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| ID | Type | Description | Link |
|---|---|---|---|
| 542931418 | Other Grant/Funding Number | German Research Foundation |
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| Name | Class |
|---|---|
| German Research Foundation | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Angiotensin II | Experimental | Intravenous infusion through a central line according to the patient's situation. Target medium arterial pressure (MAP): >65mmHg |
|
| Control | Active Comparator | Intravenous infusion through a central line according to the patient's situation. Target medium arterial pressure (MAP): >65mmHg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Angiotensin II | Drug | Intravenous infusion through a central line according to the patient's situation. Once an infusion is established, the dose will be titrated as frequently as every 5 minutes, as needed, depending on the patient's condition and target MAP. |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of AKI KDIGO stage 2 or 3 or death within 72 hours after end of cardiac surgery. | 72 hours after end of surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Major Adverse Kidney Events (MAKE90) | 1. MAKE90 (consisting of mortality, dialysis within 90 days, persistent renal dysfunction (defined as serum creatinine ≥ 2x compared to baseline value at day 90) | 90 after cardiac surgery |
| Severity of Acute Kidney Injury |
| Measure | Description | Time Frame |
|---|---|---|
| Use of additional open-label vasopressors or inotropes | within 72 h after cardiac surgery | |
| Volume of fluid application within the first 72 hours | within 72 h after cardiac surgery | |
Inclusion Criteria:
Cardiac surgery using cardiopulmonary bypass including coronary artery bypass grafting (CABG) surgery, valve surgery, or combined CABG/valve surgery
Elevated risk of AKI as predicted by a score ≥ 1.5 on the following scale:
Adult ≥ 18 years
Written informed consent
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Alexander Zarbock, MD | Contact | +49-251-8347252 | PAN-AKI@ukmuenster.de | |
| Melanie Meersch-Dini, MD | Contact | +49-251-8347255 | PAN-AKI@ukmuenster.de |
| Name | Affiliation | Role |
|---|---|---|
| Alexander Zarbock, MD | University Hospital Muenster, Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Deutsches Herzzentrum der Charité | Recruiting | Berlin | 13353 | Germany | ||
| University Hospital Bonn |
Deidentified patient data will be available up to 3 years after original manuscript publication to researchers with methodologically sound proposals approved by the principal investigator.
Supporting Materials:
Up to 3 years after original manuscript publication
Available to researchers with methodologically sound proposals approved by the principal investigator.
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| ID | Term |
|---|---|
| D056987 | Vasoplegia |
| D058186 | Acute Kidney Injury |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D000804 | Angiotensin II |
| ID | Term |
|---|---|
| D000809 | Angiotensins |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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| Noradrenalin | Drug | Intravenous infusion through a central line according to the patient's situation. Once an infusion is established, the dose will be titrated as frequently as every 5 minutes, as needed, depending on the patient's condition and target MAP. |
|
Number of patients with KDIGO stage 1, KDIGO stage 2 or KDIGO stage 3) |
| 72 hours after cardiac surgery |
| Development or progression of chronic kidney injury | Development or progression of chronic kidney disease based on albuminuria, urine creatinine (and the respective ratio) and serum creatinine or death within 120 days | 90 to 120 days after cardiac surgery |
| Volume status |
| within 72 h after cardiac surgery |
| Time to death | 30 days after cardiac surgery |
| Time to death | 60 days after cardiac surgery |
| Time to death | 90 days after cardiac surgery |
| Days alive and in (index) ICU | From start of intervention until 60 days after cardiac surgery |
| Days alive and in (index) Hospital | From start of intervention until 60 days after cardiac surgery |
| Incidence of adverse events (AEs) and serious AEs (SAEs) | From start of intervention until discharge / day 7 |
| Occurence of AKI according to the KDIGO criteria | From start of intervention unto 72 hours after cardiac surgery |
| Number of patients with persistent renal dysfunction | defined as serum creatinine ≥ 2x compared to baseline value | On day 90 after cardiac surgery |
| Number of patients with dialysis renal/replacement therapy | On day 90 after cardiac surgery |
| Mortality | On day after cardiac surgery |
| Dose of vasopressors | from start of surgery unto 72 hours after cardiac surgery |
| Days alive and free of mechanical ventilation until day 60 | From start of intervention unto 60 days after cardiac surgery |
| Duration of mechanical ventilation | From start of intervention unto discharge from hospital or day seven after cardiac surgery (whatever comes first) |
| Days alive and free of vasopressors and mechanical ventilation | From start of intervention unto 60 days after cardiac surgery |
| Number of days alive and free of vasopressors and mechanical ventilation | From start of intervention until 28 days after cardiac surgery |
| Change in total and individual organ failure scores through 72 hours | Sequential Organ Failure Assessment (SOFA) score | Start of intervention and 72 hours after cardiac surgery |
| Duration of renal replacement therapy | From start of intervention unto 90 days after cardiac surgery |
| Number of patients with renal replacement therapy | Day 90 after cardiac surgery |
| Creatinine clearance on day one after cardiac surgery | 24 hours after cardiac surgery |
| Incidence of documented new onset atrial fibrillation | From end of surgery to hospital discharge |
| Occurrence of transient (< 48 hours) and persistent (≥ 48 hours) AKI | From start of intervention to hospital discharge |
| Identification and evaluation of biomarkers | From start of intervention to 48 hours after cardiac surgery |
| Recruiting |
| Bonn |
| 53127 |
| Germany |
| University Medical Center Mainz | Recruiting | Mainz | 55131 | Germany |
| University Hospital Münster | Recruiting | Münster | 49149 | Germany |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D001685 | Biological Factors |