Dataset Information

The Role of Plasma and Urine Metabolomics in Identifying New Biomarkers in Severe Newborn Asphyxia: A Study of Asphyxiated Newborn Pigs following Cardiopulmonary Resuscitation.

ABSTRACT:

Background

Optimizing resuscitation is important to prevent morbidity and mortality from perinatal asphyxia. The metabolism of cells and tissues is severely disturbed during asphyxia and resuscitation, and metabolomic analyses provide a snapshot of many small molecular weight metabolites in body fluids or tissues. In this study metabolomics profiles were studied in newborn pigs that were asphyxiated and resuscitated using different protocols to identify biomarkers for subject characterization, intervention effects and possibly prognosis.

Methods

A total of 125 newborn Noroc pigs were anesthetized, mechanically ventilated and inflicted progressive asphyxia until asystole. Pigs were randomized to resuscitation with a FiO2 0.21 or 1.0, different duration of ventilation before initiation of chest compressions (CC), and different CC to ventilation ratios. Plasma and urine samples were obtained at baseline, and 2 h and 4 h after return of spontaneous circulation (ROSC, heart rate > = 100 bpm). Metabolomics profiles of the samples were analyzed by nuclear magnetic resonance spectroscopy.

Results

Plasma and urine showed severe metabolic alterations consistent with hypoxia and acidosis 2 h and 4 h after ROSC. Baseline plasma hypoxanthine and lipoprotein concentrations were inversely correlated to the duration of hypoxia sustained before asystole occurred, but there was no evidence for a differential metabolic response to the different resuscitation protocols or in terms of survival.

Conclusions

Metabolic profiles of asphyxiated newborn pigs showed severe metabolic alterations. Consistent with previously published reports, we found no evidence of differences between established and alternative resuscitation protocols. Lactate and pyruvate may have a prognostic value, but have to be independently confirmed.

SUBMITTER: Sachse D

PROVIDER: S-EPMC4987056 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

The Role of Plasma and Urine Metabolomics in Identifying New Biomarkers in Severe Newborn Asphyxia: A Study of Asphyxiated Newborn Pigs following Cardiopulmonary Resuscitation.

Sachse Daniel D Solevåg Anne Lee AL Berg Jens Petter JP Nakstad Britt B

PloS one 20160816 8

<h4>Background</h4>Optimizing resuscitation is important to prevent morbidity and mortality from perinatal asphyxia. The metabolism of cells and tissues is severely disturbed during asphyxia and resuscitation, and metabolomic analyses provide a snapshot of many small molecular weight metabolites in body fluids or tissues. In this study metabolomics profiles were studied in newborn pigs that were asphyxiated and resuscitated using different protocols to identify biomarkers for subject characteriz ...[more]

PMID: 27529347

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Project description:BackgroundSustained inflation (SI) during chest compression (CC = CC+SI) has been recently shown as an alternative method during cardiopulmonary resuscitation in neonates. However, the optimal peak inflation pressure (PIP) of SI during CC+SI to improve ROSC and hemodynamic recovery is unknown.ObjectiveTo examine if different PIPs of SI during CC+SI will improve ROSC and hemodynamic recovery in severely asphyxiated piglets.MethodsTwenty-nine newborn piglets (1-3 days old) were anesthetized, intubated, instrumented and exposed to 30-min normocapnic hypoxia followed by asphyxia. Piglets were randomized into four groups: CC+SI with a PIP of 10 cmH2O (CC+SI_PIP_10, n = 8), a PIP of 20 cmH2O (CC+SI_PIP_20, n = 8), a PIP of 30 cmH2O (CC+SI_PIP_30, n = 8), and a sham-operated control group (n = 5). Heart rate, arterial blood pressure, carotid blood flow, cerebral oxygenation, and respiratory parameters were continuously recorded throughout the experiment.ResultsBaseline parameters were similar between all groups. There was no difference in asphyxiation (duration and degree) between intervention groups. PIP correlated positively with tidal volume (VT) and inversely with exhaled CO2 during cardiopulmonary resuscitation. Time to ROSC and rate of ROSC were similar between piglets resuscitated with CC+SI_PIP_10, CC+SI_PIP_20, and CC+SI_PIP_30 cmH2O: median (IQR) 75 (63-193) sec, 94 (78-210) sec, and 85 (70-90) sec; 5/8 (63%), 7/8 (88%), and 3/8 (38%) (p = 0.56 and p = 0.12, respectively). All piglets that achieved ROSC survived to four hours post-resuscitation. Piglets resuscitated with CC+SI_PIP_30 cmH2O exhibited increased concentrations of pro-inflammatory cytokines interleukin-1β and tumour necrosis factor-α in the frontoparietal cerebral cortex (both p<0.05 vs. sham-operated controls).ConclusionIn asphyxiated term newborn piglets resuscitated by CC+SI, the use of different PIPs resulted in similar time to ROSC, but PIP at 30 cmH2O showed a larger VT delivery, lower exhaled CO2 and increased tissue inflammatory markers in the brain.

Project description:BackgroundCurrently, 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.Methods and findingsHypoxemia 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).ConclusionsThis 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.

Project description:Background: Evidence for recommendations on the use of volume expansion during cardiopulmonary resuscitation in newborn infants is limited. Objectives: To develop a newborn piglet model with asphyxia, hemorrhage, and cardiac arrest to test different volume resuscitation on return of spontaneous circulation (ROSC). We hypothesized that immediate red cell transfusion reduces time to ROSC as compared to the use of an isotonic crystalloid fluid. Methods: Forty-four anaesthetized and intubated newborn piglets [age 32 h (12-44 h), weight 1,220 g (1,060-1,495g), Median (IQR)] were exposed to hypoxia and blood loss until asystole occurred. At this point they were randomized into two groups: (1) Crystalloid group: receiving isotonic sodium chloride (n = 22). (2) Early transfusion group: receiving blood transfusion (n = 22). In all other ways the piglets were resuscitated according to ILCOR 2015 guidelines [including respiratory support, chest compressions (CC) and epinephrine use]. One hour after ROSC piglets from the crystalloid group were randomized in two sub-groups: late blood transfusion and infusion of isotonic sodium chloride to investigate the effects of a late transfusion on hemodynamic parameters. Results: All animals achieved ROSC. Comparing the crystalloid to early blood transfusion group blood loss was 30.7 ml/kg (22.3-39.6 ml/kg) vs. 34.6 ml/kg (25.2-44.7 ml/kg), Median (IQR). Eleven subjects did not receive volume expansion as ROSC occurred rapidly. Thirty-three animals received volume expansion (16 vs. 17 in the crystalloid vs. early transfusion group). 14.1% vs. 10.5% of previously extracted blood volume in the crystalloid vs. early transfusion group was infused before ROSC. There was no significant difference in time to ROSC between groups [crystalloid group: 164 s (129-198 s), early transfusion group: 163 s (162-199 s), Median (IQR)] with no difference in epinephrine use. Conclusions: Early blood transfusion compared to crystalloid did not reduce time to ROSC, although our model included only a moderate degree of hemorrhage and ROSC occurred early in 11 subjects before any volume resuscitation occurred.

Project description:Cell free DNA (cfDNA) in plasma has been described as a potential diagnostic indicator for a variety of clinical conditions, including neonatal hypoxia. Neonatal hypoxia or perinatal asphyxia is a severe medical condition caused by a temporary interruption in oxygen availability during birth. Previously, we have reported temporal changes of cfDNA detected in blood in a newborn piglet model of perinatal asphyxia. However, cfDNA can also be found in other body liquids, opening for a less invasive diagnostic prospective. The objective of this study was to test and establish a reliable method for the isolation and quantification of cfDNA from urine and to explore changes in the quantities of cfDNA using a newborn piglet model of asphyxia. Animals were exposed to hypoxia-reoxygenation (n = 6), hypoxia-reoxygenation + hypothermia (n = 6) or were part of the sham-operated control group (n = 6) and urine samples (n = 18) were collected at 570 minutes post-intervention. Two alternative applications of cfDNA measurement were tested, an indirect method comprising a centrifugation step together with DNA extraction with magnetic beads versus a direct assessment based on two centrifugation steps. CfDNA concentrations were determined by a fluorescent assay using PicoGreen and by qRT-PCR. Genomic (gDNA) and mitochondrial DNA (mtDNA) cfDNA were determined in parallel, taking into account potential differences in the rates of damages caused by oxidative stress. In contrast to previous publications, our results indicate that the direct method is insufficient. Application of the indirect method obtained with the fluorescence assay revealed mean cfDNA levels (SD) of 1.23 (1.76) ng/ml for the hypoxia samples, 4.47 (6.15) ng/ml for the samples exposed to hypoxia + hypothermia and 2.75 (3.62) ng/ml for the control animals. The mean cfDNA levels in piglets exposed to hypoxia + hypothermia revealed significantly higher cfDNA amounts compared to mean cfDNA levels in the samples purely exposed to hypoxia (p < 0.05); however, no significant difference could be determined when compared to the control group (p = 0.09). Application of the indirect method by qRT-PCR revealed mean cfDNA levels of mtDNA and gDNA at the detection limit of the technique and thus no reliable statistics could be performed between the observed cfDNA levels in the investigated groups. The methodology for detection and monitoring of cfDNA in urine has to be further optimized before it can be applied in a clinical setting in the future.

Dataset Information

The Role of Plasma and Urine Metabolomics in Identifying New Biomarkers in Severe Newborn Asphyxia: A Study of Asphyxiated Newborn Pigs following Cardiopulmonary Resuscitation.

Background

Methods

Results

Conclusions

Publications

The Role of Plasma and Urine Metabolomics in Identifying New Biomarkers in Severe Newborn Asphyxia: A Study of Asphyxiated Newborn Pigs following Cardiopulmonary Resuscitation.

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