Clinical trial NCT04742764: Extracorporal Cytokin Removal in Septic Shock: a Prospective, Randomized, Multicenter Clinical Trial
Official title: Dosing of Extracorporeal Cytokine Removal In Septic Shock (DECRISS): a Prospective, Randomized, Multicenter Clinical Trial
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE3
Conditions: Septic Shock
Keywords: sepsis, septic shock, cytosorb, cytokine removal
Lead sponsor: University of Pecs
Sponsor class: OTHER
First posted: 2021-02-08
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, controlled, three-arm, open-label, international, multi-centre, phase III study
Primary purpose: TREATMENT

Brief summary: Sepsis and septic shock have mortality rates between 20-50%. When standard therapeutic measures fail to improve patients' condition, additional therapeutic alternatives are applied to reduce morbidity and mortality. One of the most recent alternatives is extracorporeal cytokine hemoadsorption. One of the most tested devices is CytoSorb, however, there are a lot of open questions, such timing, dosing and of course its overall efficacy. This study aims to compare the efficacy of standard medical therapy (Group A, SMT) and continuous extracorporeal cytokine removal with CytoSorb therapy in patients with early refractory septic shock. Furthermore, we compare the dosing of CytoSorb adsorber device - as the cartridge will be changed in every (12 Group B) or 24 hours (Group C).


Eligibility criteria: Inclusion Criteria:

* Septic shock as defined by the Sepsis-3 criteria
* Septic shock both medical or surgical ethiology (except for re-operation)
* APACHE \> 25
* Mechanical ventilation
* Norepinephrine requirement ≥0.4 µg/kg/min for at least 30 minutes, when hypovolemia is highly unlikely as indicated by invasive hemodynamic measurements assessed by the attending physician
* Invasive hemodynamic monitoring to determine cardiac output and derived variables
* Procalcitonin level ≥ 10 ng/ml
* Inclusion within 6 - 24 hours after the onset of vasopressor need and after all standard therapeutic measures have been implemented without clinical improvement (i.e.: the shock is considered refractory)

Exclusion Criteria:

* Patients under 18 years and over 80
* Lack of health insurance
* Pregnancy
* Standard guideline-based medical treatment not exhausted (detailed below at 3.6) standard medical therapy)
* End stage organ failure
* New York Heart Association Class IV.
* Chronic renal failure with eGFR \< 15 ml/min/1,73 m2
* End-stage liver disease (MELD score \>30, Child-Pugh score Class C
* Unlikely survival for 24 hours according to the attending physician
* Acute onset of hemato-oncological illness
* Post cardiopulmonary resuscitation care
* Re-operation in context with the septic insult
* Immunosuppression
* systemic steroid therapy (\>10 mg prednisolon/day)
* immunosuppressive agents (i.e.: methotrexate, azathioprine, cyclosporin, tacrolimus, cyclophosphamide)
* Human immunodeficiency virus infection (active AIDS): HIV-VL \> 50 copies/mL
* Patients with transplanted vital organs
* Thrombocytopenia (\<20.000/ml)
* More than 10%-of body surface area with a third-degree burn
* Acute coronary syndrome

Primary outcomes:
measure: Shock reversal
timeFrame: At the time of shock reversal assessed up to 5 days
measure: Time to shock reversal
timeFrame: From the start of the treatment until shock reversal assessed up to 5 days
Secondary outcomes:
measure: Procalcitonine level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in procalcitonine level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Interleukin-6 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in interleukin-6 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: C-reactive protein level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in C-reactive protein level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Interleukin-1 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in interleukin-1 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Interleukin-1ra level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in interleukin-1ra level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Interleukin-8 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in interleukin-8 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Interleukin-10 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in interleukin-10 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Tumor necrosis factor alpha level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in tumor necrosis factor alpha level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Syndecan-1 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in syndecan-1 level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Heparan sulphate level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in heparan sulphate level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Arterial lactate levels
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in arterial lactate levels level
timeFrame: 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit
measure: Change in SOFA score
timeFrame: From the start of the treatment until the end of the treatment assessed up to 5 days
measure: Change in extravascular lung water (EVLW)
timeFrame: From the start of the treatment until the end of the treatment assessed up to 5 days
measure: Duration of mechanical ventilation
timeFrame: From the start of the treatment until the end of the treatment assessed up to 5 days
measure: Duration of catecholamine requirement
timeFrame: From the start of the catecholamine requirement until the end of the catecholamine requirement assessed up to 5 days
measure: Duration of renal replacement therapy
timeFrame: From the start of the renal replacement therapy requirement until the end of the renal replacement therapy requirement assessed up to 90+/-7 days at the second follow-up visit
measure: Need for dialysis
timeFrame: day 28±7, day 90±7
measure: Length of internsive care unit stay
timeFrame: From admission to intensive care unit until the end of intensive care unit assessed at study completion an avarage of 90 days
measure: Length of hospital stay
timeFrame: From admission to the hospital until the end of hospital stay assessed at study completion an avarage of 90 days
measure: Survival
timeFrame: Rate if surviving patients assessed at death, or study completion which ever happens first, up to 90 +/-7 days
measure: Adverse events
timeFrame: Recorded at the occurrance of adverse events, and study completion up to 90 +/- 7 days
Other outcomes:
Locations:
city: Pécs
country: Hungary
facility: Institute for Translational Medicine, University of Pécs
Study officials:
affiliation: Insitute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
name: Péter Hegyi, MD, PhD, DSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sogayar AM, Machado FR, Rea-Neto A, Dornas A, Grion CM, Lobo SM, Tura BR, Silva CL, Cal RG, Beer I, Michels V, Safi J, Kayath M, Silva E; Costs Study Group - Latin American Sepsis Institute. A multicentre, prospective study to evaluate costs of septic patients in Brazilian intensive care units. Pharmacoeconomics. 2008;26(5):425-34. doi: 10.2165/00019053-200826050-00006.
citation: Adrie C, Alberti C, Chaix-Couturier C, Azoulay E, De Lassence A, Cohen Y, Meshaka P, Cheval C, Thuong M, Troche G, Garrouste-Orgeas M, Timsit JF. Epidemiology and economic evaluation of severe sepsis in France: age, severity, infection site, and place of acquisition (community, hospital, or intensive care unit) as determinants of workload and cost. J Crit Care. 2005 Mar;20(1):46-58. doi: 10.1016/j.jcrc.2004.10.005.
citation: Khwannimit B, Bhurayanontachai R. The direct costs of intensive care management and risk factors for financial burden of patients with severe sepsis and septic shock. J Crit Care. 2015 Oct;30(5):929-34. doi: 10.1016/j.jcrc.2015.05.011. Epub 2015 May 20.
citation: Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine C, Remick DG. Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev. 2013 Jul;93(3):1247-88. doi: 10.1152/physrev.00037.2012.
citation: Kwan A, Hubank M, Rashid A, Klein N, Peters MJ. Transcriptional instability during evolving sepsis may limit biomarker based risk stratification. PLoS One. 2013;8(3):e60501. doi: 10.1371/journal.pone.0060501. Epub 2013 Mar 27.
citation: Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006 Feb 24;124(4):783-801. doi: 10.1016/j.cell.2006.02.015.
citation: Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013 Dec;13(12):862-74. doi: 10.1038/nri3552. Epub 2013 Nov 15.
citation: Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets--an updated view. Mediators Inflamm. 2013;2013:165974. doi: 10.1155/2013/165974. Epub 2013 Jun 18.
citation: Venet F, Lukaszewicz AC, Payen D, Hotchkiss R, Monneret G. Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol. 2013 Aug;25(4):477-83. doi: 10.1016/j.coi.2013.05.006. Epub 2013 May 28.
citation: Sharawy N. Vasoplegia in septic shock: do we really fight the right enemy? J Crit Care. 2014 Feb;29(1):83-7. doi: 10.1016/j.jcrc.2013.08.021. Epub 2013 Oct 4.
citation: Laszlo I, Trasy D, Molnar Z, Fazakas J. Sepsis: From Pathophysiology to Individualized Patient Care. J Immunol Res. 2015;2015:510436. doi: 10.1155/2015/510436. Epub 2015 Jul 15.
citation: Bellomo R, Baldwin I, Ronco C. Extracorporeal blood purification therapy for sepsis and systemic inflammation: its biological rationale. Contrib Nephrol. 2001;(132):367-74. doi: 10.1159/000060105.
citation: Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, Malcangi V, Petrini F, Volta G, Bobbio Pallavicini FM, Rottoli F, Giunta F, Ronco C. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009 Jun 17;301(23):2445-52. doi: 10.1001/jama.2009.856.
citation: Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007 Dec;35(12):2677-85.
citation: 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 Crit Care Med. 2014 Dec;18(12):822-4. doi: 10.4103/0972-5229.146321.
citation: Bedina, E., et al., Hemoadsorption by cytosorb® in septic shock with acute kidney injury: A case series. Blood Purification, 2018. 46(3): p. 183-184.
citation: Bracht, H., et al., Pattern of cytokine removal using an adsorption column CytoSorb® during severe Candia albicans induced septic shock. Infection, Supplement, 2013. 41(1): p. S64-S65.
citation: Kellum JA, Venkataraman R, Powner D, Elder M, Hergenroeder G, Carter M. Feasibility study of cytokine removal by hemoadsorption in brain-dead humans. Crit Care Med. 2008 Jan;36(1):268-72. doi: 10.1097/01.CCM.0000291646.34815.BB.
citation: Namas RA, Namas R, Lagoa C, Barclay D, Mi Q, Zamora R, Peng Z, Wen X, Fedorchak MV, Valenti IE, Federspiel WJ, Kellum JA, Vodovotz Y. Hemoadsorption reprograms inflammation in experimental gram-negative septic peritonitis: insights from in vivo and in silico studies. Mol Med. 2012 Dec 20;18(1):1366-74. doi: 10.2119/molmed.2012.00106.
citation: Peng ZY, Carter MJ, Kellum JA. Effects of hemoadsorption on cytokine removal and short-term survival in septic rats. Crit Care Med. 2008 May;36(5):1573-7. doi: 10.1097/CCM.0b013e318170b9a7.
citation: Peng ZY, Wang HZ, Carter MJ, Dileo MV, Bishop JV, Zhou FH, Wen XY, Rimmele T, Singbartl K, Federspiel WJ, Clermont G, Kellum JA. Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis. Kidney Int. 2012 Feb;81(4):363-9. doi: 10.1038/ki.2011.320. Epub 2011 Sep 14.
citation: Friesecke S, Trager K, Schittek GA, Molnar Z, Bach F, Kogelmann K, Bogdanski R, Weyland A, Nierhaus A, Nestler F, Olboeter D, Tomescu D, Jacob D, Haake H, Grigoryev E, Nitsch M, Baumann A, Quintel M, Schott M, Kielstein JT, Meier-Hellmann A, Born F, Schumacher U, Singer M, Kellum J, Brunkhorst FM. International registry on the use of the CytoSorb(R) adsorber in ICU patients : Study protocol and preliminary results. Med Klin Intensivmed Notfmed. 2019 Nov;114(8):699-707. doi: 10.1007/s00063-017-0342-5. Epub 2017 Sep 4.
citation: 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 Sep;20(3):252-259. doi: 10.1007/s10047-017-0967-4. Epub 2017 Jun 6.
citation: Kogelmann K, Jarczak D, Scheller M, Druner M. Hemoadsorption by CytoSorb in septic patients: a case series. Crit Care. 2017 Mar 27;21(1):74. doi: 10.1186/s13054-017-1662-9.
citation: 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 Feb;49:172-178. doi: 10.1016/j.jcrc.2018.11.003. Epub 2018 Nov 10.
citation: Brouwer WP, Duran S, Kuijper M, Ince C. 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. Crit Care. 2019 Sep 18;23(1):317. doi: 10.1186/s13054-019-2588-1.
citation: Öveges N, L.s.I., Forgács M, et al, Procalcitonin elimination during cytokine adsorption therapy in septic shock: a spin-off study of the ACESS trial. Crit Care, 2017. 21:383.
citation: Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
citation: Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985 Oct;13(10):818-29.
citation: Amendola A, Sberna G, Forbici F, Abbate I, Lorenzini P, Pinnetti C, Antinori A, Capobianchi MR. The dual-target approach in viral HIV-1 viremia testing: An added value to virological monitoring? PLoS One. 2020 Feb 5;15(2):e0228192. doi: 10.1371/journal.pone.0228192. eCollection 2020.
citation: Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.
citation: Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.
citation: Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, Hrobjartsson A, Mann H, Dickersin K, Berlin JA, Dore CJ, Parulekar WR, Summerskill WS, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013 Feb 5;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583.
citation: Kogelmann K, Scheller M, Druner M, Jarczak D. Use of hemoadsorption in sepsis-associated ECMO-dependent severe ARDS: A case series. J Intensive Care Soc. 2020 May;21(2):183-190. doi: 10.1177/1751143718818992. Epub 2019 Jan 8.
citation: Wani SJ, Mufti SA, Jan RA, Shah SU, Qadri SM, Khan UH, Bagdadi F, Mehfooz N, Koul PA. Combination of vitamin C, thiamine and hydrocortisone added to standard treatment in the management of sepsis: results from an open label randomised controlled clinical trial and a review of the literature. Infect Dis (Lond). 2020 Apr;52(4):271-278. doi: 10.1080/23744235.2020.1718200. Epub 2020 Jan 28.
citation: ARISE Investigators; ANZICS Clinical Trials Group; Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1.
citation: ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.
citation: Peake SL, Bailey M, Bellomo R, Cameron PA, Cross A, Delaney A, Finfer S, Higgins A, Jones DA, Myburgh JA, Syres GA, Webb SA, Williams P; ARISE Investigators, for the Australian and New Zealand Intensive Care Society Clinical Trials Group. Australasian resuscitation of sepsis evaluation (ARISE): A multi-centre, prospective, inception cohort study. Resuscitation. 2009 Jul;80(7):811-8. doi: 10.1016/j.resuscitation.2009.03.008. Epub 2009 May 20.
citation: Girbes ARJ, de Grooth HJ. Time to stop randomized and large pragmatic trials for intensive care medicine syndromes: the case of sepsis and acute respiratory distress syndrome. J Thorac Dis. 2020 Feb;12(Suppl 1):S101-S109. doi: 10.21037/jtd.2019.10.36.
citation: Vincent JL. We should abandon randomized controlled trials in the intensive care unit. Crit Care Med. 2010 Oct;38(10 Suppl):S534-8. doi: 10.1097/CCM.0b013e3181f208ac.
citation: Jozwiak M, Teboul JL, Monnet X. Extravascular lung water in critical care: recent advances and clinical applications. Ann Intensive Care. 2015 Dec;5(1):38. doi: 10.1186/s13613-015-0081-9. Epub 2015 Nov 6.
citation: David S, Thamm K, Schmidt BMW, Falk CS, Kielstein JT. Effect of extracorporeal cytokine removal on vascular barrier function in a septic shock patient. J Intensive Care. 2017 Jan 21;5:12. doi: 10.1186/s40560-017-0208-1. eCollection 2017.
citation: Riedel S. Procalcitonin and the role of biomarkers in the diagnosis and management of sepsis. Diagn Microbiol Infect Dis. 2012 Jul;73(3):221-7. doi: 10.1016/j.diagmicrobio.2012.05.002.
citation: Nylen ES, Whang KT, Snider RH Jr, Steinwald PM, White JC, Becker KL. Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis. Crit Care Med. 1998 Jun;26(6):1001-6. doi: 10.1097/00003246-199806000-00015.
citation: Schadler D, Pausch C, Heise D, Meier-Hellmann A, Brederlau J, Weiler N, Marx G, Putensen C, Spies C, Jorres A, Quintel M, Engel C, Kellum JA, Kuhlmann MK. The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial. PLoS One. 2017 Oct 30;12(10):e0187015. doi: 10.1371/journal.pone.0187015. eCollection 2017.
citation: Trasy D, Tanczos K, Nemeth M, Hankovszky P, Lovas A, Mikor A, Laszlo I, Hajdu E, Osztroluczki A, Fazakas J, Molnar Z; EProK study group. Early procalcitonin kinetics and appropriateness of empirical antimicrobial therapy in critically ill patients: A prospective observational study. J Crit Care. 2016 Aug;34:50-5. doi: 10.1016/j.jcrc.2016.04.007. Epub 2016 Apr 13.
citation: Kanjo A, Molnar Z, Zadori N, Gede N, Eross B, Szako L, Kiss T, Marton Z, Malbrain MLNG, Szuldrzynski K, Szrama J, Kusza K, Kogelmann K, Hegyi P. Dosing of Extracorporeal Cytokine Removal In Septic Shock (DECRISS): protocol of a prospective, randomised, adaptive, multicentre clinical trial. BMJ Open. 2021 Aug 26;11(8):e050464. doi: 10.1136/bmjopen-2021-050464.