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.
Similar content being viewed by others
Availability of data and material
Data sharing will be considered only on a collaborative basis with the principal investigators, after evaluation of the proposed study protocol.
Code availability
Not applicable.
References
Villet S, Chiolero RL, Bollmann MD, Revelly JP, Cayeux RNMC, Delarue J, Berger MM (2005) Clin Nutr 24:502–509. https://doi.org/10.1016/j.clnu.2005.03.006
Heidegger CP, Darmon P, Pichard C (2008) Enteral vs. parenteral nutrition for the critically ill patient: a combined support should be preferred. Curr Opin Crit Care 14:408–414. https://doi.org/10.1097/MCC.0b013e3283052cdd
Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, Griffiths R, Kreyman G, Leverve X, Pichard C, ESPEN (2009) ESPEN Guidelines on parenteral nutrition: intensive care. Clin Nutr 28:387–400. https://doi.org/10.1016/j.clnu.2009.04.024
Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G (2011) Early versus late parenteral nutrition in critically ill adults. N Engl J Med 365:506–517. https://doi.org/10.1056/NEJMoa1102662
Pepys MB, Hirschfield GM (2003) C-reactive protein: a critical update. J Clin Invest 111:1805–1812. https://doi.org/10.1172/JCI18921
Guisasola MC, Alonso B, Bravo B, Vaquero J, Chana F (2018) An overview of cytokines and heat shock response in polytraumatized patients. Cell Stress Chaperones 23:483–489. https://doi.org/10.1007/s12192-017-0859-9
Machado JR, Soave DF, da Silva MV, de Menezes LB, Etchebehere RM, Monteiro ML, dos Reis MA, Corrêa RR, Celes MR (2014) Neonatal sepsis and inflammatory mediators. Mediators Inflamm 2014:269681. https://doi.org/10.1155/2014/269681
Inforzato A, Bottazzi B, Garlanda C, Valentino S, Mantovani A (2012) Pentraxins in humoral innate immunity. Adv Exp Med Biol 946:1–20. https://doi.org/10.1007/978-1-4614-0106-3_1
Mantovani A, Garlanda C, Doni A, Bottazzi B (2008) Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol 28:1–13. https://doi.org/10.1007/s10875-007-9126-7
Póvoa P (2002) C-reactive protein: a valuable marker of sepsis. Intensive Care Med 28:235–243. https://doi.org/10.1007/s00134-002-1209-611
Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, Campbell KL, Duggan C, Foster-Schubert KE, Kong A, Mason CE, Wang CY, Blackburn GL, Bain CE, Thompson HJ, McTiernan A (2012) Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res 72:2314–2326. https://doi.org/10.1158/0008-5472.CAN-11-3092
Kalani R, Judge S, Carter C, Pahor M, Leeuwenburgh C (2006) Effects of caloric restriction and exercise on age-related, chronic inflammation assessed by C-reactive protein and interleukin-6. J Gerontol A Biol Sci Med Sci 61:211–217. https://doi.org/10.1093/gerona/61.3.211
Bosutti A, Malaponte G, Zanetti M, Castellino P, Heer M, Guarnieri G, Biolo G (2008) Calorie restriction modulates inactivity-induced changes in the inflammatory markers C-reactive protein and pentraxin-3. J Clin Endocrinol Metab 93:3226–3229. https://doi.org/10.1210/jc.2007-1684
Khalafi M, Symonds ME, Akbari A (2021) The impact of exercise training versus caloric restriction on inflammation markers: a systemic review and meta-analysis. Crit Rev Food Sci Nutr 28:1–16. https://doi.org/10.1080/10408398.2021.1873732
Heilbronn LK, Clifton PM (2002) C-reactive protein and coronary artery disease: influence of obesity, caloric restriction and weight loss. J Nutr Biochem 13:316–321. https://doi.org/10.1016/s0955-2863(02)00187-0
Miller GD, Nicklas BJ, Loeser RF (2008) Inflammatory biomarkers and physical function in older, obese adults with knee pain and self-reported osteoarthritis after intensive weight-loss therapy. J Am Geriatr Soc 56:644–651. https://doi.org/10.1111/j.1532-5415.2007.01636.x
Reed JL, De Souza MJ, Williams NI (2010) Effects of exercise combined with caloric restriction on inflammatory cytokines. Appl Physiol Nutr Metab 35:573–582. https://doi.org/10.1139/H10-046
Puglisi MJ, Fernandez ML (2008) Modulation of C-reactive protein, tumor necrosis factor-alpha, and adiponectin by diet, exercise, and weight loss. J Nutr 138:2293–2296. https://doi.org/10.3945/jn.108.097188
Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359–1367. https://doi.org/10.1056/NEJMoa011300
Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R (2006) Intensive insulin therapy in the medical ICU. N Engl J Med 354:449–461. https://doi.org/10.1056/NEJMoa052521
Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, Mesotten D, Casaer MP, Meyfroidt G, Ingels C, Muller J, Van Cromphaut S, Schetz M, Van den Berghe G (2009) Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised, controlled study. Lancet 373:547–556. https://doi.org/10.1016/S0140-6736(09)60044-1
Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S (2001) Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86:3257–3265. https://doi.org/10.1210/jcem.86.7.7623
Campos SP, Baumann H (1992) Insulin is a prominent modulator of the cytokine-stimulated expression of acute-phase plasma protein genes. Mol Cell Biol 4:1789–1797. https://doi.org/10.1128/mcb.12.4.178
Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G (2003) Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 88:1082–1088. https://doi.org/10.1210/jc.2002-021478
Casaer MP, Wilmer A, Hermans G, Wouters PJ, Mesotten D, Van den Berghe G (2013) Role of disease and macronutrient dose in the randomized controlled EPaNIC trial: a post hoc analysis. Am J Respir Crit Care Med 187:247–255. https://doi.org/10.1164/rccm.201206-0999OC
Ingels C, Vanhorebeek I, Van den Berghe G (2018) Glucose homeostasis, nutrition and infections during critical illness. Clin Microbiol Infect 24:10–15. https://doi.org/10.1016/j.cmi.2016.12.033
Weekers F, Giulietti AP, Michalaki M, Coopmans W, Van Herck E, Mathieu C, Van den Berghe G (2003) Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology 144:5329–5338. https://doi.org/10.1210/en.2003-0697
Jafar N, Edriss H, Nugent K (2016) The effect of short-term hyperglycemia on the innate immune system. Am J Med Sci 351:201–211. https://doi.org/10.1016/j.amjms.2015.11.011
Vanhorebeek I, Langouche L (2009) Molecular mechanisms behind clinical benefits of intensive insulin therapy during critical illness: glucose versus insulin. Best Pract Res Clin Anaesthesiol 23:449–459. https://doi.org/10.1016/j.bpa.2009.08.008
Ellger B, Debaveye Y, Vanhorebeek I, Langouche L, Giulietti A, Van Etten E, Herijgers P, Mathieu C, Van den Berghe G (2006) Survival benefits of intensive insulin therapy in critical illness: impact of maintaining normoglycemia versus glycemia-independent actions of insulin. Diabetes 55:1096–1105. https://doi.org/10.2337/diabetes.55.04.06.db05-1434
Lijnen HR, Van Hul M, Hemmeryckx B (2012) Caloric restriction improves coagulation and inflammation profile in obese mice. Thromb Res 129:74–79. https://doi.org/10.1016/j.thromres.2011.05.023
Allen BD, Liao CY, Shu J, Muglia LJ, Majzoub JA, Diaz V, Nelson JF (2019) Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice. Aging Cell 18:e12944. https://doi.org/10.1111/acel.12944
Camargo A, Peña-Orihuela P, Rangel-Zúñiga OA, Pérez-Martínez P, Delgado-Lista J, Cruz-Teno C, Marín C, Tinahones F, Malagón MM, Roche HM, Pérez-Jiménez F, López-Miranda J (2014) Peripheral blood mononuclear cells as in vivo model for dietary intervention induced systemic oxidative stress. Food Chem Toxicol 72:178–186. https://doi.org/10.1016/j.fct.2014.07.024
de Mello VD, Kolehmanien M, Schwab U, Pulkkinen L, Uusitupa M (2012) Gene expression of peripheral blood mononuclear cells as a tool in dietary intervention studies: What do we know so far? Mol Nutr Food Res 56:1160–1172. https://doi.org/10.1002/mnfr.201100685
Volpe CMO, Villar-Delfino PH, Dos Anjos PMF, Nogueira-Machado JA (2018) Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis 9:119. https://doi.org/10.1038/s41419-017-0135-z
Langouche L, Vander Perre S, Marques M, Boelen A, Wouters PJ, Casaer MP, Van den Berghe G (2013) Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab 98(3):1006–1013. https://doi.org/10.1210/jc.2012-2809
Tuzcu A, Bahceci M, Gokalp D, Tuzun Y, Gunes K (2005) Subclinical hypothyroidism may be associated with elevated high-sensitive c-reactive protein (low grade inflammation) and fasting hyperinsulinemia. Endocr J 52(1):89–94. https://doi.org/10.1507/endocrj.52.89
Sproston NR, Ashworth JJ (2018) Role of C-reactive protein at sites of inflammation and infection. Front Immunol 9:754. https://doi.org/10.3389/fimmu.2018.00754
Zhang D, Sun M, Samols D, Kushner I (1996) STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6. J Biol Chem 271:9503–9509. https://doi.org/10.1074/jbc.271.16.9503
Mortensen RF (2001) C-reactive protein, inflammation, and innate immunity. Immunol Res 24(2):163–176. https://doi.org/10.1385/IR:24:2:163
Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469:323–335. https://doi.org/10.1038/nature09782
Gabandé-Rodríguez E, Gómez de Las Keras MM, Mittelbrunn M (2019) Control of inflammation by calorie restriction mimetics: on the crossroad of autophagy and mitochondria. Cells 9:82. https://doi.org/10.3390/cells9010082
Ristow M, Zarse K (2010) How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 45:410–418. https://doi.org/10.1016/j.exger.2010.03.014
Derde S, Vanhorebeek I, Güiza F, Derese I, Gunst J, Fahrenkrog B, Martinet W, Vervenne H, Ververs EJ, Larsson L, Van den Berghe G (2012) Early parenteral nutrition evokes a phenotype of autophagy deficiency in liver and skeletal muscle of critically ill rabbits. Endocrinology 153:2267–2276. https://doi.org/10.1210/en.2011-2068
Hermans G, Casaer MP, Clerckx B, Güiza F, Vanhullebusch T, Derde S, Meersseman P, Derese I, Mesotten D, Wouters PJ, Van Cromphaut S, Debaveye Y, Gosselink R, Gunst J, Wilmer A, Van den Berghe G, Vanhorebeek I (2013) Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med 1:621–629. https://doi.org/10.1016/S2213-2600(13)70183-8
Arabi YM, Reintam Blaser A, Preiser JC (2019) Less is more in nutrition: critically ill patients are starving but not hungry. Intensive Care Med 45:1629–1631. https://doi.org/10.1007/s00134-019-05765-0
van Niekerk G, Isaacs AW, Nell T, Engelbrecht AM (2016) Sickness-Associated Anorexia: mother nature’s idea of immunonutrition? Mediators Inflamm 2016:8071539. https://doi.org/10.1155/2016/8071539
Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot JD, Booth CJ, Medzhitov R (2016) Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166(6):1512–1525. https://doi.org/10.1016/j.cell.2016.07.026
van Ginhoven TM, Mitchell JR, Verweij M, Hoeijmakers JH, Ijzermans JN, de Bruin RW (2009) The use of preoperative nutritional interventions to protect against hepatic ischemia-reperfusion injury. Liver Transpl 15:1183–1191. https://doi.org/10.1002/lt.21871
Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ, Vanhorebeek I, Debaveye Y, Vlasselaers D, Desmet L, Casaer MP, Garcia Guerra G, Hanot J, Joffe A, Tibboel D, Joosten K, Van den Berghe G (2016) Early versus late parenteral nutrition in critically ill children. N Engl J Med 374:1111–1122. https://doi.org/10.1056/NEJMoa1514762
Vanwijngaerden YM, Langouche L, Brunner R, Debaveye Y, Gielen M, Casaer M, Liddle C, Coulter S, Wouters PJ, Wilmer A, Van den Berghe G, Mesotten D (2014) Withholding parenteral nutrition during critical illness increases plasma bilirubin but lowers the incidence of biliary sludge. Hepatology 60:202–210. https://doi.org/10.1002/hep.26928
Jenniskens M, Güiza F, Haghedooren R, Verbruggen S, Joosten K, Langouche L, Van den Berghe G (2018) Prevalence and prognostic value of abnormal liver test results in critically ill children and the impact of delaying parenteral nutrition. Pediatr Crit Care Med 19:1120–1129. https://doi.org/10.1097/PCC.0000000000001734
Arabi YM, Casaer MP, Chapman M, Heyland DK, Ichai C, Marik PE, Martindale RG, McClave SA, Preiser JC, Reignier J, Rice TW, Van den Berghe G, van Zanten ARH, Weijs PJM (2017) The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med 43(9):1239–1256. https://doi.org/10.1007/s00134-017-4711-6
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Conflicts of interest
The authors have no conflict of interest to disclose.
Ethics approval
Institutional review board approval was obtained (ML4190).
Consent to participate
Written informed consent was acquired from all patients or their next of kin.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-021-06565-1