Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03044483 |
| Other study ID # |
214674 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 6, 2017 |
| Est. completion date |
July 1, 2020 |
Study information
| Verified date |
November 2023 |
| Source |
University Hospitals, Leicester |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
When infection strikes, the body's immune system reacts by producing chemicals in the
bloodstream and changes in white blood cells to attack the infecting organism (bacteria,
viruses or other organisms) and prevent it spreading. This is termed the 'inflammatory
response'. Though beneficial in fighting infection, this response can sometimes be excessive,
causing harmful effects on body organs. This is termed the 'systemic inflammatory response
syndrome' and when linked to infection is termed 'sepsis'.
Previous research has shown that in patients who have sepsis, the small blood vessels
supplying oxygen and nutrients to muscles and other organs (the microcirculation) become
abnormal and do not function as they would in health. However, it is difficult to assess the
function of microcirculation in clinical practice, and we want to find new, easier ways of
doing so.
The aim of this study is to test a new method for assessing the function of these small blood
vessels, by directly visualising them using a highly sensitive microscope, the size of a pen,
placed under the tongue. By understanding the flow of blood in these vessels in healthy
individuals, we will gain a better understanding of how these vessels are affected in
illness.
Description:
Background
Sepsis is a highly heterogeneous disease state brought about by a dysregulated host response
to systemic infection, with uncontrolled pro- and anti-inflammatory processes leading to
collateral tissue injury and immune suppression.
Sepsis poses a significant health burden worldwide, with deaths attributed in the UK
estimated at approximately 44,000 per annum. Prompt treatment directed by internationally
agreed management guidelines improves outcomes in sepsis. However early diagnosis of sepsis
remains difficult, with current diagnostic criteria relying on the presence of organ
dysfunction and derangement of macro haemodynamic variables. At the point of diagnosis,
mortality is in excess of 10%. At present there are no specific criteria in the diagnosis of
sepsis based on the underlying pathophysiological abnormalities, specifically on assessment
of the microcirculation.
The microcirculation in sepsis
The microcirculation consists of a dense network of arterioles, capillaries and venules,
whose diameter is less than 150 um. Its functions are to supply nutrients and oxygen for
aerobic metabolism and to reduce cellular waste products.
Sepsis affects all elements of the microcirculation, with microcirculatory dysfunction
playing an important role in the pathophysiology of severe sepsis and septic shock. Sepsis is
associated with decreased capillary density and increased perfusion heterogeneity leading to
decreased oxygen delivery, tissue hypoxia and subsequently organ dysfunction. Changes in
microcirculatory function may precede the traditional diagnostic features of sepsis,
providing earlier information on patients who will go on to develop severe sepsis and
multi-organ failure. Recognition of sepsis at this early stage would allow prompt treatment,
aimed at restoring homeostasis of the microcirculation, therefore altering disease
progression.
A number of studies have demonstrated that improvements in microcirculatory function
following early resuscitation are associated with decreasing organ dysfunction, and those
patients whose microcirculations fails to improve following resuscitation have poorer
outcomes. Despite recognition of the importance of the microcirculation in sepsis, current
goal-directed end points rely on the monitoring and restoration of global measures of
cardiovascular/organ function (e.g. heart rate, blood pressure, urine output, lactate),
partly because the microcirculation is difficult to monitor in clinical practice. However,
improvement in macro haemodynamic variables does not guarantee restoration of
microcirculatory homeostasis. Clinical assessment of microcirculatory function is presently
inferred from the measurement of by-products generated due to impaired oxygenation/metabolism
such as lactate and carbon dioxide.
Video microscopic techniques for assessment of the microcirculation
Video microscopic techniques provide in-vivo visualisation of the microcirculation, allowing
direct measurement of capillary density, perfusion and flow dynamics. Until recently, these
techniques which have included Orthogonal Polarization Spectral (OPS) imaging and Sidestream
Dark Field (SDF) imaging, have been clinically inaccessible owing to their bulky nature,
operator dependant output and time-consuming offline analysis requirement.
A third-generation handheld microscope has recently been developed (CytoCam-IDF, Braedius
Medical, NL), utilising Incident Dark Field (IDF) illumination. The device incorporates
real-time automated digital image analysis, combined with high resolution lenses and a
computer controlled image sensor for improved resolution. The CytoCam also features a novel
quantitative focusing mechanism with an integrated distance measuring system, whereby once
the focus depth has been established for a specific patient, serial measurements can be made
without having to manually readjust the focus, improving speed and ease of measurements. This
new device performs well when compared to previous devices, providing improved contrast and
image sharpness allowing an increased number of microvessels to be visualised.
Crucially, the CytoCam is equipped with bespoke software allowing images to be stored and
analysed automatically at the point of acquisition. Microcirculatory monitoring is a not a
new technique, but the combination of user friendly ergonomics, accurate image acquisition
and automated analysis opens up this potentially useful direct measurement of
microcirculatory function to bedside clinical practice.
Analysis of the sublingual microcirculation A round table discussion in 2006 by experts in
the field, sought to clarify the features that should be included in microcirculatory
analysis, concluding that assessment of the microcirculation should include measures of
vascular density, assessment of capillary perfusion and a heterogeneity index (in vessels of
<20 micrometres in diameter).
These measured variables are:
Microvascular Flow Index (MFI) - Perfusion quality Image divided in to quadrants. A number is
assigned to each quadrant according to predominant flow type (0 = no flow, 1 = intermittent,
2 = sluggish, 3 = continuous). The MFI results from the mean of the 4 values.
Total Vessel Density (TVD) Vessel density - The total length of the vessels divided by the
total surface area of the analysed area.
Perfused Vessel Density (PVD) - Functional vessel density Total length of perfused vessels
(MFI score 2/3) divided by the analysed area.
Proportional of Perfused Vessels (PPV) - Perfusion quality 100 x number of perfused vessels
divided by the total number of vessels Heterogeneity Index (HI) Measure of the heterogeneity
of flow between vessels. Highest MFI - lowest MFI divided by mean MFI across all sites
analysed
Compared to healthy volunteers, patients with sepsis display lower values for PVD, PPV and
MFI, along with increased heterogeneity index, irrespective of macro haemodynamic condition.
Total capillary density appears to be unaffected by sepsis. These findings were corroborated
by the International Study on Microcirculatory Shock Occurrence in Acutely Ill Patients
(microSOAP) study.
The microSOAP study is to date the largest trial investigating the significance of
microcirculatory alterations in a heterogeneous ICU population (i.e. not just those with
sepsis). Using the previous generation of similar technology, the investigators found that of
the 501 patients included for analysis, 86 (17%) had an abnormal MFI (defined a priori as
<2.6). Of those with an abnormal MFI, the HI was increased with decreased PPV and PVD. Total
vessel density was not affected. Abnormal MFI in conjunction with tachycardia was associated
with an increased mortality (OR 3.24).
CytoCam Tools automated analysis
CytoCam Tools is the proprietary software supplied with the aforementioned microcirculatory
monitor. It utilises a new analysis technique termed Capillary Network Analysis (CNA) whereby
the microcirculation is analysed automatically and in a user-independent nature by a
two-stage process which includes automatic vessel detection (depending on the diameter of
visualised vessels), followed by an assessment of speed of red blood cells in the vessels
identified.
The following microcirculatory variables are then automatically determined.
- Total Vessel Density (TVD) - Total length of all detected vessels divided by the
processed area.
- Speed Index (SI) - Relative number derived from the intensity variation along the
centreline of a vessel, which describes the speed detected in the vessel.
- Perfused Speed Index (PSI) - SI in a vessel where the SI is higher than the perfusion
threshold (PT).
- Average Perfused Speed Indicator (APSI) - Sum of all PSI values divided by the total
number of perfused vessels.
- Proportion of perfused vessels (PPV) - Total length of all vessels with an SI higher
than the PT, divided by the total length of all detected vessels x 100,
- Perfused Vessel Density (PVD) - Total length of all vessels with an SI higher than the
PT divided by the processed area.
- Average Perfused Speed Indicator Heterogeneity Index (APSI HI) - Image divided in to
quadrants and APSI derived for each quadrant. APSI highest minus the lowest APSI divided
by the mean APSI of all quadrants.
The assessment of PPV and PVD relies on the automated analysis of red blood cell speed in
identified vessels. In order to achieve this a predetermined Perfusion Threshold (PT) is set.
The PT describes the state of flow within identified vessels and can range from 0 to
infinite. Manufacture assessment has determined that a PT of over 1 is consistent with a
"perfused condition" and this can be subdivided further as follows:
Perfusion threshold
State of flow 0 - 1 = No flow 1 - 5 = Sluggish 5 or greater = Good flow Normal ranges for
these automatically measured variables in health are currently unknown. Understanding the
normal ranges would allow us to utilise this technique in future studies concerning the early
diagnosis of septic illness. Identification of patients at an early stage in the
pathophysiological process of sepsis before the development of traditionally diagnostic
macro-circulatory abnormalities may allow earlier implementation of treatment.
Rationale
The CytoCam system may represent a step towards a more user-friendly, reproducible,
clinically applicable approach to measuring, and acting upon changes in microvascular
function to improve clinical outcomes. However, the normal ranges for these measurements are
not known, without which further studies cannot take place. This study will identify the
normal ranges for the automatically determined measurements derived by the CytoCam system in
healthy subjects, and open new opportunities for studies, which we anticipate will be aimed
at the early identification of patients with microcirculatory dysfunction (as is found in
sepsis); whose microcirculatory parameters fall outside of these newly defined ranges. This
will be the first step in moving towards routine bedside microcirculatory monitoring in our
intensive care unit.
This work builds on projects currently in progress within the Diagnostic Development Unit
(DDU) based at Leicester Royal Infirmary. The DDU is a University of Leicester
inter-collegiate project between Medicine, Space Science and Atmospheric Chemistry, exploring
the use of novel non-invasive monitors in Emergency Medicine and Critical Care.
Population to be studied
OBJECTIVE
To identify the normal ranges for automatically measured microcirculatory variables as
determined by the CytoCam system in different adult age groups.
