Denise Rook

Higher or lower oxygen for delivery room resuscitation of preterm infants below 28 completed weeks gestation: a meta-analysis

Objective To systematically review outcomes of infants ≤28+6 weeks gestation randomised to resuscitation with low (≤0.3) vs high (≥0.6) fraction of inspired oxygen (FiO2) at delivery. Design Systematic review of randomised controlled trials of low (≤0.3) vs high (≥0.6) FiO2 resuscitation. Information was obtained from databases (Medline/Pub Med, EMBASE, ClinicalTrials.gov, Cochrane) and meeting abstracts between 1990 to 2015. Search index terms: preterm/ resuscitation/oxygen. Data for infants ≤28+6 weeks gestation were independently extracted and pooled using a random effects model. Analyses were performed with Revman V.5. Main outcome measures Death in hospital, bronchopulmonary dysplasia (BPD), retinopathy of prematurity >grade 2 (ROP), intraventricular haemorrhage >grade 2 (IVH), patent ductus arteriosus (PDA) and necrotising enterocolitis (NEC). Results A total of 251 and 253 infants were enrolled in 8 studies (6 masked, 2 unmasked) in the lower and higher oxygen groups, respectively, (mean gestation 26 weeks) between 2005 and 2014. There were no differences in BPD (relative risk, 95% CIs 0.88 (0.68 to 1.14)), IVH (0.81 (0.52 to 1.27)), ROP (0.82 (0.46 to 1.46)), PDA (0.95 (0.80 to 1.14)) and NEC (1.61 (0.67 to 3.36)) and overall mortality (0.99 (0.52 to 1.91)). Mortality was lower in low oxygen arms of masked studies (0.46 (0.23 to 0.92), p=0.03) and higher in low oxygen arms of unmasked studies (1.94 (1.02 to 3.68), p=0.04). Conclusions There is no difference in the overall risk of death or other common preterm morbidities after resuscitation is initiated at delivery with lower (≤0.30) or higher (≥0.6) FiO2 in infants ≤28+6 weeks gestation. The opposing results for masked and unmasked trials may represent a Type I error, emphasising the need for larger, well designed studies.

Urinary Lipid Peroxidation Byproducts: Are They Relevant for Predicting Neonatal Morbidity in Preterm Infants?

Preterm infants have an immature antioxidant system; however, they frequently require supplemental oxygen. Oxygen-free radicals cause both pulmonary and systemic inflammation, and they are associated with increased morbidity and mortality. Consequently, screening of metabolite profiles representing the amount of lipid peroxidation is considered of great relevance for the evaluation of in vivo oxidative stress and derived inflammation and damage. Ranges for total relative contents of isoprostanes (IsoPs), isofurans (IsoFs), neuroprostanes (NeuroPs), and neurofurans (NeuroFs) within targeted SpO2 ranges were determined in urine samples of 254 preterm infants<32 weeks of gestation within the frame of two randomized, controlled, and blinded clinical trials employing ultra-performance liquid chromatography-tandem mass spectrometry. A total of 536 serial urine samples collected during the first 4 weeks after birth in recruited infants who did not develop free radical associated conditions were analyzed. A reference range for lipid peroxidation byproducts, including isoprostanes, isofurans, neuroprostanes, and neurofurans, was calculated and possible correlations with neonatal conditions were investigated. Urinary elimination of isofurans in the first 4 days after birth correlated with later development of bronchopulmonary dysplasia. Our observations lead to the hypothesis that early urinary determination of lipid peroxidation byproducts, especially isofurans, is relevant to predict development of chronic lung conditions.

Analysis of lipid peroxidation biomarkers in extremely low gestational age neonate urines by UPLC-MS/MS

AbstractExtremely low gestational age neonates (ELGAN) frequently require the use of oxygen supply in the delivery room leading to systemic inflammation and oxidative stress that are responsible for increased morbidity and mortality. The objective of this study was to establish reference ranges of a set of representative isoprostanes and prostaglandins, which are stable biomarkers of lipid peroxidation often correlated with oxidative stress-related disorders. First, a quantitative ultra performance liquid chromatography—tandem mass spectrometry (UPLC-MS/MS) method was developed and validated. The proposed analytical method was tailored for its application in the field of neonatology, enabling multi-analyte detection in non-invasive, small-volume urine samples. Then, the lipid peroxidation product concentrations in a total of 536 urine samples collected within the framework of two clinical trials including extremely low gestational age neonates (ELGAN) were analyzed. The access to a substantially large number of samples from this very vulnerable population provided the chance to establish reference ranges of the studied biomarkers. Up to the present, and for this population, this is the biggest reference data set reported in literature. Results obtained should assist researchers and pediatricians in interpreting test results in future studies involving isoprostanes and prostaglandins, and could help assessing morbidities and evaluate effectiveness of treatment strategies (e.g., different resuscitation conditions) in the neonatal field. FigureOptimizing clinical outcomes in extremely low gestational age newborns by the determination of lipid peroxidation biomarkers in urine samples employing UPLC-MS/MS.

Observing the resuscitation of very preterm infants: Are we able to follow the oxygen saturation targets?

BACKGROUND Since 2010, the European Resuscitation Council (ERC) guidelines advise oxygen saturation (SpO2) targets for the first 10 min of resuscitation after birth. Unfortunately, the control of SpO2 in newborn infants is difficult. AIM To determine to what extent SpO2 levels match the ERC targets during the resuscitation of very preterm infants, and how well the SpO2 is kept within the high and low limits until the infants are transported to the NICU. METHODS In a single-centre observational study, the SpO2 and fraction of inspired oxygen (FiO2) were collected during the resuscitation of very preterm infants with a gestational age (GA)≤ 30 weeks. RESULTS A total of 78 infants were included [median (IQR): GA 27(4)/7 (26-28(6)/7) weeks, birth weight 945 g (780-1140)]. During the initial 10 min after birth, large variations in SpO2 were observed with deviations above the target [median (IQR)] of 4.4% SpO2 (1.4-6.5), and below the target of 8.2% SpO2 (2.8-16.0). After the first 10 min, the SpO2 levels were respectively above and below the limit for 11% (0-27) and 8% (0-23) of the time. CONCLUSION During the resuscitation of very preterm infants, large deviations of the SpO2 from the ERC targets are observed. During the first minutes of resuscitation the deviations were likely caused by an inability to control the SpO2, whereas later deviations were due to weaning, pauses in respiratory support (i.e. intubation) and over exposure to oxygen. Changing the SpO2 targets to a target range that depicts the acceptable deviation might be helpful in providing better respiratory support.

Glutathione Synthesis Rates in Early Postnatal Life

Preterm infants have diminished antioxidant defenses. Glutathione (GSH), the main intracellular antioxidant, increases upon amino acid (AA) administration in preterm infants, without an accompanying rise of the fractional synthesis rate of GSH (FSRGSH) This study investigated the mechanism behind this increased GSH concentration by determining GSH synthesis in the first days after birth using stable isotope techniques in very low-birth-weight (VLBW) infants receiving i.v. AAs. Advanced oxidized protein products (AOPPs) were determined to quantify oxidative stress. Eighteen infants (birth weight 989 ± 241 g, gestational age of 276/7 ± 14/7 weeks) were studied either on postnatal day 1 or 2 (7 or 31 h postnatally, respectively). Concentration of GSH increased with postnatal age (1.45 ± 0.48 mM versus 1.99 ± 0.40 mM, p = 0.019). FSRGSH was not significantly different, but the absolute synthesis rate of GSH (ASRGSH) tended to be higher in the infants studied on day 2 [8.1 ± 2.7 mg/(kg · d) versus 10.6 ± 2.4 mg/(kg · d), p = 0.054]. AOPP concentrations were not different between groups. In conclusion, GSH concentration in VLBW infants increases significantly after birth. A concomitant increased synthesis rate was not found, suggesting that GSH consumption decreases upon AA administration.

Simultaneous analysis of 13C-glutathione as its dimeric form GSSG and its precursor [1-13C]glycine using liquid chromatography/isotope ratio mass spectrometry

Determination of glutathione kinetics using stable isotopes requires accurate measurement of the tracers and tracees. Previously, the precursor and synthesized product were measured with two separate techniques, liquid chromatography/isotope ratio mass spectrometry (LC/IRMS) and gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). In order to reduce sample volume and minimize analytical effort we developed a method to simultaneously determine (13)C-glutathione as its dimeric form (GSSG) and its precursor [1-(13)C]glycine in a small volume of erythrocytes in one single analysis. After having transformed (13)C-glutathione into its dimeric form GSSG, we determined both the intra-erythrocytic concentrations and the (13)C-isotopic enrichment of GSSG and glycine in 150 microL of whole blood using liquid chromatography coupled to LC/IRMS. The results show that the concentration (range of micromol/mL) was reliably measured using cycloleucine as internal standard, i.e. with a precision better than 0.1 micromol/mL. The (13)C-isotopic enrichment of GSSG and glycine measured in the same run gave reliable values with excellent precision (standard deviation (sd) <0.3 per thousand) and accuracy (measured between 0 and 5 APE). This novel method opens up a variety of kinetic studies with relatively low dose administration of tracers, reducing the total cost of the study design. In addition, only a minimal sample volume is required, enabling studies even in very small subjects, such as preterm infants.

Resuscitation of very preterm infants with 30% vs. 65% oxygen at birth: study protocol for a randomized controlled trial

BackgroundResuscitation at birth with 100% oxygen is known to increase the oxidative burden with concomitant deleterious effects. Although fractions of inspired oxygen (FiO2) < 100% are widely used in preterm infants, starting resuscitation at a (too) low FiO2 may result in hypoxia. The objective of this study is to compare the safety and efficacy of resuscitating very preterm infants with an initial FiO2 of 30% versus 65%.Methods/designIn this double-blind, randomized controlled trial, 200 very preterm infants with a gestational age < 32 weeks will be randomized to start resuscitation after birth with either 30% or 65% oxygen. The FiO2 will be adjusted based on oxygen saturation measured by pulse oximetry (SpO2) and pulse rate (which should be over 100 beats per minute) in order to achieve a target SpO2 of 88–94% at 10 min of life. The FiO2 and pulse oximetry data will be continuously recorded.The primary outcome is survival without bronchopulmonary dysplasia, as assessed by a physiological test at 36 weeks postmenstrual age. The secondary outcomes include the time to achieve SpO2 > 88%, Apgar score at 5 min, cumulative O2 exposure, oxidative stress (as determined by glutathione synthesis and oxidative stress markers), retinopathy of prematurity, brain injury and neurodevelopmental outcome at 2 years of age.This study will provide insight into determining the appropriate initial FiO2 to start resuscitation of very preterm infants.Trial registrationhttp://www.trialregister.nl, NTR243.

Assessment of oxidative damage to proteins and DNA in urine of newborn infants by a validated UPLC-MS/MS approach.

The assessment of oxidative stress is highly relevant in clinical Perinatology as it is associated to adverse outcomes in newborn infants. This study summarizes results from the validation of an Ultra Performance Liquid Chromatography–tandem Mass Spectrometry (UPLC-MS/MS) method for the simultaneous quantification of the urinary concentrations of a set of endogenous biomarkers, capable to provide a valid snapshot of the oxidative stress status applicable in human clinical trials, especially in the field of Perinatology. The set of analytes included are phenylalanine (Phe), para-tyrosine (p-Tyr), ortho-tyrosine (o-Tyr), meta-tyrosine (m-Tyr), 3-NO2-tyrosine (3NO2-Tyr), 3-Cl-tyrosine (3Cl-Tyr), 2′-deoxyguanosine (2dG) and 8-hydroxy-2′-deoxyguanosine (8OHdG). Following the FDA-based guidelines, appropriate levels of accuracy and precision, as well as adequate levels of sensitivity with limits of detection (LODs) in the low nanomolar (nmol/L) range were confirmed after method validation. The validity of the proposed UPLC-MS/MS method was assessed by analysing urine samples from a clinical trial in extremely low birth weight (ELBW) infants randomized to be resuscitated with two different initial inspiratory fractions of oxygen.

Survival and neurodevelopmental outcomes of preterms resuscitated with different oxygen fractions

BACKGROUND AND OBJECTIVES: Stabilization of preterm infants after birth frequently requires oxygen supplementation. At present the optimal initial oxygen inspiratory fraction (Fio2) for preterm stabilization after birth is still under debate. We aimed to compare neurodevelopmental outcomes of extremely preterm infants at 24 months corrected age randomly assigned to be stabilized after birth with an initial Fio2 of 0.3 versus 0.6 to 0.65 in 3 academic centers from Spain and the Netherlands. METHODS: Randomized, controlled, double-blinded, multicenter, international clinical trial enrolling preterm infants <32 weeks’ gestation assigned to an initial Fio2 of 0.3 (Lowox group) or 0.6 to 0.65 (Hiox group). During stabilization, arterial pulse oxygen saturation and heart rate were continuously monitored and Fio2 was individually titrated to keep infants within recommended ranges. At 24 months, blinded researchers used the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) to assess visual acuity, neurosensory deafness, and language skills. RESULTS: A total of 253 infants were recruited and 206 (81.4%) completed follow-up. No differences in perinatal characteristics, oxidative stress, or morbidities during the neonatal period were assessed. Mortality at hospital discharge or when follow-up was completed didn’t show differences between the groups. No differences regarding Bayley-III scale scores (motor, cognitive, and language composites), neurosensorial handicaps, cerebral palsy, or language skills between groups were found. CONCLUSIONS: The use of an initial lower (0.3) or higher (0.6–0.65) Fio2 during stabilization of extremely preterm infants in the delivery room does not influence survival or neurodevelopmental outcomes at 24 months.

Defining hazards of supplemental oxygen therapy in neonatology using the FMEA tool.

Purpose:To prospectively evaluate hazards in the process of supplemental oxygen therapy in very preterm infants hospitalized in a Dutch NICU. Methods:A Failure Mode and Effects Analysis (FMEA) was conducted by a multidisciplinary team. This team identified, evaluated, and prioritized hazards of supplemental oxygen therapy in preterm infants. After accrediting “hazard scores” for each step in this process, recommendations were formulated for the main hazards. Results:Performing the FMEA took seven meetings of 2 hours. The top 10 hazards could all be categorized into three main topics: incorrect adjustment of the fraction of inspired oxygen (FiO2), incorrect alarm limits for SpO2, and incorrect pulse-oximetry alarm limits on patient monitors for temporary use. The FMEA culminated in recommendations in both educational and technical directions. These included suggestions for (changes in) protocols on alarm limits and manual FiO2 adjustments, education of NICU staff on hazards of supplemental oxygen, and technical improvements in respiratory devices and patient monitors. Conclusions:The FMEA prioritized flaws in the process of supplemental oxygen therapy in very preterm infants. Thanks to the structured approach of the analysis by a multidisciplinary team, several recommendations were made. These recommendations are currently implemented in the studys center.