Association between urea trajectory and protein dose in critically ill adults: a secondary exploratory analysis of the effort protein trial (RE-EFFORT)

Abstract

Background: Delivering higher doses of protein to mechanically ventilated critically ill patients did not improve patient outcomes and may have caused harm. Longitudinal urea measurements could provide additional information about the treatment effect of higher protein doses. We hypothesised that higher urea values over time could explain the potential harmful treatment effects of higher doses of protein.

Methods: We conducted a reanalysis of a randomised controlled trial of higher protein doses in critical illness (EFFORT Protein). We applied Bayesian joint models to estimate the strength of association of urea with 30-day survival and understand the treatment effect of higher protein doses.

Results: Of the 1301 patients included in EFFORT Protein, 1277 were included in this analysis. There were 344 deaths at 30 days post-randomisation. By day 6, median urea was 2.1 mmol/L higher in the high protein group (95% CI 1.1-3.2), increasing to 3.0 mmol/L (95% CI 1.3-4.7) by day 12. A twofold rise in urea was associated with an increased risk of death at 30 days (hazard ratio 1.34, 95% credible interval 1.21-1.48), following adjustment of baseline characteristics including age, illness severity, renal replacement therapy, and presence of AKI. This association persisted over the duration of 30-day follow-up and in models adjusting for evolution of organ failure over time.

Conclusions: The increased risk of death in patients randomised to a higher protein dose in the EFFORT Protein trial was estimated to be mediated by increased urea cycle activity, of which serum urea is a biological signature. Serum urea should be taken into consideration when initiating and continuing protein delivery in critically ill patients.

Clinicaltrials: gov Identifier: NCT03160547 (2017-05-17).

Keywords: Intensive care; Joint modelling; Multi-organ failure; Protein; Urea.

Fig. 1

Urea trajectory for high and usual protein groups from the longitudinal sub-model (A), and schematic of treatment effects (B) from the joint model. The longitudinal sub-model (A) is a linear mixed effects model and includes an interaction term for time and treatment group with random intercepts and slopes. Time is modelled with a spline with three knots to account for nonlinearity of log-transformed urea values. Shown is a prediction plot with 95% prediction intervals. Predicted values are back-transformed for the plot. B is a schematic representation of the joint model. Time-varying indirect effect shows a strong relationship between high protein and increase in urea measurements over time. This association is combined with the effect estimate of the longitudinal marker on the survival outcome to summarise the indirect effect of the intervention on the survival outcome, through urea. The survival sub-model shows no direct effect of high protein on the survival outcome. Adapted from Oudenhoven et al.[5]

Fig. 2

Association between time-varying urea and 30-day mortality during the EFFORT trial. Time-varying hazard ratio (HR) obtained from a Bayesian joint model estimating the association between per cent increase in time-varying urea (A) and 30 day mortality (n = 1277). B demonstrates the association persisted for the duration of the follow-up period. Effect on HRs illustrated by showing a twofold difference in urea at any time point during follow-up. Shaded areas represent 95% credible intervals