- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04592744
Angiotensin 2 for AKI After OLT
Intraoperative Angiotensin 2 for the Prevention of Kidney Injury After Liver Transplant
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Acute kidney injury is a common perioperative complication following liver transplantation with an incidence of approximately 55%. Due to the complex physiologic derangements present in cirrhotic patients, multiple etiologies and processes may contribute, including chronic and acute hepatorenal syndrome, ATN, renal toxic medication administration, microvascular circulatory dysfunction from vasopressors, and hypoperfusion from the vasodilatory and hypovolemic forms of shock that are common during liver transplantation. While some of the risk factors for these causes of AKI can be mitigated, our current area of investigation revolves around the modulation of the renin-angiotensin system in the prevention of perioperative AKI. In cirrhosis, poor renal blood flow causes an increase in circulating levels plasma renin. However, recent studies suggest low levels of angiotensinogen and angiotensin 2, which are associated with AKI in cirrhotic patients5 and may contribute to the risk of perioperative AKI in liver transplant patients.
Angiotensin 2 was approved for clinical use as a vasopressor in 2017. The efficacy of angiotensin 2 at increasing systemic blood pressure in patients with vasodilatory shock was demonstrated by the ATHOS 3 trial. This study found that the addition of angiotensin 2 increased MAP by close to 10mmHg compared to placebo (12.5 vs 2.9 mmHg p< 0.001) and allowed for a decrease in other vasopressor utilization. Post-hoc analysis of the ATHOS-3 trial by Tumlin et al demonstrated that patients in vasodilatory shock with AKI had higher rates of recovery from AKI and fewer days requiring dialysis than those who did not receive angiotensin 2.
As vasodilatory shock is common among patients undergoing LT, this finding is relevant to our patient population. We hypothesize that angiotensin 2 will reduce AKI in patients undergoing LT, where vasodilatory shock is also very common.
Hypothesis: We propose that a relative deficiency of angiotensin 2 predisposes cirrhotic patients to develop acute kidney injury following liver transplantation. We hypothesize that initiating angiotensin 2 infusion as a short duration infusion during the intra-operative period of liver transplant surgery will decrease the incidence of postoperative acute kidney injury.
Aim1: Evaluate the efficacy of Angiotensin 2 to reduce incidence of acute kidney injury (AKI) following liver transplantation. Rates of recovery from AKI in patients with septic shock have been established in post-hoc analysis of the ATHOS-3 study. With high rates of AKI following transplant surgery as well as a patient population with predisposition for AKI in part due to a relative angiotensin 2 deficiency, we hope to demonstrate that the addition of angiotensin 2 to standard vasopressor regimens during transplant surgery decreases the incidence of postoperative AKI.
Aim 2: Evaluate the safety of angiotensin 2 in cirrhotic patients. While cirrhotic patients were included in the two largest studies of synthetic angiotensin 2 (ATHOS-1 and ATHOS-3), those with MELD > 40 were excluded, and no specific subgroup analysis was done. While several case reports of safe administration of angiotensin 2 in patients with cirrhosis have been published, we hope to further investigate its safety during liver transplant surgery. We hypothesize that angiotensin 2 can safely be administered in cirrhotic patients
Study Type
Enrollment (Estimated)
Phase
- Phase 4
Contacts and Locations
Study Locations
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California
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Los Angeles, California, United States, 90095
- Michael Y Lin
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
A. End stage liver disease (ESLD) with acceptance of organ allocation offer. B. Stable renal function in the 48 hours prior to transplant (defined as < 30% change in serum creatinine) C. Adult patients > 18 years old
Exclusion Criteria:
A. Active use of renal replacement therapies B. Recent (within last 3 months) history of CVA or MI C. Patients with hypercoagulable state as evidenced by pre-existing venous thromboembolism or known thrombophilia (Antiphospholipid syndrome, Factor V- Leiden etc.) D. Combined liver transplant and intrathoracic surgery cases (not including chest tube placement) E. Multiple organ transplantation F. Congestive heart failure defined as left ventricular ejection fraction <45% G. Inability to obtain consent from the patient or surrogate H. Known allergy or sensitivity to any study medication I. Hepatocellular Carcinoma
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Intervention
Patients assigned to the study group will receive Ang 2 infusion in addition to standard vasopressor regimen.
Ang 2 is currently approved at UCLA as a second line vasopressor and will be used as such for the purposes of our study.
Hemodynamic goals will be established at the beginning of the case by the anesthesiology and surgical teams.
Ang 2 will be started as a second vasopressor once the norepinephrine dose has reached 0.05mcg/kg/min.
Ang 2 will be initiated at a starting dose of 5ng/kg/min.
That dose will be up titrated one time to 10ng/kg/min as vasopressor requirements escalate.
Once a patient is on the 10ng/kg/min dose of ang 2, no additional up titration will be performed.
Hemodynamic management will continue throughout the case with titration of other vasopressors as needed.
Ang 2 will be continued throughout the intraoperative period but will be weaned off prior to leaving the operating room.
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Angiotensin II infusion for Intraoperative management during liver transplantation
Vasopressor infusion for management of Intraoperative hypotension in liver transplantation.
Other Names:
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Active Comparator: Control
Patients assigned to the control group will undergo intraoperative management with a standard vasopressor regimen composed of norepinephrine, vasopressin and epinephrine based on hemodynamic goals established by the surgical and anesthesia teams prior to surgery.
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Vasopressor infusion for management of Intraoperative hypotension in liver transplantation.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of Acute kidney Injury
Time Frame: Every day for 14 days following intervention
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Measured by change in serum creatinine from baseline based on KDIGO criteria.
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Every day for 14 days following intervention
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Need for Renal Replacement therapies
Time Frame: Every day for 14 days following intervention
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Every day for 14 days following intervention
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In hospital mortalituy
Time Frame: 28 days
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28 days
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Urine output
Time Frame: 14 days
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Urine output measured in ml
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14 days
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Vasopressor doses
Time Frame: 14 days
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Vasopressor doses evaluated as norepinephrine equivalents
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14 days
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Adverse events
Time Frame: 14 days
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deep vein thrombosis, pulmonary embolus, intracardiac thrombus, stroke, myocardial infarction, peripheral ischemia, hepatic artery thrombosis, mesenteric ischemia, infusion site reaction, new infection, intraoperative tachycardia, intraoperative acidosis, lactatemia
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14 days
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Collaborators and Investigators
Publications and helpful links
General Publications
- Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.
- Tumlin JA, Murugan R, Deane AM, Ostermann M, Busse LW, Ham KR, Kashani K, Szerlip HM, Prowle JR, Bihorac A, Finkel KW, Zarbock A, Forni LG, Lynch SJ, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Bellomo R; Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Investigators. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Crit Care Med. 2018 Jun;46(6):949-957. doi: 10.1097/CCM.0000000000003092. Erratum In: Crit Care Med. 2018 Aug;46(8):e824.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Liver Failure
- Hepatic Insufficiency
- Pathologic Processes
- Kidney Diseases
- Urologic Diseases
- Renal Insufficiency
- Fibrosis
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Liver Diseases
- End Stage Liver Disease
- Liver Cirrhosis
- Acute Kidney Injury
- Physiological Effects of Drugs
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Autonomic Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Protease Inhibitors
- Adrenergic alpha-Agonists
- Adrenergic Agonists
- Natriuretic Agents
- Bronchodilator Agents
- Anti-Asthmatic Agents
- Respiratory System Agents
- Serine Proteinase Inhibitors
- Hemostatics
- Coagulants
- Adrenergic beta-Agonists
- Sympathomimetics
- Vasoconstrictor Agents
- Mydriatics
- Antidiuretic Agents
- Norepinephrine
- Epinephrine
- Vasopressins
- Angiotensin II
- Giapreza
- Angiotensinogen
Other Study ID Numbers
- 20-001402
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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