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53
3
Clinical Applications of SDF Videomicroscopy
Daniel De Backer and Jean-Louis Vincent
3.1
Introduction
In recent years, microcirculatory alterations have been increasingly implicated in
the development of organ dysfunction, failure, and death in critically ill patients.
Until recently, adequacy of tissue perfusion has been assumed from systemic
measures including blood pressure, cardiac output, and mixed venous oxygen satu-
ration and from laboratory variables such as blood lactate concentrations. However,
resuscitation aimed only at normalizing these macrocirculatory parameters may
be insufficient to improve perfusion and oxygenation at the microcirculatory level.
The development of techniques with which the microcirculation can be directly vi-
sualized at the bedside has provided us with the opportunity to study regional blood
flow in health and disease [1]. Alterations in microcirculatory blood flow have been
identified in several disease processes, and studies are beginning to evaluate the
clinical implications of these changes and the effects that currently used therapies
have on them. In Chapter 2, Dr Ince detailed the historical and technical devel-
opment of the orthogonal polarization spectral (OPS) and sidestream dark-field
(SDF) imaging techniques. In this chapter, we discuss results from clinical studies
using these instruments. Most of the data are from studies that have monitored the
microcirculation in the sublingual area, so this is assumed throughout the chapter
unless otherwise stated.
3.2
Microcirculatory Alterations Visualized with OPS/SDF Imaging
3.2.1
In Sepsis
In healthy volunteers, a single daily dose of lipopolysaccharide (LPS) was associated
with decreased flow in medium and large microvessels as visualized with SDF
after just 2 h, in association with increased cytokine levels [2]. However, by day 5,
Microcirculation Imaging, First Edition. Edited by Martin J. Leahy.
2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.
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54 3 Clinical Applications of SDF Videomicroscopy
0
20
40
60
80
100
Proportion of
perfused capillaries (%)
SepsisVolunteers
Figure 3.1 Capillary perfusion in patients with severe sep-
sis and healthy volunteers.
+++
p < 0.001 versus volunteers.
(From Ref. [3] with permission.)
the cytokine response and microcirculatory alterations were absent, suggesting
that a degree of immune tolerance had developed. Using OPS, we demonstrated
decreased capillary density and a reduced proportion of perfused capillaries in 50
patients with severe sepsis and septic shock compared to healthy volunteers or ICU
control patients (Figure 3.1) [3]. Heterogeneity of blood flow was also increased
in patients with sepsis. Importantly, these changes were unrelated to global
hemodynamic or oxygenation parameters and were more severe in nonsurvivors
than in survivors [3]. Since our original report in 2002 [3], at least 15 trials have
reported similar findings in adult patients with sepsis [4 –18] and several have
noted that these changes occur early in the course of sepsis. Using SDF imaging,
Spanos et al. [17] reported that for small vessels (<20 µm), the microvascular flow
index, the heterogeneity index, and the proportion of perfused vessels were already
lower in patients with sepsis and severe sepsis within 6 h of diagnosis compared
to healthy volunteers. Importantly, the microcirculatory alterations improve over
time in survivors, but not in nonsurvivors, suggesting a role of the microcirculation
in outcome and a potential place for microcirculatory monitoring to follow the
effects of therapeutic interventions (see later). In this context, using OPS imaging
to monitor the sublingual microcirculation on the day of onset of septic shock
and each day until resolution of shock, Sakr et al. [5] noted that the proportion of
perfused small vessels improved over time in survivors but not in nonsurvivors.
Moreover, despite similar hemodynamic and oxygenation profiles and use of
vasopressors at the end of shock, patients dying from multiple organ failure after
the resolution of shock had a lower percentage of perfused small vessels than
survivors (57.4% (46.6–64.9%) vs 79.3% (67.2–83.2%); p = 0.02).
3.2.2
In Severe Heart Failure and Cardiogenic Shock
Microcirculatory alterations have also been reported in patients with severe heart
failure and cardiogenic shock. In 40 patients with severe heart failure, including
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3.2 Microcirculatory Alterations Visualized with OPS/SDF Imaging 55
31 with cardiogenic shock, the proportion of perfused small vessels was reduced
compared to ICU control patients examined the day before cardiac surgery (63%
(46–65%) inheart failure and 49% (38–64%) in cardiogenicshock vs 92%(90– 93%)
in ICU controls, p < 0.001) [19]. Again, these alterations were greater in patients
who did not survive. Jung et al. similarly reported reduced microvascular perfusion
in patients with cardiogenic shock when compared to those without it, associated
with an increase in blood lactate levels [20].
3.2.3
During and after Cardiac Arrest
During cardiac arrest, it is expected that the microcirculation would be im-
paired. In a patient with prolonged cardiac arrest in hypothermic conditions,
Elbers et al. [21] observed that cardiopulmonary resuscitation (CPR) was able to
provide some microvascular perfusion, which disappeared during brief interrup-
tions of CPR. In patients who survived after CPR, Donadello et al. [22] reported
severe microvascular alterations, which returned towards normal after a few
days. Another interesting observation was made during aortic cross-clamping:
even though cardiac output stops abruptly, the sublingual microcirculation is
preserved for ∼20 s, first stopping in capillaries and then in larger vessels
[23]. This time interval during which microvascular perfusion is preserved af-
ter cardiac output is stopped is likely related to the time required for arterial
pressure to drop to mean systemic pressure, suggesting that perfusion pres-
sure is a more important determinant of microvascular perfusion than cardiac
output.
3.2.4
In Surgery
3.2.4.1 Cardiac Surgery
Using sublingual OPS, Bauer et al. [24] reported that functional capillary density
was reduced during cardiopulmonary bypass (CPB), returning to normal 1 h after
discontinuation of CPB. Similarly, den Uil et al. [25] observed, using SDF imaging,
that decreases in microvascular flow index occurred during CPB, irrespective of
changes in systemic blood pressure; again, these changes returned to normal once
the CPB was discontinued. We investigated the microcirculatory changes in 15
patients undergoing cardiac surgery (9 with and 6 without CPB) and compared
them to 7 patients undergoing thyroidectomy [26]. The proportion of perfused
vessels was similar in all three groups at baseline and decreased similarly after
induction of anesthesia; it decreased further during CPB. Immediately after
surgery, alterations were more severe in CPB patients than in patients undergoing
off-pump surgery and had already normalized in the thyroidectomy patients
(p = 0.0005 vs cardiac surgery). In both cardiac surgery groups, these
microcirculatory alterations decreased with time but persisted at 24 h. The severity
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56 3 Clinical Applications of SDF Videomicroscopy
of microvascular alterations correlated with peak lactate levels after cardiac surgery
(y = 11.5 − 0.15x ; r
2
= 0.65; p < 0.05) and with severity of organ dysfunction
after surgery but was not related to global hemodynamic variables. Atasever et al.
[27] reported that CPB was associated with a 43% decrease in functional capillary
density and that off-pump surgery was associated with reduced capillary blood
flow. Interestingly, in patients undergoing CPB, there were no differences in
microcirculatory parameters when pulsatile perfusion was used compared to
when nonpulsatile flow was used [28], although pulsatile flow is often promoted as
having more beneficial effects on the microcirculation [29].
3.2.4.2 Noncardiac Surgery
Anesthesia can in itself induce some microvascular alterations, but these are
usually transient. Inour study discussedabove, patients undergoingthyroid surgery
and those undergoing cardiac surgery developed similar modest microcirculatory
alterations after induction of anesthesia, which rapidly disappeared in the patients
undergoing thyroid surgery [26]. Similarly, in healthy women given propofol for
anesthesia for transvaginal oocyte retrieval, a 17% decrease in the density of
perfused capillaries was observed, which had resolved by 3 h after the propofol
infusion [30]. In 25 patients undergoing major abdominal surgery, Jhanji et al.
[31] reported that the small vessel microvascular flow index and the proportion
and density of perfused small vessels were lower in patients who developed
complications after surgery than in those who did not.
Recently, Snoeijs et al. [32] investigated the renal microcirculation in kidneys
from donors after cardiac death, which inevitably undergo some degree of ischemic
injury, and in living donor kidneys, in which the ischemic injury is minimal.
The peritubular capillaries of the donor kidneys were visualized by SDF during
transplant surgery. Capillary blood flow during the early reperfusion phase was
markedly reduced in the kidneys from donors after cardiac death compared to
the living donor kidneys. The authors suggested that these findings can help in
encouraging the development of interventions to increase microvascular perfusion
and thus improve early graft function and enable expansion of the currently limited
donor pool with kidneys that have suffered prolonged ischemia. Moreover, such
findings could also apply to other conditions associated with ischemia including
stroke, liver resection, and acute myocardial infarction. OPS has also been used to
assess microcirculatory changes in other transplanted organs, including the liver
and pancreas [33, 34].
3.2.5
Subarachnoid Hemorrhage
In patients with subarachnoid hemorrhage (SAH), OPS imaging applied to the
cerebral cortex showed initially decreased capillary density, which increased during
aneurysm surgery [35]. Microvasospasms could also be observed, which were not
apparent with other imaging modalities.
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3.2 Microcirculatory Alterations Visualized with OPS/SDF Imaging 57
3.2.6
Dermatology
The microcirculation is disturbed in various diseases affecting the skin, and
monitoring of microcirculatory changes could be used for diagnosis and to monitor
treatments. OPS imaging has been used to give information about burn wound
depth [36], and Virgini-Magalhaes et al. [37] suggested that OPS was useful for
evaluating the microangiopathy of chronic venous insufficiency. OPS has also
been used to assess and describe the microcirculatory changes present in skin
cancers [38] and to identify the early microcirculatory changes present in the oral
mucositis associated with high-dose chemotherapy in patients with hematological
malignancies [39]. Other suggested dermatological conditions in which OPS/SDF
imaging could play a role in diagnosis and prognostication include leprosy and
psoriasis [40], but further study is needed to develop fully the potential of this
technique in these fields.
3.2.7
Oncology
In a case report, Meinders and Elbers [41] reported that the microcirculation
was severely impaired in a patient with acute leukemia. These alterations were
related to leukostasis and disappeared when the white blood cell count was
decreased by chemotherapy. However, chemotherapy in itself may also induce
some microvascular alterations. The sublingual microcirculation has been shown
to be altered in patients with myeloma receiving melphalan chemotherapy, and
these alterations could at least in part be attributed to the toxicity of chemo-
therapy [39].
3.2.8
Cirrhosis
The microcirculation has been shown to be altered in patients with decompensated
cirrhosis but not in patients with cirrhosis with similar severity but not undergoing
acute decompensation [42]. As infections often trigger cirrhosis decompensation,
it is difficult to ensure from this report that these alterations were not related to an
underlying infection, even though the authors were unable to document infections
in these patients.
3.2.9
Pediatric Use
SDF is an excellent tool to evaluate the microcirculation in newborns. Even
though the sublingual area is difficult to evaluate in children (small size, need
for cooperation), the skin, particularly of the axilla or head, is easy to examine:
the epidermis is of very limited thickness and hairs are scarce, so excellent
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58 3 Clinical Applications of SDF Videomicroscopy
visualization isoften obtained. It has been shown that preterm infantsoften present
microvascular alterations that term infants do not share. Genzel-Boroviczeny et al.
[43] reported that there were no differences in vessel density or diameter between
term and preterm babies, but that red blood cell velocity increased as thehematocrit
decreased in preterm infants. Top et al. [44] made similar observations in the buccal
mucosa. These alterations were improved by red blood cell transfusions [45] and by
increasing the incubator temperature [46]. Weidlich and colleagues [47] suggested
that intraindividual changes in functional small vessel density could be used as a
marker of infection in preterm infants.
Infants suffering from severe respiratory failure present severe alterations in
sublingual microcirculation compared to same-aged controls; interestingly, these
alterations improved when these infants were placed on extracorporeal membrane
oxygenation (ECMO) [48]. Finally, Top and colleagues [49] performed daily mea-
surements (up to three days) in pediatric patients suffering from severe sepsis and
reported that nonsurvivors had persistent microcirculatory alterations, whereas
microcirculatory changes rapidly improved in survivors, confirming in pediatric
sepsis the data observed by Sakr et al. in adults [5].
3.3
Response of Microcirculatory Variables to Therapeutic Interventions
Various therapeuticinterventions havebeen demonstrated to influence microcircu-
latory changes, notably in patients with severe sepsis. Trzeciak et al. [12] used SDF
to assessthe microcirculationin patientswith sepsisundergoing earlygoal-directed
resuscitation, consistingof intravenous volume expansion, vasopressors, inotropes,
and blood products in a stepwise manner to achieve predefined quantitative end
points of resuscitation derived from invasive hemodynamic monitoring. In patients
whose organ dysfunction resolved with resuscitation, as defined by decreasing
sequential organ failure assessment (SOFA) scores, 88% had an increased mi-
crocirculatory flow index compared to only 47% of those whose SOFA scores
did not improve. We have recently observed that early fluid administration could
improve the microcirculation, while later fluid loading may be less beneficial [16];
these effects were not related to the type of solution used. As reported in earlier
studies, microcirculatory changes were correlated to changes in blood lactate levels
(Figure 3.2) but not to changes in global hemodynamic variables such as cardiac
index and mean arterial pressure. In a small study of 20 patients with severe sepsis
undergoing early goal-directed therapy, Dubin et al. [50] suggested that hydrox-
yethyl starch solutions may have more beneficial effects on the microcirculation
than normal saline solutions. In one study, blood transfusions were shown to
influence microcirculatory parameters in patients with sepsis with altered capillary
perfusion before the transfusion [11]. In patients undergoing cardiacsurgery, blood
transfusion was associated with increased microcirculatory density as assessed by
SDF imaging [51]. Simultaneous spectrophotometry showed that microcirculatory
hemoglobin concentration and hemoglobin oxygen saturation were also increased.
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3.3 Response of Microcirculatory Variables to Therapeutic Interventions 59
−30 −20 −10
−0.2
−0.4
−0.6
−0.8
−1
0.2
0.4
0.6
0
0302010 40
Absolute change in proportion
of perfused small vessels (%)
R
2
= 0.41,
p
< 0.01
Change in lactate
(mEq l
−1
)
Figure 3.2 Relationship between changes in proportion of
perfused small vessels and changes in lactate levels. Change
in lactate =−0.011, change in proportion of perfused ves-
sels = 0.064, R
2
= 0.41, and p = 0.0012. (From Ref. [16]
with permission.)
In preterm infants, blood transfusion was reported to improve functional capillary
density assessed by OPS imaging through the skin of the upper arm [45].
Dobutamine has been shown to improve capillary perfusion but with marked
individual variation [6]. Recently, Morelli et al. [52] suggested that levosimendan
(0.2 µgkg
−1
min
−1
) had more beneficial effects on the sublingual microcirculation
compared to astandarddose of dobutamine (5 µgkg
−1
min
−1
). Several groupshave
reported no changes in microvascular variables during increases in norepinephrine
dose to achieve increases in arterial pressure [13, 53]. It should be noted that many
of these trials reported a high heterogeneity in the response to the intervention,
attributed either to the timing of the intervention [16] or to the underlying state
of the microcirculation before any intervention [11, 13], with an improvement in
patients with the most severe microcirculatory alterations at baseline and lack of
change or even worsening of the microcirculation in patients with an initially
better-preserved microcirculation.
As the microcirculatory changes in sepsis are characterized by a decreased
number of vessels and increased heterogeneity, recruitment of microcirculatory
units using vasodilatory agents may be an option to improve microcirculatory
flow. In an early study, Spronk et al. [4] reported that infusion of 0.5mg of
nitroglycerin increased microvascular flow in patients with septic shock, and we
reported that topically applied acetylcholine corrected microvascular alterations
in patients with sepsis [3]. However, in a recent, randomized controlled trial
of 70 patients with septic shock, administration of 2 mg h
−1
nitroglycerin after
protocolized resuscitation had no effect on the microcirculation [15], although
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60 3 Clinical Applications of SDF Videomicroscopy
it may be that the resuscitation in these patients was so effective at restoring
the microcirculation that no further improvement could be visualized [54]. In
patients with acute heart failure, den Uil et al. [55] demonstrated that a low dose of
nitroglycerin (33 µgmin
−1
) significantly improved the microcirculation, although
there was some variability in the response to nitroglycerin among patients. In a
subsequent study, the same group used incremental doses of nitroglycerin (up
to 133 µgmin
−1
) and reported that nitroglycerin increased tissue perfusion in all
patients in a dose-dependent manner [56]. Taken together, these data suggest that
nitroglycerin may improve the microcirculation, but the variability in effective dose
and in response suggests that this drug should not be administered without further
evaluating its effects.
Hydrocortisone (HC) is frequently used in patients with septic shock despite
conflicting evidence regarding its benefits [57]. In 20 patients with septic shock,
Buchele and colleagues [14] reported that administration of moderate doses of HC
(50 mg per6 h) wasassociated with anearly and consistentimprovement in capillary
perfusion (Figure 3.3), independent of the response to an adrenocorticotropic
hormone (ACTH) test; the changes in microvascular perfusion were not related to
changes in arterial pressure. Although consistent, the magnitude of these changes
was relatively limited and risks associated with HC may outweigh its beneficial
effects on the microcirculation.
The administration of drotrecogin alfa (activated) has been demonstrated to
improve survival in patients with severe sepsis [58], although the exact mechanisms
of action are unclear. In 20 patients with severe sepsis who received drotrecogin
alfa (activated), the proportion of perfused capillaries increased already at 4 h
(from 64% (51 –80%) to 84% (71–88%), p < 0.01); these changes were not seen
in patients who were not treated with the drug because of contraindications [6].
The improvement in microvascular blood flow was associated with a more rapid
resolution of hyperlactatemia, and interestingly, at the end of the drug infusion,
microvascular perfusion decreased transiently.
Baseline HC (1 h) HC (2 h) HC (4 h)
8
PSVD (n mm
−1
)
6
4
2
0
***
Figure 3.3 Evolution of perfused small vessel density
(PSVD) over time after administration of 50 mg per 6 h hy-
drocortisone (HC) in patients with septic shock (
∗∗∗
p < 0.05
compared with baseline). (From Ref. [14] with permission.)
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3.4 Perspective 61
Several recent publications have also investigated the effect of extracorporeal
support devices on microcirculatory perfusion in patients with cardiogenic shock.
Using SDF imaging, intra-aortic balloon counterpulsation, mechanical support
devices, and ECMO were shown to increase sublingual microcirculatory flow in
patients withcardiogenic shock [59– 61]. Interestingly, weaning from an intra-aortic
balloon pump (IABP), when no longer deemed necessary, was accompanied by a
moderate improvement in the sublingual microcirculation [62], suggesting that it
is not the device or the intervention in itself that improves the microcirculation
but rather its timely implementation and, perhaps, the decrease in the release of
endogenous vasoconstrictive substances. Cardiac resynchronization therapy has
also been reported to improve the microcirculation in patients with heart failure
[63], and as already mentioned, ECMO improved the microcirculation in neonates
with severe respiratory infection [48].
3.4
Perspective
Is SDF theideal tool to monitorthe microcirculation? Microcirculatoryalterations in
critically ill patients are characterized by heterogeneity within the investigated area
(vessels without any flow or with intermittent flow in close vicinity to well-perfused
vessels), and heterogeneity is a crucial determinant of tissue oxygenation [64, 65].
In addition, it is also important to realize that therapeutic interventions should aim
at recruiting the microcirculation more than just pushing more flow into already
perfused vessels. Hence, direct visualization of the microcirculation with SDF
appears to be the technique of choice as it allows this heterogeneity of perfusion
to be detected at the bedside, something that other techniques may be unable to
do. Unfortunately, direct visualization of the microcirculation is restricted to a few
easily accessible organs, such as the sublingual area, and requires specific skills
of the investigator both for image acquisition and for image analysis. Finally, SDF
may not be applied in all patients, as it requires safe access to the sublingual
area (sedation or collaboration) and is not feasible during noninvasive mechanical
ventilation.
As we have seen, microvascular alterations frequently occur in critically ill
patients, especially in sepsis. These microvascular alterations have been associated
with severity of organ dysfunction and outcome and are often present when global
hemodynamic parameters appear normal. Various interventions have been shown
to improve microcirculatory flow, but whether monitoring the microcirculation and
titrating such therapies according to microcirculatory response could be associated
with improved outcomes has not yet been studied. In the study by Trzeciak et al.
[12], when the early goal-directed resuscitation protocol led to improved organ
dysfunction scores, 88% of patients had increased microcirculatory flow compared
to 47% of those who had no improvement in their organ function. Importantly,
there were no associated differences in global hemodynamics, suggesting that
targeting the microcirculation, rather than the macrocirculation as is currently
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62 3 Clinical Applications of SDF Videomicroscopy
done, could be beneficial in patients with sepsis. Nevertheless, the microcirculation
is fed by the macrocirculation, and without adequate global hemodynamics, the
microcirculation will never operate in an optimal manner. Microcirculatory data
cannot be taken in isolation and should be used to complement the full clinical
assessment.
Further studies are needed to demonstrate that targeting the microcirculation
can indeed improve outcomes, and until the results of such studies are available, it
would seem reasonable to ensure that the global hemodynamic status is optimized
before attempting to intervene at the microcirculatory level. Clearly, this is just the
beginning for microcirculatory research, and the potential clinical applications are
enormous. Results of more studies focusing on the impact of interventions that are
known to improve outcomes on the microcirculation and using microcirculatory
monitoring to guide therapy in different patients groups and conditions are eagerly
awaited.
References
1. De Backer, D., Ospina-Tascon, G.,
Salgado, D., Favory, R., Creteur, J., and
Vincent, J.L. (2010) Monitoring the mi-
crocirculation in the critically ill patient:
current methods and future approaches.
Intensive Care Med., 36, 1813–1825.
2. Draisma, A., Bemelmans, R., van der
Hoeven, J.G., Spronk, P., and Pickkers,
P. (2009) Microcirculation and vascular
reactivity during endotoxemia and en-
dotoxin tolerance in humans. Shock, 31,
581– 585.
3. De Backer, D., Creteur, J., Preiser, J.C.,
Dubois, M.J., and Vincent, J.L. (2002)
Microvascular blood flow is altered in
patients with sepsis. Am. J. Respir. Crit.
Care Med., 166, 98 –104.
4. Spronk, P.E., Ince, C., Gardien, M.J.,
Mathura, K.R., Oudemans-van Straaten,
H.M., and Zandstra, D.F. (2002)
Nitroglycerin in septic shock after in-
travascular volume resuscitation. Lancet,
360, 1395 –1396.
5. Sakr, Y., Dubois, M.J., De Backer, D.,
Creteur, J., and Vincent, J.L. (2004) Per-
sistent microcirculatory alterations are
associated with organ failure and death
in patients with septic shock. Crit. Care
Med., 32, 1825–1831.
6. De Backer, D., Creteur, J., Dubois,
M.J., Sakr, Y., Koch, M., Verdant, C.,
and Vincent, J.L. (2006) The effects of
dobutamine on microcirculatory alter-
ations in patients with septic shock are
independent of its systemic effects. Crit.
Care Med., 34, 403 –408.
7. De Backer, D., Verdant, C., Chierego,
M., Koch, M., Gullo, A., and Vincent,
J.L. (2006) Effects of drotrecogin alfa
activated on microcirculatory alterations
in patients with severe sepsis. Crit. Care
Med., 34, 1918–1924.
8. Creteur, J., De Backer, D., Sakr, Y.,
Koch, M., and Vincent, J.L. (2006)
Sublingual capnometry tracks micro-
circulatory changes in septic patients.
Intensive Care Med., 32, 516–523.
9. Boerma, E.C., van der Voort, P.H.,
Spronk, P.E., and Ince, C. (2007) Re-
lationship between sublingual and
intestinal microcirculatory perfusion in
patients with abdominal sepsis. Crit.
Care Med., 35, 1055 –1060.
10. Trzeciak, S., Dellinger, R.P., Parrillo,
J.E., Guglielmi, M., Bajaj, J., Abate, N.L.,
Arnold, R.C., Colilla, S., Zanotti, S., and
Hollenberg, S.M. (2007) Early micro-
circulatory perfusion derangements in
patients with severe sepsis and septic
shock: relationship to hemodynamics,
oxygen transport, and survival. Ann.
Emerg. Med., 49, 88 –98.
11. Sakr, Y., Chierego, M., Piagnerelli, M.,
Verdant, C., Dubois, M.J., Koch, M.,
Creteur, J., Gullo, A., Vincent, J.L., and
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