Intensive Care Med
DOI 10.1007/s00134-010-2005-3
REVIEW
Daniel De Backer
Gustavo Ospina-Tascon
Diamantino Salgado
Raphaël Favory
Jacques Creteur
Jean-Louis Vincent
Monitoring the microcirculation in the critically
ill patient: current methods and future
approaches
Received: 28 February 2010
Accepted: 14 July 2010
Abstract Purpose: To discuss the
techniques currently available to
evaluate the microcirculation in critically ill patients. In addition, the
most clinically relevant microcirculatory alterations will be discussed.
Methods: Review of the literature
on methods used to evaluate the
microcirculation in humans and on
microcirculatory alterations in critically ill patients. Results: In
experimental conditions, shock states
have been shown to be associated
with a decrease in perfused capillary
density and an increase in the heterogeneity of microcirculatory
perfusion, with non-perfused capillaries in close vicinity to perfused
capillaries. Techniques used to evaluate the microcirculation in humans
should take into account the heterogeneity of microvascular perfusion.
Microvideoscopic techniques, such as
orthogonal polarization spectral
(OPS) and sidestream dark field
(SDF) imaging, directly evaluate
microvascular networks covered by a
thin epithelium, such as the sublingual microcirculation. Laser Doppler
and tissue O2 measurements
Copyright jointly held by Springer and
ESICM 2010
D. De Backer ()) G. Ospina-Tascon
D. Salgado R. Favory J. Creteur
J.-L. Vincent
Department of Intensive Care,
Erasme University Hospital,
Université Libre de Bruxelles,
Route de Lennik 808,
1070 Brussels, Belgium
e-mail: ddebacke@ulb.ac.be
Tel.: ?32-2-5553380
Fax: ?32-2-5554698
Introduction
The microcirculation plays a fundamental role in gas and
nutrient exchange; it must constantly adapt by controlling
vascular tone. In disease states, increased permeability
may be necessary to provide the inflammatory response,
satisfactorily detect global decreases
in tissue perfusion but not heterogeneity of microvascular perfusion.
These techniques, and in particular
laser Doppler and near-infrared
spectroscopy, may help to evaluate
the dynamic response of the microcirculation to a stress test. In patients
with severe sepsis and septic shock,
the microcirculation is characterized
by a decrease in capillary density and
in the proportion of perfused capillaries, together with a blunted
response to a vascular occlusion test.
Conclusions: The microcirculation
in humans can be evaluated directly
by videomicroscopy (OPS/SDF) or
indirectly by vascular occlusion tests.
Of note, direct videomicroscopic
visualization evaluates the actual
state of the microcirculation, whereas
the vascular occlusion test evaluates
microvascular reserve.
Keywords Microcirculation
Cardiac output
Hemodynamic monitoring
Capillaries Oxygen delivery
Outcome
including leukocyte diapedesis. It is difficult to simultaneously evaluate these different aspects of the
microcirculation. In this review, we will focus on the role
of the microcirculation in oxygenation, dealing with the
evaluation of blood flow and its implication for cellular
oxygenation.
In experimental conditions, intravital microscopy is
considered as a gold standard, allowing measurement of
blood flow in individual vessels and could be coupled
with measurements of oxygenation, endothelial activation
(including generation of reactive oxygen species), and
permeability measurements. Unfortunately, this technique
is not applicable as such in humans, as it can only be
applied on organs that can be submitted to transillumination, with light coming from the opposite side to the
microscope objective, such as cremaster muscle, liver
edge, intestine, and dorsal skinfold. It also uses specific
dyes that are often not registered for human use.
In humans, and especially in critically ill patients, the
evaluation of the microcirculation has long been difficult.
Recent years have witnessed the development of new
techniques that can either directly visualize or indirectly
evaluate microvascular perfusion. In order to appreciate
the information provided by the various techniques, it is
important to understand the architecture of the microcirculation and its behavior in health and disease.
Characteristics of the normal and the diseased
microcirculation
The microcirculation comprises vessels smaller than
100 microns, i.e., arterioles, capillaries, and venules.
Arterioles divide into small branches, and the terminology
of A1, A2-An is used to define each vessel before bifurcation (1st bifurcation for A1, 2nd for A2,…). Arterioles
are mostly responsible for vascular tone, with a considerable decrease in blood pressure from proximal to
terminal arterioles. Local modulation of arteriolar tone in
first-order arterioles is responsible for adapting microvascular perfusion to local O2 demand [1]. Capillaries
originate from the terminal arterioles, are covered by a
thin endothelial surface, and are mostly responsible for O2
and nutrient exchange, as well as elimination of cellular
waste products. Capillary networks vary in density and
architecture. Capillary architecture differs somewhat
among organs, with arborescence being the most common
form, but the gut, liver, and kidney have different architecture. In general, arterioles divide into smaller and
smaller vessels until the capillaries, and these never
merge. The length and orientation of the capillaries may
vary from one organ to another. Capillaries flow into
small venules which merge into larger ones, and contact
between venules and arterioles/capillaries is limited. In
some organs, the specific architecture may favor countercurrent exchange mechanisms [2]. Leukocyte adhesion,
rolling, and migration, as well as permeability changes
take place mostly in venules, although again there may be
some variability among organs [3]. Although arterioles
are responsible for fine tuning microcirculatory perfusion,
events occurring at capillary and even venular sites may
affect capillary perfusion as cross-talk occurs within
endothelial cells [1, 4].
Typical microcirculatory alterations in disease states
Numerous experimental studies have reported that
microvascular blood flow is altered in sepsis. Shortly after
endotoxin administration, functional capillary density
(FCD) is decreased, and this effect is directly dosedependent [5]. This decrease in FCD is associated with an
increase in the diffusion distance for O2 [6]. As the
shutdown of capillaries is heterogeneous, some areas
become deprived of capillaries while others are not, so
that perfused capillaries are in close vicinity to non-perfused capillaries [7, 8].
Low-flow conditions such as hemorrhage or cardiogenic shock are associated with a progressive decrease in
arteriolar diameter [9], associated with a substantial
decrease in FCD [10] as a result of shutting down some
capillaries while others remain perfused with reduced flow.
The severity of the decrease in FCD is directly related to a
poor outcome [10]. When global flow returns, the microcirculation becomes more heterogeneous as a result of the
inflammatory response associated with reperfusion [10].
What are the consequences of the heterogeneity
of microvascular perfusion?
In normal circumstances, heterogeneity is minimal [11],
and matching of perfusion to metabolism improves in
hypoxic or low-flow conditions [7, 12]. In sepsis, heterogeneity cannot be improved in response to changes in O2
demand or to decreases in O2 delivery [7], and tissue
perfusion and oxygenation are, therefore, compromised
[13]. Similar findings can be observed in reperfusion
injury [11, 14].
Heterogeneity of the microvascular perfusion is associated with heterogeneity in O2 diffusion distance, with a
shift to higher median values [6]. As a result, an O2
extraction defect is observed, with an increased mixed
venous O2 saturation (SvO2) [7, 8], even though O2
extraction in a single perfused capillary may be increased
[15]. Importantly, tissues tolerate better a homogeneous
decrease in blood flow better than a heterogeneous one
[16]. As shown in a theoretical example in Fig. 1, a 50%
decrease in flow in a homogeneously perfused tissue is
accompanied by preserved tissue O2 consumption, as a
result of increased O2 extraction. A 50% reduction in
capillary density, resulting in heterogeneous perfusion, is
associated with a reduction in tissue O2 consumption
(and hence tissue hypoxia) as a result of increased diffusion distance. In these conditions, venous PO2/SO2 will
Fig. 2 Venous O2 saturation can be low in conditions associated
with microvascular shunting. When perfusion is heterogeneous, a
low venous oxygen saturation can also be encountered. If total flow
to the tissue is decreased (bottom panel), venous oxygen saturation
decreases but this fails to reflect an improvement in perfusion
heterogeneity
Fig. 1 Impact of heterogenous perfusion on tissue metabolism and
venous oxygen saturation. Normal situation (top panel): O2 is
delivered at 240 ml/min in four perfused capillaries. The tissues
extract oxygen to meet cellular oxygen consumption. Low flow but
homogeneous perfusion (middle panel): half the oxygen is delivered to the tissue but all the capillaries are perfused. The amount of
oxygen is sufficient to meet oxygen requirement of the cells. Hence,
VO2 is preserved even though venous oxygen saturation is severely
decreased. Heterogeneous flow (bottom panel): even though total
oxygen delivery is preserved (240 ml/min) only 50% of the
capillaries are perfused. Cells close to the perfused capillaries
consume the normal amount of oxygen. Cell too far away from
perfused capillaries do not receive enough oxygen to meet their
oxygen requirements and become hypoxic. As a consequence,
hypoxic zones can be encountered in the presence of an elevated
venous oxygen saturation. Note: this schematic presentation is
simplified. In normal conditions, recruitment of microcirculation is
not maximal and a mild degree of heterogeneity can be observed. In
response to systemic low flow, such as illustrated in middle panel,
the microcirculation tends to adapt by recruiting previously unfilled
capillaries and decreasing perfusion heterogeneity [13, 118]. When
endothelial dysfunction occurs and heterogeneity develops, such as
in bottom panel, these adaptive mechanisms are lost. In addition to
these, tissues try to limit the impact of decreases in perfusion by
decreasing metabolism, which leads to a decrease in O2 consumption (concept of oxygen conformance [119])
increase; this explains the typically high SvO2 in sepsis.
Nevertheless, SvO2 can still decrease in sepsis [17]: as
illustrated in Fig. 2, if blood flow decreases by 50%
without further altering heterogeneity, SvO2 will decrease
as a result of the increase in extraction in perfused
capillaries.
The heterogeneity of tissue perfusion may not be
revealed by all methods used to evaluate the microcirculation: these techniques should have a sufficient spatial
resolution to detect heterogeneity in blood flow or in PO2.
permeability, and regulation of inflammation and coagulation. In this manuscript we will focus on the transport
and exchange functions. The latter can be assessed by
using markers of microvascular perfusion and indirectly
by indices of tissue oxygenation (Table 1).
By definition, any device looking at the microcirculation can only evaluate the microcirculation in the
microvascular bed in which it is implemented. The ability
of that specific window to represent other beds depends
on the mechanisms implicated in microvascular disease
(generalized, diffuse but somewhat heterogeneous or
localized), on organ microvascular architecture, and on
local factors (local vasoconstriction/pressure). Some areas
may be more relevant than others, as illustrated by a
relationship with microcirculatory alterations in that area
with outcome. Nevertheless one should, at best, consider
that the area being investigated is a window that reflects
the minimal alterations that are likely to be observed in
other areas, provided that local factors do not exacerbate
the lesion in the investigated area.
Evaluation of microvascular perfusion
Clinical evaluation and biomarkers
An impaired microcirculation may be suspected in the
presence of mottled skin, acrocyanosis, slow recoloration
time, or increased central to toe temperature gradient [18,
19]. These signs of impaired cutaneous perfusion lack
specificity (and even sensitivity) for disclosing more
central microcirculatory alterations, including the sublingual microcirculation [19]. Skin vasoconstriction is a
physiological response to low cardiac output, in an
attempt to redistribute blood flow to more central comTechniques used to evaluate the microcirculation
partments. Accordingly, it is fair to say that these clinical
The evaluation of the microcirculation can include signs indicate the severity of cardiovascular impairment
assessment of its transport and exchange functions, [18] and are, therefore, associated with a poor outcome
Table 1 Techniques used to evaluate the microcirculation at the bedside
Variable measured
Main limitations
Techniques measuring microvascular perfusion
Laser Doppler
Flow (relative), hemoglobin content/
microvascular reactivity test
Nailfold videomicroscopy
Vascular density, heterogeneity, flow
OPS and SDF
Vascular density, perfusion
heterogeneity, flow
Techniques measuring tissue oxygenation
SvO2
O2 electrodes
Adequacy of perfusion to flow
Tissue PO2
NIRS
Tissue O2 saturation
Reflectance spectroscopy
O2 saturation/microvascular reactivity test
Gastric tonometry
Tissue CO2 (reflects inadequate perfusion
and/or anaerobic metabolism)
Sublingual capnometry
Tissue CO2 (reflects inadequate perfusion
and/or anaerobic metabolism)
Microdialysis and equilibrium dialysis
Lactate/pyruvate
Global flow to relatively large sampling
volume (mixture of arterioles,
capillaries, and venules)
Restricted to fingers/sensitivity to
temperature and vasoconstriction
Mostly restricted to semiquantitative
scoring/limited sites to investigate/
movement and pressure artifacts
Global measurement
Global measurement in sampled volume
(mixture of arterioles, capillaries, and
venules)
Global measurement in sampled volume
(mixture of arterioles, capillaries, and
venules)
Global measurement in sampled volume
(mixture of arterioles, capillaries, and
venules) unless SO2 histograms are
provided
Interference (feeding/reflux)/difficult
discrimination between low flow and
anaerobic metabolism
Availability limited/difficult
discrimination between low flow and
anaerobic metabolism
Time lag/limited sites to investigate
OPS orthogonal polarization spectral imaging technique; SDF sidestream dark field imaging technique; SvO2 mixed-venous oxygen
saturation; NIRS near-infrared spectroscopy; EMPHO Erlangen MicroPHOtometer
[20], but they do not provide relevant information on the
central microcirculation [19].
Biological markers can also be used. Blood lactate
levels may be considered, but they lack sensitivity and
specificity. Nevertheless, several trials have shown that
therapeutic interventions inducing improvement in
microvascular perfusion are associated with an inverse
and proportional decrease in lactate levels [21, 22].
In experimental conditions, increased plasma hyaluronan levels were associated with impaired microcirculation
in sepsis and therapies that improved the microcirculation
also caused a decrease in hyaluronan levels [23]. Whether
these levels can be used to detect microvascular alterations
in critically ill patients remains to be determined.
Laser Doppler flowmetry
Laser Doppler techniques are frequently used to measure
microvascular blood flow. They can be applied on various
tissues and probes can even be inserted in the upper
digestive tract through a nasogastric tube [24]. As laser
Doppler techniques provide measurements of blood flow
in relative units (mV), one can only assess relative
changes from baseline. The main limitation of this technique is that it measures flow in a variable volume of
tissue and it is unable to detect it in individual vessels.
The sampling volume of current laser Doppler devices is
between 0.5 and 1 mm3, so that the flow that is measured
represents the average flow in at least 50 vessels,
including arterioles, capillaries, and venules of variable
size, direction, and perfusion. Given the heterogeneous
aspect of microvascular alterations, these will be missed
by these devices that measure only total blood flow to a
piece of tissue.
Scanning laser Doppler and reflected-mode confocal
laser scanning microscopy are two attractive developments as they can both visualize the field of interest,
allowing semiquantitative evaluation of heterogeneity of
perfusion [25, 26]. As with traditional laser Doppler
techniques, the resolution of the beam is crucial, the
confocal aspect allowing narrowing of the laser beam.
With a confocal technique, measurements of vascular
density, diameters, and blood flow can be obtained [26,
27]. As a result of the size of the device, it can currently
only be applied in humans to study skin perfusion.
Laser Doppler devices allow a vasoreactivity test,
based on the fact that after transient ischemia obtained by
arterial occlusion with a cuff placed around the arm the
speed of flow recovery will mostly be determined by the
capacity of the microvasculature to recruit arterioles and
capillaries. The ascending slope after transient occlusion
is a marker of endothelial reactivity and blood rheology,
and can thus be used as a surrogate for the functional
integrity of the microvasculature [28]. Although it may
not reflect the actual state of the microcirculation, this test
provides quantitative information on microvascular
reserve within a couple of minutes.
Microvideoscopic techniques
Intravital microvideoscopy is used as a ‘‘classical’’ technique in experimental conditions, but in humans fixed
tissue preparations and dyes cannot be used. Microvideoscopy techniques apply light on superficial organs and
need technical devices to discard light reflected by the
superficial layers of the tissues. Their application in
humans requires that either the organ is thin enough to be
illuminated from behind (e.g., fingers) or that organs can
be made translucent by reflected light.
Fig. 3 Orthogonal polarization spectral (OPS) imaging technique.
Polarized light is directed to the tissue. Light reflected by the
superficial layers is still polarized and discarded by the orthogonal
filter. Light reflected from the depth of the tissues has encountered
many scattering events and has lost its polarized characteristics so
is not discarded by the orthogonal filter; this light is absorbed by
hemoglobin contained in red blood cells so that these will be seen
as gray/black bodies on the screen
Nailfold videocapillaroscopy
Nailfold microvideoscopy was the first method used at the
bedside [29]. The junction between cuticle and nail is
coated with transparent oil and placed on the stage of an
ordinary microscope. In addition to morphological
abnormalities, mostly encountered in chronic diseases of
the microcirculation, capillary density and microvascular
blood flow can be measured [30]. This technique is particularly suitable for investigating the microvascular
effects of chronic diseases, such as diabetes, vasculitis,
and arteritis. Unfortunately, the nailfold area is very
sensitive to changes in temperature: one can control
ambient but not body temperature. Peripheral vasoconstriction can also occur during chills and acute circulatory
failure with or without vasopressor agents. Hence, this
area is of limited use in critically ill patients.
Orthogonal polarization spectral and sidestream
darkfield imaging techniques
Orthogonal polarization spectral (OPS) and sidestream
darkfield (SDF) are two videomicroscopic imaging techniques that can be applied at the bedside. Both are based
on the same general principles developed more than
20 years ago [31, 32], but were only recently implemented in handheld devices. If one applies a light source
on a tissue, the light is reflected by the deeper layers of
the tissue providing transillumination of the superficial
layers of the tissue [32]. With both techniques, the
selected wavelength (530 nm) is absorbed by the hemoglobin contained in the red blood cells, independently of
its oxygenation state, so that these can be seen as black/
gray bodies. In OPS (Fig. 3), the applied light is polarized
Fig. 4 Sidestream dark field (SDF) imaging technique. Green light
is provided by the lateral sides of the device. Light reflected by
superficial layers fails to reach the center of the device where the
optics are located. Light reflected from the depth of the tissues
reaches the center of the device; this light is absorbed by
hemoglobin contained in red blood cells so that these will be seen
as gray/black bodies on the screen
and the reflected light is depolarized, due to multiple hits
on cells in the deep layers of the tissue [33]. The light
reflected by the surface of the tissue is still polarized and
can easily be discarded by a polarizer filter [33]. The SDF
technique (Fig. 4) uses pulsed green light which is provided to the tissue by multiple peripheral emitting diodes
while the optics are located centrally [34]. As a result of
the isolation of the light source from the inner lenses, the
light reflected by the superficial layers is perpendicular to
the light source and does not reach the optics. Both
devices provide good quality images of microvascular
vessels filled with red blood cells. As a result of the
peripheral location of multiple stroboscopic diodes and
synchronization of light emission and camera frame rate,
SDF provides more detailed visualization of capillaries,
with sharper and less granular images than OPS [34].
Using the 95 objective, the on-screen magnification is
9340 for OPS and 9380 for SDF. Importantly, the vascular wall cannot be visualized so that vessels can only be
detected if they contain red blood cells. In addition, red
blood cells that are not contained in vessels can impair
visualization of microvessels. OPS and SDF have been
validated against intravital videomicroscopy [35–37] or
nailfold capillaroscopy [38]. They can be used at wide
ranges of hematocrit [35].
These techniques can be used only on organs covered
by a thin epithelial layer. In animals or in patients during
surgery, they have been used to evaluate the microcirculation of several organs including the brain [39], lungs
[40], tongue [41–44], liver [45, 46], and gut [41–44, 47,
48]. In intact humans, this technique can be applied to the
skin [38, 49–51], conjunctiva [52], gingiva [53], sublingual area [54–57], ileostomies or colostomies [58], and
rectal mucosa [59]. In the sublingual area, which is the
area that has been investigated most, capillaries and
venules of variable size (resolution is 2–3 lm) can be
visualized; arterioles are usually not visualized because
they are located in deeper layers. Red blood cells are
identified as black bodies and tissue perfusion can be
characterized in individual vessels.
What can be measured with these techniques and what
is important? Different variables can be measured,
including vascular density, heterogeneity of perfusion,
and microvascular blood flow. As mentioned above,
estimation of heterogeneity of perfusion (measuring the
proportion of perfused vessels, mean flow index, or heterogeneity index) together with an estimate of capillary
density are the variables which are the most relevant for
tissue perfusion [60]. These are usually measured using a
semiquantitative analysis, which can easily be performed
by experienced investigators, with excellent reliability
(intra- and interobserver variabilities within 5–10% [54,
61, 62] and excellent agreement between investigators
[63]). Semiquantitative analysis can even be obtained as a
point of care measurement [64], but this kind of analysis
has been validated only for a single score and cannot be
used to assess capillary density; it should, therefore, only
be used for rapid evaluation of the microcirculation. Of
note, measurement of blood flow cannot be obtained with
these semiquantitative scores. These techniques can be
used to quantify flow in various organs. In animals,
measurements of gut microvascular perfusion can be
made in a similar way to measurements of the sublingual
microcirculation, and it has been shown that the evolution
over time during sepsis is similar in both sites [43].
However, semiquantitative measurements of gut microcirculation may be more difficult to obtain and less
reproducible than measurement of sublingual microcirculation [44], probably because of the specific gut
architecture.
New software for computer-assisted microcirculation
assessment is currently being developed. With this software, it is usually feasible to measure vessel density and
blood flow in microvessels. Unfortunately, manual intervention is still needed for vessel identification as well as
for blood flow measurement [65].
Is it relevant to measure blood flow in microvessels?
Measuring blood flow in selected microvessels is probably
irrelevant, as an increase in flow in a single vessel may
reflect improved tissue perfusion as well as an increase in
shunt flow. Measuring blood flow in all visible vessels and
comparing histograms of blood flow distribution is probably more relevant, but this is not yet feasible as it would
take hours to obtain such measurements.
Several limitations should be acknowledged. Secretions and movement artifacts may impair image quality.
In addition, movement artifacts can spuriously interrupt
flow in some microvessels. Special care should be taken
to prevent this. To limit movement artifacts and to
decrease the risk of pressure artifacts, use of stabilization
devices has been proposed [43, 66]. These are especially
convenient in experimental conditions but their application in humans is still anecdotal. Sterile cover caps need
to be used, but these do not impair image quality.
Finally, the investigation of the sublingual area is only
feasible in sedated or cooperative patients. It is also
impossible to evaluate the sublingual microcirculation in
hypoxemic patients who are being treated with noninvasive mechanical ventilation.
Evaluation of tissue oxygenation (SvO2/NIRS/PO2
electrodes/reflectance spectroscopy)
Measurements of O2 tension or saturation in a piece of
tissue reflect the balance between O2 transport and O2
consumption in that tissue. These measurements are,
therefore, influenced by flow but also by hemoglobin
content, arterial PO2, and O2 consumption.
Venous oxygen saturation
Venous O2 saturation is often considered as a gauge for
the circulation [17, 67], but this measurement can be
misleading. As illustrated in Figs. 1 and 2, venous O2
saturation is a poor indicator of microvascular dysfunction: venous O2 saturation can be high or low for the same
degree of microvascular shunting. Several studies have
shown that measuring SvO2 does not provide much
information about microvascular alterations [54, 68, 69].
PO2 electrodes
PO2 can be measured in tissues with Clark-type electrodes,
which are made of multiple platinum wires that measure
PO2 in the surrounding tissue. These electrodes accurately
measure tissue PO2 when PO2 is homogenously decreased
but they are not suitable in conditions of PO2 heterogeneity, as they are sensitive to the highest PO2 in the
sampling volume. The most modern tissue PO2 electrodes
measure PO2 on a tissue surface of 8 mm2 over a depth of
a few microns [70]. This represents a sampling volume of
at least 0.5 mm3. Such a volume includes at least 100
microvessels, including arterioles, capillaries, and venules, as well as interstitium and other cells, which all
contribute to the PO2 value.
Some investigators have used PO2 electrodes [62, 70–
73], but they are not useful to assess microvascular perfusion. They can be used to assess adequacy of perfusion
and/or oxygenation in a piece of tissue, especially in lowflow conditions [72].
Reflectance spectroscopy
Reflectance spectroscopy measures tissue SO2. Light
generated with a rapidly rotating filter disk at 64 different wavelengths of 2-nm increments in the range
502–628 nm is directed through a microlight guide to the
tissues. The use of different wavelengths allows SO2
measurement due to light absorption by oxy- and
deoxyhemoglobin. The resolution of the probe is very
sharp (1 nm) allowing SO2 measurements in a very small
area. Nevertheless, the depth of the tissue sampled is quite
large [74], so that the sampling volume is not so small. A
histogram of tissue SO2 is generated, which provides
information on the heterogeneity in tissue oxygenation.
Reporting only the mean value of tissue SO2 is misleading
[75, 76], and no conclusions can be drawn on the presence
or absence of hypoxic areas. Initially, this technique,
known under the name of Erlangen MicroPHOtometer
(EMPHO), was mostly used in experimental conditions
and heterogeneity of tissue oxygenation was reported in
several conditions [74, 77]. Some investigators have been
able to embed this technique on an endoscope, enabling
measurement of human gastric SO2 [78]. Recent developments have allowed miniaturization of the technique,
making it suitable for measurement of skin and sublingual
SO2 [76], but unfortunately these new devices only provide mean SO2.
Near-infrared spectroscopy
Near-infrared spectroscopy (NIRS) is a technique that
utilizes near-infrared light to measure chromophores
(oxy- and deoxyhemoglobin, myoglobin, and cytochrome
aa3) in tissues [79]. The fractions of oxy- and deoxyhemoglobin are used to calculate tissue O2 saturation (StO2).
In addition, total light absorption is used to compute total
tissue hemoglobin (HbT) and the absolute tissue hemoglobin index (THI), two indicators of blood volume in the
region of microvasculature sensed by the probe [80].
According to Beer’s law, the NIRS signal is limited to
vessels that have a diameter less than 1 mm (arterioles,
capillaries, and venules), but, as 75% of the blood in a
skeletal muscle is venous, NIRS StO2 measurements
mostly represent local venous hemoglobin O2 saturation.
This represents the aggregate of O2 saturations in the
sampling volume and this technique is not suitable in
conditions of heterogeneous blood flow. Indeed, even
though StO2 is slightly lower in septic patients compared
to healthy volunteers, there is a huge overlap between the
groups [81, 82]. StO2 also differs from ScvO2 saturation
in sepsis [68].
The analysis of changes in StO2 during a brief episode
of forearm ischemia enables quantification of microvascular dysfunction [83–85]. This technique, which can
easily be repeated [83], is particularly promising as it
provides quantitative information on microvascular
function within a few minutes. One should bear in mind
that NIRS does not measure microcirculatory blood flow,
making interpretation of the absolute StO2 value in terms
of tissue oxygenation difficult. As StO2 represents the
balance between O2 delivery and O2 consumption, any
change in StO2 can reflect a change in flow in the same
direction and/or a change in metabolism in the opposite
direction. More importantly, proportional changes in flow
and metabolism may be associated with unchanged StO2.
In addition, the vasoreactivity test evaluates a different
aspect of microvascular function than flow: it evaluates
microvascular reserve more than actual microvascular
perfusion.
NIRS-derived measurements are influenced by adipose tissue thickness as well as the presence of edema;
hence, in the majority of studies, the thenar eminence has
been used because the thickness of skin and adipose tissue
covering this muscle is less influenced by any increase in
fluid content or body mass index. The influence of temperature and vasoactive substances on NIRS-derived
variables obtained in the thenar eminence need to be
evaluated. Likewise, the relationship between peripheral
and more central microvascular beds need to be further
studied in critically ill patients.
Finally, NIRS devices vary in terms of wavelength and
number of wavelengths, optode spacing, and algorithms
[86]. Accordingly, the data reported with the different
devices may vary somewhat and this absence of standardization may limit comparisons of results from
different trials.
PCO2-derived measurements
Tissue CO2 represents the balance between CO2 production and flow to the tissue. It is influenced by arterial CO2,
so that the tissue to arterial gradient, or PCO2 gap, is
usually calculated. The PCO2 gap reflects more the adequacy of flow than the presence of tissue hypoxia, unless
very high PCO2 gap values are reached [87, 88]. Tissue
PCO2 can be measured by electrodes inserted in tissues,
probes in contact with the tissue, or tonometry. Even
though the sampling volume is large, the measured value
reflects the most abnormal (highest) value in the sampled
volume. Hence, this measurement can detect zones of
impaired perfusion and/or tissue hypoxia even when total
perfusion is preserved but heterogeneous.
Gastric tonometry raised a lot of interest. A gastric
PCO2 gap above 20 mmHg discriminated survivors from
non-survivors [87]. More importantly, these variables had
a stronger prognostic value when systemic variables were
already corrected [89]. But what does PCO2 gap really
measure? Does it reflect splanchnic, serosal, or mucosal
blood flow? Even though it was initially proposed as a
surrogate of splanchnic perfusion, several studies suggest
that it mostly reflects gut mucosal microcirculation. In
experimental conditions, there was a close relationship
between mucosal PCO2 and mucosal perfusion [41, 42,
48]. In patients with sepsis, there was no correlation
between the gastric PCO2 gap and total splanchnic perfusion [90], although changes in mucosal PCO2 correlated
with changes in mucosal perfusion [91]. The technique has
now been abandoned, mostly because of technical problems. In particular, duodeno-gastric reflux and feeding can
interfere with PCO2 measurements. Sublingual and buccal
PCO2 monitoring have been developed [92, 93]. Sublingual PCO2 is often increased in sepsis, especially in nonsurvivors [94–96]. Using this technique, we demonstrated
that sublingual PCO2 tracks microvascular blood flow, as
the sublingual PCO2 gap is inversely related to the proportion of perfused capillaries [97]. This technique,
although attractive, is unfortunately not easily available at
the present time (available for research purposes only).
Microdialysis and equilibrium dialysis
Microdialysis allows measurements of different molecules in the extracellular space. Soluble substances
equilibrate through a semipermeable membrane of hollow
fiber perfused at a constant rate with saline, and are
recovered in the dialysate. In the equilibrium dialysis
technique, a probe covered by a semipermeable membrane is used without infusing fluids, solutes slowly
equilibrate through the membrane, and the content of the
probe is sampled intermittently for analysis (and replaced
by saline). Lactate and pyruvate can be measured; measurements of the lactate/pyruvate ratio are particularly
appealing, as this variable is less sensitive to dialysate
perfusion rate and problems of incomplete recovery
(absence of full equilibration).
Although the sampling volume of this device is large,
measurements are influenced by the most abnormal values
so that it should be able to detect the consequence of
tissue heterogeneity. Using this technique, several studies
have shown that the lactate/pyruvate ratio may be
increased in septic shock [98–100].
Importantly, measurements of the lactate/pyruvate
ratio may be useful to detect the occurrence of tissue
hypoxia but cannot identify whether it is because of
insufficient flow or other causes of tissue hypoxia. In
addition, it cannot detect alterations in microvascular
perfusion before they are associated with cellular hypoxia.
Microcirculatory alterations in critically ill patients
In the following sections, we will illustrate some of the
main disease states with involvement of the microcirculation. The list is far from exhaustive and microcirculatory
alterations have been found in many other circumstances.
Severe sepsis and septic shock
Using the OPS technique, we [54] evaluated the sublingual microcirculation in 50 patients with severe sepsis and
in a cohort of healthy volunteers and non-infected intensive care unit (ICU) controls. We observed a significant
decrease in vessels density and, more importantly, a
decreased proportion of perfused small vessels (\20 lm),
mostly capillaries, from 90% in controls to 48% in septic
patients. This decrease in the proportion of well-perfused
small vessels was due to a combined increase in nonperfused and intermittently perfused vessels. In addition,
the heterogeneity between areas distant by a few microns
was also increased. These results are in line with experimental findings and were later confirmed by other groups
of investigators [57, 101]. These alterations can be
observed very early in the course of sepsis, even within a
few hours of hospital admission [57, 101]. Similar alterations, of lower magnitude, can be induced by low-dose
endotoxin administration in healthy volunteers [102].
Interestingly, microcirculatory alterations were more
severe in non-survivors than in survivors [54, 101, 103].
More importantly these microcirculatory changes rapidly
resolved in response to therapy in survivors but persisted
in patients dying in acute circulatory failure or later from
organ failure after recovery from shock [103]. Changes in
microvascular perfusion during the first day of ICU
admission are more strongly associated with outcome
than changes in cardiac output, arterial pressure, or SvO2
[103]. Trzeciak et al. [104] showed that early improvement in microvascular perfusion in response to goaldirected therapy was associated with an improvement
in organ function. Even though these data strongly suggest that microcirculatory alterations are implicated in
the development of organ failure, interventional studies
guiding therapy at the microcirculation should be conducted to evaluate whether improving microcirculatory
alterations may be associated with an improvement in
organ dysfunction.
Using a vascular occlusion test combined with NIRS
measurements, several studies have shown that patients
with severe sepsis frequently have profound alterations in
microvascular reactivity [81, 84, 85, 105, 106] and that
these alterations are associated with a high risk of organ
dysfunction [105] and death [81].
Cardiogenic shock
approach has been shown to improve outcome in high-risk
surgical patients [113]. Although the link between global
hemodynamics and microvascular perfusion is quite loose,
interventions aimed at improving global hemodynamics
also have microvascular effects [21, 22, 114], which may
be mediated by effects independent of changes in global
hemodynamics. Further studies should address this issue.
Microcirculatory alterations may also occur in patients
undergoing cardiac surgery. Bauer et al. [115] first
reported that microcirculatory perfusion was transiently
altered in humans after cardiopulmonary bypass. Similar
findings were reported more recently by other groups
[116, 117]. More importantly, these alterations can also
be observed in patients who undergo surgery without
cardiopulmonary bypass [117]; of note, the sublingual
microcirculation was still slightly abnormal up to 24 h
after surgery in these patients [117]. As in non-cardiac
surgery, the severity of perioperative microvascular
alterations correlated with peak lactate levels and severity
of organ dysfunction after surgery [117].
We observed that, compared to patients with coronary
artery or valvular disease who were scheduled for cardiac
surgery, patients admitted to the ICU for acute decompensation of severe heart failure or cardiogenic shock had
microvascular alterations, consisting of a decrease in
vessel density and in the proportion of perfused capillaries
[55]. These findings were later confirmed by other groups
of investigators [107–110]. More severe alterations were
observed in patients with higher lactate levels [110] and
poor outcome [55]. These alterations could be improved
by nitroglycerin [107, 108] or mechanical support such as
aortic counterpulsation [109, 111] or ventricular assist Conclusions
devices [112].
Microcirculatory alterations are frequently observed in
critically ill patients, and especially in patients with
High-risk surgery
severe sepsis. These alterations are characterized by a
decrease in capillary density and an increase in heteroHigh-risk surgery is a new area in which microcirculatory geneity of perfusion with non-perfused in close vicinity to
alterations have been observed. In patients submitted to well-perfused capillaries. As a heterogeneous decrease in
high-risk non-cardiac surgery, Jhanji et al. [62] observed perfusion is less well tolerated than a homogenously
that the density and proportion of perfused capillaries was decreased perfusion, the diagnostic tool used to assess the
lower in the 14 patients who subsequently developed microcirculation should be able to detect heterogeneity of
postoperative complications than in the 11 patients with an perfusion. This is best achieved with handheld microuneventful postoperative course. Subcutaneous tissue PO2 videoscopic techniques, such as OPS and SDF. The use of
and laser Doppler cutaneous blood flow did not differ vascular occlusion tests with laser Doppler or NIRS
between the groups, further highlighting the lack of sen- investigates microvascular reactivity, another important,
sitivity of these methods to detect heterogeneous but different, aspect of microvascular function. Combinperfusion. Interestingly, there was no significant differ- ing techniques may be of interest in the future.
ence in global O2 delivery between the groups; it would be
Guiding resuscitation with the use of these tools may
interesting to evaluate the impact of hemodynamic opti- allow more complete resuscitation and improve outcomes.
mization on these microvascular alterations, as this
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