The Effect of IV Amino Acid Supplementation on Mortality in ICU Patients May Be Dependent on Kidney Function: Post Hoc Subgroup Analyses of a Multicenter Randomized Trial

Objectives: We investigated whether preexisting kidney function determines if ICU patients may benefit from increased (2.0 g/kg/d) protein intake. Design: Post hoc, hypothesis-generating, subgroup analysis of a multicenter, phase 2, randomized clinical trial. All analyses were conducted by intention to treat and maintained group allocation. Ninety-day mortality was the primary outcome. Setting: ICUs of 16 hospitals throughout Australia and New Zealand. Patients: Adult critically ill patients expected to remain in the study ICU for longer than 2 days. Interventions: Random allocation to receive a daily supplement of up to 100 g of IV amino acids to achieve a total protein intake of 2.0 g/kg/d or standard nutrition care. Measurements and Main Results: A total of 474 patients were randomized: 235 to standard care and 239 to IV amino acid supplementation. There was a statistically significant interaction between baseline kidney function and supplementation with study amino acids (p value for interaction = 0.026). Within the subgroup of patients with normal kidney function at randomization, patients who were allocated to receive the study amino acid supplement were less likely to die before study day 90 (covariate-adjusted risk difference, –7.9%; 95% CI, –15.1 to –0.7; p = 0.034). Furthermore, amino acid supplementation significantly increased estimated glomerular filtration rate in these patients (repeated-measures treatment × time interaction p = 0.009). Within the subgroup of patients with baseline kidney dysfunction and/or risk of progression of acute kidney injury, a significant effect of the study intervention on mortality was not found (covariate-adjusted risk difference, –0.6%; 95% CI, –16.2 to 15.2; p = 0.95). Conclusions: In this post hoc, hypothesis-generating, subgroup analysis, we observed reduced mortality and improved estimated glomerular filtration rate in ICU patients with normal kidney function who were randomly allocated to receive increased protein intake (up to 2.0 g/kg/d). We strongly recommend confirmation of these results in trials with low risk of bias before this treatment is recommended for routine care. A full list of the Nephro-Protective Trial participating sites and site investigators is provided in the online-only supplement (Supplemental Digital Content 1, https://ift.tt/2GuZpzJ). Trial Registration: anzctr.org.au Identifier: ACTRN12609001015235. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (https://ift.tt/29S62lw). This work was supported, in part, by a peer-reviewed academic grant from the Australian National Health and Medical Research Council. Baxter Healthcare Pty Ltd supplied the study amino acids. Dr. Zhu reported receiving speakers’ honoraria from Nutricia Pharmaceutical (Wuxi), China, and from Fresenius Kabi SSPC, China. Dr. Allingstrup reported receiving academic research grants from Fresenius Kabi Deutschland GmbH; Medinor A/S, Denmark; and COSMED Irl, Rome, Italy, and speakers’ honoraria from Fresenius Kabi A/S, Denmark; Baxter Healthcare A/S, Denmark; and Nutricia A/S, Denmark. Dr. Perner reported receiving academic research grants from Fresenius Kabi Deutschland GmbH; Medinor A/S, Denmark; and COSMED Irl, Rome, Italy. His institution received funding from Fresenius Kabi, CSL Behring, Ferring Pharmaceuticals, and COSMED. Dr. Doig reported receiving academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare, and speakers’ honoraria from Fresenius Kabi Deutschland GmbH; Baxter Healthcare Australia; Nestle Healthcare; Vevy, Switzerland; and Nutricia Pharmaceutical (Wuxi), China. His institution received funding from National Health and Medical Research Council, Baxter Healthcare, and Fresenius Kabi Deutschland GmbH. He received support for article research from Australian National Health and Medical Research Council. For information regarding this article, E-mail: gdoig@med.usyd.edu.au Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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