Comparison of Angiotensin II to Standard Dose Vasopressors on Change in Arterial Elastance (Ang2)
Comparison of Angiotensin II to Standard Dose Vasopressors on Change in Arterial Elastance in Cirrhotic Patients With Vasodilatory Shock: A Prospective, Randomized Controlled Trial
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.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Inscripción (Actual)
Fase
- Fase temprana 1
Contactos y Ubicaciones
Ubicaciones de estudio
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Ohio
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Cleveland, Ohio, Estados Unidos, 44195
- The Cleveland Clinic
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
- Adulto
- Adulto Mayor
Acepta Voluntarios Saludables
Descripción
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
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Comparador activo: Angiotensin II
Angiotensin II will be continued for 24 hours and then discontinued, and SOC vasopressors resumed according to institutional practices.
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2.5 mg/mL
Otros nombres:
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Sin intervención: Standard of Care
Fixed-dose vasopressin and standard of care vasopressors increased as per institutional guidelines according to MAP targets.
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Change in arterial elastance
Periodo de tiempo: 6 hours
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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.
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6 hours
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Change in arterial elastance
Periodo de tiempo: 24 hours
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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.
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24 hours
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Change in arterial ventricular coupling
Periodo de tiempo: 6 hours
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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).
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6 hours
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Change in arterial ventricular coupling
Periodo de tiempo: 24 hours
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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).
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24 hours
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Change in norepinephrine equivalent dose
Periodo de tiempo: 6 hours
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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)
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6 hours
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Change in norepinephrine equivalent dose
Periodo de tiempo: 24 hours
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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)
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24 hours
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Change in renal perfusion index
Periodo de tiempo: 6 hours
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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. |
6 hours
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Change in renal perfusion index
Periodo de tiempo: 24 hours
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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. |
24 hours
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Evaluation of 28 day renal replacement therapy free survival
Periodo de tiempo: 28 days after hospital discharge
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The number of days alive free of renal-replacement therapy at 28 days
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28 days after hospital discharge
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Change in Renin levels
Periodo de tiempo: 24 hours
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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. |
24 hours
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Change in Angiotension II levels
Periodo de tiempo: 24 hours
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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. |
24 hours
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Change in Microcirculation
Periodo de tiempo: 6 hours
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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.
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6 hours
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Change in Microcirculation
Periodo de tiempo: 24 hours
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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.
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24 hours
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Investigador principal: Siddharth Dugar, M.D., The Cleveland Clinic
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
- Enfermedades urogenitales
- Procesos Patológicos
- Enfermedades urogenitales masculinas
- Enfermedades Renales
- Enfermedades urológicas
- Enfermedades urogenitales femeninas
- Enfermedades urogenitales femeninas y complicaciones del embarazo
- Infecciones
- Septicemia
- Síndrome de Respuesta Inflamatoria Sistémica
- Inflamación
- Insuficiencia renal
- Choque
- Condiciones Patológicas, Signos y Síntomas
- Lesión renal aguda
- Fibrosis
- Choque séptico
- Giapreza
- angiotensin II, Phe(4)-
Otros números de identificación del estudio
- 24-913
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
Marco de tiempo para compartir IPD
Criterios de acceso compartido de IPD
Tipo de información de apoyo para compartir IPD
- PROTOCOLO DE ESTUDIO
- SAVIA
- CIF
- CÓDIGO_ANALÍTICO
- RSC
Información sobre medicamentos y dispositivos, documentos del estudio
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