Intensive Care Med (2010) 36:12991308

DOI 10.1007/s00134-010-1912-7

REVIEW

Joachim Boldt
Can Ince

The impact of fluid therapy on microcirculation

and tissue oxygenation in hypovolemic
patients: a review

Received: 21 October 2009

Accepted: 7 March 2010
Published online: 26 May 2010
Copyright jointly held by Springer and
ESICM 2010

Abstract Purpose: An optimal

volume replacement strategy aims to
restore systemic hemodynamics with
the ultimate goals of improving organ
perfusion and microcirculation for
sustaining adequate tissue oxygenation. This review presents the
(patho)physiological basis of hypovolemia, microcirculation, and tissue
oxygenation and presents a literature
review on the effects of plasma
substitutes on microperfusion and
oxygenation in the clinical setting.
Methods: Literature review of the
effects of fluid therapy on microcirculation and tissue oxygenation
using PubMed search including original papers in English from 1988 to
2009. Results: We identified a total
of 14 articles dealing with the effects
of different crystalloids and colloids
on organ perfusion, microcirculation,
and tissue oxygenation in patients.
The results are divergent, but there is
a general trend that colloids are
superior to crystalloids in improving
organ perfusion, microcirculation,
and tissue oxygenation. Due to the
limited number of studies and

J. Boldt ())
Department of Anesthesiology
and Intensive Care Medicine,
Klinikum der Stadt Ludwigshafen,
Bremserstr. 79, 67063 Ludwigshafen,
Germany
e-mail: boldtj@gmx.net
Fax: ?49-621-5033024
C. Ince
Department of Intensive Care,
Erasmus MC University Hospital
Rotterdam, Rotterdam, The Netherlands

Introduction
Circulating volume and microcirculatory deficits may
occur in the surgical, trauma, burn, and intensive care
patient. While bleeding causes absolute volume deficits,
vasodilation mediated by vasoactive substances produces
relative volume deficits. Hypovolemia may also develop

different study conditions, a metaanalysis on the effects of the volume

replacement strategies on microcirculation is not possible.
Conclusions: Improving the microcirculation by volume replacement
appears to be a promising issue when
treating the critically ill. The growing
insights from animal experiments
have to be translated into the clinical
setting to identify the optimal fluid
regimen for correcting hypovolemia.
New techniques for monitoring
microcirculation at the bedside might
provide such endpoints, although
these have to be validated also in the
clinical setting. Whether improved
microperfusion and tissue oxygenation by fluid therapy will also
improve patient outcomes will have
to be proven by future studies.
Keywords Volume replacement

Crystalloids
Albumin
Gelatins

Hydroxyethyl starch

Microcirculation
Tissue
oxygenation
Patients

in the absence of obvious fluid loss secondary to generalized impairment of the endothelial barrier caused by
inflammation resulting in capillary leakage and fluid shift
from the intravascular to the interstitial space. Restoration
of intravascular volume can be regarded as a cornerstone
of therapy in the critically ill. Diagnosis, choice of fluids,
and identification of hemodynamic targets, however,

1300

mediators and hypoxemia result in abnormal blood flow

distributions and shunting leading to a mismatch between
oxygen delivery and oxygen need by the parenchymal
cells, and thus heterogeneous hypoxemia, and organ
dysfunction [9, 10].
Distributive shock provides the biggest challenge with
regard to identifying endpoints for assessing an adequate
fluid replacement [11]. Currently these endpoints are
aimed at correcting changes in systemic hemodynamics.
Fluid resuscitation can cause an apparent improvement in
systemic circulation while leaving regional and microcirculatory oxygenation and perfusion underresuscitated.
In animal investigations it has been shown that fluid
resuscitation improved organ blood flow of the gut and
kidneys, while leaving other areas hypoxemic [12]. This
is important in the light of recent clinical studies using
new techniques for monitoring microcirculation, which
have shown the persistence of microcirculatory underresuscitation in the presence of normalized systemic
hemodynamic variables and association with adverse
clinical outcome [5, 1315].
Adequate microcirculation relies on the function of the
different components of the microcirculation. Red and
white blood cells, endothelial cells, and smooth muscle
cells have to function in close harmony to guarantee
adequate microcirculatory blood flow to transport oxygen
to the tissues. The function of each of these cellular
Pathophysiology of the hypovolemic microcirculation and subcellular systems is affected by hypovolemia.

remain controversial. One of the reasons for this uncertainty is that fluid resuscitation has traditionally been
targeted to correct macrocirculation, whereas the physiological impact of fluids at the microcirculatory level is
still unclear. Uncorrected microcirculatory alterations
result in inadequate oxygen transport to achieve sufficient
oxidative phosphorylation and, ultimately, cause tissue
damage and organ dysfunction [14]. The primary aim of
optimal fluid resuscitation should be to achieve adequate
perfusion without compromising oxygen transport by
excessive hemodilution. It still remains unclear whether
this can be achieved by correction of hypovolemia itself
or whether the kind of volume replacement is also
of importance. The ideal volume replacement strategy
should correct hypovolemia and restorate systemic
hemodynamics, but also improve microcirculatory
perfusion and tissue oxygenation [5, 6].
The purpose of this review is to consider the current
insights into the effects of fluid therapy on microcirculation and oxygen transport to the parenchymal cells.
A review of the literature will be given with regard to the
effects of commonly used plasma substitutes on organ
perfusion, microcirculation, and tissue oxygenation in the
clinical setting.

Hypovolemia leads to inadequate perfusion of the

microcirculation resulting in insufficient oxygen availability to meet the needs of mitochondrial oxidative
phosphorylation [2, 7]. Weil and Shubin [8] in their
keynote paper classified the different types of shock
into four main categories: hypovolemic, cardiogenic,
obstructive, and distributive shock (Fig. 1, 2). Hypovolemic shock can be described as the condition whereby
there is a decrease in circulating volume. Cardiogenic
shock occurs where there is a loss of cardiac contractility
with elevation of diastolic filling pressure and volume.
Obstructive shock can occur as a result of massive pulmonary embolism, tension pneumothorax, or pericardial
tamponade where there is a physical obstruction in the
circulation resulting in impaired diastolic filling and
increased afterload. Distributive shock involves a defect
in the (micro)vascular distribution of a normal or even of
a supranormal cardiac output resulting in inadequate
regional oxygen delivery. Hypovolemia induced by distributive shock is highly heterogeneous and targets the
microcirculation. Its detection by measuring systemic
hemodynamics is complicated by shunting of the microcirculation resulting in microcirculatory alterations and
hypoxia with normal systemic hemodynamics and oxygen-derived variables [9]. Distributive shock especially
occurs under conditions of inflammation and infection
such as in sepsis and reperfusion injury. Inflammatory

Fig. 1 The classification of shock according to Weil and Shubin

[8]. I Normal conditions. II Cardiogenic shock, related to cardiac
pump failure resulting from loss of the pump function of the heart.
III Hypovolemic shock as a result of decreased circulating volume
from, for example, hemorrhage. IV Obstructive shock as result of
an obstruction in the cardiovascular circuit as a result of, for
example, massive pulmonary embolism, tension pneumothorax, or
pericardial tamponade. V Distributive shock where vascular
dysfunction is unable to distribute a normal or even high cardiac
output, resulting in underperfused microcirculatory areas being
shunted by well perfused areas

1301

Fig. 2 The impact of fluid therapy on the microcirculation. Fluid

administration is the therapy of choice following shock. The
amount and/or composition of the fluids, however, can either have
beneficial or deleterious effects on the microcirculation

Deleterious effects on the microcirculation include dysfunction of endothelial signal transductory pathways
by inflammatory mediators and reactive oxygen species, deterioration of endothelial barrier function (e.g.,
glycocalyx), alterations in red blood cell function
(deformability, aggregability), and increased leukocyte
adhesion and activation [6, 9]. Any one of these alterations either alone or acting together can lead to a loss of
functional capillary density resulting in heterogeneous
abnormalities in the distribution of blood to the microcirculatory network, enhanced oxygen diffusion distances
from the perfused intracapillary lumens to the tissue cell,
tissue hypoxemia, and finally organ dysfunction.
Administration of fluids to correct hypovolemia may
modulate microcirculatory function by various mechanisms. The most important is increasing flow by enhanced
filling of the vasculature, thus generating forcing pressure
promoting microcirculatory perfusion. Fluids also modify
the hemorheology of blood by decreasing viscosity, which
additionally promotes blood flow. There are different
effects of fluids on blood viscosity depending on the
composition of the fluid; the microcirculation can be either
improved or impaired by these effects [16]. Excessive
hemodilution can cause shunting of the microcirculation
and impair regional tissue oxygenation [14]. This effect
can differ among the different organ systems [12].
Acid-base balance has been shown to be influenced by
the administration of fluids [17]. Alterations in acid-base
status can cause deleterious effects on organ function
(e.g., kidney function [18]). Saline solution appears to
have the most negative effect on the (micro)circulation

[19]. Infusion of large amounts of saline results in

increased plasma chloride concentration and causes a
reduction in the strong ion difference, which in turn
produces an increase in free hydrogen ions [20]. This
effect can be avoided when using more plasma-adapted
(balanced) crystalloids [21].
Release of inflammatory mediators secondary to
hypovolemia is another important factor contributing to
microcirculatory dysfunction. The volume replacement
strategy can modulate inflammatory activation, generation of reactive oxygen, and leukocyte adhesion to the
microcirculatory endothelium [22]. Saline solution
appears to be the most pro-inflammatory fluid, whereas
certain colloids (especially when dissolved in a balanced
solution) may be more beneficial in controlling the
inflammatory process [2325]. Studies using intravital
microscopy have shown this to be the case by imaging the
effects of different fluids on leukocyte adherence on organ
microvascular surfaces [26, 27]. In this context colloids
showed more beneficial effects on the microcirculation
than saline resuscitation in a variety of experimental
models using direct observation of leukocyte endothelial
interaction [27, 28]. The use of crystalloids as volume
replacement has been shown to impair microcirculation
and to cause vascular leakage resulting in fluid shift to the
interstitial space [29, 30]. The negative effects on oxygen
transport pathways occur as a result of increased diffusion
path length and poor oxygen solubility in aqueous solutions causing reduced oxygen availability and impaired
cellular respiration.
The glycocalyx is a gel-like structure that forms the
interface between the intracapillary lumen and the endothelial cells, and its integrity is highly sensitive to
oxidative stress [31]. It is likely that endothelial dysfunction and microcirculatory deterioration resulting from
hypovolemia and reperfusion injury are caused by a loss
of the endothelial glycocalyx [32]. Depletion of this
barrier results in leukocyte adhesions and loss of the
endothelial barrier function [33, 34]. This in turn results
in alterations of the Starling forces promoting tissue
edema. The loss of this important supracellular compartment of the microcirculation may form an important
rationale for using colloids [32]. Of the colloids, starches
have been shown to protect the glycocalyx barrier [35]. It
is expected that modifications of the molecular and
pharmacological properties of colloids as well as of the
solvent may provide additional protection of the glycocalyx and thereby of the microcirculation.

How can the effects of volume replacement

be monitored?
Currently, endpoints of volume replacement are aimed at
correcting changes in systemic hemodynamic variables.

1302

These include giving volume challenges either by

administering a fluid bolus or by autotransfusion by
passive leg raising resulting in changes in systemic
hemodynamic variables such as stroke volume or venous
pressure [11]. Fluid resuscitation can cause an apparent
improvement in systemic circulation while leaving
regional and microcirculatory oxygenation and perfusion
uncorrected [12]. New techniques have been introduced at
the bedside aimed at monitoring various aspects of the
microcirculation and tissue oxygenation. These have been
applied to various areas of the body, and various parameters related to microcirculatory function and tissue
oxygenation have been measured. At present, no unifying
monitoring technique exists that measures all aspects of
microcirculatory function in an integrated fashion, and
each technique has its limitations in this respect. It is
worth noting that in fact all hemodynamic monitoring
modalities suffer from this drawback and that no single
technique can be used to measure the integrative function
of the cardiovascular system to achieve hemodynamic
homeostasis from lung to mitochondria. Thus each
microcirculatory monitoring technique should be interpreted for its sensitivity and specificity in identifying a
particular physiological component and its ability to
predict impending adverse events. It has to be emphasized
that these microcirculatory monitoring techniques are at
an early stage of development and have to be validated for
guiding volume therapy in the clinical setting. Currently
used bedside monitoring techniques for assessing the
influence of volume therapy on microcirculation are
described below.
Laser Doppler flowmetry (LDF) is used for nonquantitative assessment of blood flow and has been applied
mainly to the cutaneous microcirculation [36].
Tissue CO2 can be measured using gastric CO2
tonometers or by tissue CO2 electrodes [37]. These
measurements have been mostly applied either in the
stomach or intestines or sublingually and are assumed to
be a measure of the adequacy of microcirculatory perfusion [3642]. In early studies such CO2 measurements
and arterial bicarbonate were entered into the HendersonHasselbalch equation to obtain intestinal mucosal pH
(pHi). This calculation was later abandoned and instead
tissue-to-arterial gradient (pCO2 gap) was used.
A more direct method of evaluating microcirculatory
perfusion is by direct imaging of the microcirculation
using the recently introduced orthogonal polarizing
spectrum (OPS) or sidestream dark field (SDF) imaging
[43, 44]. These are optical techniques that are incorporated into hand-held microscopes for direct visual
observation of the microcirculation on mucosal organ
surfaces. In the perioperative setting these techniques
have mainly been applied to study the sublingual
microcirculation.
Tissue oxygenation has classically been measured by
use of Clark electrodes [45] although more modern

versions of such electrodes use solid state or oxygendependent fluorescence quenching methods. These electrodes are applied either trans- or subcutaneously, or as
needles that can be inserted into muscle tissue.
An alternative method to gain information about microcirculatory oxygen availability is the use of the
oxygen-dependent optical properties of microcirculatory
Hb, which can be monitored using near infrared spectroscopy (NIRS) [46]. This technique has been applied in
the thenar, calf, and forearm, and on the forehead.
A more comprehensive presentation of these techniques will be provided in another review paper to be
published in Intensive Care Medicine as part of this
current series dedicated to microcirculation.

Clinical studies on the effects of fluid therapy

on microcirculation and tissue oxygenation
A PubMed analysis was carried out to investigate the
literature on the effects of fluids on the microcirculation
and tissue oxygenation in the clinical setting. We included
all original studies published in English from 1988 to
2009 and only studies in patients (no volunteer studies)
were included (Table 1). Keywords for the search included [microcirculation], [microperfusion] [tissue blood
flow] [organ perfusion] [tissue oxygenation] in connection
with [hypovolemia], [volume therapy/replacement], [fluid
therapy/replacement], [crystalloids], [Ringers lactate],
[saline solution], [normal saline], [(human) albumin],
[gelatin(s)], [dextran(s)], [hydroxyethyl starch, HES], and
[hypertonic solution]. Articles were only included when
the methods for assessing organ perfusion, microcirculation, and tissue oxygenation were given. Obviously we
may have missed several ongoing studies and indeed
several are currently under review, but nevertheless we
feel this overview gives a comprehensive review of the
state of the current art.
Crystalloids
In two prospective, randomized studies in patients
undergoing abdominal aortic and gynecologic surgery,
the influence of Ringers lactate (RL) for intraoperative
volume replacement on gastric mucosal perfusion was
assessed by measuring gastric intramucosal pH (pHi) by
tonometry [47, 48]. In one study, RL did not improve
gastric mucosal perfusion [47], while in the other one RL
also increased gastric mucosal perfusion, but not nearly as
much as HES 200/0.5 did [48]. In patients undergoing
major abdominal surgery, volume replacement using
saline solution resulted in decreased skeletal muscle tissue
pO2 (ptiO2), whereas ptiO2 increased significantly in the
patients given HES 130/0.4 in saline [49]. This difference

1303

Table 1 Effects of volume administration on organ perfusion, microcirculation, and tissue oxygenation
Reference
(year)

Patients

Design

Fluids

Boldt [52] (1991)

Cardiac
surgery

Pros rand

Pros

Mythen [53] (1995) Cardiac

surgery

Model

Method

Main results

6% HES 200/0.5
To double
vs. HHES vs. no
reduction in
fluids
PCWP

LDF skin

HES 200/0.5 no
control

To increase stroke
volume

pHi tonometry

Both increased LDF;

HHES showed
significantly higher
increase in LDF than
HES 200/0.5
HES significantly
increased gastric
mucosal perfusion
Trauma patients: no
differences in pHi;
septic patients:
decrease in pHi
blunted only by
HES, decrease in
pHi by HA
Only HES improved
microvascular blood
flow, RL did not
pHi remained
unchanged with
HES and slightly
increased with
gelatin (from 7.27 to
7.31)
No correction of
abnormal
intramucosal pCO2
gap by HES
RL decreased (muscle)
tissue oxygenation,
whereas it was
increased by use of
HES 130/0.4
CO2 gap lower in
unbalanced volume
group indicating
improved gastric
mucosal perfusion
with balanced
volume replacement
strategy
pHi lower with gelatin
than with HES 200/
0.62; HES reduced
splanchnic perfusion
significantly less
HES significantly
improved splanchnic
blood flow; RL was
not as effective as
HES
Both regimens
increased tissue
oxygenation; more
fluids were better for
improving tissue
oxygenation;
differences were not
seen by systemic
hemodynamic
monitoring

Boldt [51] (1996)

Trauma and Pros rand

sepsis ICU

10% HES 200 vs.

20% HA

Volume
replacement on
ICU

pHi tonometry

Marik [47] (1997)

Abdominal
aortic
surgery
Sepsis

Pros rand

RL vs. HES 450/

0.7

pHi tonometry

Pros rand

HES 200/0.62 vs.

gelatin

Perioperative
volume
replacement
Hemodynamic
stabilization

Forrest [55] (2000) Sepsis

Pros

10% HES 264/0.45 Keep PAOP

[15 mmHg

pHi tonometry

Lang [49] (2001)

Abdominal
surgery

Pros rand

Saline vs. HES

130/0.4

Wilkes [59] (2001) Elective

surgeries

Pros rand
doubleblinded

Balanced vs.
unbalanced
volume therapy
HES ? cryst

Rittoo [56] (2002)

Abdominal
aortic
surgery

Pros rand

Gelatin vs. HES

200/0.62

Guo [48] (2003)

Gynecology

Pros rand

Rl vs. HES 200/0.5 Intraoperative

volume
replacement

pHi tonometry

Pros rand

Crystalloids 8 vs.
1618 mL kg-1
h-1

Polarographic
subcutaneous
tissue O2
tension

Asfar [54] (2000)

Arkilic [50] (2003) Colon

resection
surgery

pHi tonometry

Microsensory pO2
Perioperative
volume
catheters
replacement
(PCWP 12
16 mmHg)
Hemodynamic
Gastric pHi
stabilization
tonometry
(using algorithm)

Volume expansion

Perioperative fluid
replacement

pHi tonometry

1304

Table 1 continued
Reference
(year)

Patients

Design

Fluids

Model

Method

Main results

Hofman [57]
(2005)

Cardiac
surgery

Pros

HES 200/0.5 no
control

Postoperative fluid
load

pHi tonometry

Al-Rawi [62]
(2005)

SAH
patients

Observational 23.5% HS

Observation

CPP, PbO2, FV

Mahmood [58]
(2009)

Abdominal
aortic
surgery

Pros rand

Perioperative
volume
expansion over
24 h

pHi tonometry

HES increased cardiac

output, but not
splanchnic mucosal
perfusion
Significant increase in
CPP, PbO2, and FV
by 23.5% saline
Least drop in pHi with
HES 200/0.62; most
pronounced drop in
pHi with gelatin

Gelatin, HES 200/

0.62, HES 130/
0.4

HES Hydroxyethylstarch, HA human albumin, pHi gastric intramucosal pHi, RL Ringers lactate, HS hypertonic saline, HHES
hypertonic saline plus hydroxyethylstarch, pros prospective, rand
randomized, LDF laser Doppler flow, PCWP pulmonary capillary
wedge pressure, SAH subarachnoid hemorrhage (SAH), CPP

cerebral perfusion pressure, PbO2 brain tissue oxygen, FV middle

cerebral artery flow velocity, PAOP pulmonary artery occlusion
pressure, pHi gastric intramucosal pH, ICU intensive care unit,
pCO2 gap arterial-to-intramucosal pCO2 difference, ANH acute
normovolemic hemodilution

was not identified by monitoring only systemic hemodynamics. Arkilic et al. [50] investigated the effects of
conservative (2,183 972 mL) versus aggressive
(3,815 1,853 mL) unspecified crystalloid resuscitation
in elective colon resection surgery and measured subcutaneous oxygen tension using oxygen electrodes and
capillary blood flow by a thermal diffusion system. They
found that supplemental fluid administration increased
both tissue oxygen tension and capillary blood flow
showing the most increase with the higher doses of fluids.
The difference between conservative and aggressive
crystalloid resuscitation seen in the microcirculation was
not identified by monitoring systemic hemodynamics.

Hydroxethyl starch (HES)

Colloids
Human albumin (HA)
In one study in trauma intensive care unit (ICU) patients,
volume replacement with HA given over 5 days to
guarantee stable hemodynamics assessed with the help of
a pulmonary artery catheter (PAC) did not change normal
gastric mucosal perfusion measured by tonometry
(no changes in pHi). In septic patients, however, pHi was
significantly decreased by HA administration despite
adequate correction of hypovolemia, suggesting ongoing
perfusion abnormalities in this area by volume resuscitation with HA [51].

Dextrans
No study in the clinical setting during the past 20 years
was found showing the effects of dextrans on organ perfusion, microcirculation, or tissue oxygenation in patients.

Hydroxyethyl starch (HES) refers to a class of synthetic

colloid solutions that are modified natural polysaccharides, similar to glycogen. HES is derived from
amylopectin, a highly branched starch that is obtained
from waxy maize or potatoes. Polymerized D-glucose
units are joined primarily by 1-4 linkages with occasional
1-6 branching linkages. Substituting hydroxyethyl for
hydroxyl groups results in highly increased solubility and
retards hydrolysis of the compound by amylase, thereby
delaying its breakdown and elimination from the blood.
The hydroxyethyl groups are introduced mainly at carbon
positions C2, C3, and C6 of the anhydroglucose residues.
The available HES preparations are characterized by
concentration (hypooncotic: 3%; isooncotic: 6%; hyperoncotic: 10%), molar substitution (MS; low: \0.5;
medium: 0.5; high: [0.5), the mean molecular weight
[Mw, low-molecular weight (LMW)-HES: 70 kD;
medium-molecular weight (MMW)-HES: 130264 kD;
high-molecular weight (HMW)-HES: [450 kD], the origin (potato-derived versus maize-derived HES), and the
solvent (balanced and unbalanced HES preparations).
Eleven studies using HES in the clinical setting were
identified [47, 49, 5157]. Two studies in septic [54, 55]
and one study in cardiac surgery patients [57] showed
unchanged organ perfusion by HES. In all of these studies, pHi (or pCO2 gap) was measured by tonometry to
assess the influence of volume replacement therapy on
gastric mucosal perfusion. Eight studies in patients
undergoing cardiac, vessel, trauma, or gynecologic surgery showed that HES improved organ perfusion or tissue
oxygenation or that decrease in perfusion was blunted by
adminstration of HES [4749, 5153, 56, 58]. In six
of them, gastric mucosal perfusion (pHi) was measured using tonometry and administration of HES was

1305

associated with significantly improved gastric mucosal

perfusion [47, 48, 51, 53, 56, 58]. In one study in cardiac
surgery patients, LDF was used to measure skin microcirculatory perfusion [52]. Microcirculatory blood flow
showed better skin perfusion with HES 200/0.5 than with
other HES preparations (HES 70/0.5 and HES 450/0.7).
That the type of HES preparation seems to be of importance concerning modulation of the microcirculation has
also been shown in a study of patients undergoing
abdominal aortic surgery [58]. When using HES 200/0.62,
pHi was significantly less decreased compared to HES
130/0.4. In a study in patients undergoing major abdominal surgery, the influence of 6% HES 130/0.4 on tissue
pO2 was compared to patients who received saline solution for volume replacement [49]. Skeletal muscle tissue
pO2 (ptiO2) was monitored for 24 h after surgery using
flexible minimally invasive microsensory pO2 catheters.
Although systemic hemodynamics and systemic oxygenation data were similar in both groups, ptiO2 increased
significantly in the HES 130/0.4-treated patients (?59%),
but decreased in the RL group (-23%).
Gelatins
Three studies were found that used gelatins for improving
organ perfusion [54, 56, 58]. Gelatin was given for
hemodynamic stabilization in patients suffering from
sepsis or undergoing aortic surgery and compared to use
of HES. pHi was measured by tonometry to assess gastric
mucosal perfusion. In the hypovolemic septic patients
[54], use of gelatin very moderately increased pHi (from
7.27 to 7.31) suggesting improved splanchnic perfusion.
Of particular importance was also that no difference in
systemic hemodynamic variables was found between the
two volume replacement strategies, but only on gastric
tonometry data. In two other studies from one research
group performed in patients undergoing abdominal aortic
surgery, either gelatin or HES (HES 200/0.62 or HES
130/0.4) was administered for volume expansion [56, 58].
HES 200/0.62-treated patients showed significantly less
reduced splanchnic perfusion than those administered
gelatin.

hemodynamics using a specific algorithm [59]. Similar

amounts of HES (approximately 2,500 mL) and crystalloids (approximately 1,500 mL) were given in both
groups. Splanchnic perfusion was assessed by gastric
tonometry. Systemic hemodynamics were without group
differences, while hyperchloremic acidosis was seen only
in the non-plasma-adapted volume group, and better
gastric mucosal perfusion was provided by the balanced
volume replacement strategy compared with saline-based
fluids.
Hypertonic solutions
Great enthusiasm has been expressed for hypertonic
saline (HS) or hypertonic/colloid solutions (HCS) in the
treatment of hypovolemic shock (small volume resuscitation). Hypertonic volume replacement has been
proposed to correct microcirculatory dysfunction associated with hypovolemia and its subsequent inflammatory
effect. HS has been shown to increase perfusion pressure,
improve capillary flow distribution, and offer endothelial
de-swelling effects [60, 61]. Because hemodynamic
effects of HS solutions are reported to be rather transient,
HS is often mixed with colloids [hypertonic saline plus
hyperoncotic dextran (HSD) or hypertonic saline plus
hypertonic HES (HHES)].
In a study in cardiac surgery patients using HHES to
double low pulmonary capillary wedge pressure (PCWP),
skin microcirculatory blood flow measured by LDF was
significantly increased in comparison to HES 200/0.5
[52]. In an observational study in patients with subarachnoid hemorrhage, Al-Rawi et al. [62] administered
extremely hypertonic saline solution (23.5%). A significant increase in cerebral perfusion pressure, brain tissue
oxygenation, and middle cerebral artery flow velocity was
found accompanied by a significant decrease in intracranial pressure. An improvement in cerebral metabolic
status in terms of lactate-pyruvate ratio was also seen
after infusion of this extreme hypertonic solution.

Discussion
Plasma-adapted versus non-plasma-adapted volume
replacement strategy
In a prospective, randomized, blinded trial in elderly
surgical patients, either a plasma-adapted (balanced)
intraoperative fluid regimen consisting of Hartmanns
solution and 6% HES preparation dissolved in a balanced
electrolyte solution (Hextend) or a nonplasma-adapted
(unbalanced) regimen consisting of 0.9% sodium
chloride solution and 6% HES dissolved in 0.9%
sodium chloride solution was given to guarantee stable

In recent years, microcirculation has gotten increased

attention in the treatment of the critically ill patient. This
includes the choice for the ideal volume replacement
strategy to improve microcirculation. Interestingly, we
found only 14 papers on this issue over the past 20 years.
This dearth of information on the different volume
replacement strategies for organ perfusion, microcirculation, or tissue oxygenation is remarkable as there is an
ongoing controversy concerning the ideal plasma substitute to correct hypovolemia. Due to the small number
of studies and the divergent study designs, we decided not

1306

to perform a meta-analysis or a systematic review. The

identified studies differed markedly with regard to the
study design: (1) Plasma substitutes were used under
different conditions, e.g., in trauma, sepsis, hemorrhage or
surgery. (2) The amount of fluids that was administered
differed widely among the studies making it difficult to
distinguish between what effect is attributed to volume
correction/expansion alone and what effect is specific for
a certain plasma substitute. (3) Duration of volume
administration differed; cases of single-shot versus
continuous administration over hours were compared. (4)
The endpoint of volume administration was not uniformly
defined. Mostly fixed amounts of volume were given.
A goal-directed volume replacement strategy, however, is a better approach than infusing a fixed amount of
volume. (5) Although it is clear that measurement of
systemic hemodynamic variables has limited sensitivity
for identifying hemodynamic alterations associated with
shock and resuscitation, most of the techniques used for
assessing microcirculation are still at the stage of development and not yet ready for routine clinical use.
Looking at the results of the 14 identified studies, there
appears to be a trend that colloids are more effective in
beneficially modifying organ perfusion and microcirculation than crystalloids. One important objection to the
results of these studies is that most of them used gastric
tonometry to assess the effects of volume replacement on
perfusiona surrogate marker of splanchnic perfusion
whose validity has often been doubted.
There is an urgent need for more information on the
effect of fluids on microcirculation as there is a current
trend to keep the patients more on the dry side by
restricting volume administration. From the pathophysiological point of view, use of vasopressors in an
hypovolemic patient to keep up blood pressure may
initiate a fatal process on the microperfusion level with
detrimental sequel for organ function and even for the
patients outcome. It has been demonstrated that the use
of vasopressors has no effect on prompting microcirculatory flow, emphasizing that a guarantee of adequate
microperfusion may not be reached simply by maintaining or even increasing arterial blood pressure.
Whether the effects of a certain volume replacement
strategy on microcirculation can be translated into its
effects on patients outcome (survival) was beyond the
scope of this review. Up to now it has not been shown
that, by the choice of a certain volume replacement regimen, someones life was rescued, although beneficial
effects on inflammation, microcirculation, and tissue
oxygenation have been shown. This experience is similar
to the introduction of new monitoring techniques, antibiotics, feeding strategies, or renal replacement strategies
that have been shown to improve certain aspects in the
management of the critically ill without improving overall
survival. Our actual approach in the treatment of the
critically ill aims to improve different parts in the mosaic

of pathophysiology of critical illness; improving microcirculation may be one important part in this therapeutic
puzzle.
As the commonly used plasma substitutes differ with
regard to their physico-chemical characteristics, they also
may differ with regard to their effects on organ perfusion,
microcirculation, or tissue oxygenation. Based on the
insights received from animal studies, questions that have
to be addressed in the clinical setting will include how the
different fluids affect the determinants of microcirculatory
function. Important issues will be the effects on capillary
flow and capillary recruitment in terms of functional
capillary density, the extent of leukocyte endothelial
interaction and glycocalyx determination, release of
inflammatory mediators and reactive oxygen species, and
finally the effects of the various fluid types on tissue
oxygenation. These effects have to be determined for the
different types of shock and will have to be related to
organ function and clinical outcome.

Conclusions
Although it is clear from our literature search that the data
that are needed to draw definite conclusions concerning
the optimal fluid therapy and improvement in microcirculatory perfusion are not yet available, we will draw
some careful conclusions from an evidence level E
perspective. These can be summarized as follows: (1) A
robust method or protocol for identifying hypovolemia
and guiding fluid resuscitation is yet being sought. (2)
Although it is clear that fluid therapy should be effective in
correcting systemic hemodynamics, albeit based mainly
on experimental studies, it should also be successful in
correcting deficits in microperfusion and tissue oxygenation. (3) There is a need for bedside monitoring techniques
for guiding fluid therapy integrating systemic, regional,
microcirculatory, and oxygenation issues. (4) The choice
between crystalloids and colloids is probably dependent
on the patients condition and the cause of hypovolemia.
(5) Compared to colloids, large amounts of crystalloids are
needed to achieve similar systemic and microcirculatory
endpoints leading to tissue edema and impaired tissue
oxygenation. (6) It is expected that an optimal fluid
composition for correction of hypovolemia may have to
include additional components needed to support organ
perfusion, microcirculation, and tissue oxygenation.
We hope that with this paper we have set the scene
for important clinical investigations that will have to be
carried out to find the optimal fluid composition and
identify the optimal (micro)hemodynamic targets for
volume resuscitation. We expect that protection of the
microcirculatory function will play an important role in
the future and will lead to improved treatment of the
hypovolemic critically ill patient.

1307

Acknowledgments The authors gratefully acknowledge the talents (Germany); Serumwerke Bernburg (Germany); Baxter (Europe).
of Darryl Milstein who produced Figs. 1 and 2 in this paper. This Ince holds a patent on SDF imaging, has stock in Microvision
Medical, and has received educational grants from Hutchinison
study was supported only by an institutional grant.
Technology, Baxter, Novartis, and Eli Lilly.
Conflict of interest statement Boldt and his institution have
received funding from B. Braun (Germany); Fresenius-Kabi

References
1. Edouard AR, Degremont AC,
Duranteau J, Pussard E, Berdeaux A,
Samii K (1994) Heterogeneous regional
vascular responses to simulated
transient hypovolemia in man. Intensive
Care Med 20:220414
2. Ince C (2004) Microcirculation in
distress: a new resuscitation end point?
Crit Care Med 32:19631964
3. Vollmar B, Menger MD (2004) Volume
replacement and microhemodynamic
changes in polytrauma. Langenbecks
Arch Surg 389:485491
4. Perret C, Feihl F (2000) Volume
expansion during septic shock. Bull
Acad Natl Med 184:16211629
5. Sakr Y, Dubois MJ, De Backer D,
Creteur J, Vincent JL (2004) Persistent
microcirculatory alterations are
associated with organ failure and death
in patients with septic shock. Crit Care
Med 32:18251831
6. Takala J, Jakob SM (2009) Shedding
light on microcirculation. Intensive
Care Med 35:394396
7. Mythen MG, Salmon JB, Webb AR
(1993) The rational administration of
colloids. Blood Rev 7:223228
8. Weil MH, Shubin H (1971) Proposed
reclassification of states of shock. Adv
Exp Med Biol 23:1323
9. Ince C (2005) The microcirculation is
the motor of sepsis. Crit Care
9(Suppl 4):S13S19
10. De Backer D, Creteur J, Preiser JC,
Dubois MJ, Vincent JL (2002)
Microvascular blood flow is altered in
patients with sepsis. Am J Respir Crit
Care Med 166:98104
11. Vincent JL, Weil MH (2006) Fluid
challenge revisited. Crit Care Med
34:13331337
12. Van Bommel J, Siegemund M, Henny
CP, Ince C (2008) Heart, kidney, and
intestine have different tolerances for
anemia. Transl Res 151:110117
13. Trzeciak S, Dellinger RP, Parrillo JE,
Guglielmi M, Bajaj J, Abate NL (2007)
Early microcirculatory perfusion
derangements in patients with severe
sepsis and septic shock: relationship to
hemodynamics, oxygen transport, and
survival. Ann Emerg Med 49:8898

14. Van Bommel J, Henny CP, Trouwborst

A, Ince C (2001) Microvascular
shunting in severe normovolemic
hemodilution. Anesthesiology 94:152
160
15. Wang P, Hauptman JG, Chaudry IH
(1990) Hemorrhage produces
depression in microvascular blood flow
which persists despite fluid
resuscitation. Circ Shock 32:307318
16. Ehrly AM, Landgraf H (1985) Influence
of intravenous infusions of
hydroxyethylstarch (HES) (MW 40,000
and 450,000) on the blood flow
properties of healthy volunteers.
Angiology 36:4144
17. Boldt J (2007) The balanced concept of
fluid resuscitation. Br J Anaesth
99:312315
18. Powell-Tuck J, Gosling P, Lobo DN,
Allison SP, Carlson GL, Gore M,
Lewington AJ, Pearse RM, Mythen MG
(2008) British consensus guidelines on
intravenous fluid therapy for adult
surgical patients. http://www.bapen.
org.uk/pdfs/bapen_pubs/giftasup.pdf
19. Kellum JA (2002) Fluid resuscitation
and hyperchloremic acidosis in
experimental sepsis: improved shortterm survival and acid-base balance
with Hextend compared with saline.
Crit Care Med 30:300305
20. Scheingraber S, Rehm M, Sehmisch C,
Finsterer U (1999) Rapid saline
infusion produces hyperchloremic
acidosis in patients undergoing
gynecologic surgery. Anesthesiology
90:12651270
21. Boldt J (2008) Saline versus balanced
hydroxyethyl starch: does it matter?
Curr Opin Anaesthesiol 21:679683
22. Boldt J (2006) Do plasma substitutes
have additional properties beyond
correcting volume deficits? Shock
25:103116
23. Kellum JA, Song M, Almasri E (2006)
Hyperchloremic acidosis increases
circulating inflammatory molecules in
experimental sepsis. Chest 130:962
967

24. Boldt J, Suttner S, Brosch C, Lehmann

A, Rohm K, Mengistu A (2009) The
influence of a balanced volume
replacement concept on inflammation,
endothelial activation, and kidney
integrity in elderly cardiac surgery
patients. Intensive Care Med 35:462470
25. Matharu NM, Butler LM, Rainger GE,
Gosling P, Vohra RK, Nash GB (2008)
Mechanisms of the anti-inflammatory
effects of hydroxyethyl starch
demonstrated in a flow-based model of
neutrophil recruitment by endothelial
cells. Crit Care Med 36:15361542
26. Kaplan SS, Park TS, Gonzales ER,
Gidday JM (2000) Hydroxyethyl starch
reduces leukocyte adherence and
vascular injury in the newborn pig
cerebral circulation after asphyxia.
Stroke 31:22182223
27. Kupper S, Torge Mees S, Gassmann P,
Brodde M, Kehrel B, Haier J (2007)
Hydroxyethyl starch normalizes platelet
and leukocyte adhesion within
pulmonary microcirculation during
LPS-induced endotoxemia. Shock
28:300308
28. Inan N, Iltar S, Surer H, Yilmaz G,
Alemdaroglu KB, Yazar MA, Basar H
(2009) Effect of hydroxyethyl starch
130/0.4 on ischaemia/reperfusion in
rabbit skeletal muscle. Eur J
Anaesthesiol 26:160165
29. Funk W, Baldinger V (1995)
Microcirculatory perfusion during
volume therapy. A comparative study
using crystalloid or colloid in awake
animals. Anesthesiology 82:975982
30. Hoffmann JN, Vollmar B, Laschke
MW, Inthorn D, Schildberg FW,
Menger MD (2002) Hydroxyethyl
starch (130 kD), but not crystalloid
volume support, improves
microcirculation during normotensive
endotoxemia. Anesthesiology 97:460
470
31. Rubio-Gayosso I, Platts SH, Duling BR
(2006) Reactive oxygen species
mediate modification of glycocalyx
during ischemia-reperfusion injury. Am
J Physiol Heart Circ Physiol
290:H2247H2256

1308

32. Chappell D, Jacob M, Hofmann-Kiefer

K, Conzen P, Rehm M (2008) A
rational approach to perioperative fluid
management. Anesthesiology 109:723
740
33. Constantinescu AA, Vink H, Spaan JA
(2003) Endothelial cell glycocalyx
modulates immobilization of leukocytes
at the endothelial surface. Arterioscler
Thromb Vasc Biol 23:15411547
34. Mulivor AW, Lipowsky HH (2002)
Role of glycocalyx in leukocyteendothelial cell adhesion. Am J Physiol
Heart 283:H1282H1291
35. Rehm M, Zahler S, Lotsch M, Welsch
U, Conzen P, Jacob M, Becker B (2004)
Endothelial glycocalyx as an additional
barrier determining extravasation of 6%
hydroxyethyl starch or 5% albumin
solutions in the coronary vascular bed.
Anesthesiology 100:12111223
36. Leslie SJ, Affolter J, Denvir MA, Webb
DJ (2003) Validation of laser Doppler
flowmetry coupled with intra-dermal
injection for investigating effects of
vasoactive agents on the skin
microcirculation in man. Eur J Clin
Pharmacol 59:99102
37. Dubin A, Edul VSK, Ince C (2009)
Determinants of tissue pCO2 in shock
and sepsis: relationship to the
microcirculation. In: Vincent JL (ed)
Yearbook of intensive care and
emergency medicine. Springer,
Heidelberg, pp 195204
38. Russell JA (1997) Gastric tonometry:
does it work? Intensive Care Med
23:36
39. Vallet B, Lund N, Curtis S, Kelly D,
Cain S (1994) Gut and muscle tissue
PO2 in endotoxemic dogs during shock
and resuscitation. J Appl Physiol
76:793800
40. Dubin A, Edul VS, Pozo MO, Murias
G, Canullan CM, Martins EF, Ferrara
G, Canales HS, Laporte M, Estenssoro
E, Ince C (2008) Persistent villi
hypoperfusion explains intramucosal
acidosis in sheep endotoxemia. Crit
Care Med 36:535542
41. Creteur J, De Backer D, Sakr Y, Koch
M, Vincent JL (2004) Sublingual
capnometry tracks microcirculatory
changes in septic patients. Crit Care
Med 32:516523
42. Weil MH, Nakagawa Y, Tang W, Sato
Y, Ercoli F, Finegan R (1999)
Sublingual capnometry: a new
noninvasive measurement for diagnosis
and quantification of severity of
circulatory shock. Crit Care Med
27:12251229

43. Goedhart PT, Khalilzada M, Bezemer

R, Merza J, Ince C (2007) Sidestream
dark field (SDF) imaging: a novel
stroboscopic LED ring-based imaging
modality for clinical assessment of the
microcirculation. Opt Express
15:1510115114
44. Groner W, Winkelman JW, Harris AG,
Ince C, Bouma GJ, Messmer K, Nadeau
RG (1999) Orthogonal polarization
spectral imaging: a new method for
study of the microcirculation. Nat Med
5:12091212
45. Clark LC (1956) Monitor and control of
blood and tissue oxygen tension. Trans
Am Soc Artif Intern Org 2:4146
46. Jobsis FF (1977) Noninvasive, infrared
monitoring of cerebral and myocardial
oxygen sufficiency and circulatory
parameters. Science 198:12641267
47. Marik PE, Iglesias J, Maini B (1997)
Gastric intramucosal pH changes after
volume replacement with hydroxyethyl
starch or crystalloid in patients
undergoing elective abdominal aortic
aneurysm repair. J Crit Care 12:5155
48. Guo X, Xu Z, Ren H, Luo A, Huang Y,
Ye T (2003) Effect of volume
replacement with hydroxyethyl starch
solution on splanchnic oxygenation in
patients undergoing cytoreductive
surgery for ovarian cancer. Chin Med J
116:9961000
49. Lang K, Boldt J, Suttner S, Haisch G
(2001) Colloids versus crystalloids and
tissue oxygen tension in patients
undergoing major abdominal surgery.
Anesth Analg 93:405409
50. Arkilic C, Taguchi A, Sharma N,
Ratnaraj J (2003) Supplemental
perioperative fluid administration
increases tissue oxygen pressure.
Surgery 133:4955
51. Boldt J, Heesen M, Muller M, Pabsdorf
M, Hempelmann G (1996) The effects
of albumin versus hydroxyethyl starch
solution on cardiorespiratory and
circulatory variables in critically ill
patients. Anesth Analg 83:254261
52. Boldt J, Zickmann B, Herold C,
Ballesteros M, Dapper F, Hempelmann
G (1991) Influence of hypertonic
volume replacement on the
microcirculation in cardiac surgery. Br
J Anaesth 67:595602
53. Mythen MG, Webb AR (1995)
Perioperative plasma volume expansion
reduces the incidence of gut mucosal
hypoperfusion during cardiac surgery.
Ann Surg 130:423429

54. Asfar P, Kerkeni N, Labadie F, Gouello

JP, Brenet O, Alquier P (2000)
Assessment of hemodynamic and
gastric mucosal acidosis with modified
fluid gelatin versus hydroxyethyl starch:
a prospective, randomized study.
Intensive Care Med 26:12821287
55. Forrest DM, Baigorri F, Chittock DR,
Spinelli JJ, Rusel JA (2000) Volume
expansion using pentastarch does not
change gastric-arterial PCO2 gradient or
gastric intramucosal pHi in patients
who have sepsis syndrome. Crit Care
Med 28:22542258
56. Rittoo D, Gosling P, Bonnici C,
Burnley S, Millns P, Simms MH, Smith
SR, Vohra RK (2002) Splanchnic
oxygenation in patients undergoing
abdominal aortic aneurysm repair and
volume expansion with eloHAES.
Cardiovasc Surg 10:128133
57. Hofmann D, Thuemer O, Schelenz C,
van Hoot N, Sakka SG (2005)
Increasing cardiac output by fluid
loading: effects on indocyanine green
plasma disappearance rate and
splanchnic microcirculation. Acta
Anaesthesiol Scand 49:12801286
58. Mahmood A, Gosling P, Barclay R,
Kilvington F, Vohra R (2009)
Splanchnic microcirculation protection
by hydroxyethyl starches during
abdominal aortic aneurysm surgery. Eur
J Vasc Endovasc Surg 37:319325
59. Wilkes NJ, Woolf R, Mutch M, Mallett
SV, Peachey T, Stephens R, Mythen
MG (2001) The effects of balanced
versus saline-based hetastarch and
crystalloid solutions on acid-base and
electrolyte status and gastric mucosal
perfusion in elderly surgical patients.
Anesth Analg 93:811816
60. Kreimeier U, Bruckner UB, Niemczyk
S, Messmer K (1990) Hyperosmotic
saline dextran for resuscitation from
traumatic-hemorrhagic hypotension:
effect on regional blood flow. Circ
Shock 32:8399
61. Behrman SW, Fabian TC, Kudsk KA,
Proctor KG (1991) Microcirculatory
flow changes after initial resuscitation
of hemorrhagic shock with 7.5%
hypertonic saline/6% dextran 70. J
Trauma 31:589598
62. Al-Rawi PG, Zygun D, Tseng MY,
Hutchinson PJ, Matta BF, Kirkpatrick
PJ (2005) Cerebral blood flow
augmentation in patients with severe
subarachnoid haemorrhage. Acta
Neurochir (Suppl) 95:123127

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.