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Tissue oxygen delivery and the microcirculation

Hiroshi Morisaki, MDa, William J. Sibbald, MD, MPHb,*
a

Department of Anesthesiology and General Intensive Care Unit, Keio University School of Medicine, 35 Shinanomachi, Shinjuku Tokyo 160-8582, Japan b Department of Medicine, Critical Care, University of Toronto and Sunnybrook and Womens College Health Sciences Centre, 2075 Bayview Avenue, Suite D 474, Toronto, Ontario M4N 3M5, Canada

Cellular health requires that oxygen (O2) supply be matched appropriately with the tissues O2 needs. If O2 supply is not aligned with needs, ischemia will supervene, and tissue injury results. The cellular delivery of O2 is a finely regulated system. Once having passed the alveolar capillary membrane, O2 is carried in blood to the tissues. According to the formula: O2 content (CaO2) = [(hemoglobin concentration) saturation of O2 (SaO2) 1.39 + 0.003 arterial O2 tension (PaO2)], most of the O2 transported in blood is bound to red cell hemoglobin, and the amount of physically dissolved O2 is negligible under physiologic conditions. Whole body oxygenation is determined by the CaO2, cardiac output, and O2 extraction ratio. The total amount of convective O2 delivered to the organs (DO2) then is calculated as: DO2 = cardiac output CaO2. The O2 delivery equation therefore identifies key factors responsible for ensuring adequate tissue oxygenation. Blood flow is regulated at three places in the circulation, the central circulation (ie, the cardiac output), the regional circulations (ie, the distribution of blood flow between organs), and the microcirculation (ie, the distribution of blood flow within organs) levels. In critical illness, limitations to tissue oxygenation are not uncommon and can occur at all three levels, as categorized and shown in Fig. 1. Disorders affecting all three levels of the circulation are referred to collectively as circulatory hypoxia, and a depression in arterial O2 contents is called hypoxic hypoxia. Many compensatory mechanisms protect against critical reductions in tissue O2 availability, operative both acutely and chronically. Acutely, the circulation is the most reliable backup, containing a profound capacity for redundancy to ensure that O2 delivery is normally more than sufficient to satisfy cellular meta* Corresponding author. E-mail address: william.sibbald@swchsc.on.ca (W.J. Sibbald). 0749-0704/04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2003.12.003

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Fig. 1. Inter-relationships and regulation of blood flows at the central, regional, and microcirculatory levels of the circulation. Centrally, the cardiac output is governed by preload, afterload and contractility, all of which frequently are altered during critical illness. At the regional levels, the distribution of blood flow between vital and nonvital organs is important to ensure adequate oxygen availability to core organs, where oxygen extraction reserve is minimal. At the microcirculatory level, the extraction of oxygen also can be modified by a number of characteristics of critical illness.

bolic needs with respect to O2 needs. For example, during a critical reduction in arterial O2 content, compensation includes all of the following: an increase in cardiac output, a redistribution of blood flow between organs, and an increase in tissue O2 extraction because of an increase in microcirculatory perfusion. Only when the capacity of these compensatory mechanisms is exhausted, hypoxia, and subsequently ischemic tissue injury, supervene. This article describes the function of the microcirculation initially during health and then in critical illness. The goal is to provide insight as to how this level of the circulation functions when challenged by sudden depressions in O2 delivery following abnormalities in other levels of the circulation (ie, shock associated with myocardial infarction) or in arterial O2 content (ie, acute hypoxia or acute anemia). The article briefly touches on the function of the central and regional levels of the circulation in critical illness, because their performance is important to the ultimate stress imposed on the microcirculations capacity to maintain tissue O2 availability.

Physiology of oxygen delivery in the microcirculation Beginning with the central and regional circulations The cellular distribution of red blood cell (RBC)-bound O2 is a convective process, whereby (assuming a constant arterial O2 content) total systemic O2 delivery is determined by a finely tuned process, including the cardiac output and the inter- and intraorgan distribution of blood flows. This is controlled by systemic neurohumoral and local autoregulatory mechanisms. Centrally, an elevation in the cardiac output is capable of maximizing systemic O2 delivery (QO2) to 110% (or more) of preanemic control values when the hematocrit is depressed acutely [1]. Conditions predating a critical illness, however, also can influence circulatory compensation to acute anemia. For example, coronary artery disease

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(CAD) that reduces the capacity to elevate cardiac output presumably would lead to greater dependence on the regional and microcirculatory compensation to acute anemia. The Canadian trial [2] also demonstrated that the restrictive transfusion strategy improved the outcome among patients who were less acutely ill and younger, but not among patients with clinically significant cardiac disease. Within the regional circulations, blood flow regulation is integrated from the level of the capillary bed across the entire arteriolar tree and into the arterial resistance vessels. At rest, flow regulation occurs at the level of the distal arterioles. As metabolic demand increases, flow regulation of blood into tissues shifts to include larger arterioles and resistance vessels, a regulatory process involving multiple control systems responding to chemical (metabolic, O2) and physical (pressure myogenic, shear rate) signals [3,4]. According to a metabolic theory, O2 delivery is the regulated variable, and oxygen sensors adjust O2 delivery to maintain tissue oxygenation [5,6]. The RBC also has been proposed as a site of local regulation of O2 delivery [7]. This means that at the level of the regional circulations, an acute depression in O2 content with acute anemia induced by isovolemic hemodilution will be accompanied by an increase in blood flows to the heart and brain. This maintains QO2 to what are referred to as vital organs. An example of such circulatory compensation is shown in Fig. 2. In this experiment, rats randomly were allocated to one of three different hematocrits: low (21% to 28%), middle (33% to 40%), and high (45% to 52%). Organ blood

Fig. 2. The circulatory compensation to anemia in health (control) and critical illness (sepsis). (A) Changes in cardiac output with low versus high hematocrits, and after added stress induced by superimposing on normoxia (N) and acute hypoxic (H) episode. The anticipated compensatory elevation of cardiac output during acute hypoxia was not observed in septic rats with low hematocrits (black circle). (B) Comparison of organ blood flows (Q) relative to cardiac output (CO) maturing low versus high hematocrits during acute hypoxic episode. The anticipated redistribution of blood flow during acute hypoxia from the intestine to the core organs, heart, and brain was abrogated in the septic anemic rats.

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flows (Q) were measured with the radioactive microsphere technique, and thereby, QO2 to individual organs was calculated. To characterize overall metabolic O2 reserve, the capacity to acutely increase tissue O2 delivery, rats then were exposed to an episode of hypoxia, and organ QO2 was remeasured. Panel A in this figure shows the capacity of the circulation to acutely increase cardiac output in control rats, whereas septic rats with low hematocrit doses did not show any compensatory increase of cardiac output against acute hypoxia. It indicates that septic rats with low hematocrit, whose cardiac output is maximized already, cannot afford to elevate cardiac output further. Panel B in this figure shows how the regional circulations adapted to abrupt declines in O2 delivery because of anemia plus hypoxia. The anticipated redistribution of blood flow during acute hypoxia from the intestine to the core organs, heart, and brain (as seen in other septic animals) was abrogated in the septic anemic rats. Moderately transfused rats, however, could redistribute blood flow from the small intestine to the core organs. These findings indicate that compared with the anemic state, maintaining high hematocrit in sepsis preserved a physiological system of circulatory compensation against acute hypoxia and concurrently redistribution of blood flows between nonvital and vital organs. As previously mentioned, critical illness is characterized by many abnormalities that could impact adversely on the normal circulatory compensation to acute anemia. For example, sepsis is characterized by hypo-responsiveness of arterial resistance vessels [8] and depressed myocardial contractility [9], both of which theoretically could compromise the circulations ability to compensate for a sudden depressions in QO2 as imposed by acute anemia. This concern prompted the authors to undertake a series of experiments to characterize whether sepsis would significantly limit an appropriate compensation to acute anemia at the level of the central and regional circulations. Rats were rendered septic by creating an abdominal focus of infection (cecal ligation and perforation) and then randomly allocated to different hematocrit groups: low (21% to 28%), middle (33% to 40%), and high (45% to 52%). Their responses before and after an episode of acute hypoxia were compared with responses found in the nonseptic animals. Despite knowledge that myocardial contractile depression is also evident in this septic model [10], the authors found that the cardiac output remained capable of acutely elevating to maintain (or even elevate) convective QO2 when hypoxia was added to septic conditions. At the level of the regional circulations, the septic study conditions failed to perturb brain and myocardial-QO2, because an increasing proportion of cardiac output had been redistributed to these circulations from skeletal muscle and the splanchnic organs during the anemic conditions. This means that the metabolic O2 regulation of tissue-QO2 at the level of the regional circulations was preserved in this model of sepsis despite evidence that arterial vasoreactivity is depressed concurrently [8]. This experiment, however, also demonstrated that circulatory compensation to maintain myocardial and brain QO2s was likely insufficient when acute hypoxia was superimposed on hematocrit levels that are accepted as clinically appropriate in critically ill patients (ie, hemoglobin concentrations of 70 g/L). This means that

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Fig. 3. Changes in oxygen delivery (QO2) to heart and brain between normoxic and acute hypoxic conditions, in control and septic rats. There was a reduced QO2 reserve supporting the heart and brain (core organs) in septic animals, especially with a low hematocrit level (black bars). In contrast, septic rats transfused to high hematocrits had a well-maintained QO2 reserve. This observation supports the concept that maintaining higher hematocrits could be important in sepsis, if the end line was maintaining or improving QO2 reserve.

sepsis depressed the QO2 reserve to vital organs, an outcome that was especially apparent during anemic conditions with superimposed hypoxia (Fig. 3). To summarize, the central and regional circulations usually have sufficient reserve that compensation is more than adequate to maintain tissue oxygenation during acute anemia. Although diseases such as sepsis clearly blunt the extent of the compensation or reserve available, studies have shown that hematocrit as low as 21% can be tolerated. Animal studies, however, never can reproduce the clinical counterpart faithfully. Thus, especially in patients with coexisting CAD, the absence of clinical trial data leads to recommendations that transfusion be considered when the hemoglobin concentration falls below 90 g/L. The microcirculation A primary function of the microcirculation is the exchange of gas, nutrients, solutes, and heat. In the lungs, a sheet-like structure of capillaries maximizes surface area for arterial oxygenation and carbon dioxide excretion. In organs supplied by the left heart, O2 requirements vary, and a mesh-like network of capillaries helps to ensure adequate tissue oxygenation during periods of rest and activity. Tissues with the greatest metabolic rates have the greatest capillary densities. In the systemic circulation, a microvasculature unit consists of a network of blood vessels (less than 250 mm) lying between the arteries and veins. Arterioles form a diverging network of vessels ranging from sizes of 100 to 150 mm in diameter, to terminal arterioles that approximate 10 mm in diameter; arterioles actively regulate their diameter in response to many stimuli. Terminal arterioles supply the capillary bed, a network of diverging and converging vascular segments ranging from 3 to 10 mm in diameter and composed of a single layer of endothelial cells. Blood draining from the capillary bed is collected by postcapillary venules that converge into large venules. Once inside the microcirculation, O2 is transported to the cell by convection (bulk flow of blood) or diffusion (random movement of free or bound oxygen

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molecules). Through convection, substantial amounts of O2 can be moved rapidly over long distances. Diffusive O2 transport between two sites depends on the difference of tissue and blood O2 tensions. O2 diffusion, however, is not the process once envisaged, occurring for example only in a capillary bed. Thus O2 diffusion also occurs from capillaries to neighboring capillaries. And, in addition to their role in convective O2 transport, arterioles also function as a diffusive source of O2 that serves to replenish the O2 lost from the RBCs as they move along the capillaries [11]. Therefore, while the capillary bed is the primary site of O2 exchange within tissues, O2 exchange with surrounding tissues does occur in the arteriolar tree, thus leading to a precapillary fall in hemoglobin O2 saturation [12]. Reoxygenation of RBCs flowing through capillaries by diffusion from nearby arterioles helps provide homogeneous tissue oxygenation despite heterogeneous capillary blood flows [13]. When blood flow to the microcirculation elevates in response to increased tissue O2 demands, the capillary bed responds by increasing the homogeneity of its blood flows, thus leading to an increase of the effective area for O2 exchange. It is estimated that only 25% to 35% of available capillaries are perfused in ambient conditions; with stress situations, however, capillaries can be recruited to maintain metabolic autoregulation. Microcirculatory blood flow is regulated actively by changes in vascular resistance and perfusion pressures originating from parent arterioles and alterations of vascular tone within the capillary network. Blood flow within the microcirculation also may exhibit passive control, for example, when influenced by rheologic influences and network geometry (the latter may vary considerably between tissues). Microcirculatory blood flow is typically nonuniform; both temporal heterogeneity (changes over time) and spatial heterogeneity (differences between vessels) of capillary flow are common. Capillary flow heterogeneity is lessened by metabolic stress and increasing RBC supply to the tissue. Although this increase in capillary surface area has been interpreted as active capillary recruitment, how it happens remains the subject of speculation, as studies have not demonstrated precapillary sphincters or other structures that would regulate the number of perfused capillaries [14]. In health, increasing capillary density with flowing RBCs permits tissues to extract more of the available O2, since an increased capillary density reduces the diffusion distance for O2. Reduced RBC velocity also increases O2 diffusion times, and an increase in RBC supply rate per unit volume increases bulk O2 delivery. In addition, blood viscosity, O2 carrying capacity, and the position of the dissociation hemoglobin curve contribute to regulating microvascular O2 tension.

Oxygen delivery and the microcirculation in the critically ill The complexity of studying the microcirculation in vivo limits many studies of the effect of critical illness and to the use of surrogate outcomes of function. One

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of the most frequently used approaches to evaluating the integrity of the microcirculation in tissue O 2 exchange is through use of the O 2 supply:dependency relationship. Normally, O2 consumption (VO2) is independent of QO2 at high levels of O2 supply. As QO2 gradually falls, however, VO2 is maintained by circulatory compensation (inter- and intraorgan redistribution of blood flows, vide supra) until delivery reaches a critically low level (QO2crit). Below this point, the tissues VO2 becomes limited by delivery in a supplydependent manner. Additionally, this is the point where circulatory compensation (an increased cardiac output and redistribution of blood flows between organs) is exhausted, and tissue hypoxia ischemia supervenes. This relationship has been used to measure the capacity to extract O2, thereby understanding the functional capacity of the microcirculation in critical illness. Systemic QO2 can be reduced acutely [to create O2 supply-dependency (OSD)] by interventions such as acute anemia or circulatory compromise. In one experiment, OSD was created by isovolemic hemodilution with rat plasma. At this point measured systemic O2 consumption (VO2) was depressed, and plasma lactates increased (indicating the onset of acute tissue hypoxia). During OSD, rats randomized to receive 7.5 mL fresh RBCs (stored less than 6 days, hematocrit [Hct] 70%) demonstrated an immediate increase in systemic VO2, and lactate levels fell. In contrast, the introduction of sepsis in rats changed the efficacy of O2 extraction, which was measured as an increase in DO2crit (Fig. 4). Together, this means that sepsis impairs microcirculatory function, depressing its capacity to augment capillary O2 extraction. In subsequent experiments, the authors determined if the critical O2 delivery (QO2crit) was affected by the method used to decrease QO2 and whether septic

Fig. 4. This is systematic of the oxygen delivery (QO2) oxygen consumption (VO2) relationship that can be demonstrated in experimental animals. Note that circulatory compensation (redistribution of blood flow between organs and increasing oxygen extractions) is exceeded at the QO2 critical, that point where VO2 becomes directly dependent on QO2. These data confirm that the QO2 critical is right shifted in septic rats, thereby supporting the previous diagrams that showed sepsis reduced the capacity to redistribute blood flow between organs and to augment oxygen extraction capacity.

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conditions might further perturb tissue O2 delivery. They compared QO2crit in anemic and stagnant hypoxic conditions, in conscious normal and septic rats; sepsis was created by cecal ligation and perforation. VO2 was measured using expired gas analysis while QO2 was calculated. Rats then were randomized to anemic hypoxia (isovolemic hemodilution with rat plasma) or stagnant hypoxia (stepwise inflation of a Fogarty catheter in the right atrium). The authors found that QO2crit was not different between anemic and stagnant hypoxia and that critical hemoglobin (Hbcrit) in anemic hypoxia was similar between sepsis and control. This meant that QO2crit was not affected by the method used to decrease QO2 [15]. In anemic hypoxia, a reduction in hemoglobin levels is compensated for by an increase in cardiac output and O2 extraction; in stagnant hypoxia, the reduction in cardiac output is compensated for solely by an increase in O2 extraction. Capillary recruitment in response to any type of local hypoxia is crucial, because it effectively reduces intercapillary spacing, thereby allowing tissues to extract O2 to lower end capillary levels of PO2 [16]. Despite the differences in compensatory mechanism, the authors found that QO2crit is similar despite the approach to creating acute hypoxia. This indicates that the absolute level of whole body O2 delivery (convective O2 delivery) is of greater importance than the particular value of hemoglobin, arterial O2 partial pressure, or cardiac output in preventing delivery dependence [16,17]. What impairs oxygen extraction capacity in critical illness? Diseases such as sepsis begin with a focus of inflammation that initiates a cascade of inflammatory events leading to injury in remote organs and ultimately to organ failure and death. In sepsis, a decreased number of perfused capillaries reduces the surface area available for O2 delivery while increasing the distance for O2 diffusion. In a peritonitis model of sepsis in rats, the authors used intravital microscopy studies to describe the occurrence of a 30% decrease in perfused capillary density and an increase in heterogeneity of flow in the remaining perfused capillaries [18]. Although there is much uncertainty about the cause of the sepsis-induced loss of capillary density, there are several possible explanations. For example, tissue edema caused by increased microvascular permeability in critically ill patients could impair the ability to maximize capillary recruitment during changing metabolic needs, thus limiting the capacity for O2 diffusion. The authors have shown that capillary endothelial edema is a concomitant of sepsis [19] and that colloid (versus crystalloid) therapy lessened the parenchymal injury of the myocardial architectures (including myofibrillar edema) in peritonitis-induced sepsis in a sheep model. Another cause of depressed capillary recruitment in critical illness is microvascular occlusion by any of the formed blood elements. That is, the interaction of vascular endothelium with cellular elements of blood has the potential to play an important role for the immune response to acute or chronic inflammation.

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Circulating RBCs could occlude capillaries, thereby resulting in a decrease in perfused capillary density [20,21]. The activation of circulating leukocytes or a release of immature leukocytes from bone marrow (both of which are stiffer than normal) may result in a population of less deformable cells that could be entrapped in capillaries [22]. Sepsis also depresses RBC deformability [23], and endotoxin promotes a dose-dependent adhesion of erythrocytes to endothelium in a dynamic environment [24]. Disseminated intravascular coagulation (cell aggregates) also has been reported to be involved in the decrease in perfused capillary density [25]. Finally, impaired arteriolar vasoreactivity may compromise tissue oxygenation further by limiting the ability of the microvasculature to distribute flow properly within the organs. Several factors may contribute to such arteriolar dysfunction, including endothelial and smooth muscle cell damage and an excess production of nitric oxide (NO). Excess NO is generated in sepsis, and this may cause endothelial and smooth muscle cell injury, thus further interfering with arteriolar responsiveness to circulating vasoconstrictors. In addition, carbon monoxide (CO) lately has been noted to play a consequential role as the second gaseous mediator like NO. The authors demonstrated in an endotoxemic rat model that endogenous CO produced by heme oxygenase system attenuated platelet-mediated fraction of adhesion mechanisms for leukocytes in microvessels [26]. Fitzgerald et al demonstrated that storage of RBCs for 28-days impaired their ability to improve tissue oxygenation when transfused into control or septic rats placed into supply-dependence of systemic O2 delivery [27]. Simultaneously, clinical examination showed a decrease in gastric intramucosal pH resulting from transfusion of old RBC package in septic patients, indicating worsening rather than improvement of tissue oxygenation [28]. There are two potential mechanisms proposed to account for the inability of old transfused RBCs to augment systemic oxygen consumption: left shift in oxyhemoglobin dissociation curve because of 2,3-DPG depletion with storage, and loss of RBC deformability with storage, thereby impeding access to the capillary bed. Whatever the cause of a depressed capacity to extract O2 in sepsis, another finding needs to be resolved. Sielenka mper et al infused both diaspirin crosslinked hemoglobin (DCLHb) and norepinephrine, individually, in septic rats [29]. This experiment showed the altered efficacy of tissues to extract O2 induced by sepsis was restored by DCLHb and norepinephrine infusion. In rats treated with the hemoglobin solution, this effect was associated with an increased ability to extract O2, suggesting improved diffusive or convective O2 transport in the microcirculation. In a situation where microcirculatory perfusion is impaired, as in sepsis, improved O2 extraction after hemoglobin infusion may be related to a more homogeneous intravascular distribution of the DCLHb compared with RBCs. For example, it has been proposed that hemoglobin molecules could be present in narrowed capillaries, which are inaccessible to RBCs. This indicates that sepsis-induced alterations in DO2crit and loss of O2 extraction efficacy may be sensitive to treatment by chronic infusion of drugs with properties to increase vascular reactivity and mean arterial pressure.

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Summary In health, acute anemia is accompanied by changes in the distribution of blood flows at all of the central, regional, and microcirculatory levels. This redistribution in blood flows provides the capacity to maintain tissue oxygenation with hematocrit as low as 21%. What is not known with certainty is whether the capacity to maintain tissue oxygenation in the presence of acute anemia can be influenced significantly by concurrent disease such as sepsis and cardiac disease. The single clinical trial [2] found an apparent survival benefit by not exposing patients with sepsis to blood transfusions until the hemoglobin concentration was less than 70 g/L. The question remains as to whether this observation was the consequence of a protective effect anemia or an injurious effect of transfusing old stored blood.

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