Impact of combined low dose norepinephrine and simvastatin on sepsis induced acute Kidney injury in critically ill patients

ABSTRACT

Background: The role of statins in sepsis patients with acute kidney injury (AKI) is still unclear. This study was done to evaluate the effects of oral Simvastatin and low dose intravenous norepinephrine as an adjunctive therapy in early acute kidney injury associated with sepsis.

Methods:  we enrolled 60 patients with severe sepsis had early diagnosed acute kidney injury with high plasma NGAL* test.  They were randomly assigned to 2 groups; Group A (n =30) received oral Simvastatin 80 mg/day and low dose intravenous norepinephrine (2 to 4 μg /min) plus conventional sepsis treatment., Group B (n =30) received only conventional sepsis treatment. Then both were followed by: CRP*, PCT*, SOFA score* monitoring, RIFLE criteria* and Need for organ supportive measures, Length of ICU stay and 28-day Mortality.

Results: Group A showed no any statistically significant differences except a significant reduction in Mean SOFA score on day 2 and 3 only (p value = 0.012 and 0.013 respectively) and in need for vasopressor (p value = 0.004).

Conclusions: Simvastatin and low dose norepinephrine did not show any improvement in patients with sepsis associated AKI.

Abb. NGAL: Neutrophil gelatinase-associated lipocalin, CRP:C-reactive protein, PCT: Procalcitonin, SOFA score: Sequential organ failure assessment score, RIFLE criteria: Risk, Injury, and Failure, Loss and End-stage renal disease.

Keywords: Critical; Sepsis; AKI; Norepinephrine; simvastatin

REFERENCES

1. 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;315(8):801-10.
2. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama. 2016;315(8):762-74.
3. Seymour CW, Coopersmith CM, Deutschman CS, Gesten F, Klompas M, Levy M, et al. Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria. Critical care medicine. 2016;44(3):e122-30.
4. Bone RC, Sprung CL, Sibbald WJ. Definitions for sepsis and organ failure. Critical care medicine. 1992;20(6):724-6.
5. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive care medicine. 2003;29(4):530-8.
6. Lafrance J-P, Miller DR. Acute Kidney Injury Associates with Increased Long-Term Mortality. Journal of the American Society of Nephrology : JASN. 2010;21(2):345-52.
7. Ishani A, Xue JL, Himmelfarb J, Eggers PW, Kimmel PL, Molitoris BA, et al. Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol. 2009;20(1):223-8.
8. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. Jama. 2005;294(7):813-8.
9. Wan L, Bagshaw SM, Langenberg C, Saotome T, May C, Bellomo R. Pathophysiology of septic acute kidney injury: what do we really know? Critical care medicine. 2008;36(4 Suppl):S198-203.
10. Bu DX, Hemdahl AL, Gabrielsen A, Fuxe J, Zhu C, Eriksson P, et al. Induction of neutrophil gelatinase-associated lipocalin in vascular injury via activation of nuclear factor-kappaB. The American journal of pathology. 2006;169(6):2245-53.
11. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003;14(10):2534-43.
12. Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. American journal of physiology Renal physiology. 2004;286(3):F552-63.
13. Shrestha K, Borowski AG, Troughton RW, Thomas JD, Klein AL, Tang WHW. Renal Dysfunction is a Stronger Determinant of Systemic Neutrophil Gelatinase-Associated Lipocalin Levels Than Myocardial Dysfunction in Systolic Heart Failure. Journal of cardiac failure. 2011;17(6):472-8.
14. Zwiers AJM, de Wildt SN, van Rosmalen J, de Rijke YB, Buijs EAB, Tibboel D, et al. Urinary neutrophil gelatinase-associated lipocalin identifies critically ill young children with acute kidney injury following intensive care admission: a prospective cohort study. Critical Care. 2015;19(1):181.
15. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical care (London, England). 2004;8(4):R204-12.
16. Anderson WP, Korner PI, Selig SE. Mechanisms involved in the renal responses to intravenous and renal artery infusions of noradrenaline in conscious dogs. The Journal of Physiology. 1981;321:21-30.
17. Martin C, Saux P, Eon B, Aknin P, Gouin F. Septic shock: a goal-directed therapy using volume loading, dobutamine and/or norepinephrine. Acta anaesthesiologica Scandinavica. 1990;34(5):413-7.
18. Martin C, Viviand X, Leone M, Thirion X. Effect of norepinephrine on the outcome of septic shock. Critical care medicine. 2000;28(8):2758-65.
19. Deruddre S, Cheisson G, Mazoit JX, Vicaut E, Benhamou D, Duranteau J. Renal arterial resistance in septic shock: effects of increasing mean arterial pressure with norepinephrine on the renal resistive index assessed with Doppler ultrasonography. Intensive care medicine. 2007;33(9):1557-62.
20. Khanal S, Attallah N, Smith DE, Kline-Rogers E, Share D, O'Donnell MJ, et al. Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions. The American journal of medicine. 2005;118(8):843-9.
21. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nature reviews Immunology. 2006;6(5):358-70.
22. Niessner A, Steiner S, Speidl WS, Pleiner J, Seidinger D, Maurer G, et al. Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis. 2006;189(2):408-13.
23. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. Jama. 1995;273(2):117-23.
24. Moran SM, Myers BD. Course of acute renal failure studied by a model of creatinine kinetics. Kidney international. 1985;27(6):928-37.
25. Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004;110(7):880-5.
26. Merx MW, Liehn EA, Janssens U, Lutticken R, Schrader J, Hanrath P, et al. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation. 2004;109(21):2560-5.
27. Yasuda H, Yuen PS, Hu X, Zhou H, Star RA. Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. Kidney international. 2006;69(9):1535-42.
28. Mason JC. The statins--therapeutic diversity in renal disease? Current opinion in nephrology and hypertension. 2005;14(1):17-24.
29. Yokota N, O'Donnell M, Daniels F, Burne-Taney M, Keane W, Kasiske B, et al. Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia-reperfusion injury. American journal of nephrology. 2003;23(1):13-7.
30. Simon L, Saint-Louis P, Amre DK, Lacroix J, Gauvin F. Procalcitonin and C-reactive protein as markers of bacterial infection in critically ill children at onset of systemic inflammatory response syndrome. Pediatr Crit Care Med. 2008;9:407–13.
31. Sateesh Pujari, & Estari Mamidala. (2015). Anti-diabetic activity of Physagulin-F isolated from Physalis angulata fruits. The American Journal of Science and Medical Research, 1(2), 53–60. https://doi.org/10.5281/zenodo.7352308
32. Li JJ, Chen MZ, Chen X, Fang CH. Rapid effects of simvastatin on lipid profile and C-reactive protein in patients with hypercholesterolemia. Clinical cardiology. 2003;26(10):472-6.
33. Arnaud C, Burger F, Steffens S, Veillard NR, Nguyen TH, Trono D, et al. Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins. Arteriosclerosis, thrombosis, and vascular biology. 2005;25(6):1231-6.
34. Mihai Mărginean M1 a, Sebastian Trancă2, a, *, Alina Ardelean-Maghiar (Mărginean)3, a, Dan Dîrzu2, Adina Huțanu4, Oana Platon (Antal)2, Dan Dobreanu1. Comparing the anti-inammatory effects of Simvastatin and Rosuvastatin by measuring IL-1β, IL-6 and TNF-α levels using a murinic caecal ligation and puncture induced sepsis model. Revista Română de Medicină de Laborator. 2014;22(4):439-50.
35. Novack V, Eisinger M, Frenkel A, Terblanche M, Adhikari NK, Douvdevani A, et al. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive care medicine. 2009;35(7):1255-60.
36. Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, et al. Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 2005;112(1):117-24.
37. Kruger P, Bailey M, Bellomo R, Cooper DJ, Harward M, Higgins A, et al. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. American journal of respiratory and critical care medicine. 2013;187(7):743-50.
38. Kruger P, Fitzsimmons K, Cook D, Jones M, Nimmo G. Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive care medicine. 2006;32(1):75-9.
39. Eichstadt HW, Eskotter H, Hoffman I, Amthauer HW, Weidinger G. Improvement of myocardial perfusion by short-term fluvastatin therapy in coronary artery disease. The American journal of cardiology. 1995;76(2):122a-5a.
40. Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2001;33(8):1352-7.