A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients
对于重症病人的抗氧化剂和谷氨酰胺的随机使用试验 Daren Heyland, M.D., John Muscedere, M.D., Paul E. Wischmeyer, M.D., Deborah Cook, M.D., Gwynne Jones, M.D., Martin Albert, M.D.,
Gunnar Elke, M.D., Mette M. Berger, M.D., Ph.D., and Andrew G. Day, M.Sc., for the Canadian Critical Care Trials Group
BACKGROUND
Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting
重症病人有很大的氧化应激，谷氨酰胺和抗氧化剂可以提供很好的治疗效果，尽管这些和最新的数据些矛盾。
Methods
In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supple-
ments of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and en- terally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.
在这个未知的2x2析因试验中，我们将1223名重症成年病人随机分配到加拿大，美国和欧洲的40个重症监护室里，这些病人都是因多器官功能衰竭而接受机械通气并且需要提供谷氨酰胺，抗氧化剂。补充品是在24小时后进入ICU行静脉注射和伤后提供。主要结果是28天死亡。由于临时研讨工作,P值小于0.044的最终分析被认为是显示统计学意义。 Results
There was a trend toward increased mortality at 28 days among patients who re-
ceived glutamine as compared with those who did not receive glutamine (32.4% vs.
27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P = 0.05).In-hospital mortality and mortality at 6 months were significantly higher among
those who received glutamine than among those who did not. Glutamine had no
effect on rates of organ failure or infectious complications. Antioxidants had no ef- fect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P = 0.83).
有增加死亡率的趋势在28天病人谷氨酰胺相比,与那些没有收到谷氨酰胺(vs.27.2% 32.4%;调整比值比,1.28;32.4%可信区间(CI),1.00到1.64;P = 0.05)。住院死亡率和死亡率在6个月时明显高于那些比那些没有收到谷氨酰胺。谷氨酰胺没有影响器官衰竭或感染性并发症的几率。28天抗氧化剂没有影响死亡率(30.8% vs 28.8%没有抗氧化剂;调整比值比,1.09;95%置信区间,0.86至1.40;P = 0.48)或任何其他次要终点。没有差异的群体对严重不良事件(P = 0.83)。
Conclusions
Early provision of glutamine or antioxidants did not improve clinical outcomes, and
glutamine was associated with an increase in mortality among critically ill patients
with multiorgan failure. (Funded by the Canadian Institutes of Health Research;
ClinicalTrials.gov number, NCT00133978.)
早期提供谷氨酰胺或抗氧化剂并没有改善临床结果,和谷氨酰胺与死亡率的增加有关危重患者多器官衰竭。(加拿大卫生研究院资助的研究,临床试验号码,NCT00133978)。
Critically ill patients have oxidative stress. The most seriously ill patients
in intensive care units (ICUs) have increased mediators of oxidant stress and a higher
incidence of multiorgan failure than less seriouslyill patients.1-5Meta-analyses of randomized trialssuggest that glutamine and antioxidant supple-mentation in critically ill patients may be associ-ated with improved survival.6,7However, recent large studies have not confirmed such an effect.8,9The objective of the present trial was to evaluate the effect of early glutamine and antioxidant sup-plementation in critically ill patients. Our a priorihypothesis was that supplementation with thesenutrients would reduce 28-day mortality
The危重患者氧化应激。最严重的病人在重症监护病房(icu)增加氧化剂的压力和更高的调解人多器官衰竭的发生率比不认真病人。1 - 5随机试验的荟萃分析表明谷氨酰胺和抗氧化剂柔软-重症病人心理状态可能associ -给出了改善生存。6、7然而,最近的大型研究尚未证实这种效果。8、9本试验的目的是评价早期谷氨酰胺和抗氧化剂供给的影响实现在危重病人。我们的先验这些假设是,补充营养会降低28天死亡率
Study Participants
Consecutive adults who were receiving mechanical ventilation and who were admitted to participating ICUs were screened for eligibility. Patients were included if they had two or more organ failures related to their acute illness. A complete list of the eligibility criteria is
included in the Supplementary Appendix, available with the full text of this article at NEJM.org.
研究参与者连续的成年人接受icu机械通气和他们承认参与资格筛选。病人包含如果有两个或两个以上的器官故障相关的急性疾病。资格标准的完整列表包含在补充附录,提供这篇文章的全文:NEJM.org。
Study Design and Interventions
Using a factorial design, we randomly assigned patients to receive glutamine
supplementation (0.35 g per kilogram of body weight per day intravenously according to ideal body weight, provided as 0.50 g of the dipeptide alanyl glutamine [Dipeptiven,
Fresenius Kabi] per kilogram per day given intravenously and 42.5 g of alanyl glutamine and glycine glutamine dipeptides, which provide 30 g of glutamine, per day given enterally) or matching placebo solutions. In addition, patients were randomly assigned to receive 500 μg of selenium intravenously (Selenase, Biosyn) plus the following vitamins and
minerals enterally: 300 μg of selenium, 20 mg of zinc, 10 mg of beta carotene, 500 mg of vitamin E, and 1500 mg of vitamin C. The control group received placebo intravenously plus placebo enterally. Study-group assignments were concealed and stratified according to site with the use of permuted blocks of random size and a secure central Web-based system.
研究设计和干预
使用一个阶乘设计,我们随机分配病人接受补充谷氨酰胺(每天每公斤体重0.35克静脉注射根据理想体重,提供0.50 g的二肽丙氨酰谷氨酰胺[Dipeptiven,费森尤斯公司Kabi]每公斤每天静脉注射和42.5克丙氨酰谷氨酰胺和甘氨酸谷氨酸盐dipeptides,每天提供30克谷氨酰胺,伤后)或匹配的安慰剂的解决方案。此外,病人被随机分配接受500μg硒静脉注(Selenase Biosyn)加上以下维生素和矿物质伤:300μg硒,20毫克的锌、10毫克的β-胡萝卜素,500毫克的维生素E,1500毫克的维生素C。对照组接受安慰剂静脉注射加安慰剂伤。学习小组作业是隐藏和分层根据网站使用无数随机块大小和一个安全的中枢网络系统
To maintain blinding, study supplements and placebos were prepared by an unblinded local study pharmacist and delivered as masked solutions to the ICU. The administration of all study solutions was initiated as soon as possible after randomization; the solutions were administered separately from standard nutrition, were provided continuously, and were administered for a maxi mum of 28 days, until discharge from the ICU or death. All patients were fed according to the Canadian Critical Care Nutrition practice guide lines, independently of the study supplements.10 All other management decisions were at the discretion of the ICU team.
为了保持炫目,补充和学习安慰剂是由一个选取当地研究药剂师和蒙面溶解——交付
对ICU。所有的研究管理工作解决方案后,尽快启动随机化;解决方案管理分别从不断提供标准营养,马克西-管理妈妈的28天,直到出院ICU或死亡。所有患者根据加拿大的急救护理营养实践指南-行,独立研究的补充。10所有其他管理决策在ICU小组的自由裁量权。
The primary outcome was 28-day mortality. Secondary outcomes and data collected in this trial are described in the Supplementary Appendix. In a sample of patients enrolled at seven sites in North America, blood was drawn at baseline,day 4, and day 7 for measurement of plasma glutamine and selenium levels according to standard techniques.
主要结果是28天死亡。二次结果和收集的数据试验中所描述的补充附件。病人的样本在七个地点在北美,血液是基线,第四天,第七天测量血浆谷氨酰胺和硒水平的标准技术 Study Oversight
This investigator-initiated trial was designed by the first author in consultation with the steering committee. The steering committee vouches for the data, the analysis, and the decision to submit the manuscript for publication. All sites listed in the acknowledgments in the Supplementary Appendix participated in the data collection. The last author was responsible for the analysis. The first author and the writing committee wrote the man uscript. The protocol was endorsed and conducted in collaboration with the Canadian Critical
Care Trials Group.
研究监督
这个审判是由cytori公司的第一作者咨询与指导委员会。指导委员会做证明数据、分析和决定提交出版的手稿。所有网站中列出补充附件中的确认参与了数据收集。最后一个作者负责的分析。第一个作者和写作委员会写了手稿。协议支持,进行了与加拿大合作至关重要治疗试验
The study was funded by the Canadian Insti tutes of Health Research. Fresenius Kabi provided the glutamine supplements and an unrestricted grant-in-aid. Biosyn provided the intravenous selenium to all participating European sites. None of these agencies had a decision-making role in the design or conduct of the study, analysis or interpretation of data, manuscript preparation, or decision to submit the manuscript for publication.The study was conducted according to the protocol, which has been published previously 9,11,12 and is available at NEJM.org. This trial was conducted between April 2005 and December 2011 in 40 ICUs in participating countries after approval by local jurisdictional and institutional research ethics boards. Written informed consent was obtained from all patients or their legal representatives before enrollment.
这项研究是由加拿大卫生研究院资助的研究。费森尤斯公司Kabi提供补充谷氨酰胺和一个不受限制的补助金。Biosyn提供了静脉注射硒所有参与欧洲网站。这些机构的决策角色的设计或进行研究,分析或解释的数据,手稿准备,或决定提交的手稿出版。这项研究是根据协议,进行发表之前9、11、12,并可在NEJM.org。这项试验是2005年4月和2011年12月之间进行的在参与国icu在40后ap -由当地管辖权和机构同意研究伦理委员会。书面知情同意是获得所有的病人或其合法吗入学前的代表
A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients
对于重症病人的抗氧化剂和谷氨酰胺的随机使用试验 Daren Heyland, M.D., John Muscedere, M.D., Paul E. Wischmeyer, M.D., Deborah Cook, M.D., Gwynne Jones, M.D., Martin Albert, M.D.,
Gunnar Elke, M.D., Mette M. Berger, M.D., Ph.D., and Andrew G. Day, M.Sc., for the Canadian Critical Care Trials Group
BACKGROUND
Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting
重症病人有很大的氧化应激，谷氨酰胺和抗氧化剂可以提供很好的治疗效果，尽管这些和最新的数据些矛盾。
Methods
In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supple-
ments of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and en- terally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.
在这个未知的2x2析因试验中，我们将1223名重症成年病人随机分配到加拿大，美国和欧洲的40个重症监护室里，这些病人都是因多器官功能衰竭而接受机械通气并且需要提供谷氨酰胺，抗氧化剂。补充品是在24小时后进入ICU行静脉注射和伤后提供。主要结果是28天死亡。由于临时研讨工作,P值小于0.044的最终分析被认为是显示统计学意义。 Results
There was a trend toward increased mortality at 28 days among patients who re-
ceived glutamine as compared with those who did not receive glutamine (32.4% vs.
27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P = 0.05).In-hospital mortality and mortality at 6 months were significantly higher among
those who received glutamine than among those who did not. Glutamine had no
effect on rates of organ failure or infectious complications. Antioxidants had no ef- fect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P = 0.83).
有增加死亡率的趋势在28天病人谷氨酰胺相比,与那些没有收到谷氨酰胺(vs.27.2% 32.4%;调整比值比,1.28;32.4%可信区间(CI),1.00到1.64;P = 0.05)。住院死亡率和死亡率在6个月时明显高于那些比那些没有收到谷氨酰胺。谷氨酰胺没有影响器官衰竭或感染性并发症的几率。28天抗氧化剂没有影响死亡率(30.8% vs 28.8%没有抗氧化剂;调整比值比,1.09;95%置信区间,0.86至1.40;P = 0.48)或任何其他次要终点。没有差异的群体对严重不良事件(P = 0.83)。
Conclusions
Early provision of glutamine or antioxidants did not improve clinical outcomes, and
glutamine was associated with an increase in mortality among critically ill patients
with multiorgan failure. (Funded by the Canadian Institutes of Health Research;
ClinicalTrials.gov number, NCT00133978.)
早期提供谷氨酰胺或抗氧化剂并没有改善临床结果,和谷氨酰胺与死亡率的增加有关危重患者多器官衰竭。(加拿大卫生研究院资助的研究,临床试验号码,NCT00133978)。
Critically ill patients have oxidative stress. The most seriously ill patients
in intensive care units (ICUs) have increased mediators of oxidant stress and a higher
incidence of multiorgan failure than less seriouslyill patients.1-5Meta-analyses of randomized trialssuggest that glutamine and antioxidant supple-mentation in critically ill patients may be associ-ated with improved survival.6,7However, recent large studies have not confirmed such an effect.8,9The objective of the present trial was to evaluate the effect of early glutamine and antioxidant sup-plementation in critically ill patients. Our a priorihypothesis was that supplementation with thesenutrients would reduce 28-day mortality
The危重患者氧化应激。最严重的病人在重症监护病房(icu)增加氧化剂的压力和更高的调解人多器官衰竭的发生率比不认真病人。1 - 5随机试验的荟萃分析表明谷氨酰胺和抗氧化剂柔软-重症病人心理状态可能associ -给出了改善生存。6、7然而,最近的大型研究尚未证实这种效果。8、9本试验的目的是评价早期谷氨酰胺和抗氧化剂供给的影响实现在危重病人。我们的先验这些假设是,补充营养会降低28天死亡率
Study Participants
Consecutive adults who were receiving mechanical ventilation and who were admitted to participating ICUs were screened for eligibility. Patients were included if they had two or more organ failures related to their acute illness. A complete list of the eligibility criteria is
included in the Supplementary Appendix, available with the full text of this article at NEJM.org.
研究参与者连续的成年人接受icu机械通气和他们承认参与资格筛选。病人包含如果有两个或两个以上的器官故障相关的急性疾病。资格标准的完整列表包含在补充附录,提供这篇文章的全文:NEJM.org。
Study Design and Interventions
Using a factorial design, we randomly assigned patients to receive glutamine
supplementation (0.35 g per kilogram of body weight per day intravenously according to ideal body weight, provided as 0.50 g of the dipeptide alanyl glutamine [Dipeptiven,
Fresenius Kabi] per kilogram per day given intravenously and 42.5 g of alanyl glutamine and glycine glutamine dipeptides, which provide 30 g of glutamine, per day given enterally) or matching placebo solutions. In addition, patients were randomly assigned to receive 500 μg of selenium intravenously (Selenase, Biosyn) plus the following vitamins and
minerals enterally: 300 μg of selenium, 20 mg of zinc, 10 mg of beta carotene, 500 mg of vitamin E, and 1500 mg of vitamin C. The control group received placebo intravenously plus placebo enterally. Study-group assignments were concealed and stratified according to site with the use of permuted blocks of random size and a secure central Web-based system.
研究设计和干预
使用一个阶乘设计,我们随机分配病人接受补充谷氨酰胺(每天每公斤体重0.35克静脉注射根据理想体重,提供0.50 g的二肽丙氨酰谷氨酰胺[Dipeptiven,费森尤斯公司Kabi]每公斤每天静脉注射和42.5克丙氨酰谷氨酰胺和甘氨酸谷氨酸盐dipeptides,每天提供30克谷氨酰胺,伤后)或匹配的安慰剂的解决方案。此外,病人被随机分配接受500μg硒静脉注(Selenase Biosyn)加上以下维生素和矿物质伤:300μg硒,20毫克的锌、10毫克的β-胡萝卜素,500毫克的维生素E,1500毫克的维生素C。对照组接受安慰剂静脉注射加安慰剂伤。学习小组作业是隐藏和分层根据网站使用无数随机块大小和一个安全的中枢网络系统
To maintain blinding, study supplements and placebos were prepared by an unblinded local study pharmacist and delivered as masked solutions to the ICU. The administration of all study solutions was initiated as soon as possible after randomization; the solutions were administered separately from standard nutrition, were provided continuously, and were administered for a maxi mum of 28 days, until discharge from the ICU or death. All patients were fed according to the Canadian Critical Care Nutrition practice guide lines, independently of the study supplements.10 All other management decisions were at the discretion of the ICU team.
为了保持炫目,补充和学习安慰剂是由一个选取当地研究药剂师和蒙面溶解——交付
对ICU。所有的研究管理工作解决方案后,尽快启动随机化;解决方案管理分别从不断提供标准营养,马克西-管理妈妈的28天,直到出院ICU或死亡。所有患者根据加拿大的急救护理营养实践指南-行,独立研究的补充。10所有其他管理决策在ICU小组的自由裁量权。
The primary outcome was 28-day mortality. Secondary outcomes and data collected in this trial are described in the Supplementary Appendix. In a sample of patients enrolled at seven sites in North America, blood was drawn at baseline,day 4, and day 7 for measurement of plasma glutamine and selenium levels according to standard techniques.
主要结果是28天死亡。二次结果和收集的数据试验中所描述的补充附件。病人的样本在七个地点在北美,血液是基线,第四天,第七天测量血浆谷氨酰胺和硒水平的标准技术 Study Oversight
This investigator-initiated trial was designed by the first author in consultation with the steering committee. The steering committee vouches for the data, the analysis, and the decision to submit the manuscript for publication. All sites listed in the acknowledgments in the Supplementary Appendix participated in the data collection. The last author was responsible for the analysis. The first author and the writing committee wrote the man uscript. The protocol was endorsed and conducted in collaboration with the Canadian Critical
Care Trials Group.
研究监督
这个审判是由cytori公司的第一作者咨询与指导委员会。指导委员会做证明数据、分析和决定提交出版的手稿。所有网站中列出补充附件中的确认参与了数据收集。最后一个作者负责的分析。第一个作者和写作委员会写了手稿。协议支持,进行了与加拿大合作至关重要治疗试验
The study was funded by the Canadian Insti tutes of Health Research. Fresenius Kabi provided the glutamine supplements and an unrestricted grant-in-aid. Biosyn provided the intravenous selenium to all participating European sites. None of these agencies had a decision-making role in the design or conduct of the study, analysis or interpretation of data, manuscript preparation, or decision to submit the manuscript for publication.The study was conducted according to the protocol, which has been published previously 9,11,12 and is available at NEJM.org. This trial was conducted between April 2005 and December 2011 in 40 ICUs in participating countries after approval by local jurisdictional and institutional research ethics boards. Written informed consent was obtained from all patients or their legal representatives before enrollment.
这项研究是由加拿大卫生研究院资助的研究。费森尤斯公司Kabi提供补充谷氨酰胺和一个不受限制的补助金。Biosyn提供了静脉注射硒所有参与欧洲网站。这些机构的决策角色的设计或进行研究,分析或解释的数据,手稿准备,或决定提交的手稿出版。这项研究是根据协议,进行发表之前9、11、12,并可在NEJM.org。这项试验是2005年4月和2011年12月之间进行的在参与国icu在40后ap -由当地管辖权和机构同意研究伦理委员会。书面知情同意是获得所有的病人或其合法吗入学前的代表