Angiotensin II for Septic Shock Treatment

Angiotensin II for Septic Shock Treatment: Effects On Macro- and Microcirculation A Randomized, Controlled Pilot Trial (ANGSTROM Trial)

This study aims to investigate the effect of angiotensin II on microcirculation and peripheral perfusion in patients with septic shock.

Study Overview

• Status: Suspended
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Angiotensin II; Drug: Norepinephrine; Drug: Normal saline

Detailed Description

Shock is a syndrome characterized by acute circulatory failure resulting in impaired peripheral tissue perfusion. Distributive shock is the most common type of shock and is usually caused by severe sepsis. Distributive shock is characterized by profound vasodilatation leading to decreased arterial blood pressure and impaired organ perfusion despite high cardiac output.

The use of vasopressors is an essential management line for distributive sock. Two groups of vasopressors are usually used for management of shock: catecholamines and vasopressin-like peptides. There is a continuous need for other vasopressors because:

1- Available vasopressors have narrow therapeutic window. 2- Patients with severe hypotension refractory to the currently available classes usually die.

A third system is usually engaged in the physiology of shock which is Renin-Angiotensin-aldosterone system. Angiotensin II is a natural hormone which is a potent vasopressor; moreover, angiotensin II stimulates the production of both antidiuretic hormone and adrenocorticotropin hormone.

In a pilot study, angiotensin II was reported as an effective rescue vasopressor in septic shock patients on multiple vasopressors. Angiotensin II improved mean arterial pressure and helped in reduction of the doses of catecholamines. In a recent large randomized controlled trial, angiotensin II improved blood pressure in catecholamine-resistant distributive shock patients.

Microcirculation is the primary site of oxygen and nutrient exchange. Maintenance of microcirculatory perfusion is a prerequisite for preservation of organ function. Multiple organ failure is common in patients with distributive shock despite maintenance of parameters of global perfusion due to disrupted microcirculatory perfusion. Furthermore, restoration of microcirculatory perfusion was correlated with improvement in survival. This study aims to investigate the effect of angiotensin II on peripheral microcirculation in patients with septic shock.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Cairo University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Septic shock patients.
• Aged above 18 years.
• With cardiac index > 2.4 L/min/BSA 1.73 m2.
• On high dose vasopressors (defined as norepinephrine infusion above 0.1 mcg/Kg/min)

Exclusion Criteria:

• Acute coronary syndrome.
• Impaired cardiac contractility
• Bronchospasm.
• Major burns
• Liver failure.
• Active bleeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Angiotensin group; Patients will receive Angiotensin II at a starting dose of 20 ng/Kg/min. During the first 30 minutes after randomization, the angiotensin II infusion will be titrated to achieve a mean arterial pressure of 65-75 mmHg while the norepinephrine infusion will be withdrawn and stopped. Following a stabilization of 60 minutes, the angiotensin II infusion is titrated to achieve a mean arterial pressure of 85-95 mmHg. Following a 30 minutes wash-in period and a 60 minutes stabilization period, a third set of measurements will be taken. Then, the angiotensin II infusion will be withdrawn in small steps and replaced by a norepinephrine infusion which will then be titrated to achieve a mean arterial pressure of 65-75 mmHg. Then, the final set of measurements will be taken.	Drug: Angiotensin II; Patients will receive angiotensin-II at a starting dose of 20 ng/Kg/min.; Drug: Norepinephrine; patients will receive norepinephrine infusion adjusted according to blood pressure; Other Names: Noradrenaline
Placebo Comparator: Normal saline group; Patients will receive normal saline infusion in addition to norepinephrine infusion. The same mean arterial pressure levels (65-75 mmHg > 85-95 mmHg > 65-75 mmHg) will be achieved by titration of the norepinephrine infusion. Identical wash-in and stabilization periods will be kept as in the study group. Measurements will be taken at the same time points as in the study group. The maximum dose of norepinephrine applied will be 0.7 mcg/kg/min.	Drug: Norepinephrine; patients will receive norepinephrine infusion adjusted according to blood pressure; Other Names: Noradrenaline; Drug: Normal saline; Patients will receive normal saline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean flow index	Mean flow index measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands). The microvascular flow index (MFI) will be used to quantify microvascular blood flow. In this score, flow is characterized as absent (0), intermittent (1), sluggish (2), or normal (3), for each patient the values from 5 videos will be averaged. Since our investigation will be focused on small vessels, calculations will be separately performed for vessels with a diameter less than 20 ųm.	6 Hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of perfused vessels	Proportion of perfused vessels measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands)	6 Hours
Perfused vessel density	Perfused vessel density measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands)	6 Hours
systolic blood pressure	systolic blood pressure measured in mmHg	6 hours
Diastolic blood pressure	diastolic blood pressure measured in mmHg	6 hours
Heart rate	heart rate in beats per minute	6 hours
Serum lactate	Serum lactate measured in milligrams per deciliter	6 hours
Urine output	quantity of urine in milliliters	6 hours
Serum Creatinine	serum creatinine measured in milligrams per deciliter	24 hours
Serum Sodium	Serum sodium measured in milligrams per deciliter	24 hours
Serum potassium	Serum potassium measured in milligrams per deciliter	24 hours
Cardiac output	quantity of blood pumper by the heart measured by electrical cardiometry in liters per minute	6 hours
systemic vascular resistance	systemic vascular resistance measured by electrical cardiometry	6 hours
Norepinephrine requirements	total requirement of norepinephrine needed to maintain mean arterial blood pressure above 65 mmHg	6 hours
perfusion index	proportion of pulsatile to non-pulsatile portions in peripheral circulation	6 hours
total fluid intake	amount of fluids received by the patient in milliliters	24 hours

Collaborators and Investigators

• Sponsor: Cairo University
• Investigators: Study Director: Martin W Dünser, Professor, Department of critical care, University of London college hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2019
• Primary Completion (Anticipated): August 1, 2019
• Study Completion (Anticipated): August 15, 2019

Study Registration Dates

• First Submitted: October 1, 2017
• First Submitted That Met QC Criteria: October 1, 2017
• First Posted (Actual): October 5, 2017

Study Record Updates

• Last Update Posted (Actual): January 16, 2019
• Last Update Submitted That Met QC Criteria: January 14, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; 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; Serine Proteinase Inhibitors; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine; Angiotensin II; Giapreza; Angiotensinogen
• Other Study ID Numbers: N-68-2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No