interleukin-6 (IL-6) concentration ≥ 17.5 pg/mL and histopathological chorioamnionitis. Because NLR is highly associated with FIRS, we have hypothesized that NLR is associated with the elevation of both G-CSF and IL-6. This is the first report to measure multiple cytokines in NLR at the same time. The study comprised 19 preterm infants with FIRS: 8 with NLR (study group) and 11 without NLR (control group). Serum G-CSF and IL-6 concentrations were significantly higher in the study group than the control group. There was a positive correlation between G-CSF and IL-6 levels in the study group but not in the control group. These results suggest that elevated serum G-CSF and IL-6 may underlie NLR. Thus, G-CSF and IL-6 concentrations may be predictive of the onset of NLR. Measuring these cytokines is useful for judging the prognosis of preterm infants and for their post-natal clinical management.

Study on the Usefulness of APR Scores from the Viewpoint of Proinflammatory Cytokines

Background. Delayed diagnosis and treatment of newborn infection adversely impact outcomes. Clinical laboratory parameters have aimed to obtain the most correct and prompt diagnosis and treatment of this disease. This study simultaneously observed changes over time in APR as well as proinflammatory cytokines and anti-proinflammatory cytokines and aims to clarify usefulness of APR scores. Methods. We evaluated the usefulness of acute phase reactants (APR) in 46 newborns whose serum up to age 7 days had been stored, with comparison of three types (Group I: infection 15, Group F: fetal inflammatory response syndrome 17, and Group C: control 14) of APR-based scores, those of C-reactive protein (CRP), alpha1-acid glycoprotein (AGP), and haptoglobin (Hp), with proinflammatory cytokine levels. APR scores for CRP, AGP, and Hp and the levels of the proinflammatory cytokines IL-1β, IL-6, IL-8, IL-10, and TNFα were determined. Results. The cytokine levels started to increase from age 0 days and then decreased rapidly. The three APR scores, CRP, AG, and Hp, were elevated at age 0 days and then gradually decreased in infection (Group I) and fetal inflammatory response syndrome (Group F). The duration of antibiotic administration according to APR scores was significantly shorter in Group F than in Group I. Conclusion. This study demonstrated APR scores to be more useful for deciding whether antibiotics should be discontinued than proinflammatory cytokine levels.