Clinical trial NCT05898126: Renin-guided Hemodynamic Management in Patients With Shock
Official title: Effect of Personalized Hemodynamic Management Based on Serum Renin Concentration on Acute Kidney Injury Progression in Patients With Shock: a Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Shock
Keywords: Shock
Renin
Vasopressor
Lactate
Acute Kidney Injury
Intensive Care Unit
Mortality
Quality of life
Lead sponsor: Università Vita-Salute San Raffaele
Sponsor class: OTHER
First posted: 2023-06-12
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Clinical trial in which patients affected by shock, randomly receive either renin-guided hemodynamic management or usual care.
Primary purpose: TREATMENT

Brief summary: Shock is a major risk factor for mortality among patients admitted to intensive care units (ICUs). Since various hemodynamic strategies uniformly delivered to patients with shock have failed to improve clinically relevant outcomes, individualized approaches for shock supported by robust evidence are required. This study will be a prospective, multicenter, parallel-group, single-blind, randomized controlled trial. The investigators will randomly assign 800 critically ill patients requiring norepinephrine infusion to the renin-guided or usual care groups. The investigators hypothesize that renin-guided hemodynamic management, compared to usual care, can reduce a composite of mortality and acute kidney injury (AKI) progression in patients requiring vasopressor support.

Detailed description: Shock is a common cause of death among patients admitted to intensive care units. Acute kidney injury (AKI) frequently occurs in patients with shock (3, 4). Maintaining adequate perfusion pressure and oxygen delivery is crucial in the hemodynamic management of shock (5). Several randomized controlled trials have evaluated the effect of various hemodynamic protocols treating shock patients with a "one size fits all" approach. However, such protocols did not reduce mortality (6-8). The task force of the surviving sepsis campaign identified the personalization of sepsis resuscitation as a research priority (9). Moreover, a large RCT showed that personalizing blood pressure targets reduced the risk of postoperative organ dysfunction in patients undergoing major surgery (10). These findings suggest that applying individualized hemodynamic strategy may optimize shock treatment and potentially improve outcomes (11).

Recent studies have investigated renin as a novel marker of tissue hypoperfusion in critically ill patients. While serum lactate level has been the most common and validated marker for tissue hypoperfusion (12), several studies are now suggesting that renin may predict mortality better than lactate in critically ill patients (13, 14). Notably, relative renin increase is associated with adverse clinical outcomes and shock reversal has been shown to decrease renin concentration (15).

The investigators aim to perform the Randomized Evaluation of persoNalized hemodynamIc maNagement based on serum renin concentration (RENIN) trial to test the hypothesis that renin-guided hemodynamic management can reduce a composite of mortality and acute kidney injury (AKI) progression during the hospital stay in patients requiring vasopressors compared with usual care.

Eligibility criteria: Inclusion Criteria:

* ≥18 years old
* Admitted to an intensive care unit (ICU)
* Requiring norepinephrine infusion at any dose to maintain a mean arterial pressure (MAP) of ≥65 mmHg after initial fluid resuscitation
* Expected to stay in the ICU for at least 24 hours
* Written informed consent from the patient him-/herself or the patient's next of kin as requested by the ethics committee.

Exclusion Criteria:

* Pregnancy
* Refused informed consent
* Current enrollment into another randomized controlled trial that does not allow concomitant enrollment
* Requiring vasopressors for \>12 hours before the enrollment
* Renal failure with an imminent need for renal replacement therapy (RRT)
* Intention to use RRT by clinical judgment despite lack of urgent clinical indication
* AKI stage 2 and 3 at enrollment according to the KDIGO criteria
* Prior enrollment in this study
* Severe liver disease (Child-Pugh score \>7 points)
* Chronic kidney disease (CKD) equal to or worse than CKD stage IV (eGFR \<30 mL/min/1.73 m2)
* History of kidney transplant
* Any condition explicitly requiring a higher or lower blood pressure target according to clinical judgment

Primary outcomes:
measure: A composite of mortality or AKI progression at 30 days after randomization.
timeFrame: 30 days
Secondary outcomes:
measure: All-cause mortality at intensive care unit discharge, hospital discharge, and 90 days after randomization.
timeFrame: 90 days
measure: The need for and duration of vasopressors at 30 days after randomization
timeFrame: 30 days
measure: Days alive and free from mechanical ventilation
timeFrame: 30 days
measure: Day alive and free from renal replacement therapy.
timeFrame: 30 days
measure: Days alive and outside the ICU.
timeFrame: 30 days
measure: Duration of hospital stay.
timeFrame: 30 days
measure: Major adverse kidney events at day 90.
timeFrame: 90 days
measure: Quality of life at day 90.
timeFrame: 90 days
measure: Adverse events during hospital stay.
timeFrame: 30 days
Other outcomes:
Locations:
city: Catanzaro
country: Italy
facility: Ospedale Mater Domini
state: Calabria
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
Study officials:
References:
citation: Orban JC, Walrave Y, Mongardon N, Allaouchiche B, Argaud L, Aubrun F, Barjon G, Constantin JM, Dhonneur G, Durand-Gasselin J, Dupont H, Genestal M, Goguey C, Goutorbe P, Guidet B, Hyvernat H, Jaber S, Lefrant JY, Malledant Y, Morel J, Ouattara A, Pichon N, Guerin Robardey AM, Sirodot M, Theissen A, Wiramus S, Zieleskiewicz L, Leone M, Ichai C; AzuRea Network. Causes and Characteristics of Death in Intensive Care Units: A Prospective Multicenter Study. Anesthesiology. 2017 May;126(5):882-889. doi: 10.1097/ALN.0000000000001612.
citation: Mayr VD, Dunser MW, Greil V, Jochberger S, Luckner G, Ulmer H, Friesenecker BE, Takala J, Hasibeder WR. Causes of death and determinants of outcome in critically ill patients. Crit Care. 2006;10(6):R154. doi: 10.1186/cc5086.
citation: Marenzi G, Assanelli E, Campodonico J, De Metrio M, Lauri G, Marana I, Moltrasio M, Rubino M, Veglia F, Montorsi P, Bartorelli AL. Acute kidney injury in ST-segment elevation acute myocardial infarction complicated by cardiogenic shock at admission. Crit Care Med. 2010 Feb;38(2):438-44. doi: 10.1097/CCM.0b013e3181b9eb3b.
citation: Bagshaw SM, Lapinsky S, Dial S, Arabi Y, Dodek P, Wood G, Ellis P, Guzman J, Marshall J, Parrillo JE, Skrobik Y, Kumar A; Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group. Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy. Intensive Care Med. 2009 May;35(5):871-81. doi: 10.1007/s00134-008-1367-2. Epub 2008 Dec 9.
citation: Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014 Dec;40(12):1795-815. doi: 10.1007/s00134-014-3525-z. Epub 2014 Nov 13.
citation: Hernandez G, Ospina-Tascon GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegria L, Teboul JL, Cecconi M, Ferri G, Jibaja M, Pairumani R, Fernandez P, Barahona D, Granda-Luna V, Cavalcanti AB, Bakker J; The ANDROMEDA SHOCK Investigators and the Latin America Intensive Care Network (LIVEN); Hernandez G, Ospina-Tascon G, Petri Damiani L, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegria L, Teboul JL, Cecconi M, Cecconi M, Ferri G, Jibaja M, Pairumani R, Fernandez P, Barahona D, Cavalcanti AB, Bakker J, Hernandez G, Alegria L, Ferri G, Rodriguez N, Holger P, Soto N, Pozo M, Bakker J, Cook D, Vincent JL, Rhodes A, Kavanagh BP, Dellinger P, Rietdijk W, Carpio D, Pavez N, Henriquez E, Bravo S, Valenzuela ED, Vera M, Dreyse J, Oviedo V, Cid MA, Larroulet M, Petruska E, Sarabia C, Gallardo D, Sanchez JE, Gonzalez H, Arancibia JM, Munoz A, Ramirez G, Aravena F, Aquevedo A, Zambrano F, Bozinovic M, Valle F, Ramirez M, Rossel V, Munoz P, Ceballos C, Esveile C, Carmona C, Candia E, Mendoza D, Sanchez A, Ponce D, Ponce D, Lastra J, Nahuelpan B, Fasce F, Luengo C, Medel N, Cortes C, Campassi L, Rubatto P, Horna N, Furche M, Pendino JC, Bettini L, Lovesio C, Gonzalez MC, Rodruguez J, Canales H, Caminos F, Galletti C, Minoldo E, Aramburu MJ, Olmos D, Nin N, Tenzi J, Quiroga C, Lacuesta P, Gaudin A, Pais R, Silvestre A, Olivera G, Rieppi G, Berrutti D, Ochoa M, Cobos P, Vintimilla F, Ramirez V, Tobar M, Garcia F, Picoita F, Remache N, Granda V, Paredes F, Barzallo E, Garces P, Guerrero F, Salazar S, Torres G, Tana C, Calahorrano J, Solis F, Torres P, Herrera L, Ornes A, Perez V, Delgado G, Lopez A, Espinosa E, Moreira J, Salcedo B, Villacres I, Suing J, Lopez M, Gomez L, Toctaquiza G, Cadena Zapata M, Orazabal MA, Pardo Espejo R, Jimenez J, Calderon A, Paredes G, Barberan JL, Moya T, Atehortua H, Sabogal R, Ortiz G, Lara A, Sanchez F, Hernan Portilla A, Davila H, Mora JA, Calderon LE, Alvarez I, Escobar E, Bejarano A, Bustamante LA, Aldana JL. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):654-664. doi: 10.1001/jama.2019.0071.
citation: Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le Tulzo Y, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Herve F, du Cheyron D, Guerin C, Mercat A, Teboul JL, Radermacher P; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014 Apr 24;370(17):1583-93. doi: 10.1056/NEJMoa1312173. Epub 2014 Mar 18.
citation: Lamontagne F, Richards-Belle A, Thomas K, Harrison DA, Sadique MZ, Grieve RD, Camsooksai J, Darnell R, Gordon AC, Henry D, Hudson N, Mason AJ, Saull M, Whitman C, Young JD, Rowan KM, Mouncey PR; 65 trial investigators. Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial. JAMA. 2020 Mar 10;323(10):938-949. doi: 10.1001/jama.2020.0930.
citation: Lat I, Coopersmith CM, De Backer D, Coopersmith CM; Research Committee of the Surviving Sepsis Campaign. The surviving sepsis campaign: fluid resuscitation and vasopressor therapy research priorities in adult patients. Intensive Care Med Exp. 2021 Mar 1;9(1):10. doi: 10.1186/s40635-021-00369-9.
citation: Futier E, Lefrant JY, Guinot PG, Godet T, Lorne E, Cuvillon P, Bertran S, Leone M, Pastene B, Piriou V, Molliex S, Albanese J, Julia JM, Tavernier B, Imhoff E, Bazin JE, Constantin JM, Pereira B, Jaber S; INPRESS Study Group. Effect of Individualized vs Standard Blood Pressure Management Strategies on Postoperative Organ Dysfunction Among High-Risk Patients Undergoing Major Surgery: A Randomized Clinical Trial. JAMA. 2017 Oct 10;318(14):1346-1357. doi: 10.1001/jama.2017.14172.
citation: Saugel B, Vincent JL, Wagner JY. Personalized hemodynamic management. Curr Opin Crit Care. 2017 Aug;23(4):334-341. doi: 10.1097/MCC.0000000000000422.
citation: Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Moller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247. doi: 10.1007/s00134-021-06506-y. Epub 2021 Oct 2. No abstract available.
citation: Gleeson PJ, Crippa IA, Mongkolpun W, Cavicchi FZ, Van Meerhaeghe T, Brimioulle S, Taccone FS, Vincent JL, Creteur J. Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients. Crit Care Med. 2019 Feb;47(2):152-158. doi: 10.1097/CCM.0000000000003544.
citation: Jeyaraju M, McCurdy MT, Levine AR, Devarajan P, Mazzeffi MA, Mullins KE, Reif M, Yim DN, Parrino C, Lankford AS, Chow JH. Renin Kinetics Are Superior to Lactate Kinetics for Predicting In-Hospital Mortality in Hypotensive Critically Ill Patients. Crit Care Med. 2022 Jan 1;50(1):50-60. doi: 10.1097/CCM.0000000000005143.
citation: Kullmar M, Saadat-Gilani K, Weiss R, Massoth C, Lagan A, Cortes MN, Gerss J, Chawla LS, Fliser D, Meersch M, Zarbock A. Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients. Am J Respir Crit Care Med. 2021 May 1;203(9):1119-1126. doi: 10.1164/rccm.202005-2050OC.
citation: Kellum JA, Lameire N; KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013 Feb 4;17(1):204. doi: 10.1186/cc11454.
citation: Semler MW, Rice TW, Shaw AD, Siew ED, Self WH, Kumar AB, Byrne DW, Ehrenfeld JM, Wanderer JP. Identification of Major Adverse Kidney Events Within the Electronic Health Record. J Med Syst. 2016 Jul;40(7):167. doi: 10.1007/s10916-016-0528-z. Epub 2016 May 27.
citation: Kotani Y, Landoni G, Belletti A, Khanna AK. Response to: norepinephrine formulation for equivalent vasopressive score. Crit Care. 2023 Mar 28;27(1):125. doi: 10.1186/s13054-023-04404-x. No abstract available.
citation: Kotani Y, Belletti A, D'Andria Ursoleo J, Salvati S, Landoni G. Norepinephrine Dose Should Be Reported as Base Equivalence in Clinical Research Manuscripts. J Cardiothorac Vasc Anesth. 2023 Sep;37(9):1523-1524. doi: 10.1053/j.jvca.2023.05.013. Epub 2023 May 11. No abstract available.