Renin-guided Hemodynamic Management in Patients With Shock (RENIN)

Effect of Personalized Hemodynamic Management Based on Serum Renin Concentration on Acute Kidney Injury Progression in Patients With Shock: a Randomized Controlled Trial.

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.

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.

Shock, Renin, Vasopressor, Lactate, Acute Kidney Injury, Intensive Care Unit, Mortality, Quality of life

Clinical trial in which patients affected by shock, randomly receive either renin-guided hemodynamic management or usual care.

We will measure serum renin values every six hours. If the measured renin concentration increases by more that 20% compared with the last value, the target mean arterial pressure (MAP) will be elevated to 75-80 mmHg. If the subsequent renin level is still rising, the target MAP will be further raised to 85-90 mmHg and the addition of inotropes will be considered. If the first subsequent renin level decreases or increases by ≤20%, the target MAP will be kept at 75-80 mmHg. If the renin level at the subsequent measurement after reaching the highest step of management protocol is still increasing, a failure of the intervention will be declared, the target MAP will return to 65-70 mmHg. If renin level further decreases or increases ≤20% for two consecutive measurements, we will downgrade the target MAP to the previous step.

Patients in the usual care group will be managed according to standard of practice at each participating center.

If normalization of renin levels is achieved (values within the normal laboratory range), we will continue with usual care according to local protocols.

The primary outcome will be a composite of mortality or AKI progression at 30 days after randomization. We will define AKI progression as increasing at least two AKI stages compared to the AKI stage at study enrollment. We will define and stage AKI according to the current international criteria, the KDIGO guidelines (16). We will use both creatinine and urine output criteria.

All-cause mortality at intensive care unit discharge, hospital discharge, and 90 days after randomization.

Deaths within the initial 30 days were assigned zero days alive and free from mechanical ventilation at day 30.

Deaths within the initial 30 days were assigned zero days alive and free from renal replacement therapy at day 30.

Major adverse kidney events are defined as a composite of death, the dependence of renal replacement therapy, and persistent renal dysfunction (defined as a 25% or greater decline in estimated glomerular filtration rate (eGFR) from the baseline) (17).

Adverse events will include atrial fibrillation, acute myocardial infarction, ventricular fibrillation or tachycardia, digital ischemia, mesenteric ischemia, bleeding, reintubation, need for non-invasive ventilation, delirium, and stroke.

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

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