ATP = adenosine triphosphate; ENHANCE = Extended Evaluation of Recombinant Human Activated Protein C; iNOS = inducible form of nitric
oxide synthase; LPS = lipopolysaccharide; NO = nitric oxide; PROWESS = Recombinant Human Activated Protein C Worldwide Evaluation in
Severe Sepsis; RBC = red blood cell; SNO = S-nitrosothiol.
Available online http://ccforum.com/supplements/9/S4/S3
This review examines experimental evidence that the microvascular
dysfunction that occurs early in sepsis is the critical first stage in
tissue hypoxia and organ failure. A functional microvasculature
maintains tissue oxygenation despite limitations on oxygen delivery
from blood to tissue imposed by diffusion; the density of perfused
(functional) capillaries is high enough to ensure appropriate
diffusion distances, and arterioles regulate the distribution of
oxygen within the organ precisely to where it is needed. Key
components of this regulatory system are the endothelium, which
communicates and integrates signals along the microvascular
network, and the erythrocytes, which directly monitor and regulate
oxygen delivery. During hypovolemic shock, a functional
microvasculature responds to diminish the impact of a decrease in
oxygen supply on tissue perfusion. However, within hours of the
onset of sepsis, a dysfunctional microcirculation is, due to a loss of
functional capillary density and impaired regulation of oxygen
delivery, unable to maintain capillary oxygen saturation levels and
prevent the rapid onset of tissue hypoxia despite adequate oxygen
supply to the organ. The mechanism(s) responsible for this
dysfunctional microvasculature must be understood in order to
develop appropriate management strategies for sepsis.
One of the primary functions of the microcirculation is to
ensure adequate oxygen delivery to meet the oxygen
demands of every cell within an organ. In order to achieve
this, the healthy microvasculature will respond to changes in
metabolic demand or blood flow to the organ. However, if the
microvasculature is dysfunctional, as it is in sepsis, then
tissue hypoxia can occur despite supranormal oxygen delivery
values. In order to understand how sepsis can result in tissue
hypoxia in organs remote to the initial site of injury, we first
need to understand oxygen transport and the regulation of
oxygen delivery under normal physiological conditions.
Diffusion limitation for oxygen
More than 80 years ago, Krogh  published the first oxygen
transport model that described diffusion of oxygen from a
single capillary cross-section into the surrounding cylinder of
tissue. This model highlighted the impact of diffusion
limitation on tissue oxygenation and hence explained why
capillary density was greater in tissues with higher oxygen
consumption rates. The model also demonstrated that it is
not sufficient to simply supply an adequate amount of oxygen
to the organ as a whole, but that oxygen must be distributed
within the organ precisely to where it is needed.
Integration of arteriolar regulation
Arterioles, which control the vascular resistance of an organ
and hence its total blood flow, are also responsible for
regulating the distribution of oxygen within the organ itself. To
achieve this degree of control, the response of the micro-
vasculature to changing conditions (e.g. increased oxygen
demand, reduced oxygen delivery) must be highly integrated
across the entire microvascular bed [2-4]. The endothelial
cells play a critical role in conducting and integrating local
stimulatory signals via cell-to-cell communication along the
microvascular endothelium [5-7] or by responding to changes
in blood flow as signal transducers of local shear stress .
For example, if there is a dilatory stimulus originating in one
region of the capillary bed, the vascular endothelium will
conduct this stimulus to the arterioles supplying these
capillaries, causing them to dilate, thus increasing blood flow.
Endothelium lining larger arterioles and resistance arteries
further upstream will respond to the increase in shear stress
by dilating to the point that local shear stress is restored back
to baseline, and thus further reducing vascular resistance.
The microcirculation as a functional system
Christopher G Ellis1, Justin Jagger2and Michael Sharpe3
1Professor, Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada
2MD/PhD, Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada
3MD, FRCPC, Professor, Department of Anesthesia and Perioperative Medicine, Program in Critical Care Medicine, The University of Western Ontario,
London Health Sciences Center, London, Ontario, Canada
Corresponding author: Christopher G Ellis, firstname.lastname@example.org
Published online: 25 August 2005
This article is online at http://ccforum.com/supplements/9/S4/S3
© 2005 BioMed Central Ltd
Critical Care 2005, 9(suppl 4):S3-S8 (DOI 10.1186/cc3751)
Critical Care August 2005 Vol 9 Suppl 4Ellis et al.
Without this integrated response, a local dilatory stimulus
could “steal” flow from other regions of the tissue.
Precapillary fall in oxygen saturation
Thirty-five years ago, Duling and Berne  reported that
oxygen levels diminished along the arteriolar tree and that up
to two-thirds of the oxygen delivered to a tissue has already
been extracted by the time blood reaches the capillary bed.
Using a variety of techniques in different organs and species,
numerous researchers have documented these experimental
observations [10,11]. Although we do not fully understand
why there is such a large precapillary decrease in oxygen,
Ellsworth and Pittman  provided experimental evidence to
show that some of the oxygen leaving the arterioles can
reoxygenate red blood cells (RBCs) flowing through nearby
capillaries by diffusion. If oxygen can be transported from
arterioles to capillaries, it is also likely that oxygen exchange
occurs between capillaries with different oxygen levels ,
and between arterioles and venules . In addition,
quantitative studies of microvascular blood flow have
demonstrated considerable spatial heterogeneity of capillary
perfusion [14,15]. The unique rheological properties of RBC
flow through branching networks of small vessels (Fahreaus
effect and plasma skimming at bifurcations ) results in
wide distributions of capillary hematocrits and RBC flow rates.
The heterogeneity of microvascular
precapillary drop in oxygen saturation, and the diffusional
exchange of oxygen among microvessels mean that blood flow
by itself is not a good indicator of adequate oxygen delivery to
tissue. This has important implications for the regulation of the
oxygen supply, particularly during disease states and the
investigation of microvascular oxygen delivery in vivo.
The role of RBCs in local regulation of oxygen delivery
The automatic feedback system responsible for regulating
local oxygen delivery must be able to monitor and regulate
oxygen delivery throughout the microvascular bed. Bergfeld
and Forrester  were the first to demonstrate that RBCs
exposed to hypoxic conditions released adenosine tri-
phosphate (ATP). Since ATP is a potent vasodilator, they
proposed that RBCs flowing through a hypoxic region could
stimulate local vasodilation and an increase in blood flow.
Ellsworth and colleagues [18,19] demonstrated that ATP
injected into arterioles results in local vasodilation that is also
conducted along the arteriole, thus demonstrating the
presence of purinergic receptors (P2y1and P2y2) on the
endothelium of these vessels. ATP binding to P2y1and P2y2
on vascular endothelium causes vasodilation of vascular
smooth muscle by inducing the endothelium to produce nitric
oxide (NO) , prostaglandin , or endothelium-derived
hyperpolarizing factor [22,23]. Collins and colleagues 
demonstrated that ATP injected into postcapillary venules
results in vasodilation of the feeding arteriole. Dietrich and
colleagues  showed that isolated cerebral arterioles
dilate in response to a fall in oxygen in their environment only
if the arterioles are perfused with RBCs, and not if they are
perfused with a physiological solution without RBCs. They
also observed that this vasodilation was caused by the efflux
of ATP from the RBCs , and demonstrated that the
oxygen-dependent release of ATP occurred rapidly enough to
be physiologically relevant. Jagger and colleagues  have
shown that ATP efflux is linearly related to hemoglobin oxygen
saturation and that the regulation of glycolysis by deoxy-
hemoglobin in RBCs is the first step in the signaling pathway
for ATP release. Also, ATP injected into larger venules results
in vasodilation of the paired arteriole [27-29]. Saltin and
colleagues, studying exercising human volunteers, have
reported that ATP released from RBCs in response to a fall in
hemoglobin oxygen saturation was responsible for regulating
oxygen delivery to skeletal muscle [30,31].
In 1996, Stamler and his colleagues  also proposed that
RBCs are responsible for regulating oxygen delivery through
the transport of NO, produced in the lungs, to the periphery in
the form of the bioactive compound S-nitrosothiol (SNO).
SNO, reported to be a potent vasodilator, is carried by hemo-
globin and released as the hemoglobin oxygen saturation falls
in response to local oxygen demand. Although Stamler’s group
have published numerous papers supporting their theory
[33,34], a number of groups have questioned the physiological
role of SNO in vivo [35,36] as well as the accuracy of measure-
ments of SNO from biological samples . In 2003, Cosby
and colleagues  reported that deoxyhemoglobin acts as a
nitrite reductase, converting nitrite to NO, and hence making it
possible for RBCs to vasodilate arterioles in response to hypoxia.
The potential for hemoglobin to play a key role in regulating
vascular tone and hence oxygen delivery has generated
considerable excitement , and has elevated the RBC
from a simple carrier of oxygen to a cell ideally suited to
monitor and regulate oxygen delivery across the entire
microvascular bed .
Sepsis and microvascular dysfunction
What is the cause of organ failure in sepsis? A review article
from 2000 suggests that clinical and experimental evidence
“clearly indicate that microcirculatory dysfunction lies at the
centre of sepsis pathogenesis” .
Loss of capillaries in remote organs
In 1994, Lam and colleagues  reported that a 24-hour
peritonitis model of sepsis (cecal ligation and puncture) in
rats caused a decrease in the number of perfused capillaries
(i.e. decrease in functional capillary density) in skeletal
muscle, with increased heterogeneity of blood flow. The loss
of perfused capillaries in experimental models of sepsis has
been reported in the microvasculature of intestinal villi
[43,44], the diaphragm , and the liver .
Maldistribution of oxygen delivery
Using intravital video microscopy, we have studied the impact
of the loss of capillary density on capillary oxygen saturation
in a fluid resuscitated, normotensive, peritonitis model of
sepsis similar to that used by Lam and colleagues . Using
a dual-wavelength system for spectrophotometric analysis of
RBC oxygen saturation, video images of microvascular blood
flow were analyzed for perfused capillary density, RBC
hemodynamics, and the oxygen saturation levels at the
entrance and exit of the capillary bed . This study
confirmed the presence of stopped-, normal-, and high-flow
capillaries in the same field of view. We demonstrated that
the loss of capillaries (from 20% to 50% stopped flow) leads
to a significant fall in oxygen saturation in normally perfused
capillaries (from 60% to 20% saturation) and an increase in
capillary oxygen extraction , as shown in Fig. 1. There
was no evidence that the local oxygen regulatory system was
effective in redistributing oxygen supply to offset the fall in
capillary oxygen saturation levels, a result that is in
accordance with the reported impaired hyperemic response
to exercise observed by Lam and colleagues in the same
sepsis model .
Hypovolemic shock versus septic shock
The situation is very different if the microvasculature is still
functional and able to regulate oxygen distribution within the
capillary bed. Nakajima and colleagues  compared
microvascular perfusion in intestinal villi in mouse models of
septic shock and hypovolemic shock (hemorrhage). They
demonstrated that, at the same level of hypotension,
hemodynamic and mucosal perfusion disorders were
considerably more pronounced
hypotension than in hemorrhagic hypotension. RBC velocity
was maintained in hemorrhagic shock but not during septic
shock. During hypovolemic shock the microvasculature was
still able to regulate microvascular perfusion, but during
sepsis the regulatory response was impaired.
Experiment-based mathematical model of oxygen
transport in sepsis
Our simple interpretation of the increase in oxygen extraction
following a loss of perfused capillaries in sepsis was that
each perfused capillary would need to support a larger
volume of tissue to compensate for the loss of oxygen supply
from stopped-flow capillaries
interpretation did not take into account the possibility of an
increase in oxygen consumption rate or the potential
contribution of oxygen from fast-flow capillaries. To address
this limitation, Goldman and colleagues  developed a
mathematical model of capillary oxygen delivery in a three-
dimensional volume of tissue that was based on our
experimental data on capillary hemodynamics and oxygen
saturation in sepsis. Tissue oxygen consumption rates were
adjusted in the model to yield oxygen extraction values that
were consistent with our experimental measurements of
capillary oxygen extraction. The model predicted that oxygen
consumption increases from between two- to fourfold
depending upon the severity of sepsis, and that the loss of
perfused capillaries leads to significant tissue hypoxia but not
. However, this
to anoxia. Despite the loss of capillaries and increased
oxygen consumption, the model predicted that the tissue is
protected from zero oxygen levels by the high-flow capillaries
that supply a substantial fraction of the total oxygen delivered
to the tissue. However, these high-flow capillaries do have
higher venular end-oxygen saturations than normal-flow
capillaries, and hence “shunt” oxygen through the capillary
bed, thus elevating venular oxygen saturation levels. If the
excess oxygen carried by these capillaries is uniformly
distributed to all perfused capillaries, then the fall in tissue
oxygen levels would be less.
Implications from experimental and mathematical
models of sepsis
Based on our experiments and mathematical model, we
propose that loss of perfused capillaries and impaired
regulation of oxygen delivery within the microcirculation leads
to a maldistribution of microvascular blood flow and tissue
hypoxia early in sepsis, and that this is the first step in the
progression to organ failure . The tissue is still capable of
extracting oxygen, but oxygen is not being delivered to where
it is needed. Early in sepsis, the inability of the micro-
vasculature to compensate for a loss of functional capillary
density is the critical factor that leads to tissue hypoxia and
thus organ dysfunction.
Are these results from our experimental models of sepsis
clinically relevant? Using orthogonal polarization spectral
imaging, De Backer and colleagues demonstrated that the
density of perfused capillaries in sublingual tissue was
reduced in septic patients , similar to what we have
Available online http://ccforum.com/supplements/9/S4/S3
Oxygen saturation of red blood cells at the venous end of normally
perfused capillaries versus the percentage of capillaries with stopped-
flow (%CDstop) in extensor digitorum longus muscle in rat. No
relationships existed in the sham animals between these parameters. In
animals that underwent a 24-hour peritonitis model of sepsis (cecal
ligation and perforation [CLP]), there was a decrease in oxygen saturation
with increasing %CDstop (linear regression: y = 98.8 – 1.8x;
r2= 0.64; P < 0.05). Reproduced with permission .
observed in our animal models. Recently, this group has
reported that survivors of septic shock show an improvement
in perfused capillary density, but those who die have a
persistent loss of perfused capillaries . The loss of
perfused capillaries in organs remote to the initial site of
inflammation occurs in septic patients and may be an
important indicator of outcomes. The key questions from an
oxygen transport perspective are why does capillary blood
flow stop in sepsis and why has the local oxygen regulatory
system not responded to the fall in capillary oxygen saturation
by distributing blood flow and oxygen to where it is needed?
Mechanisms underlying the maldistribution
of oxygen delivery in sepsis
Occlusion of capillaries
There are several proposed mechanisms for the occlusion of
capillaries early in sepsis: stiff leukocytes, stiff RBCs,
endothelial cell swelling, and platelet/fibrin clots .
Piper and colleagues  investigated the time course (from
6–48 hours) of leukocyte rolling, adhesion, and extravasation
in postcapillary venules in skeletal muscle using the same
peritonitis model of sepsis as that of Lam and colleagues
. Although Piper and colleagues observed an increase in
rolling at 24 hours, they found that leukocyte adhesion in
venules was reduced due to a fall in circulating white blood
cell count. However, Goddard and colleagues presented
evidence from endotoxemia models of sepsis that leukocytes
have a prolonged capillary transit time and are retained in the
coronary capillaries of pigs  and rabbits , making the
leukocyte a good candidate for occluding capillaries.
Although the results of Piper and colleagues might at first
seem to contradict that of Goddard and colleagues, both
studies support the concept that the loss of capillaries is not
due to occlusion of venules by an accumulation of leukocytes
but due to the direct occlusion of capillaries.
We developed a 6-hour peritonitis model of sepsis in the rat
to follow the progression of remote inflammatory injury in
skeletal muscle (Fig. 2). Using this model, Bateman and
colleagues  observed that the time course for loss of
RBC deformability, excess NO production, and increased
numbers of stopped-flow capillaries were correlated.
Treatment of the septic rats with aminoguanidine (an inhibitor
of the inducible form of NO synthase [iNOS]) to maintain
plasma nitrite/nitrate levels at baseline prevented the loss of
RBC deformability and the loss of perfused capillaries .
Our report of a subpopulation of RBCs with very low
deformability at 37°C [55,56] very early in sepsis was
recently confirmed . These results support the role of stiff
RBCs in capillary plugging .
There is convincing evidence that disseminated intravascular
coagulation plays a central role in organ failure in sepsis .
Treatment of severely septic patients with activated protein
C, which targets both the coagulation and inflammation
pathways in sepsis, has been shown to be effective in
reducing mortality [59,60]. Although the success of the
Recombinant Human Activated Protein C Worldwide
Evaluation in Severe Sepsis (PROWESS) and Extended
Evaluation of Recombinant Human Activated Protein C
(ENHANCE) trials supports the possibility of platelet/fibrin
clots impairing microvascular perfusion, experimental studies
are needed to further elucidate the mechanisms of action of
activated protein C on the microcirculation during the early
stages of sepsis.
It is likely that a combination of these mechanisms
contributes to the loss of functional capillary density in sepsis.
Since the loss of capillaries in remote organs begins to occur
several hours after the initial injury, and hence several hours
after leukocyte activation, we speculate that activation and/or
injury of the microvascular endothelium in remote organs is
the critical first step leading to capillary loss.
Impaired local regulation of oxygen delivery
In addition to an impaired arteriolar response to vasoactive
stimuli in animal models of sepsis [61-63], Tyml and
colleagues have shown that there is impaired communication
of signals between endothelial cells in culture exposed to
lipopolysaccharide (LPS) [64,65] and along the vascular
endothelium in vivo in peritonitis  and LPS models of
sepsis [64,66]. The mechanism responsible for impaired
arteriolar responsiveness to stimuli appears to be excess NO
production in endothelial cells via iNOS . Impaired
communication along the vascular endothelium is reported to
be due to an LPS-induced increase in intercellular resistance
 that may be mediated by tyrosine phosphorylation of
Critical Care August 2005 Vol 9 Suppl 4Ellis et al.
Functional images of the same capillary bed in the extensor digitorum
longus muscle of the rat at 2.5 and 3.5 hours after induction of a
peritonitis model of sepsis (cecal ligation and perforation [CLP]). The
functional images were generated from captured video sequences
(30 seconds) and show those capillaries through which red blood cells
were flowing. At 2.5 hours after CLP, most capillaries in the field of
view are perfused. One hour later, individual capillary segments from
within the capillary network no longer have red blood cell flow,
indicating the rapid progression of the remote injury to the
microvasculature of this muscle. The procedure used for generating
functional (variance) images was described by Japee et al. .
connexin 43, a gap-junction molecule [68,69]. The inability of
the arteriolar tree to properly integrate its response to the
tissue’s needs may be a significant factor in the maldistribution
of oxygen delivery to tissue in sepsis. We can also speculate
that erythrocyte injury in sepsis, as indicated by a loss of RBC
deformability, may mean that the ability of RBCs to regulate
oxygen delivery through ATP release is also impaired.
In metabolically active tissue, diffusion limitation places strict
constraints on how far cells can be from an oxygen source.
This determines not only functional capillary density but also
the characteristics of the microvascular control systems.
Vascular endothelium and RBCs play a significant role in
coordinating the response of the arteriolar tree to changes in
oxygen demand or oxygen delivery to the organ. As long as
the regulatory system is functional and capillary density is
sufficient, the microvasculature will deliver all available oxygen
to where it is needed within an organ. In hemorrhagic shock,
a “functional” microvasculature reduces the impact of a
decrease in oxygen supply on tissue hypoxia by efficiently
distributing oxygen to where it is needed. During the early
stages of sepsis, however, the loss of capillary density and
the impaired ability to regulate local oxygen delivery results in
the rapid onset of tissue hypoxia despite more than adequate
oxygen supply to the organ. Clearly we need to understand
the mechanism(s) responsible for this dysfunctional micro-
vasculature in order to develop appropriate management
strategies for sepsis.
CGE received reimbursement for travel expenses and an
honorarium for speaking at the Global Medical Conference in
Brussels 2005 and for preparing this manuscript. CGE’s
sepsis research is supported by an operating grant from the
Canadian Institutes for Health Research (MOP-49416), and
his research on the erythrocyte role in local regulation of
oxygen delivery by an operating grant from Heart and Stroke
Foundation of Ontario.
The authors wish to thank Graham Fraser for his comments, and
Stephanie Milkovich and Karen Donais for their assistance with the
video data for Fig. 2.
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