Clinical trial NCT05199493: Reducing Acute Kidney Injury Occurence by Administering Angiotensin II
Official title: Biomarker-guided Implementation of Angiotensin-II (AT-II) to Reduce the Occurrence of Kidney Damage After Cardiac Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiac Surgery
Vasoplegia
Hyperreninemia
Keywords: Cardiac Surgery
Acute kidney injury
Biomarker
Angiotensin II
Renin
Lead sponsor: Universität Münster
Sponsor class: OTHER
Collaborators: name: German Research Foundation
First posted: 2022-01-20
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this study is to evaluate whether adding angiotensin II to the standard of care is superior compared to the standard of care alone with respect to kidney damage (personalized approach) after cardiac surgery.

Detailed description: Vasoplegic syndrome is a form of distributive shock that is characterized by low arterial pressure with reduced systemic vascular resistance and normal or elevated cardiac output that occurs in 5 to 25% of patients undergoing cardiac surgery. Patients with vasoplegic shock after cardiac surgery are at higher risk of organ failure, including acute kidney injury (AKI). Postsurgical AKI is associated with several adverse outcomes. Attempts to prevent AKI have largely been futile so far. Prior studies often started with the interventions after an AKI event, when a decline of kidney function (i.e. glomerular filtration rate) was already established. Application of norepinephrine is currently considered as the first-line therapy for vasoplegic shock, but all catecholamines have adverse effects, including myocardial ischemia and arrhythmias. In a recent observational trial, we demonstrated that there is a dysregulation in the renin-angiotensin-aldosterone system (RAAS) likely caused by a reduced angiotensin-converting enzyme (ACE) activity after cardiac surgery. Elevated renin levels identified patients at risk for AKI and were associated with cardiovascular instability and increased AKI rate after cardiac surgery. Furthermore, elevated renin levels could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention with angiotensin II that could improve their outcomes. Therefore, the application of angiotensin II to treat a postoperative hypotension would mean a hormone substitution.Shock after cardiac surgery is associated with increased mortality. Cardiopulmonary bypass (CPB) represents a common clinical setting of sympathetic nervous system activation and cardiovascular instability. Vasoplegia is a form of distributive shock that is characterized by low arterial pressure with reduced systemic vascular resistance and normal or elevated cardiac output. It occurs in 5 to 25% of patients undergoing cardiac surgery. Patients with vasoplegia after cardiac surgery are at higher risk of organ failure, including AKI, and have an increased mortality rate and longer hospital length of stay.

Clinical trials focusing on septic patients suggest that AT-II is a potent vasopressor. However, no human data exist whether the application of AT-II in cardiac surgery patients with y hyperreninemia high-risk patients identified by renin levels (individualized approach) reduces kidney damage and improves kidney function after cardiac surgery.

Eligibility criteria: Inclusion Criteria:

* Adult patients undergoing cardiac surgery with CPB
* Cardiac index 2.1l/min per square meter
* Written informed consent
* D-renin (difference between post- and preoperative) ≥ 3.7 micro Unit/ml 4 h after CPB
* Postoperative hypotension requiring vasopressors

Exclusion Criteria:

* Preexisting AKI (stage 1 and higher)
* Patients with cardiac assist devices
* Pregnant women, nursing women and women of childbearing potential
* Known (Glomerulo-) Nephritis, interstitial nephritis or vasculitis
* chronic kidney disease with estimated glomerular filtration rate (eGFR) \< 30 ml/min
* Dialysis dependent chronic kidney disease
* Prior kidney transplant within the last to 12 months
* Emergency surgery in the context of an acute coronary syndrome
* Hypersensitivity to the active substance, or to any of the excipients of the study medication
* Bronchospasm
* Liver failure
* Mesenteric ischemia
* Participation in another intervention trial in the past 3 months
* Persons with any kind of dependency on the investigator or employed by the institution responsible or investigator
* Persons held in an institution by legal or official order

Primary outcomes:
measure: • kidney damage after cardiac surgery identified by the difference between [TIMP-2]*[IGFBP7] levels 12h after randomization and [TIMP-2]*[IGFBP7] levels at randomization
timeFrame: 12 hours after start of intervention
Secondary outcomes:
measure: Occurence of Acute Kidney Injury (AKI) according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria
timeFrame: 72 hours after cardiac surgery
measure: Severity of Acute Kidney Injury
timeFrame: 72 hours after cardiac surgery
measure: Amount of volume application
timeFrame: 12 hours after start of intervention
measure: Fluid status
timeFrame: 12 hours after start of intervention
measure: Dose of vasopressor use during intervention
timeFrame: During intervention, an average of 12 hours
measure: Creatinine clearance on day one after cardiac surgery
timeFrame: One day after cardiac surgery
measure: Free-days through day 28 of vasoactive medications and mechanical ventilation
timeFrame: 28 days after cardiac surgery
measure: Renal Recovery
timeFrame: 90 days after cardiac surgery
measure: Mortality
timeFrame: 30 days after cardiac surgery
measure: Mortality
timeFrame: 60 days after cardiac surgery
measure: Mortality
timeFrame: 90 days after cardiac surgery
measure: Length of ICU (Intensive Care Unit) stay
timeFrame: up to 90 days after cardiac surgery (until discharge)
measure: Length of hospital stay
timeFrame: up to 90 days after cardiac surgery (until discharge)
measure: Use and duration of renal replacement therapy
timeFrame: up to 90 days after cardiac surgery
measure: Major adverse kidney events (MAKE)
timeFrame: 90 days after cardiac surgery
measure: Effect of Angiotensin converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARBs) use on the effect of angiotensin II
timeFrame: 12 hours after intervention
measure: Correlation between the severity of hyperreninemia and the effect of angiotensin II
timeFrame: 12 hours after intervention
Other outcomes:
Locations:
city: Münster
country: Germany
facility: University Hospital Muenster
Study officials:
affiliation: University Hospital Muenster, Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy
name: Alexander Zarbock, MD
role: STUDY_CHAIR
References: