The clinical potential of GDF15 as a "ready-to-feed indicator" for critically ill adults

Abstract

Background: Circulating growth-differentiation factor-15 (GDF15), a cellular stress marker, abruptly increases during critical illness, but its later time course remains unclear. GDF15 physiologically controls oral intake by driving aversive responses to nutrition. Early parenteral nutrition (PN) in ICU patients has overall been shown not beneficial. We hypothesized that low GDF15 can identify patients who benefit from early PN, tolerate enteral nutrition (EN), and resume spontaneous oral intake.

Methods: In secondary analyses of the EPaNIC-RCT on timing of PN initiation (early PN versus late PN) and the prospective observational DAS study, we documented the time course of circulating GDF15 in ICU (N = 1128) and 1 week post-ICU (N = 72), compared with healthy subjects (N = 65), and the impact hereon of randomization to early PN versus late PN in propensity score-matched groups (N = 564/group). Interaction between upon-admission GDF15 and randomization for its outcome effects was investigated (N = 4393). Finally, association between GDF15 and EN tolerance in ICU (N = 1383) and oral intake beyond ICU discharge (N = 72) was studied.

Results: GDF15 was elevated throughout ICU stay, similarly in early PN and late PN patients, and remained high beyond ICU discharge (p < 0.0001). Upon-admission GDF15 did not interact with randomization to early PN versus late PN for its outcome effects, but higher GDF15 independently related to worse outcomes (p ≤ 0.002). Lower GDF15 was only weakly related to gastrointestinal tolerance (p < 0.0001) and a steeper drop in GDF15 with more oral intake after ICU discharge (p = 0.05).

Conclusion: In critically ill patients, high GDF15 reflected poor prognosis and may contribute to aversive responses to nutrition. However, the potential of GDF15 as "ready-to-feed indicator" appears limited.

Trial registration: ClinicalTrials.gov , NCT00512122, registered 31 July 2007, https://www.clinicaltrials.gov/ct2/show/NCT00512122 (EPaNIC trial) and ISRCTN, ISRCTN 98806770, registered 11 November 2014, http://www.isrctn.com/ISRCTN98806770 (DAS trial).

Keywords: Critical illness; Feeding intolerance; GDF15; Outcome; Parenteral nutrition.

Fig. 1

Patient selection. Studied samples are depicted in gray. Randomization group refers to early PN versus late PN. GDF15, growth-differentiation factor-15; ICU, intensive care unit

Fig. 2

Time course of GDF15 during critical illness. Serum concentrations of GDF15 were quantified in 65 healthy controls and in 564 early PN and 564 late PN ICU patients, who were matched for upon ICU admission characteristics, on the admission day, on day 4 or the last day in ICU for patients with a shorter ICU stay (d4/LD), on day 7 for patients still in ICU on that day, and on the last ICU day (left panels). In addition, in a smaller subset of patients with an ICU stay of at least 4 days, serum GDF15 concentrations were also quantified on day 1, day 2, and day 3 in the ICU (right panels). Numbers below each graph indicate, for each time point, how many patients had sufficient serum available for GDF15 measurement and were included in the analyses. P values, adjusted for multiple comparisons, for each time point are shown at the top of the graphs. Geometric shapes represent medians, and whiskers represent interquartile ranges. a Comparison of all patients with 65 control subjects (gray area representing interquartile ranges) who had never been admitted to an ICU. b Comparison of patients randomized to early PN versus late PN. c Comparison of ICU survivors and non-survivors

Fig. 3

Relation of GDF15 with oral intake after ICU discharge. Plasma concentrations of GDF15 were quantified in 72 ICU patients on the last day in ICU and 7 days after ICU discharge. Macronutrient intake was scored semi-quantitatively based on estimated nutrient intake (low, moderate, and high intake meaning respectively < 40%, 40–60%, or > 60% of a normal intake). Geometric shapes represent means, and error bars represent standard errors of the mean. Numbers in the figure legend indicate the number of patients per group. Data are shown on a logarithmic scale