oxygen delivery

7/30/2019 Oxygen Delivery

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Tissue oxygen delivery and

the microcirculation

Hiroshi Morisaki, MDa, William J. Sibbald, MD, MPHb,*aDepartment of Anesthesiology and General Intensive Care Unit, Keio University School of Medicine,

35 Shinanomachi, Shinjuku Tokyo 160-8582, JapanbDepartment 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 regu-

lated 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 arte-rial 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 convec-

tive 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 regionalcirculations (ie, the distribution of blood flow between organs), and the mic-

rocirculation (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 toensure that O2 delivery is normally more than sufficient to satisfy cellular meta-

0749-0704/04/$ see front matterD 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.ccc.2003.12.003

* Corresponding author.

E-mail address: [email protected] (W.J. Sibbald).

Crit Care Clin 20 (2004) 213 223


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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 O2delivery 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 pro-

cess, whereby (assuming a constant arterial O2 content) total systemic O2 delivery

is determined by a finely tuned process, including the cardiac output and theinter- and intraorgan distribution of blood flows. This is controlled by sys-

temic 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

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.

H. Morisaki, W.J. Sibbald / Crit Care Clin 20 (2004) 213223214


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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 trans-fusion 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 re-

sistance 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

(pressuremyogenic, 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.

H. Morisaki, W.J. Sibbald / Crit Care Clin 20 (2004) 213223 215


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flows (Q) were measured with the radioactive microsphere technique, and

thereby, QO2 to individual organs was calculated. To characterize overall meta-

bolic O2 reserve, the capacity to acutely increase tissue O2 delivery, rats thenwere 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 indi-

cates 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. Mod-

erately 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 abnormali-

ties that could impact adversely on the normal circulatory compensation to

acute anemia. For example, sepsis is characterized by hypo-responsiveness ofarterial 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 anepisode 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 thelevel of the regional circulations was preserved in this model of sepsis despite

evidence that arterial vasoreactivity is depressed concurrently [8]. This experi-

ment, 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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sepsis depressed the QO2 reserve to vital organs, an outcome that was espe-

cially 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 aslow 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 maximizessurface 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 den-

sities. 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. Termi-nal 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

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, septicrats 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.



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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 pro-cess once envisaged, occurring for example only in a capillary bed. Thus O2diffusion 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 hetero-geneous 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 capillarynetwork. Blood flow within the microcirculation also may exhibit passive con-

trol, for example, when influenced by rheologic influences and network geom-

etry (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 in-

creasing RBC supply to the tissue. Although this increase in capillary surface

area has been interpreted as active capillary recruitment, how it happens re-

mains the subject of speculation, as studies have not demonstrated precapil-lary 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 diffu-

sion 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 O2 exchange is through use of the O2 sup-

ply:dependency relationship. Normally, O2 consumption (VO2) is independentof 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 supply-

dependent 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 measuredusing expired gas analysis while QO2 was calculated. Rats then were random-

ized 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 reduc-tion 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 ulti-

mately 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% decreasein 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 myo-cardial architectures (including myofibrillar edema) in peritonitis-induced sepsis

in a sheep model.

Another cause of depressed capillary recruitment in critical illness is micro-

vascular 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 stifferthan 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 andan 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 microves-

sels [26].

Fitzgerald et al demonstrated that storage of RBCs for 28-days impaired theirability 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 mecha-

nisms 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. Sielenkamper et al infused both diaspirin cross-

linked 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 relatedto 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 redistribu-

tion 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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