Effect of Cysteine Supplementation on Glutathione Production in Critically Ill Neonates
试验速览
- 阶段
- 2 期
- 入组人数
- 108
- 试验地点
- 2
- 主要终点
- Total RBC glutathione
研究概览
简要总结
Critically ill babies less than 1 month of age have deficient amounts of the antioxidant glutathione and a high incidence of disease associated with oxidative injury compared to healthy babies. These diseases include but are not limited to damage to the eyes, lungs, and intestines. Frequently becoming chronic and potentially life threatening, these diseases result in a significantly decreased quality of life to the infant along with increased costs to the infant's family and society.
The amino acid cysteine comprises a third of the tripeptide glutathione and directly influences glutathione production. Older children ill with infection and stable, premature neonates administered cysteine supplementation to their diet have been previously shown to increase their glutathione production and concentrations. Furthermore, cysteine supplementation in the ill children resulted in a quicker resolution of their illness.
Although most critically ill babies require IV nutrition (i.e., TPN) before and during their illness, commercially available TPN does not include cysteine as a significant nutrient. Cysteine has effectively become a safe and standard supplement to routine TPN in a few major hospitals in the U.S.
The purpose of this study is to evaluate the ability of cysteine supplementation to increase glutathione production and concentrations in critically ill babies. Furthermore, the investigators want to evaluate whether cysteine supplementation results in less oxidative tissue injury and ultimately less severe illnesses. The study will enroll babies admitted to the UCLA Medical Center Neonatal Intensive Care Unit (NICU) and they will be chosen at random and in a blinded fashion to receive either cysteine or non-cysteine supplementation to their routine TPN. Small blood samples along with a single 6 hour infusion of a non-radioactive, stable isotope labeled amino acid will be used to measure the production of glutathione as well as other compounds in the blood to give a quantitative assessment to the severity of illness. Clinical information relevant to the babies' illness and subsequent recovery will be recorded.
The results will be compared between cysteine vs. non-cysteine groups and before vs. after individual supplementation. By demonstrating the effect of cysteine supplementation on glutathione production, the incidence and/or severity of disease from oxidative injury in critically ill babies may be decreased if glutathione production is improved.
详细描述
Specific Aims:
Critically ill neonates have demonstrated low concentrations of the antioxidant glutathione and a high incidence of disease associated with oxidative injury compared to healthy neonates. Cysteine is considered to be a conditionally essential amino acid for neonates and is the rate limiting substrate for the synthesis of glutathione. We hypothesize that parenterally-fed, critically ill neonates administered cysteine supplementation will have higher concentrations of total glutathione, lower ratios of oxidized to reduced glutathione, higher glutathione synthetic rates, lower levels of inflammatory cytokine production and lipid peroxidation, and decreased severity of disease associated with oxidative injury compared to similarly ill parenterally fed neonates without cysteine supplementation. To test this hypothesis, critically ill, parenterally fed neonates assigned randomly to receive a cysteine or an isonitrogenous cysteine-free supplement to their TPN (total parenteral nutrition) regimen will be prospectively studied in a double-blind fashion according to the following specific aims:
- to measure total concentrations of erythrocyte glutathione, oxidized to reduced (GSSG:GSH) erythrocyte glutathione ratios, and the in vivo fractional and absolute synthetic rates of erythrocyte glutathione utilizing a [13C]-glycine tracer,
- to measure plasma interleukin-6 (IL-6), tumor necrosis factor (TNF-a), and malondialdehyde concentrations as determinants of illness severity and degree of oxidative injury reflected by lipid peroxidation,
- and, to measure duration of mechanical ventilation, duration of supplemental oxygen, and duration of hospitalization as the primary clinical outcomes of disease severity.
By demonstrating whether cysteine supplementation increases the synthesis and concentration of glutathione along with the subsequent decrease in oxidative injury and associated disease, the widespread morbidity and mortality for vulnerable, critically ill neonates may be improved.
Background:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- — 至 30 Days（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •mechanically ventilated neonates of all gestational ages and birth weights
- •less than 1 month of postnatal age admitted to the NICU
- •SNAP (Score of Neonatal Acute Physiology) > 10
- •projected requirement for continued parenteral nutrition of at least 1 week duration
排除标准
- •renal or hepatic failure
- •requiring insulin administration
- •requiring extracorporeal life support
- •known inherited metabolic disorders
- •known uniformly fatal congenital anomalies
结局指标
主要结局
Total RBC glutathione
时间窗: 0 days, 7 days, 60 days
次要结局
- Tumor necrosis factor (TNF)(0 days, 7 days, 60 days)
- Interleukin-6 (IL-6)(0 days, 7 days, 60 days)
- Oxygen dependency(through to discharge)
- Ventilation dependency(through to discharge)
- Erythrocyte oxidized:reduced glutathione ratio(0 days, 7 days, 60 days)
- In vivo erythrocyte glutathione synthetic rate(7 days, 60 days)
- Plasma malondialdehyde concentration(0 days, 7days, 60 days)