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

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.

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