Changes in Microvascular Perfusion During Blood Purification With Cytosorb® in Septic Shock

March 7, 2018 updated by: Abele Donati, MD, Università Politecnica delle Marche

Sepsis is defined as a life-threatening event due to a dysregulated immune response to an host. Blood purification techniques may be considered as a therapeutic weapon to front sepsis and septic shock.

Haemoadsorption is one of the known blood purification technique that is employed in this study, and it is based on the principle that whole blood, contacting the surface of proper designed sorbent, would be cleared of certain substrates. With haemoadsorption it is possible to de-circulate from bloodstream high molecular weight substances, such as cytokines.In this study Cytosorb® cartridge, based on haemoadsorption principle is applied on septic patients, suffering for acute kidney failure, along with continuous veno-venous haemodialysis (CVVH-D).Microcirculation has a crucial role in the natural history of sepsis.

In this prospective observational non interventional study, 10 septic patients with an acute kidney failure that need CVVH are enrolled.

The primary endpoint of the study is to verify an improvement in the density of microcirculatory vessels and in the quality of blood flow after exposure to Cytosorb®. These two parameters are well described synthetically by the Perfused Vessel Density (PVD).

As secondary endpoints we also want to analyze the modification of microcirculation after haemoadsorption therapy: microvascular blood flow, described by the microvascular flow index (MFI) and peripheral tissue oxygen perfusion during Cytosorb® exposure using near infrared spectroscopy technique (NIRS)

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Introduction Sepsis is defined as a life-threatening event due to a dysregulated immune response to an infection. Blood purification techniques may be considered as a therapeutic weapon to front sepsis and septic shock.

The rationale of blood purification in sepsis is to modulate a dysregulated profile of immune response to the host in order to reduce tissue damage due to over production of pleiotropic pro-inflammatory cytokines.

Blood purification may also control elevated levels of anti-inflammatory cytokines that may lead to a down-modulation of immune system and immunoparalysis.

Haemoadsorption is one of the known blood purification technique that is employed in this study, and it is based on the principle that whole blood, contacting the surface of proper designed sorbent, would be cleared of certain substrates. With haemoadsorption it is possible to de-circulate from bloodstream high molecular weight substances, such as cytokines.

In this study Cytosorb® cartridge, based on haemoadsorption principle is applied on septic patients, suffering for acute kidney failure, along with continuous veno-venous haemodialysis (CVVH-D).

The immune system is involved in the pathogenesis of sepsis, but also the microcirculation has a crucial role in the natural history of this syndrome.

When a proinflammatory subset of cytokines is over-expressed, inducible nitric oxide synthase is activated and leads to an extra production on nitric oxide that results in a disrupted regulation of microvascular and capillary tone. The microcirculation plays a fundamental role to regulate gas, nutrients and metabolites exchange between bloodstream and cells. When microvascular perfusion is altered, tissue hypoxia may occur and result in organ dysfunction.

Microcirculation analysis can be performed at the bedside using a non-invasive video microscopy technique.

The primary endpoint of the study is to verify an improvement in the density of microcirculatory vessels and in the quality of blood flow after exposure to Cytosorb®. These two parameters are well described synthetically by the Perfused Vessel Density (PVD).

As secondary endpoints the investigators will analyze the modification of microcirculatory blood flow after haemoadsorption therapy. The microvascular blood flow, described by the microvascular flow index (MFI), is altered in sepsis. MFI values go from 0 to 3, where 0 means absence of flow, and 3 continuous blood flow. In septic shock MFI generally results to be inferior than 2.6, which is the cut off value between normal and altered MFI. Increasing value of MFI is a sign of microcirculation good response to therapy.

The investigators will also evaluate peripheral tissue oxygenation during Cytosorb exposure using near infrared spectroscopy (NIRS, Inspectra model 560 Hutchinson®). This technique evaluates microvascular perfusion on the thenar eminence muscle. A vascular occlusion test, that reproduces a stagnant ischemia condition, is performed to evaluate microvascular reactivity to an ischemia-reperfusion insult.

An improvement in tissue perfusion and microvascular reactivity is expected during the treatment.

Invasive haemodynamic monitoring will be performed using Picco2®. Changes in macro-haemodynamic parameters are expected in response to therapy.

The Sequential Organ Failure Assessment (SOFA) score will be calculated at the enrollment in this study and during the therapy.

Heart rate, SpO2, temperature, mean arterial pressure, arterial and central venous blood gas analyses will be collected during the study.

Materials and methods

In this prospective observational non interventional study, 10 septic patients with an acute kidney failure that need continuous veno-venous haemodialysis will be enrolled.

Prior to enrollment a formal informed consent is obtained. This study is approved by the local ethical committee.

Statistical analysis

The Kolmogorov-Smirnov test will be performed to define the normal or non-normal distribution of the variables. The ANOVA test for repeated measures with Bonferroni post hoc test or Dunn's post hoc test will be applied to evaluate differences over time. The Friedman test will be applied for not normally distributed data.

Blood sampling

At baseline (T0) participants will undergo arterial blood gas analysis to obtain the following values: arterial O2 tension (PaO2), arterial carbon dioxide tension, pH, base excess, lactate concentration, PaO2/FiO2 ratio, and central venous gas analysis to determine central venous O2 saturation.

The plasmatic concentration of the main pleiotropic cytokines will be measured, including interleukin (IL)1-beta, IL6, IL8, IL10, tumor necrosis factor-alpha.

After enrollment, these essay will be repeated at T1 (after 6h of exposure to Cytosorb®) and at T2 after 24h of therapy.

Routine blood cell count, clotting profile and leukocyte formula will be performed at baseline and at T2 along with proCalcitonine essay.

Microcirculation analysis

The investigators will analyse the microcirculation using sidestream dark field video microscopy technique applied to the sublingual mucosa, this technique is not invasive and painless.

In this study the investigators will use the Microscan by Microvision Medical (The Netherlands).

Three short videos of the microcirculation will be collected, captured in three different areas of the sublingual mucosa. These videos will be analysed using Automated Vascular Analysis (AVA 3.2 software, Microvision Medical, Amsterdam, NL). Microcirculation density is described by Total Vessel Density (TVD) and the De Backer score; microcirculation quality of flow is defined by the Microvascular flow index (MFI) and Percentage of Perfused Vessel (PPV). The Perfused Vessel Density (PVD) describes the density of well perfused vessel. Microcirculation analysis will be performed at T0, T1 and T2.

Tissue oxygenation

Tissue oxygenation will be assessed using near infrared spectroscopy (NIRS) applied on the thenar eminence muscle.

The device Inspectra® (Hutchinson model 560) measures the tissue oxygen saturation, and estimates the tissue haemoglobin content that is summarized in the tissue haemoglobin index (THI).

A vascular occlusion test will be performed, which simulates an ischemia-reperfusion condition of the tissue in order to evaluate microvascular reactivity.

A cuff is applied to the forearm and inflated at 300 mmHg in order to generate a stagnant ischemia. Inspectra screen generates a curve of desaturation named Downslope. When a value of tissue O2 saturation of 40% is reached, the occlusion cuff is deflated and the Inspector screen draws a curve of resaturation of the tissue, named Upslope. Upslope and Downslope values are measured. In the phase of resaturation an Hyperemia Area is obtained as tissue O2 saturation generally exceeds for a certain period of time the basal value. The hyperemia area is measured as an index of microvascular reactivity.

NIRS with a vascular occlusion test will be performed at T0, T1 and T2.

Haemodynamic monitoring

Each participant will undergo haemodynamic monitoring with transpulmonary thermodilution based devices (Picco2® by Pulsion and EV1000® by Edwards). Thermodilution based calibration are obtained ad basal time, at T1 and T2.

Vasopressor dose, haemodynamic parameters and SOFA score will be recorded at t0, t1, t2..

Study Type

Observational

Enrollment (Actual)

10

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

patients with septic shock requiring renal replacement therapy for acute renal failure and undergoing haemoadsorption with Cytosorb cartridge

Description

Inclusion Criteria:

  • age>18
  • septic patients with acute kidney failure that need to undergo CHHV treatment.

Exclusion Criteria:

  • hypersensitivity or allergy to the components of the cartridge
  • pregnancy
  • maxillary-facial trauma that prohibits mouth access and sublingual microcirculation evaluation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Haemoadsorption with Cytosorb cartridge
patients with septic shock and acute renal failure requiring renal replacement therapy with the haemoadsorption cartridge Cytosorb
Device: Haemoadsorption with Cytosorb cartridge
microcirculatory monitoring in septic shock patients requiring renal replacement therapy for acute renal failure and haemoadsorption with Cytosorb cartridge

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
improvement in perfused vessel density
Time Frame: 24 hours
improvement in perfusion of the sublingual microcirculation
24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
improvement in microvascular flow index
Time Frame: 6 hours and 24 hours
improvement in microvascular blood flow quality
6 hours and 24 hours
improvement in tissue oxygenation
Time Frame: 6 hours and 24 hours
improvement in NIRS-derived parameters of tissue oxygenation and microvascular reactivity
6 hours and 24 hours
improvement in perfused vessel density
Time Frame: 6 hours
improvement in perfusion of the sublingual microcirculation
6 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Università Politecnica delle Marche

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 9, 2016

Primary Completion (Actual)

December 15, 2017

Study Completion (Actual)

December 15, 2017

Study Registration Dates

First Submitted

February 28, 2018

First Submitted That Met QC Criteria

February 28, 2018

First Posted (Actual)

March 7, 2018

Study Record Updates

Last Update Posted (Actual)

March 8, 2018

Last Update Submitted That Met QC Criteria

March 7, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • cyto2018

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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