Splanchnic oxygen saturation during reoxygenation with 21% or 100% O-2 in newborn piglets

Background Increasing evidence recognizes the harm of excess oxygen to lungs, eyes, and brain of preterm infants, but not yet to the intestine. We assessed changes in splanchnic oxygenation during reoxygenation with 21% compared to 100% O-2 in a newborn piglet model of perinatal asphyxia. Methods We randomized 25 piglets to control or intervention. Intervention groups underwent global hypoxia until acidosis and hypotension occurred. Piglets were reoxygenated for 30 min with 21% or 100% O-2 and observed for 9 h. We continuously measured regional splanchnic oxygen saturation (r(s)SO(2)) using near-infrared spectroscopy (NIRS). We calculated mean r(s)SO(2) and r(s)CoVar (as SD/mean). We measured PaO2 and SaO(2), sampled from the right carotid artery.  Results Reoxygenation after global hypoxia restored r(s)SO(2). Reoxygenation with 100% O-2 increased r(s)SO(2) to values significantly higher than baseline. In intervention groups, r(s)CoVar decreased during observation compared to baseline. We found a correlation between r(s)SO(2) and PaO2 (r = 0.420, P < 0.001) and between r(s)SO(2) and SaO(2) (r = 0.648, P < 0.001) in pooled data from the entire experiment. Conclusion Reoxygenation after global hypoxia improves splanchnic oxygenation, but is associated with reduced variability of r(s)SO(2). Reoxygenation with 100% O-2 exposes the intestine to hyperoxia. Splanchnic NIRS is able to detect intestinal hypoxia and hyperoxia. Impact Splanchnic oxygenation improves during reoxygenation after global hypoxia, though reoxygenation with 100% O2 exposes the intestine to hyperoxia. Decreased variability of splanchnic oxygenation several hours after hypoxia and reoxygenation seems to be independent of the resuscitation strategy, and may indicate intestinal injury. Splanchnic NIRS monitoring was able to detect intestinal hypoxia and exposure to hyperoxia, as evidenced by a strong correlation between splanchnic oxygenation and arterial oxygen content

Metabolomic Analyses of Plasma Reveals New Insights into Asphyxia and Resuscitation in Pigs

Currently, a limited range of biochemical tests for hypoxia are in clinical use. Early diagnostic and functional biomarkers that mirror cellular metabolism and recovery during resuscitation are lacking. We hypothesized that the quantification of metabolites after hypoxia and resuscitation would enable the detection of markers of hypoxia as well as markers enabling the monitoring and evaluation of resuscitation strategies.Hypoxemia of different durations was induced in newborn piglets before randomization for resuscitation with 21% or 100% oxygen for 15 min or prolonged hyperoxia. Metabolites were measured in plasma taken before and after hypoxia as well as after resuscitation. Lactate, pH and base deficit did not correlate with the duration of hypoxia. In contrast to these, we detected the ratios of alanine to branched chained amino acids (Ala/BCAA; R(2).adj = 0.58, q-value<0.001) and of glycine to BCAA (Gly/BCAA; R(2).adj = 0.45, q-value<0.005), which were highly correlated with the duration of hypoxia. Combinations of metabolites and ratios increased the correlation to R(2)adjust = 0.92. Reoxygenation with 100% oxygen delayed cellular metabolic recovery. Reoxygenation with different concentrations of oxygen reduced lactate levels to a similar extent. In contrast, metabolites of the Krebs cycle (which is directly linked to mitochondrial function) including alpha keto-glutarate, succinate and fumarate were significantly reduced at different rates depending on the resuscitation, showing a delay in recovery in the 100% reoxygenation groups. Additional metabolites showing different responses to reoxygenation include oxysterols and acylcarnitines (n = 8-11, q<0.001).This study provides a novel strategy and set of biomarkers. It provides biochemical in vivo data that resuscitation with 100% oxygen delays cellular recovery. In addition, the oxysterol increase raises concerns about the safety of 100% O(2) resuscitation. Our biomarkers can be used in a broad clinical setting for evaluation or the prediction of damage in conditions associated with low tissue oxygenation in both infancy and adulthood. These findings have to be validated in human trials

Comparison of whole genome expression profile between preterm and full-term newborns

Objectives: Evaluate the time dependent expression of genes in preterm neonates and verify the influence of ontogenic maturation and the environmental factors on the gene expression after birth. Material and methods: The study was carried out on 20 full-term newborns and 62 preterm newborns (mean birth weight = 1002 [g] (SD: 247), mean gestational age = 27.2 weeks (SD: 1.9)). Blood samples were drawn from all the study participants at birth and at the 36th week postmenstrual age from the preterm group to assess whole genome expression in umbilical cord blood and in peripheral blood leukocytes, respectively. (SurePrint G3 Human Gene Expression v3, 8x60K Microarrays (Agilent)). Results: A substantial number of genes was found to be expressed differentially at the time of birth and at 36 PMA in comparison to the term babies with more genes being down-regulated than up-regulated. However, the fold change in the majority of cases was &lt; 2.0. Extremely preterm and very preterm infants were characterized by significantly down-regulated cytokine and chemokine related pathways. The number of down-regulated genes decreased and number of up-regulated genes increased at 36 PMA vs. cord blood. There were no specific gene expression pathway profiles found within the groups of different gestational ages. Conclusions: Preterm delivery is associated with a different gene expression profile in comparison to term delivery. The gene expression profile changes with the maturity of a newborn measured by the gestational age

Antioxidant Protects against Increases in Low Molecular Weight Hyaluronan and Inflammation in Asphyxiated Newborn Pigs Resuscitated with 100% Oxygen

BACKGROUND: Newborn resuscitation with 100% oxygen is associated with oxidative-nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxidant, N-acetylcysteine (NAC), on lung 3-nitrotyrosine (3-NT), LMW HA, inflammation, TNFα and IL1ß in a newborn pig model of resuscitation. METHODS & PRINCIPAL FINDINGS: Newborn pigs (n = 40) were subjected to severe asphyxia, followed by 30 min ventilation with either 21% or 100% oxygen, and were observed for the subsequent 150 minutes in 21% oxygen. One 100% oxygen group was treated with NAC. Serum, bronchoalveolar lavage (BAL), lung sections, and lung tissue were obtained. Asphyxia resulted in profound hypoxia, hypercarbia and metabolic acidosis. In controls, HA staining was in airway subepithelial matrix and no 3-NT staining was seen. At the end of asphyxia, lavage HA decreased, whereas serum HA increased. At 150 minutes after resuscitation, exposure to 100% oxygen was associated with significantly higher BAL HA, increased 3NT staining, and increased fragmentation of lung HA. Lung neutrophil and macrophage contents, and serum TNFα and IL1ß were higher in animals with LMW than those with HMW HA in the lung. Treatment of 100% oxygen animals with NAC blocked nitrative stress, preserved HMW HA, and decreased inflammation. In vitro, peroxynitrite was able to fragment HA, and macrophages stimulated with LMW HA increased TNFα and IL1ß expression. CONCLUSIONS & SIGNIFICANCE: Compared to 21%, resuscitation with 100% oxygen resulted in increased peroxynitrite, fragmentation of HA, inflammation, as well as TNFα and IL1ß expression. Antioxidant treatment prevented the expression of peroxynitrite, the degradation of HA, and also blocked increases in inflammation and inflammatory cytokines. These findings provide insight into potential mechanisms by which exposure to hyperoxia results in systemic inflammation

Lung Injury in Asphyxiated Newborn Pigs Resuscitated from Cardiac Arrest - The Impact of Supplementary Oxygen, Longer Ventilation Intervals and Chest Compressions at Different Compression-to-Ventilation Ratios

Introduction: Non-specific lung inflammatory events caused by severe asphyxia may be intensified by the way we resuscitate the newly born. Assessing lung injury is potentially important because if alternative resuscitation approaches induces similar inflammatory responses or less lung injury. then we may choose the resuscitation approach that is most gentle, and easiest to perform and learn. We investigated the levels of lung inflammatory markers by comparing different ventilation, chest compression and inhaled oxygen fraction strategies in resuscitation of newly born pigs at cardiac arrest. Materials and Methodology: Progressive asphyxia in newborn pigs was induced until asystole occurred. With current resuscitation guidelines as a reference group, pigs were randomized to receive initial ventilation before chest compressions for 30s, 60s or 90s, or to compression-to-ventilation ratios 3:1or 9:3, or to resuscitation using pure oxygen or air. We analysed inflammatory markers in bronchoalveolar lavage fluid (BAL), IL8 and TNFα, and lung tissue qPCR for genes matrix metalloproteinases (MMP)2, MMP9, TNFα and ICAM-1. Results: BAL-levels of TNFα and IL8 tended to be higher in the 30s group compared to 60s group (p = 0.028 and p = 0.023, respectively) as was gene expression in lung tissue of ICAM-1 and MMP2 (p=0.012 and p=0.043, respectively). MMP2 expression was slightly higher in the 30s group compared to 90s group (p = 0.020). No differences were found between pigs resuscitated with C:V ratio 9:3 and 3:1 or pure oxygen versus air. Conclusion: Compared to current guidelines, with respect to lung injury, resuscitation with longer initial ventilation should be considered. Longer series of chest compressions did not change the lung inflammatory response, neither did the use of air instead of pure oxygen in severely asphyxiated pigs resuscitated from asystole

Oxygen Saturation Targets in Preterm Infants and Outcomes at 18–24 Months: A Systematic Review

CONTEXT: The optimal oxygen saturation target for extremely preterm infants remains unclear. OBJECTIVE: To systematically review evidence evaluating the effect of lower (85%–89%) versus higher (91%–95%) pulse oxygen saturation (Spo(2)) target on mortality and neurodevelopmental impairment (NDI) at 18 to 24 months. DATA SOURCES: Electronic databases and all published randomized trials evaluating lower versus higher Spo(2) target in preterm infants. STUDY SELECTION: A total of 2896 relevant citations were identified; 5 trials were included in the final analysis. DATA EXTRACTION: Data from 5 trials were analyzed for quality of evidence and risk of bias. LIMITATIONS: Limitations include heterogeneity in age at enrollment and comorbidities between trials and change in oximeter algorithm midway through 3 trials. RESULTS: There was no difference in the incidence of primary outcome (death/NDI at 18–24 months) in the 2 groups; risk ratio,1.05, 95% confidence interval 0.98–1.12, P = .18. Mortality before 18 to 24 months was higher in the lower-target group (risk ratio,1.16, 95% confidence interval 1.03–1.31, P = .02). Rates of NDI and severe visual loss did not differ between the 2 groups. Proportion of time infants spent outside the target range while on supplemental oxygen ranged from 8.2% to 27.4% <85% and 8.1% to 22.4% >95% with significant overlap between the 2 groups. CONCLUSIONS: There was no difference in primary outcome between the 2 Spo(2) target groups. The collective data suggest that risks associated with restricting the upper Spo(2) target limit to 89% outweigh the benefits. The quality of evidence was moderate. We speculate that a wider target range (lower alarm limit, 89% and upper, 96%) may increase time spent within range, but the safety profile of this approach remains to be determined