A nationwide survey on the management of neonatal respiratory distress syndrome: insights from the MUNICH survey in 394 Chinese hospitals.

BACKGROUND: At present, preterm infants with respiratory distress syndrome (RDS) in China present higher mortality and morbidity rates than those in high-income countries. The aim of this nationwide survey was to assess the clinical management of RDS in China. METHODS: A nationwide cross-sectional survey to assess adherence to RDS management recommendations was performed. One neonatologist per hospital was randomly selected. The primary outcome was the key care of RDS management. RESULTS: Among the 394 participating hospitals, 88·3% were birthing centres. The number of doctors and nurses per bed were 0·27 and 0·72, respectively. Antenatal corticosteroids (any dose) were administered to 90% of the women at risk of preterm birth at < 34 weeks of gestation (90·0% inborn vs. 50·0% outborn, p < 0·001). The median fraction of inspired oxygen (FiO2) for initial resuscitation was 0·30 for babies born at ≤ 32 weeks of gestation and 0·25 for those born at > 32 weeks. T-piece resuscitators were available in 77·8% of delivery rooms (DRs) (tertiary hospitals: 82·5% vs. secondary hospitals: 63·0%, p < 0·001). Surfactant was used in 51·6% of the DRs. Less invasive surfactant administration (LISA) was used in 49·7% of the hospitals (tertiary hospitals: 55·3% vs. secondary hospitals: 31·5%, p < 0·001). Primary non-invasive ventilation was initiated in approximately 80·0% of the patients. High-frequency oscillation ventilation was primarily reserved for rescue after conventional mechanical ventilation (MV) failure. Caffeine was routinely used during MV in 59·1% of the hospitals. Bedside lung ultrasonography was performed in 54·3% of the health facilities (tertiary hospitals: 61·6% vs. secondary hospitals: 30·4%, p < 0·001). Qualified breast milk banks and Family Integrated Care (FICare) were present in 30·2% and 63·7% of the hospitals, respectively. CONCLUSIONS: Significant disparities in resource availability and guidelines adherence were evident across hospitals. Future strategies should address DR facilities and medication access, technical training, staff allocation, and ancillary facility development for a better management of RDS patients in China.

Delivery room resuscitation intensity and associated neonatal outcomes of 24+0-31+6 weeks' preterm infants in China: a retrospective cross-sectional study.

BACKGROUND: The aim of this study was to review current delivery room (DR) resuscitation intensity in Chinese tertiary neonatal intensive care units and to investigate the association between DR resuscitation intensity and short-term outcomes in preterm infants born at 24+0-31+6 weeks' gestation age (GA). METHODS: This was a retrospective cross-sectional study. The source population was infants born at 24+0-31+6 weeks' GA who were enrolled in the Chinese Neonatal Network 2019 cohort. Eligible infants were categorized into five groups: (1) regular care; (2) oxygen supplementation and/or continuous positive airway pressure (O2/CPAP); (3) mask ventilation; (4) endotracheal intubation; and (5) cardiopulmonary resuscitation (CPR). The association between DR resuscitation and short-term outcomes was evaluated by inverse propensity score-weighted logistic regression. RESULTS: Of 7939 infants included in this cohort, 2419 (30.5%) received regular care, 1994 (25.1%) received O2/CPAP, 1436 (18.1%) received mask ventilation, 1769 (22.3%) received endotracheal intubation, and 321 (4.0%) received CPR in the DR. Advanced maternal age and maternal hypertension correlated with a higher need for resuscitation, and antenatal steroid use tended to be associated with a lower need for resuscitation (P < 0.001). Severe brain impairment increased significantly with increasing amounts of resuscitation in DR after adjusting for perinatal factors. Resuscitation strategies vary widely between centers, with over 50% of preterm infants in eight centers requiring higher intensity resuscitation. CONCLUSIONS: Increased intensity of DR interventions was associated with increased mortality and morbidities in very preterm infants in China. There is wide variation in resuscitative approaches across delivery centers, and ongoing quality improvement to standardize resuscitation practices is needed.

The variation of antenatal corticosteroids administration for the singleton preterm birth in China, 2017 to 2018.

BACKGROUND: The administration of antenatal corticosteroids (ACS) to women who are at risk of preterm birth has been proven to reduce not only the mortality, but also the major morbidities of the preterm infants. The rate of ACS and the risk factors associated with ACS use in Chinese population is unclear. This study aimed to investigate the rate of ACS use and the associated perinatal factors in the tertiary maternal centers of China. METHODS: Data for this retrospective observational study came from a clinical database of preterm infants established by REIN-EPIQ trial. All infants born at < 34 weeks of gestation and admitted to 18 tertiary maternal centers in China from 2017 to 2018 were enrolled. Any dose of dexamethasone was given prior to preterm delivery was recorded and the associated perinatal factors were analyzed. RESULTS: The rate of ACS exposure in this population was 71.2% (range 20.2 - 92%) and the ACS use in these 18 maternal centers varied from 20.2 to 92.0% in this period. ACS exposure was higher among women with preeclampsia, caesarean section delivery, antibiotic treatment and who delivered infants with lower gestational age and small for gestational age. ACS use was highest in the 28-31 weeks gestational age group, and lowest in the under 26 weeks of gestational age group (x2 = 65.478, P < 0.001). ACS exposure was associated with lower odds of bronchopulmonary dysplasia or death (OR, 0.778; 95% CI 0.661 to 0.916) and invasive respiration requirement (OR, 0.668; 95% CI 0.585 to 0.762) in this population. CONCLUSION: The ACS exposure was variable among maternity hospitals and quality improvement of ACS administration is warranted.

Video Laryngoscopy Improves the Success of Neonatal Tracheal Intubation for Novices but Not for Experienced Medical Staff.

Background: There is limited evidence on the use of video laryngoscopy (VL) in neonatal tracheal intubation (NTI) during neonatal resuscitation. In this study, we aimed to compare the difference between direct laryngoscopy (DL) and VL in NTI of trainees during neonatal resuscitation training. Materials and Methods: A prospective observational study was conducted during a neonatal resuscitation training course to examine three circumstances: NTI by experienced medical staff (EMS) and less-experienced medical staff (LEMS) in a neonatal resuscitation scenario; NTI by EMS and LEMS with an ongoing chest compression; and NTI by midwives who were novices in the procedure. The trainees were given scenarios or were shown demonstrations on newborn simulation manikins and were required to perform an NTI on a simulation manikin using DL and/or VL. The mean intubation time and success rate of intubation were measured. Results: The mean NTI time for EMS using VL (24.1 ± 7.2 s) was significantly longer than that using DL intubation (18.1 ± 6.9 s, P < 0.001), whereas there was no significant difference between using VL and DL for LEMS. EMS spent slightly less time on NTI than did LEMS using both VL and DL, but there were no statistically significant differences (both p > 0.05). The NTI success rate for EMS using VL (48.0%, 12/25) was significantly lower than that using DL (88.0%, 22/25, P = 0.004), while the NTI success rate for LEMS using VL (68.2%, 15/22 vs. 40.9%, 9/22) was higher than that using DL, but there was no statistical significance. When NTI was required with ongoing chest compressions, there was no significant difference in the mean NTI time and success rate between using VL and DL for EMS or LEMS. In the group of midwives who were novices in NTI, after they watched a demonstration teaching NTI, the intubation time using VL (19.6 ± 9.0 s) was significantly shorter than that using DL (28.0 ± 6.7 s, P < 0.001). The success rate of NTI using VL was significantly higher (96.2%; 25/26) than that using DL (69.2%; 18/26). Conclusion: The video laryngoscopy could be an effective training tool for inexperienced staff in developing the skill of tracheal intubation.

Perinatal risk factors for pulmonary hemorrhage in extremely low-birth-weight infants.

BACKGROUND: Pulmonary hemorrhage (PH) is a life-threatening respiratory complication of extremely low-birth-weight infants (ELBWIs). However, the risk factors for PH are controversial. Therefore, the purpose of this study was to analyze the perinatal risk factors and short-term outcomes of PH in ELBWIs. METHODS: This was a retrospective cohort study of live born infants who had birth weights that were less than 1000 g, lived for at least 12 hours, and did not have major congenital anomalies. A logistic regression model was established to analyze the risk factors associated with PH. RESULTS: There were 168 ELBWIs born during this period. A total of 160 infants were included, and 30 infants were diagnosed with PH. Risk factors including gestational age, small for gestational age, intubation in the delivery room, surfactant in the delivery room, repeated use of surfactant, higher FiO2 during the first day, invasive ventilation during the first day and early onset sepsis (EOS) were associated with the occurrence of PH by univariate analysis. In the logistic regression model, EOS was found to be an independent risk factor for PH. The mortality and intraventricular hemorrhage rate of the group of ELBWIs with PH were significantly higher than those of the group of ELBWIs without PH. The rates of periventricular leukomalacia, moderate-to-severe bronchopulmonary dysplasia and severe retinopathy of prematurity, and the duration of the hospital stay were not significantly different between the PH and no-PH groups. CONCLUSIONS: Although PH did not extend hospital stay or increase the risk of bronchopulmonary dysplasia, it increased the mortality and intraventricular hemorrhage rate in ELBWIs. EOS was the independent risk factor for PH in ELBWIs.

Comparing the Quality of Cardiopulmonary Resuscitation Performed at the Over-the-Head Position and Lateral Position of Neonatal Manikin.

Background: Recent neonatal resuscitation guidelines suggest to perform chest compression (CC) at over-the-head (OTH) position instead of lateral position when further interventions including umbilical venous access are needed. Little information is available regarding the quality of cardiopulmonary resuscitation at different positions. Our study compared the quality of CC and ventilation at OTH position vs. lateral position in simulated neonatal resuscitation. Methods: Thirty-nine neonatal practitioners who attended the NRP®-based Provider renewal course workshop participated this study. Laerdal QCPR infant model were used to collect the data (2-miutes continuous recording) on quality of CC and ventilation of all participants at OTH position and lateral position in randomized order, both coordinated with mask ventilation or endotracheal ventilation through a Neopuff© T-piece system. The quality of CC and ventilation were compared. Participants also reported their demographics and opinions in anonymous questionnaires after the session. Results: The quality of CC and ventilation was not different when CPR was performed at OTH position and lateral position, in both mask and endotracheal ventilation. When CPR was performed with endotracheal ventilation, there were small faster frequencies of CC and ventilation at OTH position, compared with those at lateral position (p = 0.004). Most participants (87%) liked the CC performed at OTH position and had no adverse feedback. Conclusions: Performing CC at OTH position was generally well-received in simulated resuscitation; the quality of CC and ventilation at OTH position was not significantly different from that at lateral position, irrespective of mask or endotracheal ventilation.

Effects of home and education environments on children's motor performance in China.

AIM: The aim of this study was to examine the effects of home and educational environments on children's motor performance in China. METHOD: We conducted a cross-sectional study of 4001 preschool children selected from 160 classes. The children's motor performance was assessed using the Movement Assessment Battery for Children, 2nd edition (MABC-2). Home and educational environments were evaluated using validated checklists. The effects of home and educational environments on motor performance were analysed using mixed and multilevel logistic regression models. RESULTS: The results showed that one score increase in the outside space of the family home was positively associated with the increase in total test score (0.104) subtest score of aiming and catching (0.037), and balance (0.034) of the MABC-2, after adjusting for potential confounders (each p<0.05). Possession of motor toys at home and parental rearing behaviours were also related to total test score, manual dexterity, and balance (ß=0.022-0.104, each p<0.05). Space and furnishings, activity, and interaction in the classroom had a significant positive association with total test score (ß=0.069-0.201), and with subtest scores of manual dexterity, aiming and catching, and balance respectively (ß=0.115-0.206). Space and furnishings of classrooms and possession of toys in the household were protective factors for 'at risk' or significant poor performance (odds ratio 0.942-0.973, each p<0.05). INTERPRETATION: A permissive and accepting family and educational environment made a positive contribution to children's motor performance. Access to sufficient space and furnishings within the classroom, as well as toys in the family, were protective factors for poor motor performance. Future assistance is needed to support an advantageous environment in early childhood programmes in China.

Improvement of Expressed Breast Milk in Mothers of Preterm Infants by Recording Breast Milk Pumping Diaries in a Neonatal Center in China.

OBJECTIVES: Because inadequate expression of human milk (EBM) in mothers of hospitalized infants were noticed in a neonatal center of our hospital, family education program was carried out to increase the EBM. METHODS: A breast milk pumping diary was introduced to the mothers with preterm infant(s) admitted in the NICU. The ratios of EBM (days of EBM to NICU/hospitalized days), breast milk feeding (BMF) (days of infants fed with exclusive human milk/hospitalized days), mixed feeding (MF) (days of infants fed with partial breast milk and partial formula/hospitalized days), and formula feeding (FF) (days of infants fed with preterm formula/hospitalized days) were evaluated. RESULTS: During January to April, 2014, the ratios of EBM to the NICU, BMF, MF and FF were 28.11%, 6.6%, 32.8% and 60.6%, respectively. After the introduction of breast milk pumping diary to the mothers from May 2014, the ratio of EBM to the NICU increased significantly to 53.3% (p<0.01) within the following eight months. Both the ratios of BMF and MF also rose to 23.8% and MF 55.3%, respectively. Consequently, the ratio of FF was reduced to 20.9%. Exclusive breast milk feeding also significantly reduce the duration of nil per oral (NPO) of the very low birth weight infants during hospital stay as compared to those fed with mixed feeding and formula feeding. CONCLUSION: The introduction of a breast milk pumping diary was associated with a significant increase in the intake of EBM of the hospitalized preterm newborns.

The reliability and validity of the Developmental Coordination Disorder Questionnaire'07 for children aged 4-6 years in mainland China.

An effective population-based screening tool is needed to identify possible cases of Developmental Coordination Disorder (DCD) among preschool children in mainland China. We examined the psychometric properties of the DCD questionnaire'07 (DCDQ'07) in Chinese children aged 4-6. A total of 3316 children from 10 nursery schools were involved in the study. Internal consistency and test-retest reliability of the DCDQ'07 were estimated using Cronbach's alpha, item-total correlation and intraclass correlation co-efficient (ICC). The construct validity was evaluated using the exploratory and confirmatory factor analysis. Receiver operating characteristic (ROC) analysis was used to measure the accuracy of the DCDQ'07. The results showed that both internal consistency (Cronbach's alpha value of all items were above 0.85) and test-retest reliability (ICCs of 13 items and subscales were above 0.9) were excellent. Confirmatory factor analysis showed that each goodness-of-fit indices of the 3-factor model was above 0.9, indicating a satisfactory fit of the data to the model. Area under the ROC curve was comparatively small (0.641). With the exception of construct validity in younger children (4 years old) and discriminative validity, the Chinese version of the DCDQ'07 achieves satisfactory reliability and construct validity in mainland China. Nevertheless, the questionnaire should be not used in younger children, and further studies are needed to explore the use of Little DCD-Q in Chinese preschool children.

Postresuscitation cyclosporine treatment attenuates myocardial and cardiac mitochondrial injury in newborn piglets with asphyxia-reoxygenation.

OBJECTIVES: Cardiovascular dysfunction occurs in the majority of asphyxiated neonates and has been suggested to be a major cause of neonatal morbidity and mortality. We previously demonstrated that cyclosporine A treatment during resuscitation can significantly improve cardiovascular performance in asphyxiated newborn piglets. However, the mechanisms through which cyclosporine elicits its protective effect in neonates have not yet been fully characterized. We hypothesized that cyclosporine A treatment would attenuate myocardial and cardiac mitochondrial injury during the resuscitation of asphyxiated newborn piglets. DESIGN: After acute instrumentation, piglets received normocapnic alveolar hypoxia (10% to 15% oxygen) for 2 hours followed by reoxygenation with 100% oxygen (0.5 hr) and then 21% oxygen (3.5 hr). At 4 hours of reoxygenation, plasma troponin level, left ventricle myocardial levels of lipid hydroperoxides, cytochrome-c, and mitochondrial aconitase activity were determined. SETTING: Neonatal asphyxia and reoxygenation. SUBJECTS: Twenty-four newborn (1-4 days old) piglets. INTERVENTIONS: Piglets were randomized to receive an IV bolus of cyclosporine A (10 mg/kg) or normal saline (placebo, control) at 5 minutes of reoxygenation (n=8/group). Sham-operated piglets (n=8) underwent no asphyxia-reoxygenation. MEASUREMENTS AND MAIN RESULTS: Asphyxiated piglets treated with cyclosporine had lower plasma troponin and myocardial lipid hydroperoxides levels (vs. controls, both p<0.05, analysis of variance). Cyclosporine treatment also improved mitochondrial aconitase activity and attenuated the rise in cytosol cytochrome-c level (vs. controls, all p<0.05). The improved mitochondrial function significantly correlated with cardiac output (p<0.05, Spearman rank-correlation test). CONCLUSIONS: We demonstrate that the postresuscitation administration of cyclosporine attenuates myocardial and cardiac mitochondrial injury in asphyxiated newborn piglets following resuscitation.

Cyclosporine treatment reduces oxygen free radical generation and oxidative stress in the brain of hypoxia-reoxygenated newborn piglets.

Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H(2)O(2)) production and markers of oxidative stress. Piglets (1-4 d, 1.4-2.5 kg) were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation) (n = 8/group). At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls) or cyclosporine (2.5 or 10 mg/kg i.v. bolus) in a blinded-randomized fashion. An additional sham-operated group (n = 4) underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H(2)O(2) production (electrochemical sensor), cerebral tissue glutathione (ELISA) and cytosolic cytochrome-c (western blot) levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40-48% of baseline), hypotension (mean arterial pressure 27-31 mmHg) and acidosis (pH 7.04) at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg), significantly attenuated the increase in cortical H(2)O(2) concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H(2)O(2) production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.

Infusing sodium bicarbonate suppresses hydrogen peroxide accumulation and superoxide dismutase activity in hypoxic-reoxygenated newborn piglets.

BACKGROUND: The effectiveness of sodium bicarbonate (SB) has recently been questioned although it is often used to correct metabolic acidosis of neonates. The aim of the present study was to examine its effect on hemodynamic changes and hydrogen peroxide (H(2)O(2)) generation in the resuscitation of hypoxic newborn animals with severe acidosis. METHODS: Newborn piglets were block-randomized into a sham-operated control group without hypoxia (n = 6) and two hypoxia-reoxygenation groups (2 h normocapnic alveolar hypoxia followed by 4 h room-air reoxygenation, n = 8/group). At 10 min after reoxygenation, piglets were given either i.v. SB (2 mEq/kg), or saline (hypoxia-reoxygenation controls) in a blinded, randomized fashion. Hemodynamic data and blood gas were collected at specific time points and cerebral cortical H(2)O(2) production was continuously monitored throughout experimental period. Plasma superoxide dismutase and catalase and brain tissue glutathione, superoxide dismutase, catalase, nitrotyrosine and lactate levels were assayed. RESULTS: Two hours of normocapnic alveolar hypoxia caused cardiogenic shock with metabolic acidosis (PH: 6.99 ± 0.07, HCO(3)(-): 8.5 ± 1.6 mmol/L). Upon resuscitation, systemic hemodynamics immediately recovered and then gradually deteriorated with normalization of acid-base imbalance over 4 h of reoxygenation. SB administration significantly enhanced the recovery of both pH and HCO(3-) recovery within the first hour of reoxygenation but did not cause any significant effect in the acid-base at 4 h of reoxygenation and the temporal hemodynamic changes. SB administration significantly suppressed the increase in H(2)O(2) accumulation in the brain with inhibition of superoxide dismutase, but not catalase, activity during hypoxia-reoxygenation as compared to those of saline-treated controls. CONCLUSIONS: Despite enhancing the normalization of acid-base imbalance, SB administration during resuscitation did not provide any beneficial effects on hemodynamic recovery in asphyxiated newborn piglets. SB treatment also reduced the H(2)O(2) accumulation in the cerebral cortex without significant effects on oxidative stress markers presumably by suppressing superoxide dismutase but not catalase activity.

Cyclosporine treatment improves cardiac function and systemic hemodynamics during resuscitation in a newborn piglet model of asphyxia: a dose-response study.

OBJECTIVES: Asphyxiated neonates often have myocardial depression, which is a significant cause of morbidity and mortality. Cardioprotective effects of cyclosporine have been observed in adult patients and animals with myocardial infarction. However, the cardioprotective effect of cyclosporine in neonates has not yet been studied. We hypothesize that cyclosporine will improve cardiac function and reduce myocardial injury in asphyxiated newborn piglets. DESIGN: Thirty-six piglets (1-4 days old, weighing 1.4-2.5 kg) were acutely instrumented for continuous monitoring of cardiac output and systemic arterial pressure. After stabilization, normocapnic alveolar hypoxia (10% to 15% oxygen) was instituted for 2 hrs followed by reoxygenation with 100% oxygen for 0.5 hrs and then 21% for 3.5 hrs. A nonasphyxiated, sham-operated group was included (n = 4) to control for effects of the surgical model. Plasma troponin and myocardial lactate concentrations were determined as well as morphologic examinations. SETTING: Neonatal asphyxia and reoxygenation. SUBJECTS: Newborn (1-4 days old) piglets. INTERVENTIONS: Piglets were block-randomized to receive intravenous boluses of cyclosporine A (2.5, 10, or 25 mg/kg) or normal saline (control) at 5 mins of reoxygenation (n = 8/group). MEASUREMENTS AND MAIN RESULTS: Cardiac index, heart rate, systemic oxygenation, plasma troponin, and left ventricular lactate were measured. Hypoxic piglets had cardiogenic shock (cardiac output 40% to 48% of baseline), hypotension (mean arterial pressure 27-31 mm Hg), and acidosis (pH 7.04). Cyclosporine treatment caused bell-shaped improvements in cardiac output, stroke volume, and systemic oxygen delivery (p < .05 vs. controls). Plasma troponin and left ventricle lactate were higher in controls than that of 2.5 and 10 mg/kg cyclosporine-treated groups (p < .05). Although histologic features of myocardial injury were not different among groups, severe damage was observed in mitochondria of control piglets but attenuated in that of cyclosporine (10 mg/kg) treatment. CONCLUSIONS: Postresuscitation administration of cyclosporine causes preservation of cardiac function and attenuates myocardial injury in newborn piglets after asphyxia-reoxygenation.

Vasopressin improves systemic hemodynamics without compromising mesenteric perfusion in the resuscitation of asphyxiated newborn piglets: a dose-response study.

PURPOSE: Hypoxia and reoxygenation (H-R) contributes to multi-organ failure in neonates, including cardiac and systemic complications. Use of vasopressin, an endogenous vasoconstrictive hormone commonly used to treat refractory hypotension in adults, in neonates with shock remains limited and not yet fully studied. We hypothesize that vasopressin will improve mean arterial pressure (MAP), without compromising cardiac, mesenteric, or carotid hemodynamics using a swine model of neonatal asphyxia. METHODS: Anesthetized piglets (1-4 days old, 1.4-2.5 kg, n = 33) were instrumented for continuous monitoring of cardiac index (CI), MAP, and regional arterial [common carotid (CA), superior mesenteric (SMA)] flow. The animals underwent hypoxia at 10-15% oxygen (2 h) followed by reoxygenation at 100% (0.5 h) and 21% (3.5 h) oxygen. Vasopressin infusion was initiated after 2 h reoxygenation at 0.005, 0.01, or 0.02 units/kg/h i.v. for 2 h (n = 7/group). H-R control (saline infusion) and sham-operated (non-asphyxiated) groups were also included. Intermittent blood gases and plasma lactate were determined as well as tissue lactate levels. Statistical significance was determined using ANOVA. RESULTS: All H-R piglets had hypotension (36-49% decrease in MAP) and decreased regional blood flows (CA -28 to -34%, SMA -12 to +32% of baseline) at 2 h reoxygenation. Vasopressin infusion dose-dependently increased MAP (14% at 0.02 units/kg/h, P < 0.05) without significant detrimental effects in CI, regional blood flows, and intestinal or cerebral tissue lactate levels. CONCLUSIONS: Vasopressin treatment causes a dose-dependent baro-specific effect, while preserving cardiac function and cerebral and mesenteric hemodynamics in newborn piglets following H-R.

Effects of tanshinone IIA, a major component of Salvia miltiorrhiza, on platelet aggregation in healthy newborn piglets.

ETHNOPHARMACOLOGICAL RELEVANCE: Tanshinone IIA (STS), an active ingredient of the Chinese herb Danshen (Salvia miltiorrhiza) for angina and stroke in adults, has been reported to inhibit platelet function. However, its effect on platelet and underlying mechanism remain largely unknown, particularly in neonates. MATERIALS AND METHODS: To investigate the effect of STS on the platelet aggregation and its interaction with various platelet activation pathways, platelet aggregatory function was studied in whole blood stimulated by collagen (2-10 µg/ml) ex vivo in newborn piglets receiving intravenous STS (0.1-10mg/kg, n=8) and in vitro in whole blood from newborn piglets (n=6) incubated with STS (0.1-100 µg/ml). The respective morphological changes of platelets were also examined by scanning electron microscopy. Plasma levels of nitrite/nitrate (NOx) and thromboxane B(2) (TxB(2)), matrix metalloproteinase (MMP)-2 and -9 activities were also examined. To further delineate the mechanistic pathway, the effect of STS on endothelial microparticles release from cultured human umbilical vein endothelial cells (HUVECs) was quantified by flow cytometry. RESULTS: STS impaired the ex vivo, but not in vitro, collagen-stimulated platelet aggregation. Infusion of STS elevated the plasma level of TxB(2) at 10mg/kg. However, STS had no effect on NOx level. Incubating cultured HUVECs with STS (1 and 10 µg/ml) caused a significant release of endothelial microparticles. Morphologically, STS elicited platelet activation in vivo, but not in vitro. CONCLUSIONS: STS impairs the ex vivo whole blood platelet aggregatory function by activating platelet in vivo in healthy newborn piglets. It implies that STS may elicit its effects by stimulating endothelial microparticles production and eicosanoid metabolism pathway.

Improved renal recovery with postresuscitation N-acetylcysteine treatment in asphyxiated newborn pigs.

Renal injury is one of the severe and common complications that occurs early in neonates with asphyxia, and reactive oxygen species have been implicated to play an important role on its pathogenesis. Improved renal recovery has been shown previously with N-acetyl-l-cysteine (NAC) in various acute kidney injuries. Using a subacute swine model of neonatal hypoxia-reoxygenation (H/R), we examined whether NAC can sustain its beneficial effect on renal recovery for 48 h. Newborn piglets were randomly assigned into a sham-operated group (without H/R, n = 6) and two H/R experimental groups (n = 8 each) with 2 h normocapnic alveolar hypoxia and 1 h 100% oxygen of reoxygenation followed by 21% oxygen for 47 h. Five minutes after reoxygenation, piglets received either normal saline (H/R control) or NAC (150-mg/kg bolus and 20 mg/kg per hour i.v. for 24 h) in a blinded, randomized fashion. All piglets were acidotic and in cardiogenic shock after hypoxia. Treating the piglets with NAC significantly increased both renal blood flow and oxygen delivery throughout the reoxygenation period. N-acetyl-l-cysteine treatment also improved the renal function with the attenuation of elevated urinary N-acetyl-ß-d-glucosaminidase activity and plasma creatinine concentration observed in H/R controls (both P < 0.05). The tissue levels of lipid hydroperoxides and caspase 3 in the kidney of NAC-treated animals were significantly lower than those of H/R controls. Conclusively, postresuscitation administration of NAC elicits a prolonged beneficial effect in improving renal functional recovery and reducing oxidative stress in newborn piglets with H/R insults for 48 h.

Hypoxia-ischemia upregulates TRAIL and TRAIL receptors in the immature rat brain.

The immature brain is susceptible to inflammatory injury induced by hypoxia-ischemia (HI) or infection, which causes serious neurodevelopmental disabilities in the survivors of preterm births. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (death receptor DR4/5 and decoy receptor DcR1/2) were reported to mediate various neuroinflammatory responses. However, little information is available regarding the role of TRAIL and its receptors in the immature brain after HI. The purpose of this study was to evaluate the expression of TRAIL and its receptors in the immature brain after HI and relate this expression to neurological function. We performed right common carotid artery ligation followed by hypoxia (6% O(2), 37°C) for 2.5 h to induce HI in postnatal day 3 rats. The distribution of TRAIL and its receptors, caspase-3 and CD68-labeled microglia/macrophages was evaluated 24 h after HI by immunostaining. The protein and mRNA expression of TRAIL and DR5 was measured by Western blot and real-time PCR, respectively. Delayed neuronal loss was evaluated by NeuN and Nissl staining 7 days after HI. Furthermore, neurological deficits were evaluated by a righting reflex test, time of eye opening and T-maze test. The expression of TRAIL, DR5 and DcR1/2 receptors and caspase-3 was more pronounced in the ipsilateral hemisphere compared with the contralateral part and the control group 24 h after HI. DR5/active caspase-3 double-positive cells were observed at 24 h after HI in the ipsilateral hemisphere but not in the contralateral hemisphere. The TRAIL and CD68 double-labeled cells were more pronounced in the ipsilateral cortical regions compared with the corresponding regions of the contralateral part. HI also resulted in a significant increase in TRAIL and DR5 protein and mRNA expression at 24 h, which corresponded to neuronal cell loss 7 days after HI. Furthermore, the HI group displayed impaired neurobehavioral development compared with the control group (p < 0.05). Altogether our results show that the TNF-α superfamily ligand TRAIL is induced on CD68+ microglia/macrophages after perinatal HI and that one of its receptors, DR5, is induced on neocortical neurons and glial cells. That many DR5+ cells were also caspase-3+ strongly supports the conclusion that these signaling molecules are involved in the delayed loss of neurons in the neocortex and in the neurobehavioral deficits that are often seen after perinatal HI.

N-acetylcysteine improves hemodynamics and reduces oxidative stress in the brains of newborn piglets with hypoxia-reoxygenation injury.

Reactive oxygen species have been implicated in the pathogenesis of hypoxic-ischemic injury. It has been shown previously that treating an animal with N-acetyl-L-cysteine (NAC), a scavenger of free radicals, significantly minimizes hypoxic-ischemic-induced brain injury in various acute models. Using a subacute swine model of neonatal hypoxia-reoxygenation (H-R), we evaluated the long-term beneficial effect of NAC against oxidative stress-induced brain injury. Newborn piglets were randomly assigned to a sham-operated group (without H-R, n = 6), and two H-R experimental groups (n = 8 each), with 2 h normocapnic alveolar hypoxia and 1 h of 100% oxygen reoxygenation followed by 21% oxygen for 47 h. Five minutes after reoxygenation, the H-R piglets received either normal saline (H-R controls) or NAC (150 mg/kg bolus and 20 mg/kg/h IV for 24 h) in a blinded randomized fashion. Treating the piglets with NAC significantly increased both common carotid arterial flow (CCAF) and oxygen delivery during the early phase of rexoygenation, while both CCAF and carotid oxygen delivery of the H-R group remained lower than the sham-operated groups throughout the experimental period. Compared with H-R controls, significantly higher amounts of anesthetic and sedative medications were required to maintain the NAC-treated piglets in stable condition throughout the experimental period, indicating a stronger recovery. Post-resuscitation NAC treatment also significantly attenuated the increase in cortical caspase-3 and lipid hydroperoxide concentrations. Our findings suggest that post-resuscitation administration of NAC reduces cerebral oxidative stress with improved cerebral oxygen delivery, and probably attenuates apoptosis in newborn piglets with H-R insults.

Effects of post-resuscitation treatment with N-acetylcysteine on cardiac recovery in hypoxic newborn piglets.

AIMS: Although N-acetylcysteine (NAC) can decrease reactive oxygen species and improve myocardial recovery after ischemia/hypoxia in various acute animal models, little is known regarding its long-term effect in neonatal subjects. We investigated whether NAC provides prolonged protective effect on hemodynamics and oxidative stress using a surviving swine model of neonatal asphyxia. METHODS AND RESULTS: Newborn piglets were anesthetized and acutely instrumented for measurement of systemic hemodynamics and oxygen transport. Animals were block-randomized into a sham-operated group (without hypoxia-reoxygenation [H-R, n = 6]) and two H-R groups (2 h normocapnic alveolar hypoxia followed by 48 h reoxygenation, n = 8/group). All piglets were acidotic and in cardiogenic shock after hypoxia. At 5 min after reoxygenation, piglets were given either saline or NAC (intravenous 150 mg/kg bolus + 20 mg/kg/h infusion) via for 24 h in a blinded, randomized fashion. Both cardiac index and stroke volume of H-R controls remained lower than the pre-hypoxic values throughout recovery. Treating the piglets with NAC significantly improved cardiac index, stroke volume and systemic oxygen delivery to levels not different from those of sham-operated piglets. Accompanied with the hemodynamic improvement, NAC-treated piglets had significantly lower plasma cardiac troponin-I, myocardial lipid hydroperoxides, activated caspase-3 and lactate levels (vs. H-R controls). The change in cardiac index after H-R correlated with myocardial lipid hydroperoxides, caspase-3 and lactate levels (all p<0.05). CONCLUSIONS: Post-resuscitation administration of NAC reduces myocardial oxidative stress and caused a prolonged improvement in cardiac function and in newborn piglets with H-R insults.