Acute Kidney Injury, Cirrhosis, Septic Shock, Vasodilatory Shock
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGGiapreza
2.5 mg/mL
Sponsors
The Cleveland Clinic
Innoviva Specialty Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
For the angiotensin 2 arm, SOC vasopressors will be continued at fixed dose after initiation of angiotensin 2 (e.g. norepinephrine 12-15 mcg/min). * If MAP \< goal (MAP goal of 65-70 per physician discretion), angiotensin II will be initiated per the following titration schema: • Initial dose 10 ng/kg/min, titrate by 10-15 ng/kg/min every 5-15 min to target MAP goal. Max dose 80 ng/kg/min * Once Angiotensin II is at a max dose of 80 ng/kg/min and MAP \< goal, SOC vasopressor may be increased per institutional guideline. * If MAP \> goal during Angiotensin II therapy, SOC vasopressor should be weaned first until SOC vasopressor at norepinephrine of 15 mcg/min followed by angiotensin 2. Angiotensin II will be continued for 24 hours and then discontinued, and SOC vasopressors resumed according to institutional practices. For the SOC arm, patients will be continued on SOC vasopressors per institutional practices to MAP target.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in arterial elastance | 6 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in arterial ventricular coupling | 6 hours | 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). |
| Change in norepinephrine equivalent dose | 6 hours | The change in norepinephrine equivalent dose at (6 hours and 24 hours) using the following formula6 Norepinephrine dose (µg/kg/min) + epinephrine dose (µg/kg/min) + 1/150 × dopamine dose (µg/kg/min) + 1/10 × phenylephrine dose (µg/kg/min) + 2.5 × vasopressin dose (U/min) |
| Change in renal perfusion index | 6 hours | Improvement in renal perfusion index (Renal Resistive index) at (6 hours and 24 hours). The Doppler-based renal restrictive index (RI) will be used for measurement using spectral Doppler at the arcuate arteries or interlobar arteries. The formula for calculating the RI is: RI = (Peak Systolic Velocity - End Diastolic Velocity) / Peak Systolic Velocity. The normal range for the RI is 0.50 to 0.70, and elevated values are associated with poorer prognosis in various renal disorders and renal transplant outcomes. |
| Evaluation of 28 day renal replacement therapy free survival | 28 days after hospital discharge | The number of days alive free of renal-replacement therapy at 28 days |
| Change in Renin levels | 24 hours | A blood sample will be obtained at two time points. The first sample will be obtained when the participant is randomized but before infusion in initiated. The second sample will be obtained at 24 hours after the initiation of the drug. Plasma Renin Activity (PRA) is measured in ng/mL/h. |
| Change in Angiotension II levels | 24 hours | A blood sample will be obtained at two time points. The first sample will be obtained when the participant is randomized but before infusion in initiated. The second sample will be obtained at 24 hours after the initiation of the drug. Angiotensin II will be expressed in ng/dL. |
| Change in Microcirculation | 6 hours | Tissue oxygen saturation (StO₂) will be measured using near-infrared spectroscopy (NIRS) at the thenar eminence. Microvascular reactivity will be assessed using a vascular occlusion test (VOT). Dynamic variables derived from the VOT will include baseline StO₂, minimum StO₂ during occlusion, and reperfusion slope. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSiddharth Dugar, M.D.
The Cleveland Clinic
Outcome results
None listed