Rheology for clinicians

Dan Longrois*, Philippe Guerci**,***, Patrick Menu***

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Introduction
The physiology and pathophysiology of the cardiovascular system are taught and integrated into clinical reasoning (diagnosis and therapy). The relevance of the present day teaching strategy in this domain can be questioned
because there is little teaching on the microvasculature and even less on
blood rheology. One example to illustrate these assertions is the cristalloids
versus colloids controversy for resuscitation of critically ill patients (1-3).
The question being asked is whether there is a benefit (in terms of improved survival) for colloids versus cristalloids when resuscitating a variety of
critical illnesses such as hemorrhagic or septic shock. The answer to this
question, for the moment is no (1-3) but the explanations to this lack of
measurable effect are not clear.
Part of the difficulty to find explanations arises from the fact that the
physiology, pathophysiology, as well as monitoring of microcirculation and
especially rheology are not well known by the clinicians. The goal of this
article is to present and explain several features of the physiology and pathophysiology of blood rheology. We will focus in this article on only two
mechanisms of shock: hemorrhagic and septic.
 Department of Anesthesia and Intensive Care, Hpital Bichat-Claude Bernard 46, rue
Henri Huchard, 75877 Paris Cedex 18; Laboratoire INSERM U698, Universit Ren
Descartes, Paris VII, France
 Department of Anesthesia and Intensive Care, Hpital Brabois-Adultes, 4, rue du
Morvan 54500 Vandoeuvre-les-Nancy, France
 Laboratoire dingenierie cellulaire et tissulaire, physiologie et pharmacologie articulaires UMR 7561, Universit Henri Poincar-Nancy 1, France
Address correspondence to: Professor Dan Longrois, Department of Anesthesia and Intensive Care, Hpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75877 Paris Cedex
18, France, e-mail: dan. longrois@bch.aphp.fr
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The sequential goals of resuscitation in hemorrhagic shock are (i) restoration of circulating volume (and consequently of cardiac output and arterial
pressure); (ii) restoration of microvascular perfusion and oxygen supply to
vital organs; (iii) to prevent or correct end organ damage due to cardiac
output redistribution (to protect the heart and the brain at the expense of
splanchnic organs such as the liver or the kidney as well as other territories
such as skeletal muscles or skin).
Despite controversy concerning the best diagnostic tools to assert restoration of the circulating blood volume and the critical level of hemoglobin,
these goals are fairly well integrated into clinical practice. On the contrary,
restoration of microvascular perfusion and oxygen supply to vital organs is
a more difficult task.

A model of micro-circulation
Organ and tissue blood flow is controlled by the vascular tone of resistance
vessels (small arteries and arterioles) that modify their diameter thus regulating flow as well as by the pressure drop across the microvascular bed (4).
Downstream from the resistance vessels, flow is passively distributed within
the capillary network (4). Two main factors control flow in the capillary
network: the resistance (in its turn the result of the interaction between
diameter and length) and rheology (that mainly depends on whole blood
and plasma viscosity as well as red blood cells or RBC deformability). In the
capillaries, RBC flow single line and must undergo deformation in order to
progress through capillaries with smaller diameters. It was proposed that
the most important factor accounting for capillary heterogeneity are the
rheological properties of blood (4). This model of microcirculation has several characteristics among which the fact that there is integration to ensure
that oxygen delivery meets oxygen demand. The mechanisms responsible for
this integration are complex and it has been suggested that the endothelial cells, by way of intercellular communications, could represent a major
integrator (4). The second integrator could be the RBCs themselves. It has
been suggested that RBCs could release ATP and nitrosothiols in response to
increased PO2 gradients and mechanical deformation (4,5). Decreased RBC
deformability (a method-dependent measurement )(6) could be due to decreases of membrane viscosity, or, more probably, to increased RBC shear
elastic modulus, as a result of oxidative damage, increased cytosolic calcium
triggering changes of RBC membrane skeletal proteins (6). Decreased RBC
deformability, probably potentiated by decreased white blood cells deforRecomandri i Protocoale n Anestezie, Terapie Intensiv i Medicin de Urgen

mability, could be a major factor, along with endothelial cells abnormalities

that could explain the heterogeneities within the capillaries encountered in
shock states (7).

A brief overview of blood rheology

Whole blood viscosity (WBV) is mainly determined by hematocrit, plasma
viscosity as well as RBC aggregation and deformability. In the systemic circulation, (i.e.; aorta, major arteries, veins) WBV is the major factor generating shear stress. According to Poiseuilles equation, vascular resistance is
related to blood viscosity. Although this relationship is frequently used for
calculation, it holds for stiff and straight tubes, Newtonian fluids, steady
laminar flow and a fully developed parabolic velocity profile, conditions that
are not met in vivo. Poiseuilles equation does not take into account the
variable-geometry of the vascular network (autoregulatory processes), since
vasomotion alters vessel radius and hence has a direct influence on vascular
resistance/hindrance. Current studies have shown that if blood viscosity is
severely decreased by hemodilution, microvascular function is impaired and
tissue survival is jeopardized due to the local microscopic maldistribution of
blood flow, rather than the deficit in oxygen delivery.
In the microcirculation (especially in the capillaries), hematocrit is lower
due to a skimming effect; as the microvessel diameter decreases, the number of RBC is lower, and apparent viscosity decreases. Thus, plasma viscosity
(PV) remains the major regulatory factor of wall shear stress in microcirculation. Function capillary density (FCD), which quantifies capillary perfusion
by measuring the total length of capillaries with transit of RBCs during a
period (30s) per unit area of tissue analyzed, determines functional perfusion. Maintenance of FCD is crucial for improving survival in hemorrhagic
shock. It has been demonstrated that FCD is independent of oxygen carrying
capacity and tissue pO2. These findings suggest that a threshold of plasma
viscosity is required to maintain microvascular perfusion, especially FCD.
One of the least understood aspects of microcirculation has been described
by Intagliettas group. These authors have shown that in hamsters, if the
plasma viscosity is maintained, FCD is maintained despite very low perfusion
pressures (8). Although these results were obtained in hamsters, it still raises
the question of the physiological importance (and for the moment neglected in clinical reasoning) of plasma viscosity.
The physiology and pathophysiology of PV is not well understood. Comparative biology (9-10) demonstrates that there is wide interspecies variability
in terms of WBV and PV. Interestingly, intraspecies interindividual variability
is much lower for PV as compared to other rheological measures. FurtherTimioara 2010

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more, there is now a large number of publications concerning the changes

in plasma viscosity associated with chronic diseases such as diabetes, hypertension, obesity and other conditions (11-18).
Nevertheless, the mechanisms that regulate PV under physiologic and pathophysiologic situations are not known. Depending on the species, PV is
mainly determined by fibrinogen or plasma protein concentrations (19,20).
The increased PV values in several clinical pathologic (cardiovascular disease,
diabetes, chronic inflammatory disease (11-18)) or physiologic (pregnancy(21,22)) conditions seems to be related to an increase in plasma fibrinogen
concentrations. This factor could have a vasoactive effect and modulate
endothelial cells functions. The clinical significance of an increased plasma
viscosity in the different clinical situations cited above is not explained yet,
since we dont know if it is the result of the disease or rather its cause. Despite
these observations, we have to distinguish between chronic and acute phenomena. Hemodilution generated by fluid resuscitation during hemorrhagic
shock, leads to a decrease in plasma protein and fibrinogen concentrations
and thus to lower PV values whatever plasma expander used. Shear forces
and NO release decrease and therefore FCD could be impaired. Although,
a recent experiment concerning hemorrhagic shock in dogs was unable to
show an improvement in microcirculatory parameters, there is evidence that
the concept of hyperviscous fluid resuscitation induces vasodilatation.

Microcirculatory abnormalities in sepsis

It is widely accepted that severe sepsis and septic shock are characterized
by micro-hemodynamic abnormalities (23,24) even before macro-hemodynamic (such as arterial hypotension are clinically evident). It has also been
shown that the microcirculatory abnormalities in patients with sepsis increase with the severity of sepsis (25). The microcirculatory abnormalities
concern all parts of the microcirculation (arterioles, capillaries and venules) (26). The alterations of the microcirculation seem organ-specific with
the mesenteric circulation characterized by arteriolar constriction whereas
there is size-specific vasoconstriction or vasodilation in other organs such as
the diaphragm or the liver (4).
A nearly constant finding in experimental models of sepsis is the change
in skeletal muscle capillary perfusion (27). In non septic (sham) animals, skeletal muscle capillary flow is characterized by uniform distribution of capillaries perfused with RBCs in a steady pattern from arterioles to venules. In
sham animals there are very few vessels with stopped RBCs or with intermittent perfusion. In sharp contrast, in the septic animals, there are numerous
capillaries with stopped RBCs. It was shown that in skeletal muscle of septic
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animals total blood flow was maintained, but capillary flow distribution was
varied from 60/30/10% (normal/fast/stopped) in control to 33/33/33% (normal/fast/stopped) in average sepsis and 25/25/50% (normal/fast/stopped)
in extreme sepsis (28). Using a sophisticated mathematical model, the same
authors found approximately two- and fourfold increases in tissue VO2 in
average and extreme sepsis, respectively. Average (minimum) tissue oxygen
tension (PtiO2) decreased from 43 (40) mmHg in control to 34 (27) and 26
(15) mmHg in average and extreme sepsis, respectively, and clustering fastflow capillaries (increased flow heterogeneity) reduced minimum PtiO2 to
14.5 mmHg. The mechanisms responsible for stopped-flow in the capillaries
could be activation and structural changes of endothelial cells, activation of
coagulation, activation of leukocytes, decreased deformability of RBC and
possibly microthrombi (4). There are two additional changes in the microcirculation of septic animals, as compared to shams: (i) the population of
continuously perfused vessels is characterized by a greater proportion of
capillaries with high velocities (27); (ii) there are many capillaries with intermittent flow and large low-frequency flow reversals (oscillations about
zero velocity)(27).
There are many arguments that support the hypothesis that alteration
of tissue O2ER is mainly, and at least initially, the result of maldistribution
of O2 delivery and not of inability to utilize O2 (27). It has been proposed
that maldistribution of microvascular blood flow leads to a mismatching
of O2 supply and demand, analogous to the mismatching of ventilation and
perfusion in the lung (27). It has been suggested that the degree of stopped capillary flow could be considered as one index of the microvascular
dysfunction (27).
One important issue raised by the observations concerning the relationship between capillary heterogeneity and impaired O2ER concerns the mechanisms of this alteration. Indeed, the expected response to a fall in RBC
haemoglobin saturation (SO2) values in the normal-velocity capillaries would be diverting excess flow to these vessels to increase their O2 supply and
thus compensate for the loss of perfused capillaries. The presence of low
SO2 levels in capillaries suggests that in septic animals, the microvasculature is unable to properly redistribute O2 delivery in response to the local
metabolic requirements of the tissue. This inability to redistribute flow has
been attributed to alteration of the communications between capillaries
and arterioles as well as to alterations of the vasoreactivity of arterioles. It
is probable that alteration of arteriolar vasoreactivity could be that main
factor accounting for the inability to redistribute flow to capillaries with
low SO2 levels. The altered arteriolar vasoreactivity could explain the obserTimioara 2010

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ved decreased hyperemic response after muscle stimulation in experimental

models of sepsis. In one of the few clinical investigations of microcirculatory
abnormalities in sepsis it has been shown that the vasodilatory response to
both endothelium-dependent (acetylcholine) and endothelium-independent
(sodium nitroprusside) of the forearm skin microcirculation (measured with
laser Doppler) was decreased in patients with sepsis as compared to non
septic ICU patients and non ICU patients used as controls (29). An alterative
explanation would be the alteration of systemic integration. It has been
shown in experimental models that sepsis was associated with increased
sympathetic outflow to the systemic vasculature, as indicated by the increase in low frequency spectral power of arterial blood pressure. The increase
in low frequency variability of the mesenteric microvascular blood flow was
shown to be secondary to the increase in low frequency spectral power of
arterial pressure, since it could be attenuated by systemic and not by local
intestinal sympathectomy (30).

Endothelial cells as the source of dysfunction in the capillaries?

Many substances produced by the endothelial cells have been shown to contribute the microcirculatory abnormalities of sepsis. For instance it has been
shown that an antagonist of the endothelin receptors, bosentan, attenuated
the sepsis (fecal peritonitis)-induced decreased microcirculatory flow in the
splanchnic circulation but not in the skeletal muscle (31). Other mediators
produced by the endothelial cells seem to play a protective role. It has been
shown that the administration of a non specific inhibitor of nitric oxide
synthases (L-NAME) worsened the liver microcirculatory abonormalities in
a rodent model of sepsis (32). In contrast, a NOS2 (inducible NOS isoform)specific inhibitor administered in the same experimental model preserved
liver microcirculation (33). These results suggest a beneficial role of NOS3derived NO to preserve liver microcirculation, at least at the initial phases
of septic shock. It has been suggested that endothelial and microvascular
dysfunction of severe sepsis could be modulated by the angiotensin converting enzyme activity related to a defined polymorphism (34). Also, recently
published results suggest that the beneficial effects of drugs with proved
beneficial effects on survival in patients with septic shock, such as activated
protein C (aPC), could be explained by their effect on microcirculation. Indeed, it has been shown in a rodent model of lipopolysaccharide (LPS)-induced
septic shock that aPC attenuated the LPS-triggered interaction between leukocytes and endothelial cells and also attenuated the LPS-induced decrease of functional capillary density (35). Other natural anticoagulants such
as antihrombin have also been shown in experimental models to attenuate
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the leukocytes-endothelial cells interactions in sepsis (36). Interestingly, it

was shown that the beneficial effects of antithrombin in attenuating the
leukocytes-endothelial cells interactions and in preserving the functional
capillary density could be antagonized by the co-administration of unfractionated as well as low molecular weight heparin (37). These observations suggest that endothelial cells are a major site of microcirculatory dysfunction
and demonstrate that drugs that can restore endothelial cell function have
complex effects and interactions with many drugs administered in septic
shock patients.
In conclusion, there are numerous arguments that suggest that in microcirculation and rheology interact to preserve oxygen delivery to the cells.
For the moment, clinicians have only started to introduce microvascular
monitoring devices into clinical practice (38-40). Rheology is for the moment neglected and few articles or conferences ever mention rheology. Improved understanding of the physiologic and pathophysiologic changes in
key rheologic parameters are the first step before defining monitoring and
therapeutic goals strategies based on the rheologic parameters.
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