Reducing Cardiac-surgery Associated Acute Kidney Injury Occurence by Administering Angiotensin II

Phase 3

Not yet recruiting

• Conditions: Cardiac Surgery; Vasoplegia
• Interventions: Drug: Angiotensin II; Drug: Noradrenalin

• Registration Number: NCT06615102
• Lead Sponsor: Universität Münster

Brief Summary

The study intervention focuses on exploring the use of angiotensin II as a primary vasopressor compared to norepinephrine in cardiac surgery patients to investigate whether angiotensin II can reduce the occurrence of moderate/severe acute kidney injury (AKI). Despite its potential, as suggested by trials involving surgical patients, there is currently no human data confirming its effectiveness in preventing moderate/severe AKI in this context. The intervention aims to address this gap by evaluating angiotensin II's impact compared to norepinephrine.

Detailed Description

Acute kidney injury (AKI) is defined by changes in serum creatinine and/or urine output, according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In cardiac surgical patients, the AKI rate is up to 30%, with 1-2% of the patients requiring renal replacement therapy (RRT). Cardiac-surgery associated AKI (CSA-AKI) is associated with increased short- and long-term morbidity and mortality as well as increased hospital costs.

Shock after cardiac surgery is also associated with increased mortality. In the context of cardiac surgery with the use of the cardiopulmonary bypass (CPB), sympathetic nervous system activation and cardiovascular instability are common sequelae. Vasoplegic syndrome is a form of distributive shock that is characterized by low arterial pressure, reduced systemic vascular resistance, and normal or elevated cardiac output. It occurs in 5 to 25% of the patients undergoing cardiac surgery. Patients with vasoplegic shock are at higher risk of organ failure, including AKI, and show increased mortality rates and longer hospital length of stays. Currently, norepinephrine is the established first-line vasopressor for the treatment of vasoplegic shock, but all vasopressors have adverse effects, including myocardial ischemia and arrhythmias. Moreover, in vasoplegic situations, vascular smooth muscle cells may become unresponsive to vasopressors. The underlying mechanisms are complex and include adrenoceptor desensitization, increased nitric oxide (NO) synthesis, activation of adenosine triphosphate-sensitive K+ channels, and vasopressin and corticosteroid deficiency.

Physiologically, the renin-angiotensin-aldosterone system (RAAS) is a hormone system that plays a central role in regulating blood pressure and fluid balance, glomerular filtration rate, and electrolyte levels. Renin, a proteolytic enzyme released by juxtaglomerular cells in response to hypotension, decreases sodium delivery to the distal tubule, activates the sympathetic nervous system, and cleaves angiotensinogen to angiotensin I which is a precursor of the vasoactive angiotensin II. RAAS is regulated by a biofeedback loop. Angiotensin II generation inhibits renin release, whereas renin levels increase when there is insufficient activation of the angiotensin II type 1 receptor. Administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) and reduced angiotensin II generation cause a corresponding increase in renin levels.

Despite numerous clinical trials using several interventions, a reliable means to prevent AKI remains elusive. Clinical trials focusing on surgical patients suggest that angiotensin II is a potent vasopressor. However, no human data exist whether the application of angiotensin II as a primary vasopressor reduces the occurrence of AKI in patients undergoing cardiac surgery.

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-09-23
• Study First Submitted QC: 2024-09-23
• Last Update Submitted: 2024-09-23
• Study First Posted: 2024-09-26
• Last Update Posted: 2024-09-26
• Study Start: 2025-01
• Primary Completion: 2027-01
• Study Completion: 2027-04

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1022

Inclusion Criteria

1. Cardiac surgery using cardiopulmonary bypass including coronary artery bypass grafting (CABG) surgery, valve surgery, or combined CABG/valve surgery

2. Elevated risk of AKI as predicted by a score ≥ 1.5 on the following scale:

   1. hemoglobin < 130g/l = 2
   2. creatinine > 1.1 mg/dl = 2
   3. age > 70 years =1.5
   4. New York Heart Association Classification (NYHA) 4 =1.5
   5. Body Mass Index (BMI) > 30 =1.5

3. Adult ≥ 18 years

4. Written informed consent

Exclusion Criteria

1. Major aortic surgery (aortic arch replacement), transplant surgery, pulmonary thrombendarterectomy, ventricular assist device placement
2. Already receiving inotropic/vasopressor support before surgery
3. Dialysis dependent
4. Pre-existing AKI within the last 30 days
5. Pre-existing chronic kidney injury with an eGFR<20 ml/min/1.73m2
6. Pre-existing significant hypertension (persistent SBP > 180mmHg)
7. Significant pulmonary hypertension (ePSAP > 70mmHg, mPAP > 40mmHg) with right ventricular systolic dysfunction (graded more severe than mild)
8. Hypersensitivity to the active substance or to any of the excipients
9. Pregnancy (a negative pregnancy test for women of childbearing age) or breastfeeding women
10. Persons with any kind of dependency on the investigator or employed by the sponsor/investigator
11. Participation in another interventional trial within the last three months that investigates kidney function

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Angiotensin II	Angiotensin II	Intravenous infusion through a central line according to the patient's situation. Target medium arterial pressure (MAP): \>65mmHg
Control	Noradrenalin	Intravenous infusion through a central line according to the patient's situation. Target medium arterial pressure (MAP): \>65mmHg

Primary Outcome Measures

Name	Time	Method
Rate of AKI KDIGO stage 2 or 3 or death within 72 hours after end of cardiac surgery.	72 hours after end of surgery

Secondary Outcome Measures

Name	Time	Method
Major Adverse Kidney Events (MAKE90)	90 after cardiac surgery	1. MAKE90 (consisting of mortality, dialysis within 90 days, persistent renal dysfunction (defined as serum creatinine ≥ 2x compared to baseline value at day 90)
Severity of Acute Kidney Injury	72 hours after cardiac surgery	Number of patients with KDIGO stage 1, KDIGO stage 2 or KDIGO stage 3)
Development or progression of chronic kidney injury	90 to 120 days after cardiac surgery	Albuminuria and on two serum creatinine measurements between day 90 and 120