Reduction in Perinatal Mortality after Implementation of HBB Training at a District Hospital in Mali.

BACKGROUND: Mali has a high neonatal mortality rate of 38/1000 live births; in addition the fresh stillbirth rate (FSR) is 23/1000 births and of these one-third are caused by intrapartum events. OBJECTIVES: The aims are to evaluate the effect of helping babies breathe (HBB) on mortality rate at a district hospital in Kati district, Mali. METHODS: HBB first edition was implemented in April 2016. One year later the birth attendants were trained in HBB second edition and started frequent repetition training. This is a before and after study comparing the perinatal mortality during the period before HBB training with the period after HBB training, the period after HBB first edition and the period after HBB second edition. Perinatal mortality is defined as FSR plus neonatal deaths in the first 24 h of life. RESULTS: There was a significant reduction in perinatal mortality rate (PMR) between the period before and after HBB training, from 21.7/1000 births to 6.0/1000 live births; RR 0.27, (95% CI 0.19-0.41; p < 0.0001). Very early neonatal mortality rate (24 h) decreased significantly from 6.3/1000 to 0.8/1000 live births; RR 0.12 (95% CI 0.05-0.33; p = 0.0006). FSR decreased from 15.7/1000 to 5.3/1000, RR 0.33 (95% CI 0.22-0.52; p < 0.0001). No further reduction occurred after introducing the HBB second edition. CONCLUSION: HBB may be effective in a local first-level referral hospital in Mali.

Physical activity and the risk of preterm birth: a systematic review and meta-analysis of epidemiological studies.

BACKGROUND: Physical activity has been inconsistently associated with risk of preterm birth, and the strength of the association and the shape of the dose-response relationship needs clarification. OBJECTIVES: To conduct a systematic review and dose-response meta-analysis to clarify the association between physical activity and risk of preterm birth. SEARCH STRATEGY: PubMed, Embase and Ovid databases were searched for relevant studies up to 9 February 2017. SELECTION CRITERIA: Studies with a prospective cohort, case-cohort, nested case-control or randomized study design were included. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and checked for accuracy by a second reviewer. Summary relative risks (RRs) were estimated using a random effects model. MAIN RESULTS: Forty-one studies (43 publications) including 20 randomized trials and 21 cohort studies were included. The summary RR for high versus low activity was 0.87 [95% confidence interval (CI): 0.70-1.06, I2 = 17%, n = 5] for physical activity before pregnancy, and it was 0.86 (95% CI: 0.78-0.95, I2 = 0%, n = 30) for early pregnancy physical activity. The summary RR for a 3 hours per week increment in leisure-time activity was 0.90 (95% CI: 0.85-0.95, I2 = 0%, n = 5). There was evidence of a nonlinear association between physical activity and preterm birth, Pnonlinearity < 0.0001, with the lowest risk observed at 2-4 hours per week of activity. CONCLUSION: This meta-analysis suggests that higher leisure-time activity is associated with reduced risk of preterm birth. Further randomized controlled trials with sufficient frequency and duration of activity to reduce the risk and with larger sample sizes are needed to conclusively demonstrate an association. TWEETABLE ABSTRACT: Physically active compared with inactive women have an 10-14% reduction in the risk of preterm birth.

Resuscitating preterm infants with 100% oxygen is associated with higher oxidative stress than room air.

AIM: The starting fraction of inspired oxygen for preterm resuscitation is a matter of debate, and the use of room air in full-term asphyxiated infants reduces oxidative stress. This study compared oxidative stress in preterm infants randomised for resuscitation with either 100% oxygen or room air titrated to internationally recommended levels of preductal oxygen saturations. METHODS: Blood was collected at birth, two and 12 hours of age from 119 infants <32 weeks of gestation randomised to resuscitation with either 100% oxygen (n = 60) or room air (n = 59). Oxidative stress markers, including advanced oxidative protein products (AOPP) and isoprostanes (IsoP), were measured with high-performance liquid chromatography and mass spectrometry. RESULTS: Significantly higher levels of AOPP were found at 12 hours in the 100% oxygen group (p < 0.05). Increases between two- and 12-hour AOPP (p = 0.004) and IsoP (p = 0.032) concentrations were significantly higher in the 100% oxygen group. CONCLUSION: Initial resuscitation with room air versus 100% oxygen was associated with lower protein oxidation at 12 hour and a lower magnitude of increase in AOPP and IsoP levels between two and 12 hours of life. Correlations with clinical outcomes will be vital to optimise the use of oxygen in preterm resuscitation.

New guidelines for newborn resuscitation--a critical evaluation.

UNLABELLED: The 2010 International Liaison Committee on Resuscitation guidelines for newborn resuscitation represent important progress. The criteria for assessment are simplified based on heart rate and respiration only and there is no timing of stages after the first 60 sec. Instead of giving supplemental oxygen, the guidelines state that 'it is best to start with air'. However, the optimal oxygen concentration later in the process and for premature babies is not yet clear. A description of an adequate heart rate response is not given, and the cut-off of 100 bpm may be arbitrary. There are still no clear recommendations regarding ventilation, inspiratory time, use of positive end expiratory pressure or continuous positive airway pressure. The guidelines do not mention which paCO2 level might be optimal. As colour pink assessment and routine suctioning of airways are not recommended anymore, there is an urgent need to obtain international consensus and create a new and revised Apgar score without these two variables. CONCLUSION: In spite of improved guidelines for newborn resuscitation, there is still a number of unanswered questions and a need for more delivery room studies.

A new tool for the validation of umbilical cord acid-base data.

OBJECTIVE: To identify the distribution of carbon dioxide tension (pCO(2) ) relative to pH in validated umbilical cord acid-base data. DESIGN: Observational study. SETTING: European hospital labour wards. POPULATION: Data for 36,432 term newborns were obtained from three sources: two trials of fetal monitoring with electrocardiography (ECG; the Swedish randomised controlled trial and the European Union Fetal ECG trial) and data from Mölndal Hospital. METHODS: From the total study population, cases with missing values or obvious typing errors were excluded. The remaining data were validated based on specified criteria. Percentiles of arterial pCO(2) by pH were calculated using multilevel regression modelling. MAIN OUTCOME MEASURES: Umbilical cord pH, pCO(2) and base deficit. RESULTS: Acid-base values were considered invalid in one out of seven cases. Percentiles for arterial pCO(2) corresponding to specified values of arterial pH were developed from the validated data of 26, 690 cases. CONCLUSIONS: Percentiles for arterial pCO(2) for a specified arterial pH can be used as a tool to identify cases with erroneously low pCO(2) values, and thus avoid an incorrect interpretation of the newborn's acid-base status.

Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide.

BACKGROUND: After perinatal asphyxia, the cerebellum presents more damage than previously suggested. OBJECTIVES: To explore if the antioxidant N-acetylcysteine amide (NACA) could reduce cerebellar injury after hypoxia-reoxygenation in a neonatal pig model. METHODS: Twenty-four newborn pigs in two intervention groups were exposed to 8% oxygen and hypercapnia, until base excess fell to -20 mmol/l or the mean arterial blood pressure declined to <20 mmHg. After hypoxia, they received either NACA (NACA group, n = 12) or saline (vehicle-treated group, n = 12). One sham-operated group (n = 5) served as a control and was not subjected to hypoxia. Observation time after the end of hypoxia was 9.5 hours. RESULTS: The intranuclear proteolytic activity in Purkinje cells of asphyxiated vehicle-treated pigs was significantly higher than that in sham controls (p = 0.03). Treatment with NACA was associated with a trend to decreased intranuclear proteolytic activity (p = 0.08), There were significantly less mutations in the mtDNA of the NACA group compared with the vehicle-treated group, 2.0 × 10-4 (±2.0 × 10-4) versus 4.8 × 10-5(±3.6 × 10-4, p < 0.05). CONCLUSION: We found a trend to lower proteolytic activity in the core of Purkinje cells and significantly reduced mutation rate of mtDNA in the NACA group, which may indicate a positive effect of NACA after neonatal hypoxia. Measuring the proteolytic activity in the nucleus of Purkinje cells could be used to assess the effect of different neuroprotective substances after perinatal asphyxia.

Oxygen and retinopathy of prematurity.

Retinopathy of prematurity is on the rise and a third epidemic has been identified. In spite of extensive research and progress in the understanding of this disease in recent years, 50 000 children worldwide are blinded by this condition each year. The relation between hyperoxia, low-gestational age, growth retardation, oxygen dependent growth factors, and oxidative stress are now being understood more clearly. We know that in the first phase of retinopathy of prematurity, hyperoxia inhibits vascular endothelial growth factor. In the second phase, vascular endothelial growth factor rises, and when insulin-like growth factor-1 reaches a threshold around 32 to 34 weeks postconceptional age, uncontrolled neovascularization may occur. It is not known whether this new knowledge will have implications for future therapy. However, by strictly avoiding hyperoxia, that is, SaO2>92-93% and avoiding fluctuations in SaO2, it is possible to control and prevent severe retinopathy of prematurity in most cases.

The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy.

Neonatal hypoxemic respiratory failure (HRF), a deficiency of oxygenation associated with insufficient ventilation, can occur due to a variety of etiologies. HRF can result when pulmonary vascular resistance (PVR) fails to decrease at birth, leading to persistent pulmonary hypertension of newborn (PPHN), or as a result of various lung disorders including congenital abnormalities such as diaphragmatic hernia, and disorders of transition such as respiratory distress syndrome, transient tachypnea of newborn and perinatal asphyxia. PVR changes throughout fetal life, evident by the dynamic changes in pulmonary blood flow at different gestational ages. Pulmonary vascular transition at birth requires an interplay between multiple vasoactive mediators such as nitric oxide, which can be potentially inactivated by superoxide anions. Superoxide anions have a key role in the pathophysiology of HRF. Oxygen (O2) therapy, used in newborns long before our knowledge of the complex nature of HRF and PPHN, has continued to evolve. Over time has come the discovery that too much O2 can be toxic. Recommendations on the optimal inspired O2 levels to initiate resuscitation in term newborns have ranged from 100% (pre 1998) to the currently recommended use of room air (21%). Questions remain about the most effective levels, particularly in preterm and low birth weight newborns. Attaining the appropriate balance between hypoxemia and hyperoxemia, and targeting treatments to the pathophysiology of HRF in each individual newborn are critical factors in the development of improved therapies to optimize outcomes.

Estimation of time since death by vitreous humor hypoxanthine, potassium, and ambient temperature.

Measurement of vitreous humor potassium (K(+)) has since the 1960s been recognized as an adjunct for estimation of time since death. In 1991 we introduced hypoxanthine (Hx) as a new marker. Furthermore we demonstrated that time since death estimation was more accurate when ambient temperature was included in the calculations, both for K(+) and for Hx. In this paper we present a refined method. The subjects consist of 132 cases with known time of death and ambient temperature. One sample from each subject was used in the calculations. Vitreous humor Hx levels were available in all subjects, while K(+) was measured in 106 of the subjects, due to insufficient volume of vitreous humor. Linear regression analysis was applied to model the correlation between vitreous humor Hx and K(+), taking the interactions with temperature into consideration. The diagrams published in 1991, which also included ambient temperature, estimated median time since death with range between the 10th and 90th percentile, whereas the linear regression analysis presented in this paper estimates mean time since death with a corresponding 95% interval of confidence. We conclude that time since death may be estimated with relatively high precision applying vitreous humor Hx and K(+) concentrations combined with ambient temperature.

Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate.

Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.

Development of a reliable analytical method to determine lipid peroxidation biomarkers in newborn plasma samples.

This paper describes a reliable analytical method based on ultra-performance liquid chromatography coupled to tandem mass spectrometry to determine F2-isoprostanes and other total byproducts (isoprostanes, isofurans, neuroprostanes and neurofurans) as lipid peroxidation biomarkers in newborn plasma samples. The proposed procedure is characterized by a simple sample treatment employing a reduced sample volume (100µL). Also, it shows a high throughput and high selectivity to determine simultaneously different isoprostane isomers in a large number of samples. The reliability of the described method was demonstrated by analysis of spiked plasma samples, obtaining recoveries between 70% and 130% for most of the analytes. Taking into account the implementation of further clinical studies, it was demonstrated the proper sensitivity of the method by means of the analysis of few human newborn plasma samples. In addition to this, newborn piglet plasma samples (n=80) were analyzed observing that the developed method was suitable to determine the analyte levels present in this kind of samples. Therefore, this analytical method could be applied in further clinical research about establishment of reliable lipid peroxidation biomarkers employing this experimental model.

Restoration of cardiopulmonary function with 21% versus 100% oxygen after hypoxaemia in newborn pigs.

OBJECTIVE: To assess the consequences of hypoxaemia and resuscitation with room air versus 100% O(2) on cardiac troponin I (cTnI), cardiac output (CO), and pulmonary artery pressure (PAP) in newborn pigs. DESIGN: Twenty anaesthetised pigs (12-36 hours; 1.7-2.7 kg) were subjected to hypoxaemia by ventilation with 8% O(2). When mean arterial blood pressure fell to 15 mm Hg, or arterial base excess was < or = -20 mmol/l, resuscitation was performed with 21% (n = 10) or 100% (n = 10) O(2) for 30 minutes, then ventilation with 21% O(2) for 120 minutes. Blood was analysed for cTnI. Ultrasound examinations of CO and PAP (estimated from tricuspid regurgitation velocity (TR-Vmax)) were performed at baseline, during hypoxia, and at the start of and during reoxygenation. RESULTS: cTnI increased from baseline to the end point (p<0.001), confirming a serious myocardial injury, with no differences between the 21% and 100% O(2) group (p = 0.12). TR-Vmax increased during the insult and returned towards baseline values during reoxygenation, with no differences between the groups (p = 0.11) or between cTnI concentrations (p = 0.31). An inverse relation was found between increasing age and TR-Vmax during hypoxaemia (p = 0.034). CO per kg body weight increased during the early phase of hypoxaemia (p<0.001), then decreased. Changes in CO per kg were mainly due to changes in heart rate, with no differences between the groups during reoxygenation (p = 0.298). CONCLUSION: Hypoxaemia affects the myocardium and PAP. During this limited period of observation, reoxygenation with 100% O(2) showed no benefits compared with 21% O(2) in normalising myocardial function and PAP. The important issue may be resuscitation and reoxygenation without hyperoxygenation.

Role of xanthine oxidase and its inhibitor in hypoxia: reoxygenation injury.

OBJECTIVE: This article reviews the biochemistry and function of xanthine dehydrogenase (XDH) and xanthine oxidase (XO) as well as their role in hypoxia-reoxygenation injury. Possible benefits of XO blockade are discussed. METHODOLOGY: The available literature was reviewed. RESULTS: It is evident that relatively high activities of XO are restricted to a few organs in man. Because positive effects of XO blockade with allopurinol have been reported even in organs containing relatively low activities of XO, two other possible favorable actions of allopurinol are mentioned. First it may act as an oxygen radical scavenger, and second, it may augment the adenine nucleotides and, hence, adenosine triphosphate concentration in the cell. CONCLUSIONS: XDH and XO may play an important role in a series of pathophysiologic conditions. Their role in hypoxia-reoxygenation injury has been critically reviewed. However, care should be exercised in starting randomized trials to prevent hypoxia-reoxygenation injury with allopurinol, especially in newborn infants. SPECULATION: XDH and XO are released from the liver during hypoxic conditions, for instance, and consequently, they may reach a number of organs via the circulation.

Hypoxanthine levels in vitreous humor: evidence of hypoxia in most infants who died of sudden infant death syndrome.

Postmortem changes of the hypoxanthine in vitreous humor in humans were investigated. Hypoxanthine is formed from hypoxic degradation of adenosine monophosphate. Repeated sampling was performed in 13 deceased adults. Keeping the bodies at +6 degrees C, the increase of the hypoxanthine levels was estimated to 3.5 mumol/L per hour when sampling was started more than 12 hours after death (range 2.8 to 5.6 mumol/L per hour). Results of hypoxanthine measurements from vitreous humor in 73 infants with sudden infant death syndrome, 17 infants and children who died sudden violent deaths, and 6 neonates who died suddenly without hypoxemia prior to death were corrected according to the expected postmortem hypoxanthine increase. The time between death and autopsy was similar in the three groups studied. The corrected median hypoxanthine level in the group with sudden infant death syndrome was 227 mumol/L, which is significantly higher than in the other groups; 22 mumol/L in the group who had violent deaths (P less than .01), and 0 mumol/L in the neonate group (P less than .01). The findings seem to confirm that sudden infant death is preceded by a relatively long period of tissue hypoxia in most cases.

High postmortem levels of hypoxanthine in the vitreous humor of premature babies with respiratory distress syndrome.

To test whether or not premature babies at risk for retinopathy of prematurity have elevated hypoxanthine levels in the eye, the vitreous humor of 13 premature babies who died of severe respiratory distress syndrome and lung failure, was analyzed for hypoxanthine. Their hypoxanthine level was 459 +/- 171 mumol/L (mean +/- SD) compared with 54 +/- 71 mumol/L in seven newborn babies who died suddenly (P less than .001). In 53 adults who died suddenly, the hypoxanthine concentration was 136 +/- 119 mumol/L (P less than .001 when compared with babies with respiratory distress syndrome). Babies with respiratory distress syndrome underwent a significantly longer period with arterial PO2 levels less than 40 mm Hg (5.3 kPa) and they required supplementation with 100% oxygen significantly longer than control babies. The hypoxanthine concentration was correlated with the time during which the arterial PO2 was lower than 40 mm Hg (5.3 kPa) before death, and a significant positive correlation was found (R = .59, P less than .12). The study shows that high levels of hypoxanthine are found in vitreous humor of premature babies with respiratory distress syndrome. Because hypoxanthine is a potential oxygen radical generator and premature babies might have lower levels of antioxidants than full-term babies, it is suggested that the hypoxanthine accumulation in the eyes of premature babies with respiratory distress syndrome could play a pathogenetic role in the development of retinopathy of prematurity.

Elevated levels of hypoxanthine in vitreous humor indicate prolonged cerebral hypoxia in victims of sudden infant death syndrome.

Hypoxanthine levels in vitreous humor from 32 infants who died of sudden infant death syndrome (SIDS) were determined and compared with levels found in eight children who died of trauma, drowning, or hanging and with levels from seven neonates dying suddenly without long-standing antemortem hypoxia. Determination of hypoxanthine level was done with either a PO2 electrode method or high-performance liquid chromatography. The results obtained by both methods were significantly correlated; therefore they were pooled. The median hypoxanthine level in victims of SIDS (380 mumol/L) was significantly higher (P less than .001) than in the children who died violently (118 mumol/L). Moreover, the levels from the SIDS victims were significantly higher (P less than .001) than those from the neonates who died without long-standing hypoxia (53 mumol/L). It is concluded that SIDS is probably not a sudden event but may be preceded by a relatively long period of respiratory failure and hypoxia.

Oxygen delivery and consumption in surfactant-depleted newborn piglets.

OBJECTIVE: To study the relationship between oxygen (O2) delivery (DO2) and O2 consumption (VO2) in surfactant-depleted newborn piglets. DESIGN: Prospective animal study. SETTING: Hospital surgical research laboratory. SUBJECTS: Twenty-six anesthetized and ventilated newborn piglets. INTERVENTIONS: Twenty of the animals were subjected to repeated saline lung lavages, and then assigned to either the saline group or the L-NAME group. The other six animals without lavage were studied as the control group. Piglets in the L-NAME group and the control group received 3 mg/kg of N(omega)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase) i.v.; and those in the saline group received the same volume of saline i.v. MEASUREMENTS AND RESULTS: Cardiac output (CO) was measured and arterial and mixed venous blood gases were analyzed. DO2, O2 extraction ratio (O2ER) and VO2 were calculated. Plasma hypoxanthine was analyzed. In the lung lavaged groups, cardiac index, DO2 and VO2 decreased significantly after L-NAME i.v. but not after saline i.v. Further, the decrease in VO2 in the L-NAME group correlated with the decrease in DO2 (r = 0.83, p < 0.001). In the control group, cardiac index and DO2, but not VO2, decreased significantly after L-NAME i.v. Simultaneously, O2ER increased significantly. Plasma hypoxanthine was not modified by lung lavage but increased after L-NAME i.v. in both the L-NAME and control groups. CONCLUSION: These data suggest that O2 supply dependency is present in surfactant-depleted newborn piglets.

Acute and chronic effects of xanthine oxidase on lung thorax-compliance in guinea pigs.

Xanthine oxidase was given intratracheally in a single dose to guinea pigs. Lung compliance was measured after 4 h and 14 days respectively. Lung-thorax compliance was significantly lower compared with saline-treated controls both 4 h and 14 days after application of fluid. At 14 days there was a dose-related response between lung-thorax compliance and xanthine oxidase administered in the range 0-1.0 U. Superoxide dismutase (SOD) had a protective effect on xanthine oxidase action at 4 h, but not after 14 days. We suggest that the decreased lung-thorax compliance was caused by superoxide radicals, produced by the hypoxanthine-xanthine oxidase system, damaging lung tissue. We speculate that free oxygen radicals produced by the hypoxanthine-xanthine oxidase system could be an important contributory pathogenetic factor in producing both acute and chronic lung damage in, for instance, premature babies or adults, with respiratory distress syndrome.

Cerebral blood flow and evoked potentials during reoxygenation with 21 or 100% O2 in newborn pigs.

The effects of resuscitation with 21 or 100% O2 on cerebral blood flow (CBF) and somatosensory evoked potentials (SEPs) were studied in 19 newborn pigs anesthetized with pentobarbital sodium. They were ventilated with 8% O2 until base excess reached -20 mmol/l and then were randomly reoxygenated with 21% O2 (n = 10) or 100% O2 (n = 9) for 25 min followed by 21% O2. Mean duration of hypoxemia in the two groups was 57 +/- 6 (SE) and 59 +/- 6 min, respectively. CBF determined by radioactive microspheres was significantly increased in all areas in both groups after 5 and 20 min of reoxygenation. At 5 min of reoxygenation forebrain O2 uptake (CMRo2) had increased significantly compared with baseline values in the 21% O2 group (2.5 +/- 0.1 to 3.2 +/- 0.2 ml.100 g-1.min-1) but not in the 100% O2 group. There were, however, no significant differences between the two groups in CBF or CMRo2 at any time, and by 60 min of reoxygenation both had returned to baseline levels. SEPs were not significantly different in the two groups. We conclude that, as judged by CBF, CMRo2, and SEP, 21% O2 is not inferior to 100% O2 when hypoxemic newborn pigs are reoxygenated.