Microcirculation Recruitment Using Albumin 20% and Terlipressin in Septic Patients

Recruitment of Microcirculation Using Albumin 20% and Terlipressin in Patients With Septic Shock: a Randomized Controlled Double-blinded Study.

The aim of this study is to evaluate the effect of combining HSA 20% and terlipressin on the microcirculation in patients with septic shock using the following;-

• Microcirculation recruitment by Cytocam-IDF.
• Cardiac output by LiDCOrapid.
• Measuring serum lactate level.

Study Overview

• Status: Not yet recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Albumin 20% and terlipressin

Detailed Description

Sepsis is one of the major medical problems and is responsible for high morbidity and mortality. Surviving Sepsis Campaign Guideline 2016 introduced 3-hours and 6-hours bundles in management of septic shock. The 2018 update of the Surviving Sepsis Campaign guidelines introduced the 'Hour-1 Bundle' which recommends treatment with intravenous fluids, measurement of serum lactate concentration as a marker of illness severity, administration of vasopressors, obtaining blood cultures and administering broad-spectrum antibiotics, all within the first hour.

The usual targets for resuscitation of patients with septic shock are the macro-circulatory parameters such as mean arterial blood pressure and heart rate; however, it is believed that restoration of microcirculatory parameters is not sufficient to avoid organ failure unless it was associated with improved microcirculatory perfusion. The loss of coherence between macro- and micro-circulatory parameters increases the need to evaluate the microcirculatory blood flow. So impaired microvascular perfusion is increasingly recognized as a major determinant of tissue hypoxia during sepsis and is a key factor in the pathogenesis of sepsis-induced organ failure.

Fluid resuscitation is recommended to be initiated immediately and completed within the first hour. Guidelines recommend at least a 30-mL/kg bolus of crystalloid fluid as the initial resuscitation. Crystalloid is the fluid of choice for initial resuscitation and subsequent intra-vascular volume replacement in patients with sepsis and septic shock.

Albumin in addition to crystalloids is suggested when patients require a substantial amount of crystalloids. Although the guidelines make no recommendation regarding which concentration of albumin should be used, 5% albumin is most commonly used in patients with hypovolemia to administer as much volume as possible.

In 2016, a study showed that in a rat model of normotensive endotoxemia, the infusion of 4% or 20% Human Serum Albumin "HSA" restored microvascular perfusion in otherwise unresuscitated animals. A more stable microvascular improvement noticed with 20% HSA.

Sepsis is also characterized by an enhanced activation of inflammatory and oxidative stress pathways, which leads to endothelial dysfunction and vascular hyporeactivity.

For its ability to counteract oxidative and nitrosative stress, albumin may represent not only a plasma expander but also an endothelium-modulating agent. In an experimental rodent model of endotoxemia, (HSA) prevented endothelial dysfunction and vascular hyporeactivity.

In patients with septic shock requiring vasopressors, a targeted mean arterial pressure "MAP" of 65 mm Hg within the first hour is recommended. Norepinephrine is the recommended first-line vasopressor in septic shock. If MAP is not maintained at 65 mm Hg or greater with norepinephrine alone or if the norepinephrine dose needs to be decreased, either vasopressin (up to 0.03 unit/minute) or epinephrine can be added to norepinephrine. Although norepinephrine is widely regarded as the first-line vasoactive medication in sepsis, literature continues to debate whether the early addition of vasopressin should be common practice.

Terlipressin is a synthetic analogue of vasopressin which has greater selectivity for the V1 receptor that cause vascular smooth muscle vasoconstriction in response to vasopressin and thus could be associated with fewer side effects than vasopressin.

In 2016 a study showed that terlipressin therapy was associated with good improvement in hemodynamic variables and kidney functions more than adrenaline in patients with refractory septic shock despite adequate fluid resuscitation and the use of norepinephrine.

No data was found on effect of combination of albumin and terlipressin on microcirculation in septic patients.

This study aims to investigate the effect of this combination on microcirculation using Cytocam-IDF (incident dark-field illumination), Braedius.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Amany Mousa Salama, Assistant lecturer; Phone Number: +201004820018; Email: dr.amany.mousa@gmail.com
• Study Contact Backup: Name: Mohamed Sayed Arafa, Lecturer; Phone Number: +201003752053; Email: dr.3arafa1@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The presence of septic shock meeting all of the following criteria less than 24 hours:-

  1. Clinically possible or probable or microbiologically confirmed infection taking into account the definitions of the "International Sepsis Forum (ISF)"
  2. Despite adequate volume therapy, vasopressors are required to maintain mean arterial pressure (MAP) ≥ 65 mm Hg.
  3. Serum lactate level > 2 mmol/l (18 mg/dl) despite adequate volume therapy.

Exclusion Criteria:

• Patients who failed to achieve target MAP despite adequate resuscitation with fluids and maximum dose of noreadrenaline.
• Acute coronary artery disease or underlying cardiac dysfunction [cardiac index (CI) <2.2 l/min/m 2 ].
• Severe liver disease (Child-Pugh grade C)
• Chronic renal failure.
• Known hypersensitivity to Norepinephrine, terlipressin and human albumin.
• Those having Raynaud's phenomenon, or a vasospastic diathesis and
• Other causes of shock e.g.; hemorrhagic hypovolaemia, cardiogenic shock, anaphylactic shock, neurogenic shock.
• Pregnant patients and lactation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group AT; will receive a bolus of albumin (1gm/kg) and terlipressin loading dose of 1 mg over 20 minutes followed by infusion at rate (2 μ g/kg/h)	Drug: Albumin 20% and terlipressin; Evaluation the effect of adding 20% HSA and terlipressin on microvascular flow index (MFI), flow heterogeneity index, total vessel density (TVD), and perfused vessel density (PVD) in comparison to the standard care in patient with septic shock.; Other Names: Microcirculation
Placebo Comparator: Controlled; will receive the routine management of septic shock patients as culture-based IV antibiotics, IV fluids and intropic support plus a placebo (as lactated ringer solution in the same infusion rates for blinding).	Drug: Albumin 20% and terlipressin; Evaluation the effect of adding 20% HSA and terlipressin on microvascular flow index (MFI), flow heterogeneity index, total vessel density (TVD), and perfused vessel density (PVD) in comparison to the standard care in patient with septic shock.; Other Names: Microcirculation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Flow Index 6hs	Determination the degree the mean flow index (MFI) 6 hrs after administration albumin and terlipressin in patient with septic shock	6 hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Flow Index 24hs	Determination the degree the mean flow index (MFI) 24 hrs after administration albumin and terlipressin in patient with septic shock.	24 hs

Collaborators and Investigators

• Sponsor: Amany Mousa Salama Muhammed

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): October 1, 2022

Study Registration Dates

• First Submitted: September 29, 2021
• First Submitted That Met QC Criteria: October 13, 2021
• First Posted (Actual): October 15, 2021

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: October 13, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Microcirculation; Terlipressin; Human Albumin 20%
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic; Antihypertensive Agents; Vasoconstrictor Agents; Terlipressin
• Other Study ID Numbers: Microcirculation septic shock

Drug and device information, study documents

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