U-Shape Relationship between Plasma Leucine Level and Mortality in the Intensive Care Unit

Abstract

Patients in the intensive care unit (ICU) are at high risk of mortality which is not well predicted. Previous studies noted that leucine has prognostic value in a variety of diseases. This study investigated whether leucine concentration was a useful biomarker of metabolic and nutritional status and 6-month mortality in ICU. We recruited 454 subjects admitted to ICU (348 and 106 in the initiation and validation cohorts, respectively) with an acute physiology and chronic health evaluation (APACHE II) score ≥ 15. We measured plasma leucine concentrations, traditional biomarkers, and calculated APACHE II and sequential organ failure assessment (SOFA) scores. Leucine levels were weakly correlated with albumin, prealbumin, and transferrin levels (r = 0.30, 0.12, and 0.15, p = 0.001, 0.029, and 0.007, respectively). During follow-up, 116 (33.3%) patients died. Compared to patients with leucine levels between 109 and 174 μM, patients with leucine > 174 μM or <109 μM had a lower cumulative survival rate. Death was also associated with age, higher APACHE II and SOFA scores, C-reactive protein, and longer stays in the ICU, but with lower albumin, prealbumin, and transferrin. Patients with leucine levels > 174 μM had higher alanine aminotransferase levels, but no significant differences in other variables; patients with leucine levels < 109 μM had higher APACHE II and SOFA scores, higher incidence of using inotropic agents, longer ICU and hospital stays, but lower albumin and transferrin levels. Multivariable analysis demonstrated that leucine > 174 μM was an independent predictor of mortality, especially early mortality. However, among patients who stayed in ICU longer than two weeks, leucine < 109 μM was an independent predictor of mortality. In addition, leucine < 109 μM was associated with worse ventilator weaning profiles. These findings were similar in the validation cohort. Our study demonstrated a U-shape relationship between leucine levels and mortality rate in ICU.

Figure 1

The flow diagram of the study.

Figure 2

Prognostic value of plasma leucine concentration. (a) Association between leucine level and risk of mortality in the additive Cox regression models (dotted lines indicate 95% confidence interval). (b) The Kaplan-Meier curves for three different groups (for all-cause death).

Figure 3

Prognostic value of plasma leucine concentration in patients who survived longer than two weeks. (a) The Kaplan-Meier curves for three different groups (for all-cause death). Leucine levels were measured at baseline. (b) The Kaplan-Meier curves for patients with leucine < 109 μM versus ≥109 μM (for all-cause death). Leucine levels were measured at two weeks after admission to the intensive care unit in patients who remained in the intensive care unit.