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Predictive Role of F2-Isoprostanes as Biomarkers for Brain Damage after Neonatal Surgery 时间:2017-10-10 15:37 来源:未知作者:admin 点击: 次 Abstract:Objective. Neonates have a high risk of oxidative stress during anesthetic procedures. The predictive role of oxidative stress biomarkers on the occurrence of brain injury in the perioperative period has not been reported before. Methods. A prospective cohort study of patients requiring major surgery in the neonatal period was conducted. Biomarker levels of nonprotein-bound iron (NPBI) in plasma and F2-isoprostane in plasma and urine before and after surgical intervention were determined. Brain injury was assessed using postoperative MRI. Results. In total, 61 neonates were included, median gestational age at 39 weeks (range 31–42) and weight at 3000 grams (1400–4400). Mild to moderate brain lesions were found in 66%. Logistic regression analysis showed a significant difference between plasma NPBI in patients with nonparenchymal injury versus no brain injury: 1.34 umol/L was identified as correlation threshold for nonparenchymal injury (sensitivity 67%, specificity 91%). In the multivariable analysis, correcting for GA, no other significant relation was found with the oxidative stress biomarkers and risk factors. Conclusion. Oxidative stress seems to occur during anaesthesia in this cohort of neonates. Plasma nonprotein-bound iron showed to be associated with nonparenchymal injury after surgery, with values of 1.34 umol/L or higher. Risk factors should be elucidated in a more homogeneous patient group.
1. Introduction
The impact of surgery and anaesthesia on the young infants’ brain is a subject of ongoing debate. Major surgery has been shown to give a higher risk of death or neurodevelopmental impairment in a large, retrospective cohort study in very low-birth-weight infants [1]. Commonly used inhalational anaesthetics are reported to be neurotoxic in experimental studies and induce neuronal apoptosis [2, 3]. Studies on the clinical effect of anaesthetics on the developing brain are challenging. Infants with major noncardiac congenital anomalies requiring neonatal surgery (esophageal atresia, intestinal atresia, anorectal malformation, and gastroschisis) have an increased risk of a neurodevelopmental delay [4]. These patients are at risk of oxidative stress due to the anaesthetic procedure including administration of sevoflurane, the fraction of inspired oxygen, and pain, especially since the tendency is to keep them highly saturated during surgery [5]. Fluctuations in blood pressure, arterial CO2, and duration of anaesthesia pose a risk for the neonatal brain in terms of developing brain injury [6]. In 63% of patients with noncardiac congenital anomalies in this cohort study, brain lesions were visible on their postoperative MRI [7]. The exact timing of the brain injury may help to discover the pathogenesis of these lesions. In this process, biomarkers of oxidative stress might provide insight into aetiology and pathogenic factors. To date, very few reported on the role of the anaesthesic procedure in this patient group. In this study, we hypothesize that biomarkers of oxidative stress (i.e., plasma and urinary F2-isoprostane and plasma nonprotein-bound iron) are associated with brain injury and aim to clarify the aspects of oxidative stress during anaesthesia. The association between perioperative parameters, such as mean arterial blood pressure, arterial CO2, administration of opioids and duration of anaesthesia, and biomarkers for neuronal injury, was investigated.
2. Material and Methods
2.1. Patients
This prospective, cohort study was performed from January 2014 to December 2015 at the Neonatal Intensive Care Unit of the Wilhelmina Children’s Hospital Utrecht, Utrecht, the Netherlands. All eligible newborns with noncardiac congenital anomalies, requiring major neonatal surgery, were enrolled. This study was approved by the Medical Ethical Committee of the University Medical Center Utrecht. Parents were asked for written informed consent, in accordance to the principles of the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013).
Exclusion criteria consisted of critical cardiac congenital malformations, major congenital anomalies of the central nervous system, and insufficient Dutch language proficiency of the parents.
3. Methods
3.1. Biomarkers
Heparinized blood samples of 1 ml were drawn from the indwelling peripheral arterial catheter and inserted for clinical purposes. These samples were centrifuged immediately, to obtain platelet-poor plasma, and butylated hydroxytoluene (BHT) 1% w/v in methanol (5 μl per ml of plasma) was added to prevent the in vitro lipid peroxidation [8]. Urine samples of 4 ml were collected from already inserted urinary catheters or noninvasively from a gauze placed in the infants’ diaper. Six time points were chosen: within 24 hours prior to surgery; immediately after surgery; and 6, 24, and 72 hours after surgery for measurement of biomarkers of neuronal injury (Figure 1). Blood and urine samples were stored in a refrigerator at −80°C until analysis. Plasma levels of NPBI were detected by high-performance liquid chromatography (HPLC) as described by Paffetti et al. [9] using an HPLC system consisted of quaternary pumps, vacuum degassers, thermostated autosampler, DAD detector, and fluorimeter detector (Agilent 1100 series). The method is based on preferential chelation of NPBI by a large excess of the low-affinity ligand of nitrilotriacetic acid (NTA).