Biomarkers of Systemic Inflammation in Assessing the Efficacy of Extracorporeal Hemocorrection in the Treatment of Abdominal Sepsis

Introduction Biomarkers such as procalcitonin (PCT), C-reactive protein (CRP), presepsin (PSP), and interleukin-6 (IL-6) are closely associated with systemic inflammation. The results of their testing were analyzed to determine the benefits of early use of extracorporeal hemocorrection (ECHC) in the treatment of abdominal sepsis.

The Aim of the study was to analyze the results of simultaneous testing of PCT, CRP, PSP, and IL-6 biomarkers; to investigate the association between initial blood biomarker levels and disease outcome; to determine whether this relationship differed when using ECHC in the treatment of abdominal sepsis.

Hypothesis tested the early use of ECHC in the treatment of abdominal sepsis has a survival advantage.

Study design prospective cohor

Material and methods Method description. Blood samples were taken at two time points — on the first postoperative day and after 5 days of intensive care — to determine systemic inflammation biomarkers. We analyzed the association between initial blood biomarker levels and outcome, as well as their dynamics after 5 days of intensive care.

Sample characteristics. The study included 113 patients aged 23 to 90 years who underwent emergency laparotomy due to disseminated peritonitis and abdominal sepsis. The gender distribution was 67 men and 46 women. In 50 cases (group 1), ECHC was performed early; in 63 cases (group 2), ECHC was not used.

Results Baseline PCT and PSP levels were statistically significantly and strongly associated with disease outcome; the relationship was direct for a negative outcome and inverse for a positive one. For each unit (mcg/ml) of PCT, the chance of survival decreased by 0.016 times (OR=0.984; 95% CI 0.974–0.994) and by 25.7 times over the entire range of values (OR=0.0389; 95% CI 0.0049–0.3050). For each unit (pg/mL) of PSP, the odds of a favorable outcome decreased by 1.00046 times (OR=0.99954; 95% CI 0.99919–0.99988) and by 117.6 times across the entire range (OR=0.0085; 95% CI 0.0002–0.2982). AUC 0.762; 95% CI 0.670–0.855 and 0.776; 95% CI 0.682–0.870.

Early use of ECHC increased survival in patients with high baseline PCT and PSP levels. With standard sepsis therapy, the chances of survival were 1.040 times lower for each unit of PCT and 1.0006 times lower for each unit of PSP; 2387 times lower across the range of PCT values and 1.5 times lower across the range of PSP values compared to the use of ECHC in treatment.

The use of ECHC allowed the survival of patients with higher initial levels of PCT (Me 29.4 (11.0–71.4) ng/ml versus Me 4.9 (2.1–10.5) ng/ml, p=0.000001) and PSP (Me 891 (504; 1686) pg/ml versus 386 (200; 848), p=0.007) compared to patients in whose treatment ECHC was not used.

Unlike PCT, CRP, and IL-6, elevated PSP levels did not decrease with ECHC (p=0.38), while with standard sepsis therapy, the decrease was statistically significant (p<0.001). Conducting ECHC presumably contributes to maintaining elevated blood PSP levels.

The emergence of a highly statistically significant positive moderate correlation between IL-6 and PCT, PSP, CRP (p=0.001, p=0.00008, p=0.0003), as well as APACHE II and SOFA scores (p=0.000007 and p=0.000006) after treatment using ECG, and the absence of similar correlations in the standard therapy group at both testing points, may indicate a positive effect of ECHC in stabilizing intercellular relationships and synchronizing adaptive mechanisms.

Baseline CRP levels were not associated with outcome.

Conclusion Of the four biomarkers tested, procalcitonin best predicted the effectiveness of extracorporeal hemocorrection in the treatment of abdominal sepsis. The study revealed an unusual effect of extracorporeal hemocorrection on presepsin. A highly statistically significant positive association was observed between interleukin-6 and procalcitonin, presepsin, C-reactive protein, and APACHE II and SOFA scores after treatment with extracorporeal hemocorrection.

1. Triantafilou M, Triantafilou K. Sepsis: molecular mechanisms underlying lipopolysaccharide recognition. Expert Rev Mol Med. 2004;6(4):1,18. PMID: 14987416 https://doi.org/10.1017/S1462399404007409

2. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840–851. PMID: 23984731 https://doi.org/10.1056/NEJMra1208623

3. Moriyama К, Nishida О. Targeting Cytokines, Pathogen-Associated Molecular Patterns, and Damage-Associated Molecular Patterns in Sepsis via Blood Purification. Int J Mol Sci. 2021;22(16):8882. PMID: 34445610 https://doi.org/10.3390/ijms22168882

4. Ronko K, Pichchinni P, Rozner MG (eds.) Endotoksemiya i endotoksicheskiy shok. patogenez, diagnostika i lechenie. Moscow: Balabanov I.B. Publ.; 2012. (In Russ.)

5. Xiao Z, Wilson C, Robertson HL, Roberts DJ, Ball CG, Jenne CN, et al. Inflammatory mediators in intraabdominal sepsis or injury, a scoping review. Crit Care. 2015;27;19:373. PMID: 26502877 https://doi.org/10.1186/s13054,015,1093,4

6. Barichello T, Generoso JS, Singer M, Dal Pizzol F. Biomarkers for sepsis: more than just fever and leukocytosis – a narrative review. Crit Care. 2022;6;26(1):14. PMID: 34991675 https://doi.org/10.1186/s13054,021,03862,5

7. Cong S, Ma T, Di X, Tian C, Zhao M, Wang K. Diagnostic value of neutrophil CD64, procalcitonin, and interleukin,6 in sepsis: a meta-analysis. BMC Infect Dis. 2021;26;21(1):384. PMID: 33902476 https://doi.org/10.1186/s12879,021,06064,0

8. Pierrakos C, Velissaris D, Bisdorff M, Marshall JC, Vincent JL. Biomarkers of sepsis: time for a reappraisal. Crit Care. 2020;24(1):287. PMID: 32503670 https://doi.org/10.1186/s13054,020,02993,5

9. Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013;50(1):23,36. PMID: 23480440 https://doi.org/10.3109/10408363.2013.764490

10. Hung SK, Lan HM, Han ST, Wu CC, Chen KF. Current Evidence and Limitation of Biomarkers for Detecting Sepsis and Systemic Infection. Biomedicines. 2020;8(11):494. PMID: 33198109 https://doi.org/10.3390/biomedicines8110494

11. Reinhart K, Bauer M, Riedemann NC, Hartog CS. New Approaches to Sepsis: Molecular Diagnostics and Biomarkers. Clin Microbiol Rev. 2012;25(4):609–634. PMID: 23034322 https://doi.org/10.1128/CMR.00016,12

12. Tan M, Lu Y, Jiang H, Zhang L. The diagnostic accuracy of procalcitonin and C-reactive protein for sepsis: A systematic review and meta-analysis. J Cell Biochem. 2018;120(4):5852–5859. PMID: 30417415 https://doi.org/10.1002/jcb.27870

13. Velissaris D, Zareifopoulos N, Karamouzos V, Karanikolas E, Pierrakos C, Koniari I, et al. Presepsin as a Diagnostic and Prognostic Biomarker in Sepsis. Cureus. 2021;13(5):e15019. PMID: 34150378 https://doi.org/10.7759/cureus.15019

14. Piccioni A, Santoro MC, de Cunzo T, Tullo G, Cicchinelli S, Saviano A, et al. Presepsin as Early Marker of Sepsis in Emergency Department: A Narrative Review. Medicina (Kaunas). 2021;29;57(8):770. PMID: 34440976 https://doi.org/10.3390/medicina57080770

15. Galliera E, Massaccesi L, de Vecchi E, Banfi G, Romanelli MMC. Clinical application of presepsin as diagnostic biomarker of infection: overview and updates. Clin Chem Lab Med. 2019;58(1):11,17. PMID: 31421036 https://doi.org/10.1515/cclm,2019,0643

16. McElvaney OJ, Curley GF, Rose-John S, McElvaney NG. Interleukin-6: obstacles to targeting a complex cytokine in critical illness. Lancet Respir Med. 2021;9(6):643–654. PMID: 33872590 https://doi.org/10.1016/S2213,2600(21)00103,X

17. Franco DM, Arevalo-Rodriguez I, Roqué I Figuls M, Montero Oleas NG, Nuvials X, Zamora J. Plasma interleukin-6 concentration for the diagnosis of sepsis in critically ill adults. Cochrane Database Syst Rev. 2019;30;4(4):CD011811. PMID: 31038735 https://doi.org/10.1002/14651858.CD011811.pub2

18. Mierzchała-Pasierb M, Lipińska-Gediga M. Sepsis diagnosis and monitoring , procalcitonin as standard, but what next? Anaesthesiol Intensive Ther. 2019;51(4):299–305. PMID: 31550871 https://doi.org/10.5114/ait.2019.88104

19. Linder MM, Wacha H, Feldmann U, Wesch G, Streifensand RA, Gundlach E. The Mannheim peritonitis index. An instrument for the intraoperative prognosis of peritonitis]. Chirurg. 1987;58(2):84–92. PMID: 3568820

20. Charlson ME, Pompei P, Ales KL, McKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987;40(5):373–383. PMID: 3558716 https://doi.org/10.1016/0021,9681(87)90171,8

21. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis,3). JAMA. 2016;23;315(8):801–810. PMID: 26903338 https://doi.org/10.1001/jama.2016.0287

22. KDIGO. Clinical Practice Guideline for Acute Kidney Injury. Kidney international supplements. 2012;2(1). Available at: https://kdigo.org/wp,content/uploads/2016/10/KDIGO,2012,AKI,Guideline,English.pdf [Accessed September 28, 2022]

23. GOST R ISO 16269-7-2004 Statisticheskoe predstavlenie dannykh. Mediana. Opredelenie tochechnoy otsenki i doveritel’nykh intervalov. Data vvedeniya 2004-06-01. (In Russ.) Available at: https://docs.cntd.ru/document/1200035332?ysclid=l797j7r44i406293902 [Accessed Sep 28, 2022]

24. Vel’kov VV. Ispol’zovanie biomarkera “Presepsin” dlya ranney i vysokospetsifichnoy diagnostiki sepsisa. Klinicheskie rekomendatsii. Moscow, 2014. Available at: http://www.presepsintest.ru/upload/iblock/348/34881968fad4b85ab857a41431bde6db.pdf [Accessed Sep 28, 2022]

25. Lee S, Song J, Park DW, Seok H, Ahn S, Kim J, et al. Diagnostic and prognostic value of presepsin and procalcitonin in non-infectious organ failure, sepsis, and septic shock: a prospective observational study according to the Sepsis, 3 definitions. BMC Infect Dis. 2022;4;22(1):8. PMID: 34983420 https://doi.org/10.1186/s12879,021,07012,8

26. Memar MY, Baghi HB. Presepsin: A promising biomarker for the detection of bacterial infections. Biomed Pharmacother. 2019;111:649–656. PMID: 30611989 https://doi.org/10.1016/j.biopha.2018.12.124

27. Masson S, Caironi P, Fanizza C, Thomae R, Bernasconi R, Noto A, et al. Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial. Intensive Care Med. 2015;41(1):12–20. PMID: 25319385 https://doi.org/10.1007/s00134,014,3514,2

28. Kahveci U, Ozkan S, Melekoglu A, Usul E, Ozturk G, Cetin E, et al. The role of plasma presepsin levels in determining the incidence of septic shock and mortality in patients with sepsis. J Infect Dev Ctries. 2021;31;15(1):123–130. PMID: 33571154 https://doi.org/10.3855/jidc.12963

29. Okamura Y, Thomae R. Usefulness of Presepsin Measurement: A New Biomarker for Sepsis. Rinsho Byori. 2015;63(1):62–71. PMID: 26524880

30. Abramov AV, Zaytsev RR, Yakovlev AYu. Sposob kontrolya effektivnosti sorbtsii lipopolisakharida pri provedenii selektivnoy lipopolisakharidnoy gemosorbtsii. Patent RF RU 2627653 C1, 09.08.2017. Bull. 22, decl. 10.03.2016, publ. 09.08.2017 (In Russ.) Available at: https://patents.s3.yandex.net/RU2627653C1_20170809.pdf [Accessed Sep 28, 2022]

31. Yousif AS, Ronsard L, Shah P, Omatsu T, Sangesland M, Moreno TB, et al. The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells. Immunity. 2021;54(2):235–246. PMID: 33357409 https://doi.org/10.1016/j.immuni.2020.12.001

32. Rose-John S. IL-6 Trans-Signaling via the Soluble IL,6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6. Int J Biol Sci. 2012;8(9):1237–1247. PMID: 23136552 https://doi.org/10.7150/ijbs.4989

33. Uciechowski P, Dempke WCM. Interleukin,6: A Masterplayer in the Cytokine Network. Oncology. 2020;98(3):131,137. PMID: 31958792 https://doi.org/10.1159/000505099

34. Wilkinson AN, Gartlan KH, Kelly G, Samson LD, Olver SD, Avery J, et al. Granulocytes Are Unresponsive to IL-6 Due to an Absence of gp130. J Immunol. 2018;200(10):3547–3555. PMID: 29626088 https://doi.org/10.4049/jimmunol.1701191