Comparison of Angiotensin II to Standard Dose Vasopressors on Change in Arterial Elastance

Early Phase 1Active Not RecruitingNCT07568275

The Cleveland Clinic30 enrolled

Overview

A study to see whether a medication called Angiotensin II works better than the routinely used medication to raise blood pressure in people with liver disease who are experiencing a serious drop in blood pressure. The investigators want to find out if Angiotensin II can help the heart and blood vessels work together more effectively than standard treatments.

Sepsis and septic shock remain associated with significant mortality, especially in cirrhotic where the mortality with septic shock exceeds 70%. Cirrhotic cardiomyopathy is a well-recognized consequence of advanced liver dysfunction and is associated with a hyperdynamic circulatory state due to vasoplegia in this population. Our group has shown septic patients with cirrhosis had higher LV systolic function as assessed by Left ventricle Ejection fraction (LVEF %), stroke volume and cardiac output with a significantly higher percentage of patients with hyperdynamic state (LVEF \> 70%) than those without cirrhosis. The investigators measured arterial elastance and ventricular elastance using echocardiography and found cirrhotic patient to have significantly lower arterial elastance with higher ventricular elastance. AII (Angiotensin II) exert its effect after the hydrolysis of Ang-1 by angiotensin converting enzyme (ACE) and is the principal product of the renin-angiotensin-aldosterone system. Advance cirrhosis is associated with reduction in Ang II levels accompanied by an increased Ang-(1-7)/Ang II ratio in the splanchnic circulation may be, at least in part, responsible for changes in vascular splanchnic tone. In addition, the relative decrease in Ang II compared to Ang (1-7), the vasodilator component of RAS causes hyperdynamic circulation from lower SVR in cirrhotic. This study also showed that with progression of liver disease leads to continual splanchnic vasodilation from higher Ang (1-7)/Ang II ratio. In advance stages this resultant hyperdynamic circulation is still insufficient to compensate for the effective arterial hypovolemia. Similar finding was observed in our large study, where the VAC was significantly lower in cirrhotic with sepsis shock despite elevation in LV elastance compared to non-cirrhotic with septic shock. Angiotensin II, a naturally occurring octapeptide hormone increases blood pressure through various mechanisms, including vasoconstriction of peripheral vessels, potentiation of antidiuretic hormone (ADH) and adrenocorticotropin hormone (ACTH) release, and direct actions on postganglionic sympathetic fibers. The external Ang II administration will be able to reverse the altered Ang (I-7)/Ang II ratio in systemic circulation reversing vasodilation. The investigators hypothesize that external administration of Ang II will cause a higher increase in SVR in cirrhotic with septic shock compared to Standard of Care (SOC) by decreasing arterial elastance restoring non-invasive arterial ventricular coupling.

Conditions

Septic Shock Cirrhosis Vasodilatory Shock Acute Kidney Injury

Interventions

GiaprezaDRUG

2.5 mg/mL

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥ 18 years at the time of enrollment * Septic shock as defined by Sepsis-3 criteria (highly suspected or confirmed infection, requiring norepinephrine to maintain a MAP ≥ 65 mmHg, and serum lactate \> 2 mmol/L after adequate fluid resuscitation) within a 48 hour window prior to enrollment * Confirmed cirrhotic patient (Radiological/Biopsy/Physician confirmed) * Preserved cardiac function as assessed using point-of-care ultrasonography or a non-invasive hemodynamic monitoring device with either LVOT VTI \> 18 cm or stroke volume \> 50 ml Within 48 hours of onset of shock. * Standard of care vasopressors are at a norepinephrine equivalent of 15 mcg/min Exclusion Criteria: * Declined consent. * Pregnancy * CKD-Stage IV/V * ESRD on long-term hemodialysis * On Dialysis or planned dialysis to be initiated within 24 hours of study of enrollment. * Clinically determined to have primarily hepatorenal syndrome. * On other vasoactive medication (phenylephrine, Terlipressin, epinephrine, dobutamine, dopamine) * Hemorrhagic, obstructive, or hypovolemic shock is not the primary cause of shock based on clinical judgement. * DNR * Patients declared Brain dead. * Anticipated death within 48 hours of enrollment * Echocardiographic windows not available * Acute mesenteric Ischemia * Active gastrointestinal bleeding * Active cardiac ischemic event defined as NSTEMi, STEMI * Acute DVT/Pulmonary embolism/Portal vein thrombosis * \> 48 h since initiation of vasopressor agent * Cardiac function assessment show LVOT VTI \< 18 cm or stroke volume \< 50 ml/min * Norepinephrine equivalent dose \> 50mcg/min

Locations (1)

The Cleveland Clinic

Cleveland, Ohio, United States

Outcomes

Primary Outcomes

Change in arterial elastance

Change in arterial elastance will be measure by echocardiography at baseline, 6 hours and 24 hours. Dynamic arterial elastance will be calculated as the ratio between pulse pressure variation and stroke volume variation obtained from arterial line waveform.

Time frame: 6 hours

Change in arterial elastance

Time frame: 24 hours

Secondary Outcomes

Change in arterial ventricular coupling

Change in arterial ventricular coupling will be measured by echocardiogram at baseline, 6 hours and 24 hours. The ventricular-arterial coupling will be assessed using previously validated method where Left ventricular end-systolic elastance will be calculated by a modified single-beat method employing systolic and diastolic pressure from the arterial line, echo-Doppler stroke volume (SV), echo-derived ejection fraction (EF) and an estimated normalized ventricular elastance at arterial end-diastole (E(Nd)): E(es(sb)) = \[P(d) - (E(Nd(est)) x P(s) x 0.9)\[/(E(Nd(est)) x SV).

Time frame: 6 hours

Change in arterial ventricular coupling

Time frame: 24 hours

Data from ClinicalTrials.gov

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