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

Abstract

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

Time-varying intensity of oxygen exposure is associated with mortality in critically ill patients with mechanical ventilation

“…We first used piece-wise exponential additive mixed models (PAMMs) [14][15][16] to estimate the association of subject-specific longitudinal profiles of either TWA-PaO 2 or TWA-FiO 2 with 28-day mortality. PAMMs allow one to examine the time-varying effect of a time-varying exposure (time-varying TWA-PaO 2 or TWA-FiO 2 in the present study) on a time-to-event outcome (Additional file 1).…”

Medical nutrition therapy and clinical outcomes in critically ill adults: a European multinational, prospective observational cohort study (EuroPN)

“…To our knowledge, this is one of the largest prospective studies providing real-world evidence about nutrition and its associations with clinical outcomes in a mixed population of critically ill adult patients treated in European ICUs during a minimum ICU LOS of 5 days. Associations were assessed using a novel combination of established statistical techniques which considered time dependency of medical nutrition therapy effects, and interferences from confounding by indication [ 22 , 23 ].…”

“…Finally, a bias might arise from including patients in our analysis up to a BMI of 45 kg/m 2 . According to recent results, however, associations between hypothetical diets and outcomes in patients with a BMI > 30 kg/m 2 are qualitatively comparable to those with a lower BMI [ 23 ].…”

Protein metabolism in critical illness

“…Of note, a recent large posthoc analysis of observational data evaluated 16 489 patients to determine associations between protein intake and in-hospital mortality and alive hospital discharge using an advanced cox regression model based on simulated feeding strategies. This posthoc reported that late (days 5–11) standard protein intake (0.8–1.2 g/kg/day) was associated with a lower hazard of in-hospital mortality (minimum 0.75 (95% confidence interval [CI] 0.64–0.87)) and a higher hazard of alive hospital discharge (maximum HR 1.98 (95% CI 1.72–2.28)) when compared to a low protein diet, while an earlier (days 1–11) standard or high protein intake was not associated with further improvement in outcome [11 ▪▪ ]. Although a number of noninterventional studies report conflicting impacts of augmented protein on outcomes [12 ▪▪ ,13 ▪ ,14], few randomized controlled trials (RCTs) have been conducted.…”