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C-reactive protein rise in response to macronutrient deficit early in critical illness: sign of inflammation or mediator of infection prevention and recovery

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Abstract

Purpose

Withholding parenteral nutrition (PN) early in critical illness, late-PN, has shown to prevent infections despite a higher peak C-reactive protein (CRP). We investigated whether the accentuated CRP rise was caused by a systemic inflammatory effect mediated by cytokines or arose as a consequence of the different feeding regimens, and whether it related to improved outcome with late-PN.

Methods

This secondary analysis of the EPaNIC-RCT first investigated, with multivariable linear regression analyses, determinants of late-PN-induced CRP rise and its association with cytokine responses (IL-6, IL-10, TNF-α) in matched early-PN and late-PN patients requiring intensive care for ≥ 3 days. Secondly, with multivariable logistic regression and Cox proportional-hazard analyses, we investigated whether late-PN-induced CRP rises mediated infection prevention and enhanced recovery or reflected an adverse effect counteracting such benefits of late-PN.

Results

CRP peaked on day 3, higher with late-PN [216(152–274)mg/l] (n = 946) than with early-PN [181(122–239)mg/l] (n = 946) (p < 0.0001). Independent determinants of higher CRP rise were lower carbohydrate and protein intakes (p ≤ 0.04) with late-PN, besides higher blood glucose and serum insulin concentrations (p ≤ 0.01). Late-PN did not affect cytokines. Higher CRP rises were independently associated with more infections and lower likelihood of early ICU discharge (p ≤ 0.002), and the effect size of late-PN versus early-PN on these outcomes was increased rather than reduced after adjusting for CRP rise, not confirming a mediating role.

Conclusions

The higher CRP rise with late-PN, explained by the early macronutrient deficits, did not relate to cytokine responses and thus did not reflect more systemic inflammation. Instead of mediating clinical benefit on infection or recovery, the accentuated CRP rise appeared an adverse effect reducing such late-PN benefits.

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Data sharing will be considered only on a collaborative basis with the principal investigators, after evaluation of the proposed study protocol.

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Funding

This work was supported by the Research Foundation Flanders (FWO), Belgium (Clinical Doctoral Research Fellowship to C. Ingels); the Clinical Research Foundation of the University Hospitals Leuven (Doctoral Research Fellowship to C. Ingels); the Clinical Research and Education Council of the University Hospitals Leuven (postdoctoral research fellowship to C. Ingels and J. Gunst); the Research Foundation Flanders (FWO) (1832817 N to M. Casaer), the KU Leuven (C24/17/070 to M. Casaer and J. Gunst); the Methusalem program of the Flemish government (through the University of Leuven to G. Van den Berghe, I. Vanhorebeek, and L. Langouche METH14/06); the European Research Council Advanced Grants (AdvG-2012-321670 and AdvG-2017-785809) to G. Van den Berghe. The funders of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication.

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CI, LL, IV and GB conceived and designed the study. CI, JD, ID, SVP, PJW JG, MC and IV collected material and data. IV and FG analyzed the data. CI, JD, IV and GB wrote the manuscript, which was critically reviewed and approved by all authors.

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Correspondence to Catherine Ingels.

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Ingels, C., Langouche, L., Dubois, J. et al. C-reactive protein rise in response to macronutrient deficit early in critical illness: sign of inflammation or mediator of infection prevention and recovery. Intensive Care Med 48, 25–35 (2022). https://doi.org/10.1007/s00134-021-06565-1

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