An observational study on intracutaneous sodium storage in intensive care patients and controls

Autoři: Marjolein van IJzendoorn aff001;  Jacob van den Born aff002;  Ryanne Hijmans aff002;  Rianne Bodde aff002;  Hanneke Buter aff001;  Wendy Dam aff002;  Peter Kingma aff001;  Gwendolyn Maes aff001;  Tsjitske van der Veen aff001;  Wierd Zijlstra aff003;  Baukje Dijkstra aff003;  Gerjan Navis aff002;  Christiaan Boerma aff001
Působiště autorů: Intensive Care, Medical Centre Leeuwarden, Friesland, the Netherlands aff001;  Department of Internal Medicine–Nephrology, University Medical Centre Groningen, Groningen, the Netherlands aff002;  Department of Orthopaedic Surgery, Medical Centre Leeuwarden, Friesland, the Netherlands aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


The development of ICU-acquired sodium disturbances is not fully understood. Alterations in non-osmotic skin sodium storage, hypothetically inflammation-driven, could play a role. To investigate this in critically ill patients we conducted a patient-control study with skin punch biopsies in patients with sepsis (n = 15), after coronary artery bypass grafting (CABG, n = 15) and undergoing total hip arthroplasty (THA-controls, n = 15) respectively, together representing a range in severity of systemic inflammation. Biopsies were taken within 24 hours (sepsis) and within 2 hours (CABG) after ICU-admission, and prior to arthroplasty. Biopsies were analysed for sodium content. In addition immunostainings and quantitative real time PCR were performed. The primary aim of this study was to detect possible differences in amounts of cutaneous sodium. The secondary aims were to quantify inflammation and lymphangiogenesis with concomitant markers. The highest amounts of both water and sodium were found in patients with sepsis, with slightly lower values after CABG and the lowest amounts in THA-controls. Correlation between water and sodium was 0.5 (p<0.01). In skin biopsies in all groups comparable amounts of macrophages, T-cells and lymph vessels were found. In all groups comparable expression of inflammation markers were found. However, higher mRNA transcript expression levels of markers of lymphangiogenesis were found in patients with sepsis and after CABG. The conjoint accumulation of water and sodium points towards oedema formation. However, the correlation coefficient of 0.5 leaves room for alternative explanations, including non-osmotic sodium storage. No signs of dermal inflammation were found, but upregulation of markers of lymphangiogenesis could indicate future lymphangiogenesis.

Klíčová slova:

Biopsy – Inflammation – Inflammatory diseases – Macrophages – Sepsis – T cells – Coronary artery bypass grafting – Lymph


1. Padtberg J. Über die Bedeutung der Haut als Chlordepot. Archiv für experimentelle Pathologie und Pharmakologie. 1910;63(1):60–79.

2. Garnett ES, Ford J, Golding PL, Mardell RJ, Whyman AE. The mobilizaton of osmotically inactive sodium during total starvation in man. Clin Sci. 1968;35(1):93–103. 4878417

3. Wahlgren V. Über die Bedeutung der Gewebe als Chlordepots. Archiv für experimentelle Pathologie und Pharmakologie. 1909;61(2):97–112.

4. Titze J. Water-free sodium accumulation. Semin Dial. 2009;22(3):253–255. doi: 10.1111/j.1525-139X.2009.00569.x 19573004

5. Titze J, Lang R, Ilies C, Schwind KH, Kirsch KA, Dietsch P, et al. Osmotically inactive skin Na+ storage in rats. Am J Physiol Renal Physiol. 2003;285(6):F1108–1117. doi: 10.1152/ajprenal.00200.2003 12888617

6. Titze J, Maillet A, Lang R, Gunga HC, Johannes B, Gauquelin-Koch G, et al. Long-term sodium balance in humans in a terrestrial space station simulation study. Am J Kidney Dis. 2002;40(3):508–516. doi: 10.1053/ajkd.2002.34908 12200802

7. Kopp C, Linz P, Dahlmann A, Hammon M, Jantsch J, Müller DN, et al. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension. 2013;61(3):635–640. doi: 10.1161/HYPERTENSIONAHA.111.00566 23339169

8. Reitsma S, Slaaf DW, Vink H, van Zandvoort MAMJ, oude Egbrink MGA. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345–59. doi: 10.1007/s00424-007-0212-8 17256154

9. Mouta C, Heroult M. Inflammatory triggers of lymphangiogenesis. Lymphat Res Biol. 2003;1(3):201–218. 15624438

10. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–1655. doi: 10.1378/chest.101.6.1644 1303622

11. Celie JW, Rutjes NW, Keuning ED, Soininen R, Heljasvaara R, Pihlajaniemi T, et al. Subendothelial heparan sulfate proteoglycans become major L-selectin and monocyte chemoattractant protein-1 ligands upon renal ischemia/reperfusion. Am J Pathol. 2007;170(6):1865–1878. doi: 10.2353/ajpath.2007.070061 17525255

12. Hijmans RS, Shrestha P, Sarpong KA, Yazdani S, El Masri R, de Jong WHA, et al. High sodium diet converts renal proteoglycans into pro-inflammatory mediators in rats. PloS one. 2017;12(6):e0178940. Available from doi: 10.1371/journal.pone.0178940 28594849

13. Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care. 2013;28(2):216.e11–20.

14. Linz P, Santoro D, Renz W, Rieger J, Ruehle A, Ruff J, et al. Skin sodium measured with 23Na MRI at 7.0 T. NMR Biomed. 2015;28(1)54–62.

15. Hijmans RS, van Londen M, Sarpong KA, Bakker SJL, Navis GJ, Storteboom TTR, et al. Dermal tissue remodelling and non-osmotic sodium storage in kidney patients. J Transl Med. 2019;17:88. Available from 30885222

16. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third International consensus definitions for aepsis and aeptic ahock (Sepsis-3). JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287 26903338

17. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 1997;276(5317):1423–1425. doi: 10.1126/science.276.5317.1423 9162011

18. Kerjaschki D. The crucial role of macrophages in lymphangiogenesis. J Clin Invest. 2005;115(9):2316–2319. doi: 10.1172/JCI26354 16138185

19. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009;15(5):545–552. doi: 10.1038/nm.1960 19412173

20. Crescenzi R, Marton A, Donahue PM, Mahany HB, Lants SK, Wang P, et al. Tissue aodium xontent is elevated in the skin and subcutaneous adipose tissue in women with lipedema. obesity. Silver Spring. 2018;26(2):310–317.

21. Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M, Schwind KH, et al. Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol. 2004;287(1):H203–208. doi: 10.1152/ajpheart.01237.2003 14975935

22. Titze J, Krause H, Hecht H, Dietsch P, Rittweger J, Lang R, et al. Reduced osmotically inactive Na storage capacity and hypertension in the Dahl model. Am J Physiol Renal Physiol. 2002;283(1):F134–141. doi: 10.1152/ajprenal.00323.2001 12060595

23. Titze J, Bauer K, Schafflhuber M, Dietsch P, Lang R, Schwind KH, et al. Internal sodium balance in DOCA-salt rats: a body composition study. Am J Physiol Renal Physiol. 2005;289(4):F793–802. doi: 10.1152/ajprenal.00096.2005 15914779

24. Schafflhuber M, Volpi N, Dahlmann A, Hilgers KF, Maccari F, Dietsch P, et al. Mobilization of osmotically inactive Na+ by growth and by dietary salt restriction in rats. Am J Physiol Renal Physiol. 2007;292(5):F1490–1500. doi: 10.1152/ajprenal.00300.2006 17244896

25. Day J, Taylor K. The systemic inflammatory response syndrome and cardiopulmonary bypass. International Journal of Surgery. 2005;3(2):129–140. doi: 10.1016/j.ijsu.2005.04.002 17462274

26. Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol. 1995;57:827–872. doi: 10.1146/ 7778885

27. Carr MW, Roth SJ, Luther E, Rose SS, Springer TA. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994;91:3652–3656. doi: 10.1073/pnas.91.9.3652 8170963

28. Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, et al. Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest. 2008;118(11):3725–3737. doi: 10.1172/JCI36077 18924607

29. van IJzendoorn MCO, Buter H, Kingma WP, Navis GJ, Boerma EC. The development of intensive care unit acquired hypernatremia is not explained by sodium overload or water deficit: a retrospective cohort study on water balance and sodium handling. Critical care research and practice. 2016;2016:9571583. Available from doi: 10.1155/2016/9571583 27703807

30. Bihari S, Peake SL, Seppelt I, Williams P, Bersten A, George Institute for Global Health, et al. Sodium administration in critically ill patients in Australia and New Zealand: a multicentre point prevalence study. Crit Care Resusc. 2013;15(4):294–300. 24289511

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden