Routine Microcirculation Measurements in Intensive Care Unit Patients and Validation by PiCCO Technology. ROUMI-study

The microcirculation is the final destination of the systemic circulation and
is comprised of microvessels with a diameter less than 20 µm consisting of
arterioles, venules, and capillaries. Under physiological conditions, the
microcirculation consists of about 10% of circulating blood and plays a vital
role in oxygen transport to the tissue, carbondioxide (CO2) removal,
inflammation, hemostasis, and substrate and hormonal transport. Furthermore,
capillaries are the primary interface between the circulating blood and the
parenchymal cells. Hand-held videomicroscope (HVM) techniques are used to
directly visualize the microcirculation of all organ surfaces. The sublingual
area is the most commonly used target of HVMs due to its easy accessibility
although other organ surfaces also in surgery have been explored. Sublingual
area may represent the global microcirculation since it origins from the same
point where the intestinal system stem from and blood supply of this area is
provided by the arteria carotis which also provide blood to the brain.
HVMs are useful to directly monitor the convective and diffusive function of
the microcirculation, which is quantified as the flow of red blood cells (RBCs)
in the capillaries (mean flow index and proportion of perfused vessel (PPV))
and the density of perfused capillaries (also referred to as functional
capillary density(FCD)), respectively. Blood flow in the microvessels indicates
the quality of perfusion and is described as microvascular flow index (MFI).
Heterogeneity index (HI) is used to estimate the flow heterogeneity in the
microcirculation specifically seen in conditions of sepsis and is calculated as
the difference between the highest and lowest MFI divided by mean MFI. Overall,
the perfusion of the tissues depends on the amount, distribution, and diameters
of the capillaries. The density of the vessels is estimated as the proportion
of total vessels present in the field of view. The total vessel density (TVD)
is calculated as the total length of vessels divided by the total surface area
of the field of view as units mm/mm2. Perfused vessel density (PVD) is
estimated as the proportion of perfused vessels divided by the TVD. The
perfusion of a tissue depends on the number, distribution, and diameters of the
capillaries in combination with blood viscosity and driving pressure across the
capillaries. There are two main hemodynamic principles governing how oxygen in
red blood cells reaches the tissue cells; the first is the convection based on
red blood cell flow, and the second is the diffusion distance oxygen must
travel from the red blood cells in the capillaries to the parenchymal cells.
Convection is quantified by measurement of flow in the microvessels, and
diffusion is quantified by the density of the perfused microvessels (FCD). The
convection and the diffusion are both deteriorated in the critically ill
patients which in turn leads to impaired tissue oxygenation. Therefore,
monitoring the microcirculation in combination with macrohemodynamic parameters
provide a comprehensive evaluation of the cardiovascular system notability in
critically ill patients.
The fundamental aim of resuscitation of critically ill patients from states of
shock and severe inflammatory conditions is to restore tissue perfusion and
oxygenation [10]. In order to maintain optimal tissue perfusion, large vessels
should transmit the adequate blood from heart into the tissues. This transport
is largely depends on the function of the heart, resistance of the vessels and
the amount of the intravascular volume. Based on the guidelines regarding the
resuscitation of shock, intravenous fluids and vasopressors are used to improve
tissue perfusion by increasing heart contractility and vascular resistance, and
expanding intravascular volume. Systemic macro-hemodynamic parameters such as
blood pressure, heart rate, cardiac output, stroke volume, systemic vascular
resistance are conventionally used to assess and monitor resuscitation success
in routine clinical practice, assuming that tissue perfusion and oxygenation
recover parallel to systemic hemodynamic parameters. However, only maintaining
the tissue perfusion is not enough to achieve tissue oxygenation which may
remain impaired despite the correction of systemic circulatory parameters.
Unfortunately, normalization of routinely used macrocirculatory parameters may
not always be accompanied with normalization of microcirculatory parameters
resulting in an unknown under-resuscitation of the patient. Inconsistency
between micro- and macrocirculation is a key feature of shock status has been
recently defined as *loss of hemodynamic coherence*. Various studies have shown
that improvement of the macrocirculation in conditions of shock can occur
independently from the microcirculatory blood flow, especially in critically
ill patients and has shown to be an independent predictor of organ dysfunction
and adverse outcome. Direct visualization of sublingual microcirculation using
hand-held video microscopes such as the Cytocam-IDF (Braedius Medical, Huizen
the Netherland) imaging device can be used to identify such loss of hemodynamic
coherence and may provide an opportunity to monitor resuscitation therapy with
vasopressors and fluids by potentially preventing unnecessary and inappropriate
administration of large volumes of fluids and/or vasopressor therapy. The
reason behind that is the published studies which showed the success of
Cytocam-IDF in displaying loss of hemodynamic coherence in critically ill
patients while macrohemodynamic parameters cannot. Moreover, Cytocam-IDF allows
more physiologically based approaches for the diagnosis and treatment of
intensive care patients.
For the reasons stated the importance of using the hand held video microscopes
for measuring sublingual microcirculation has been underscored by intensive
care specialist as witnessed the reason publication in Intensive Care Medicine
of international guidelines for sublingual microcirculation measurement
endorsed by the European Society of Intensive care Medicine. Despite the
usefulness of microcirculatory monitoring in critically ill patients, however,
it is as yet not part of routine monitoring in intensive care where systemic
hemodynamic parameters are still the main variables being monitored, and for
this reason, it requires validation. PiCCO monitorization is one of the most
common invasive technique used to assess systemic hemodynamic status in severe
critically ill patients. Although invasive hemodynamic monitorization is
adopted as the gold standard in intensive care, during the few last years,
monitorization of macro-hemodynamic parameters have evolved considerably from
invasiveness to less or no invasiveness to decrease the complications like
infection, bleeding, thrombosis, pneumothorax. In addition, continuous and
real-time measurements of macro-hemodynamic variables are preferred to
intermittent macro-hemodynamic parameters. Emphasizing non-invasive nature,
easy to apply, and success in detecting hemodynamic coherence in critically ill
patients, microcirculatory imaging with Cytocam-IDF becomes a candidate for
integral hemodynamic monitorization. However, microcirculatory imaging has not
been validated with an invasive hemodynamic monitoring tool such as PiCCO
technology.
To use a new technique, parameter or device as a monitoring method in clinical
practice, it should fulfil the conditions safety, efficacy, effectiveness, and
efficiency. Once the technique meets these conditions, clinical appraisal and
efficacy are possible. Efficacy indicates whether the technique indeed measures
what it claims to measure, and this has been shown in several studies in the
literature. A gold standard should exist to evaluate the efficacy of the
measurement, and currently, this can only be a systemic hemodynamic variable
such as cardiac output or mean arterial pressure. Based on such information the
clinical utility of the technique on the diagnosis of circulatory compromise
can be evaluated. Another crucial point to be evaluated is the safety. Due to
its non-invasive nature (an optical measurement under the tongue), however,
Cytocam-IDF imaging is not associated with any adverse effect. Measurement of
the microcirculation using the device requires only a disposable sterile cap to
be placed on the light guide of microscope making it a cheap technique to
implement. The technique is easy to use and can also be used by nurses and
circulation practitioners.
With this project, we aim to assess the correlation of PiCCO technology and
Cytocam-IDF imaging as a routine monitoring tool in critically ill patients
with circulatory compromise. To this end, we will compare Cytocam-IDF imaging
to an invasive hemodynamic monitorization tool (PiCCO) in terms of
comparability and linearity in critically ill patients. In addition, we will
create a cut-off range for total vessel density, perfused vessel density and
proportion of perfused vessels since there has been no range defined yet so as
to assess the severity of the microcirculatory dysfunction. Therefore, we
sought to examine the most common parameters used in PICCO viz. cardiax index
and (stroke) volume index to respectively microvascular flow index (MFI) and
the vessel density parameters of sublingual microcirculation viz. total vessel
density and perfused vessel density. To our knowledge, this study is the first
that compares microcirculatory parameters with the invasive macro-hemodynamic
parameters obtained by a gold standard and invasive technique in critically ill
patients.

With this project, we aim to validate Cytocam-IDF imaging as a routine
monitoring tool in critically ill patients. To this end, we will compare
Cytocam-IDF imaging to an invasive hemodynamic monitorization tool (PiCCO) in
terms of comparability and linearity in critically ill patients.

o Single-centre, prospective, observational study in the adult Intensive Care
Unit.

Assessment of sublingual microcirculation is a non-invasive procedure which
takes a few minutes to perform associated with no risk or burden to the
patient. Additional blood tests will not be required. The patients will have
been treated and diagnosed using conventional modalities