Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models

Background: Proteins are an essential part of medical nutrition therapy in critically ill patients. Guidelines almost universally recommend a high protein intake without robust evidence supporting its use.

Methods: Using a large international database, we modelled associations between the hazard rate of in-hospital death and live hospital discharge (competing risks) and three categories of protein intake (low: < 0.8 g/kg per day, standard: 0.8-1.2 g/kg per day, high: > 1.2 g/kg per day) during the first 11 days after ICU admission (acute phase). Time-varying cause-specific hazard ratios (HR) were calculated from piece-wise exponential additive mixed models. We used the estimated model to compare five different hypothetical protein diets (an exclusively low protein diet, a standard protein diet administered early (day 1 to 4) or late (day 5 to 11) after ICU admission, and an early or late high protein diet).

Results: Of 21,100 critically ill patients in the database, 16,489 fulfilled inclusion criteria for the analysis. By day 60, 11,360 (68.9%) patients had been discharged from hospital, 4,192 patients (25.4%) had died in hospital, and 937 patients (5.7%) were still hospitalized. Median daily low protein intake was 0.49 g/kg [IQR 0.27-0.66], standard intake 0.99 g/kg [IQR 0.89- 1.09], and high intake 1.41 g/kg [IQR 1.29-1.60]. In comparison with an exclusively low protein diet, a late standard protein diet was associated with a lower hazard of in-hospital death: minimum 0.75 (95% CI 0.64, 0.87), and a higher hazard of live hospital discharge: maximum HR 1.98 (95% CI 1.72, 2.28). Results on hospital discharge, however, were qualitatively changed by a sensitivity analysis. There was no evidence that an early standard or a high protein intake during the acute phase was associated with a further improvement of outcome.

Conclusions: Provision of a standard protein intake during the late acute phase may improve outcome compared to an exclusively low protein diet. In unselected critically ill patients, clinical outcome may not be improved by a high protein intake during the acute phase. Study registration ID number ISRCTN17829198.