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E X PE RT O P I N I O N

Assessment of microperfusion in sepsis


D. DE BACKER, K. DONADELLO
Department of Intensive Care, Erasme University Hospital, Universit Libre de Bruxelles, Bruxelles, Belgium.

ABSTRACT
Microcirculatory alterations are frequent in sepsis and different mechanisms can be implied and variously studied. The
severity of microvascular alterations is associated with organ dysfunction and mortality. The aim of this review is to
make an overview of the most actual and used techniques applied on septic humans. We aimed at focus on the impact
of different techniques on the evaluation of patients management and outcome. (Minerva Anestesiol 2015;81:533-40)
Key words: Sepsis - Microcirculation - Perfusion - Cell respiration - Multiple organ failure.

epsis is characterized by several hemodynamic alterations, as relative hypovolemia,


a decrease in vascular tone, and myocardial depression, that contribute to the impairement of
organ perfusion and may be associated with organ dysfunction.1 In addition, these microcirculatory alterations also occur in sepsis 2 and their
severity is associated with a poor outcome.2-6
These microcirculatory alterations may persist
also after the correction of systemic hemodynamic variables.2 The impact of therapeutic interventions on microcirculatory function, and
thus its monitoring, is still little evaluated.7-9 In
this manuscript, we discuss the techniques that
are the most currently used at the bedside to assess the alterations in microvascular perfusion
during sepsis, their impact on therapy management and outcome.
Techniques to investigate
the microcirculation
Microvascular perfusion can be measured
directly by various methods or evaluated indirectly by indices of tissue oxygenation.10 Before
discussing the different techniques, it is important to remember that we always evaluate the

Vol. 81 - No. 5

microcirculation in a given window and that


the capacity of this latter to be representative of
other vascular beds depends on the mechanisms
implicated in the microcirculatory dysfunction
(generalized, diffuse, localized, heterogeneous),
on organ microvascular architecture, and on local factors (local vasoconstriction, temperature
and pressure).
Direct measurements/estimates
Tissue blood flow can be determined with
various Laser Doppler techniques; these allow a
dynamic evaluation of the global flow present in
a volume of tissue of around 0.5 mm3, measuring (in mV) its changes from the baseline. Thus,
the measured flow is the result of an aggregate
flow in multiple small vessels, and does not enable the detection of microvascular heterogeneity.
The recently developed Scanning Laser Doppler,
Reflected-Mode Confocal Laser Scanning Microscopy, allow an evaluation of both perfusion
and of its heterogeneity.11, 12 Due to the large size
of the devices these techniques can only be used
to evaluate skin perfusion, even though these can
be applied on most organs in the experimental
setting.

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DE BACKER

Assessment of microperfusion in sepsis

Microvascular reserve, that is capacity of the


microvasculature to recruit arterioles and capillaries after transient ischemia, may also be assessed with Laser Doppler. During a vasoreactivity test, the capacity of the microvasculature
to recruit arterioles and capillaries after transient
ischemia (ascending slope after arterial occlusion caused by a cuff placed around the arm) determines the quality of flow recovery.13
Laser speckle imaging is another laser modality that also allows characterization of blood flow
heterogeneity.14, 15 Laser speckle is a random interference effect that gives a grainy appearance
to objects illuminated by a monochrome laser
light. Red blood cells consist in individual moving scatters; these alter the speckle pattern which
fluctuates with movement of the scatter. These
fluctuations provide information about the velocity distribution of the scatters. Speckle and
Doppler approaches are different ways of looking at the same phenomenon, application of
scanning allowing determination of blood flow
heterogeneity. Using this technique, it has been
feasible to evaluate heterogeneity in renal perfusion in septic animals 14 and skin perfusion in
humans.15
Microvideoscopy is based on the application
of a microscope on organ surfaces. Its application in humans requires that either the organ is
transilluminated if thin enough, such as fingers
in nailfold videocapillaroscopy 16 or that organs
can be made translucent by reflected light. Nailfold capillaroscopy uses transillumination but is
limited in critically ill patients due to peripheral
vasoconstriction. Other videoscopic techniques
use the reflection by deeper tissue layers to illuminate the tissue and several ways to discard the
light reflected by tissular superficial layers. The
use of polarized light was the first option, as the
light reflected by deeper layers loses its polarized
aspect and can be discarded by filters. The optimization of the geometry of emitting diodes and
receiving optic paths is the alternative way which
is used in more recent devices. orthogonal polarization spectral (OPS), sidestream dark-field
(SDF) and incident dark-field (IDF) are three
imaging techniques that can be applied at the
bedside on critically ill patients with handheld
devices. Vascular red blood cells can be seen as

534

dark/grey bodies as the used wavelength is absorbed by the hemoglobin. In septic animal,
these have been used to evaluate the microcirculation of several organs as the tongue,17-19 conjunctiva,20 gut,17, 18, 21 and brain.22, 23 In septic
humans, these techniques have been mostly used
to study the sublingual area.2, 4, 24-27 Secretions
and movement artifacts may impair image quality, and the investigation of the sublingual area is
only feasible in sedated or cooperative patients.
Vascular (capillary) density and heterogeneity
of perfusion (the proportion of perfused vessels,
mean flow index, heterogeneity index), should
be measured.28 The microvascular flow index
(MFI) is a composite and non linear score that
combines gross evaluation of perfusion and its
heterogeneity. These are measured using a semiquantitative analysis, which can easily be performed by experienced investigators, with excellent reliability.2, 27, 29 The measurement of blood
flow cannot be obtained with the scores in use.
Computer-assisted microcirculation assessment
allows the measurement of vessel density 30 and
blood flow in microvessels but still require major human intervention. Measuring blood flow
in selected microvessels is irrelevant but measuring blood flow in all visible vessels is probably
more relevant, but this is not yet feasible, at least
in clinical practice. This quantitative assessment
was performed in patients with severe sepsis.31
Indirect measurements/estimates
An impaired microvascular perfusion may be
inferred from a general clinical examination.32-34
However, the link between skin hypoperfusion
and more central beds is loose, as well as with
biological markers; indeed, blood lactate levels
also have poor sensitivity and specificity to detect microcirculatory alterations.4, 6-8 Evaluation
of tissue oxygenation is an indirect evaluation of
tissue perfusion, inferring the balance between
O2 transport (DO2) and O2 consumption (VO2)
in a tissue. Flow, hemoglobin content, arterial
PO2, and VO2 are all of influence. Near-infrared
spectroscopy (NIRS) uses near-infrared light
to measure tissue oxy- and deoxyhemoglobin,
myoglobin, and cytochrome aa3 (the so-called
chromophores). Tissue O2 saturation (StO2)

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Assessment of microperfusion in sepsis

DE BACKER

mostly represents the saturation of all vessels in


the sampling volume, while total tissue hemoglobin (HbT) and the tissue hemoglobin index
(THI) indicate the amount of blood present in
the tested region. NIRS limitations are related to
the fact that StO2 values are mostly influenced by
local venous hemoglobin O2 saturation and that
perfusion heterogeneity cannot be detected. The
interpretation of StO2 is also difficult as it does
not reflect capillary O2 saturation and it is does
not well correlate with ScvO2 saturation in sepsis.35, 36 Of interest, NIRS technique allows the
researcher/clinician to evaluate the microvascular reactivity: a brief episode of forearm ischemia
(Vaso-Occlusive Test, VOT) determines changes
in StO2 (Figure 1) that may reflect the degree
of microcirculatory alterations or the response
to therapy.5, 37 This provides quantitative information within few minutes and can be repeated
and reproduced. However, the vasoreactivity test
does not evaluate regional nor microvascular
perfusion, but the actual microvascular reserve.
The thenar eminence is usually used for NIRS
measurements as both adipose tissue thickness
and edema can modify the collected data.
Tissue PCO2 (PtCO2) derived measurements
can also be used to evaluate the microcirculation. The three major determinants of PtCO2 are
PaCO2, VCO2 and the tissue blood flow. In normal conditions, an increased tissue metabolism
(thus VCO2) is coupled with an increased tissue

perfusion, largely reducing any PtCO2 increase


(washout phenomenon). Therefore, if PaCO2 is
constant, an increase in PtCO2 reflects an inadequate relationship between metabolism and
tissue perfusion. PtCO2 thus represents a good
estimate of tissue perfusion. To overcome the influence of PaCO2 on PtCO2, it is convenient to
use the PCO2 gap (tissue-arterial CO2 gradient,
normal <7 mmHg). Very high PCO2 gap values
may in addition suggest the presence of tissue
hypoxia 38 while moderately elevated PCO2 gaps
may represent either flow stagnation or tissue
hypoxia.
Different techniques can be used to measure
tissue PCO2 (inserted electrodes, contact probes,
tonometry). PCO2 measurements can detect
zones of impaired perfusion and/or tissue hypoxia even when total perfusion is preserved but
heterogeneous, as the measured value reflects the
most abnormal (highest) value in the sampled
volume. Tissue PCO2 has been measured mostly
in the stomach and sublingual area but these
techniques are no more available. Measurements
of ear lobe PCO2 have been proposed.39 Recently, the measurement of the gradient between
venous and arterial PCO2 have been suggested
to be a potential surrogate of microvascular perfusion.40 Even though tissue PCO2 was demonstrated to be altered in sepsis and also associated
with outcome, the selection of the best site for
monitoring remains to be determined.
Microcirculatory alterations in sepsis

Figure 1.Evaluation of microvascular reactivity with NIRS.


A vascular occlusion test is performed by transient inflation of
a cuff placed around the arm. Oxygen saturation is measured
with a near infrared probe positioned at the level of thenar eminence during the test.

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Normal microcirculation is characterized by


a dense network of perfused capillaries (Figure
2). In sepsis, in opposition, capillary density is
decreased and some capillaries may be either intermittently or not perfused, leading to heterogeneous tissue perfusion 18, 41, 42 (Figure 3). These alterations have been reported after administration
of endotoxin, live bacteria and during bacterial
peritonitis,18, 22, 23, 42 and observed in all studied
organs, including the brain.22, 23 This is a dynamic process, as capillary perfusion may change
minute by minute, and non-perfused capillaries
suddenly become perfused and vice-versa. When
submitted to hypovolemia, the normal microcirculation decreases its minimal heterogeneity

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DE BACKER

Assessment of microperfusion in sepsis

Figure 2.Sublingual microcirculation of a healthy volunteer.


Visualization of sublingual microcirculation of a healthy volunteer using a SDF imaging technique. Note the rich density
of capillaries.

Figure 3.Sublingual microcirculation of a septic patient. Visualization of sublingual microcirculation of a patient with septic shock
using a SDF imaging technique. Note the decreased density of
capillaries and the presence of many capillaries with stopped flow.

in order to match microvascular oxygen delivery


to oxygen consumption while the heterogeneity
further increases in the septic microcirculation
leading to mismatch between flow and oxygen
requirements.43
Similar events were demonstrated in septic
patients. Compared to non-infected critically ill
patients and healthy volunteers, the sublingual
microcirculation of patients with severe sepsis, is
characterized by a significant decrease in vessels
density and in the proportion of perfused small
vessels (48% in septic patients compared to 90%
in controls) related to an increase in non-perfused
as well as in intermittently perfused vessels.2 This
indicates that the heterogeneity of perfusion is increased both inside the visualized area but also between areas close by a few microns. Many groups
confirmed these data,25, 44 and also demonstrated
that these alterations can be observed very early
in the course of sepsis.44 These alterations are
very similar to those occurring in experimental
conditions. These alterations are more severe in
non-survivors than in survivors.4 Of note, these
alterations do not occur in patients with infection
without signs of severity.45 Analyzing data of 252
patients, survival rate progressively decreased with
quartiles of severity in alteration of the microcirculation. Alterations in microvascular perfusion
were one of the strongest predictor of outcome
and remained independently associated with
outcome in multivariate analysis. Evolution over
time and in response to therapy is very informa-

tive. Trzeciak et al.46 evaluated the impact of early


changes in microvascular perfusion in response to
goal resuscitation therapies and the consequent
changes in organ function. They observed that
when microvascular perfusion improved, organ
function also subsequently improved, while organ
function deteriorated when microvascular perfusion failed to improve or even deteriorated.6, 46
This nicely illustrates the link between microvascular perfusion and organ dysfunction. In addition, the time course of microvascular alterations
also differs between survivors and non-survivors.
Microvascular alterations improved over time in
response to therapy in survivors but not in nonsurvivors.3
What do the other techniques demonstrate in
patients with sepsis? The PCO2 gap is increased in
sepsis, in gastric, sublingual and ear lobe.17, 39, 47, 48
Importantly, an inverse relationship was found
between microvascular perfusion and the PCO2
gap in the ileum 17 and in sublingual area.47
StO2 was demonstrated to be lower in septic patients compared to healthy volunteers,
but with a major overlap between the groups.37
NIRS-dynamic derived measurements (VOT
test) demonstrated profound alterations in microvascular reactivity in septic patients compared
to controls.5, 37 Alterations in microvascular reactivity are associated with organ function,49, 50
length of stay,50 and mortality.5, 37 These alterations can already be demonstrated in the Emergency Department and are more severe in non-

536

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Assessment of microperfusion in sepsis

DE BACKER

survivors.5 VOT appears helpful for monitoring


and patients management.50
Impact of therapeutic interventions
on microvascular perfusion
Could the available techniques be used to
evaluate and monitor our therapeutic approach?
Interventions aimed at improving global hemodynamics may also have microvascular effects
but these were independent from the changes in
global hemodynamics (Table I).7, 8, 51 Nevertheless, one should bear in mind that microvascular
alterations are heterogeneous and that all interventions should aim at recruiting the microcirculation more than increasing flow in already
perfused vessels.
Fluids can improve microvascular perfusion,
increasing the proportion of perfused capillaries
and decreasing perfusion heterogeneity,7, 51 with
microcirculatory effects being quite independent from systemic effects. Interestingly, the earlier
the fluid administration, the greater the effect on
microcirculatory alterations.7 This response may
nevertheless by limited as only the first fluid bolus was associated to microvascular perfusion improvement.51 The type of fluid mostly associated
with microvascular responses is debated,52 but the
superiority of colloids on crystalloids could not
be confirmed.7 Recently, it has been proposed
to use the microcirculation to guide fluid resuscitation. In septic patients identified as fluid responders in term of systemic circulation, organ
dysfunction improved only in the patients who
improved their microcirculation in response to
fluids.53 Interestingly, these patients also had an
impaired microcirculation at baseline, suggesting that evaluation of the microcirculation may
be used to better identify the patients who may
benefit from fluid administration. The effects of

red blood cell transfusions may depend on the severity of underlying microcirculatory alterations,
with an improvement in microvascular perfusion
in the most severe septic patients and a worsening
in patients with microcirculation closer to normal
values;54 even though blood was leukodepleted in
that trial, recent data suggest that transfusion of
leukodepleted blood may better preserve the microcirculation than non leukodepleted blood.55
Beta-adrenergic agents were shown to improve microvascular perfusion,8 independently
from their effects on systemic hemodynamics,8
even though these effects can be quite variable
among individuals.8, 56, 57 Of note, both enoximone 58 and, on a greater degree, levosimendan,
demonstrated similar effects on microvascular
perfusion.59
Vasopressor agents, when used to reverse severe
hypotension, may improve microvascular perfusion,60, 61 but increasing mean arterial pressures
to higher levels (65-75-85 mmHg) had variable
effects on microvascular perfusion.62, 63 Increasing arterial pressure with norepinephrine was
beneficial only in the most severe cases, while it
was detrimental on sublingual microcirculation
in patients with close to normal microcirculation
at baseline.63
Could vasodilatory agents be used? In septic
patients the topical administration of a large dose
of acetylcholine, an endothelium-dependent vasodilating agent, restored the microcirculation,
which achieved a state similar to that of healthy
volunteers and non-septic ICU patients.2 Subsequently, nitroglycerin administration was shown
to improve the microcirculation in a small series
of patients with septic shock 26 but these effects
were not confirmed in a randomized trial.27 Vasodilating agents such as nitroglycerin are not
selective and may vasodilate not only the nonperfused vessels but also the already perfused ves-

Table I.Effects of selected hemodynamic interventions on microvascular perfusion.


Intervention

Effects

Comments

Fluids
Red blood cells

Improve or ineffective
Variable

Inotropic agents
Vasopressor agents

Improve or ineffective
Variable

Increase microvascular perfusion when altered at early stages


Increase microvascular perfusion only when microcirculation
impaired, especially when leukodepleted blood is used. May
deteriorate microvascular perfusion in selected patients
Effect cannot be predicted from systemic effect
Effective when correcting severe hypotension. Effective in
patients with markedly altered microcirculation

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537

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DE BACKER

Assessment of microperfusion in sepsis

sels, which may led to unnecessary overperfusion


of some areas. Other vasodilating agents also
failed to improve the microcirculation, as magnesium sulfate 64 and the angiotensin converting enzyme inhibition.65 An attractive pathway
may be modulation of endothelial NO synthase
(eNOS) which is actively involved in the control
of blood flow at the microcirculatory levels and is
often dysfunctional during sepsis. The administration of tetrahydrobiopterin (BH4), a cofactor
of endothelial NOS, was tested in a sheep model
of septic shock induced by fecal peritonitis, and
it blunted the decrease in the proportion of perfused capillaries and in functional capillary density, limiting the increase in capillary perfusion
heterogeneity.66 Similarly the administration of
vitamin C improved the microcirculation in rats
with peritonitis.67 These agents have not yet been
tested in patients with septic shock.
Various anticoagulant agents were shown to
improve the microcirculation, including activated
protein C,68-70 antithrombin,71 and low molecular weight heparin.72 Indeed, the dysfunctioning
endothelium and its interaction with circulating
cells can activate the different coagulation processes, without leading to formal clot formation,
sustaining and worsening microvascular dysfunction.73 However, in experimental settings, their
microcirculatory effects were not related only
to their anticoagulant function.71 Some experimental data suggest that decreased white blood
cell and platelet rolling and adhesion,69 preservation of glycocalyx size,68 and improvement in
endothelial reactivity 13, 74 are various factors involved in the improvement in perfusion induced
by these agents. Unfortunately, the use of anticoagulant agents cannot be recommended as large
scale randomized trials failed to demonstrate an
impact on outcome, maybe as a result of a narrow
benefit/risk profile.
Conclusions
Different techniques can be used to evaluate
and understand what happens at a microcirculatory levels during sepsis. Microcirculatory alterations occur in sepsis and they may play a role in
the development of organ dysfunction. Despite
various experiences evaluating the impact of differ-

538

ent therapeutic interventions on organ failure and


outcome, microcirculatory endpoints for resuscitation have not yet been defined and this may, at
least in part, explain why microcirculation monitoring is not yet part of routine clinical practice.
Key messages
In sepsis both global hemodynamic
alterations and microvascular dysfunction
participate to the pathophysiology of organ
failure and contribute to poor outcome.
The monitoring of microcirculation
and the effects of its manipulation are an
important field of experimental and clinical
research.
Direct estimates of the microcirculation can be obtained by Laser and microvideoscopic techniques. Indirect estimates
include clinical and biological evaluation,
monitoring of tissue oxygenation and and
PCO2 derived measurements.
The effects of different therapies
such as fluids, transfusions, beta-adrenergic
agents, vasopressors, vasodilators, anticoagulant agents are quite variable in septic
patients, and these effects are independent
from their impact on global hemodynamics.
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.

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Assessment of microperfusion in sepsis

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Conflicts of interest.The authors certify that there is no conflict of interest with any financial organization regarding the material discussed
in the manuscript.
Received on January 9, 2014. - Accepted for publication on June 17, 2014. - Epub ahead of print on June 19, 2014.
Corresponding author: D. De Backer,Department of Intensive Care,Erasme University Hospital,Route de Lennik 808,B-1070 Brussels,
Belgium. E-mail: ddebacke@ulb.ac.be

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