OBJECTIVES: 

Ongoing risk of death and poor functional outcomes are important consequences of prolonged critical illness. Characterizing the catabolic phenotype of prolonged critical illness could illuminate biological processes and inform strategies to attenuate catabolism. We aimed to examine if urea-to-creatinine ratio, a catabolic signature of prolonged critical illness, was associated with mortality after the first week of ICU stay.

DESIGN: 

Reanalysis of multicenter randomized trial of glutamine supplementation in critical illness (REducing Deaths due to OXidative Stress [REDOXS]).

SETTING: 

Multiple adult ICUs.

PATIENTS: 

Adult patients admitted to ICU with two or more organ failures related to their acute illness and surviving to day 7.

INTERVENTIONS: 

None.

MEASUREMENTS AND MAIN RESULTS: 

The association between time-varying urea-to-creatinine ratio and 30-day mortality was tested using Bayesian joint models adjusted for prespecified-covariates (age, kidney replacement therapy, baseline Sequential Organ Failure Assessment, dietary protein [g/kg/d], kidney dysfunction, and glutamine-randomization). From 1,021 patients surviving to day 7, 166 (16.3%) died by day 30. After adjustment in a joint model, a higher time-varying urea-to-creatinine ratio was associated with increased mortality (hazard ratio [HR], 2.15; 95% credible interval, 1.66–2.82, for a two-fold greater urea-to-creatinine ratio). This association persisted throughout the 30-day follow-up. Mediation analysis was performed to explore urea-to-creatinine ratio as a mediator-variable for the increased risk of death reported in REDOXS when randomized to glutamine, an exogenous nitrogen load. Urea-to-creatinine ratio closest to day 7 was estimated to mediate the risk of death associated with randomization to glutamine supplementation (HR, 1.20; 95% CI, 1.04–1.38; p = 0.014), with no evidence of a direct effect of glutamine (HR, 0.90; 95% CI, 0.62–1.30; p = 0.566).

CONCLUSIONS: 

The catabolic phenotype measured by increased urea-to-creatinine ratio is associated with increased risk of death during prolonged ICU stay and signals the deleterious effects of glutamine administration in the REDOXS study. Urea-to-creatinine ratio is a promising catabolic signature and potential interventional target.

中文翻译：

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危重疾病中的分解代谢：减少氧化应激 (REDOXS) 试验导致的死亡的重新分析*

目标： 

持续的死亡风险和功能不良是长期危重疾病的重要后果。表征长期危重疾病的分解代谢表型可以阐明生物过程并为减弱分解代谢的策略提供信息。我们的目的是检查尿素肌酐比（长期危重疾病的分解代谢特征）是否与入住 ICU 第一周后的死亡率相关。

设计： 

对危重疾病补充谷氨酰胺的多中心随机试验的重新分析（减少氧化应激所致死亡 [REDOXS]）。

环境： 

多个成人 ICU。

患者： 

因急性疾病相关的两个或多个器官衰竭而入住 ICU 并存活至第 7 天的成年患者。

干预措施： 

没有任何。

测量和主要结果： 

使用针对预先指定的协变量（年龄、肾脏替代治疗、基线序贯器官衰竭评估、膳食蛋白质 [g/kg/d]）调整的贝叶斯联合模型测试随时间变化的尿素肌酐比与 30 天死亡率之间的关联。 、肾功能障碍和谷氨酰胺随机化）。1,021 名患者存活至第 7 天，其中 166 名 (16.3%) 患者在第 30 天死亡。在联合模型中进行调整后，较高的时变尿素与肌酐比与死亡率增加相关（风险比 [HR]，2.15； 95% 可信区间，1.66–2.82，尿素与肌酐比值增大两倍）。这种关联在 30 天的随访中持续存在。进行中介分析，以探索尿素与肌酐比作为氧化还原试验中报告的死亡风险增加的中介变量，当随机分配谷氨酰胺（一种外源氮负荷）时。据估计，最接近第 7 天的尿素肌酐比可介导与随机补充谷氨酰胺相关的死亡风险（HR，1.20；95% CI，1.04–1.38；p = 0.014），没有证据表明尿素与肌酐比有直接影响谷氨酰胺（HR，0.90；95% CI，0.62–1.30；p = 0.566）。

结论： 

通过增加尿素与肌酐比率来测量的分解代谢表型与延长 ICU 住院期间死亡风险的增加相关，并表明氧化还原研究中谷氨酰胺施用的有害影响。尿素肌酐比是一个有前途的分解代谢特征和潜在的干预目标。