Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study

Willem Pieter Brouwer, Servet Duran, Martijn Kuijper, Can Ince, Willem Pieter Brouwer, Servet Duran, Martijn Kuijper, Can Ince

Abstract

Background and aims: Innovative treatment modalities have not yet shown a clinical benefit in patients with septic shock. To reduce severe cytokinaemia, CytoSorb as an add-on to continuous renal replacement therapy (CRRT) showed promising results in case reports. However, there are no clinical trials investigating outcomes.

Methods: In this investigator-initiated retrospective study, patients with septic shock were treated with CRRT + CytoSorb (n = 67) or CRRT alone (n = 49). The primary outcome was the 28-day all-cause mortality rate. Patients were weighted by stabilized inverse probability of treatment weights (sIPTW) to overcome differences in baseline characteristics.

Results: At the start of therapy, CytoSorb-treated patients had higher lactate levels (p < 0.001), lower mean arterial pressure (p = 0.007) and higher levels of noradrenaline (p < 0.001) compared to the CRRT group. For CytoSorb, the mean predicted mortality rate based on a SOFA of 13.8 (n = 67) was 75% (95%CI 71-79%), while the actual 28-day mortality rate was 48% (mean difference - 27%, 95%CI - 38 to - 15%, p < 0.001). For CRRT, based on a SOFA of 12.8 (n = 49), the mean predicted versus observed mortality was 68% versus 51% (mean difference - 16.9% [95%CI - 32.6 to - 1.2%, p = 0.035]). By sIPTW analysis, patients treated with CytoSorb had a significantly lower 28-day mortality rate compared to CRRT alone (53% vs. 72%, respectively, p = 0.038). Independent predictors of 28-day mortality in the CytoSorb group were the presence of pneumosepsis (adjusted odds ratio [aOR] 5.47, p = 0.029), higher levels of lactate at the start of CytoSorb (aOR 1.15, p = 0.031) and older age (aOR per 10 years 1.67, p = 0.034).

Conclusions: CytoSorb was associated with a decreased observed versus expected 28-day all-cause mortality. By IPTW analysis, intervention with CytoSorb may be associated with a decreased all-cause mortality at 28 days compared to CRRT alone.

Keywords: Cytosorb; Cytosorbent; Hemofiltration; Mortality; Outcome; Sepsis; Septic shock; Treatment.

Conflict of interest statement

WPB, MK and SD declare that they have no competing interests. CI has received a grant from CytoSorb to commence a randomized controlled trial on the effect of the adsorber on the microcirculation of critically ill patients at the department of Intensive Care of the Erasmus Medical Center Rotterdam.

Figures

Fig. 1
Fig. 1
Patient and analysis flowchart
Fig. 2
Fig. 2
a Observed versus predicted mortality rate according to the SOFA score for CytoSorb- and CRRT-treated patients. b CytoSorb is associated with a reduced 28-day mortality in sIPTW analysis

References

    1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–2128. doi: 10.1016/S0140-6736(12)61728-0.
    1. Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I, Lipman J, Reinhart K, Antonelli M, Pickkers P, Njimi H, et al. Assessment of the worldwide burden of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med. 2014;2(5):380–386. doi: 10.1016/S2213-2600(14)70061-X.
    1. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259–272. doi: 10.1164/rccm.201504-0781OC.
    1. Levy MM, Artigas A, Phillips GS, Rhodes A, Beale R, Osborn T, Vincent JL, Townsend S, Lemeshow S, Dellinger RP. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012;12(12):919–924. doi: 10.1016/S1473-3099(12)70239-6.
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287.
    1. Bellomo R, Tipping P, Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med. 1993;21(4):522–526. doi: 10.1097/00003246-199304000-00011.
    1. Rimmele T, Kellum JA. Clinical review: blood purification for sepsis. Crit Care. 2011;15(1):205. doi: 10.1186/cc9411.
    1. Hoffmann JN, Faist E. Removal of mediators by continuous hemofiltration in septic patients. World J Surg. 2001;25(5):651–659. doi: 10.1007/s002680020027.
    1. Houschyar KS, Pyles MN, Rein S, Nietzschmann I, Duscher D, Maan ZN, Weissenberg K, Philipps HM, Strauss C, Reichelt B, et al. Continuous hemoadsorption with a cytokine adsorber during sepsis - a review of the literature. Int J Artif Organs. 2017;40(5):205–211. doi: 10.5301/ijao.5000591.
    1. Gruda MC, Ruggeberg KG, O'Sullivan P, Guliashvili T, Scheirer AR, Golobish TD, Capponi VJ, Chan PP. Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb(R) sorbent porous polymer beads. PLoS One. 2018;13(1):e0191676. doi: 10.1371/journal.pone.0191676.
    1. Schadler D, Pausch C, Heise D, Meier-Hellmann A, Brederlau J, Weiler N, Marx G, Putensen C, Spies C, Jorres A, et al. The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial. PLoS One. 2017;12(10):e0187015. doi: 10.1371/journal.pone.0187015.
    1. Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp. 2018;6(1):12. doi: 10.1186/s40635-018-0177-2.
    1. Peng ZY, Carter MJ, Kellum JA. Effects of hemoadsorption on cytokine removal and short-term survival in septic rats. Crit Care Med. 2008;36(5):1573–1577. doi: 10.1097/CCM.0b013e318170b9a7.
    1. Linden K, Scaravilli V, Kreyer SF, Belenkiy SM, Stewart IJ, Chung KK, Cancio LC, Batchinsky AI. Evaluation of the Cytosorb hemoadsorptive column in a pig model of severe smoke and burn injury. Shock (Augusta, Ga) 2015;44(5):487–495. doi: 10.1097/SHK.0000000000000439.
    1. Basu R, Pathak S, Goyal J, Chaudhry R, Goel RB, Barwal A. Use of a novel hemoadsorption device for cytokine removal as adjuvant therapy in a patient with septic shock with multi-organ dysfunction: a case study. Indian J Critical Care Med. 2014;18(12):822–824. doi: 10.4103/0972-5229.146321.
    1. Hetz H, Berger R, Recknagel P, Steltzer H. Septic shock secondary to beta-hemolytic streptococcus-induced necrotizing fasciitis treated with a novel cytokine adsorption therapy. Int J Artif Organs. 2014;37(5):422–426. doi: 10.5301/ijao.5000315.
    1. Bruenger F, Kizner L, Weile J, Morshuis M, Gummert JF. First successful combination of ECMO with cytokine removal therapy in cardiogenic septic shock: a case report. Int J Artif Organs. 2015;38(2):113–116. doi: 10.5301/ijao.5000382.
    1. Hinz B, Jauch O, Noky T, Friesecke S, Abel P, Kaiser R. CytoSorb, a novel therapeutic approach for patients with septic shock: a case report. Int J Artif Organs. 2015;38(8):461–464. doi: 10.5301/ijao.5000429.
    1. Friesecke S, Trager K, Schittek GA, Molnar Z, Bach F, Kogelmann K, Bogdanski R, Weyland A, Nierhaus A, Nestler F, et al. International registry on the use of the CytoSorb(R) adsorber in ICU patients: study protocol and preliminary results. Med Klin Intensivmed Notfmed. 2017. 10.1007/s00063-017-0342-5.
    1. Friesecke S, Stecher SS, Gross S, Felix SB, Nierhaus A. Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: a prospective single-center study. J Artif Organs. 2017;20(3):252–259. doi: 10.1007/s10047-017-0967-4.
    1. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286(14):1754–1758. doi: 10.1001/jama.286.14.1754.
    1. de Grooth HJ, Geenen IL, Girbes AR, Vincent JL, Parienti JJ, Oudemans-van Straaten HM. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care. 2017;21(1):38. doi: 10.1186/s13054-017-1609-1.
    1. Harder VS, Stuart EA, Anthony JC. Propensity score techniques and the assessment of measured covariate balance to test causal associations in psychological research. Psychol Methods. 2010;15(3):234–249. doi: 10.1037/a0019623.
    1. Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550–560. doi: 10.1097/00001648-200009000-00011.
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–710. doi: 10.1007/BF01709751.
    1. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344–353. doi: 10.1097/01.CCM.0000194725.48928.3A.
    1. Silva JM, Jr, de Oliveira AM, Nogueira FA, Vianna PM, Pereira Filho MC, Dias LF, Maia VP, Neucamp Cde S, Amendola CP, Carmona MJ, et al. The effect of excess fluid balance on the mortality rate of surgical patients: a multicenter prospective study. Crit Care. 2013;17(6):R288. doi: 10.1186/cc13151.
    1. Smith SH, Perner A. Higher vs. lower fluid volume for septic shock: clinical characteristics and outcome in unselected patients in a prospective, multicenter cohort. Crit Care. 2012;16(3):R76. doi: 10.1186/cc11333.
    1. Lee SJ, Ramar K, Park JG, Gajic O, Li G, Kashyap R. Increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: a retrospective cohort study. Chest. 2014;146(4):908–915. doi: 10.1378/chest.13-2702.
    1. Pro CI, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683–1693. doi: 10.1056/NEJMoa1401602.
    1. Investigators A, Group ACT. Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496–1506. doi: 10.1056/NEJMoa1404380.
    1. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–1311. doi: 10.1056/NEJMoa1500896.
    1. Burger Raphaël, Guidi Monia, Calpini Valérie, Lamoth Frédéric, Decosterd Laurent, Robatel Corinne, Buclin Thierry, Csajka Chantal, Marchetti Oscar. Effect of renal clearance and continuous renal replacement therapy on appropriateness of recommended meropenem dosing regimens in critically ill patients with susceptible life-threatening infections. Journal of Antimicrobial Chemotherapy. 2018;73(12):3413–3422. doi: 10.1093/jac/dky370.
    1. Hawchar F, Laszlo I, Oveges N, Trasy D, Ondrik Z, Molnar Z. Extracorporeal cytokine adsorption in septic shock: a proof of concept randomized, controlled pilot study. J Crit Care. 2019;49:172–178. doi: 10.1016/j.jcrc.2018.11.003.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다