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).