Physiologic aspects of anemia

Crit Care Clin 20 (2004) 187–212

Physiologic aspects of anemia

Paul C. Hebert, MD, FRCPC, MHSca,b,*,Phillipe Van der Linden, MD, PhDc, George Biro, MD, PhDd,

Ling Qun Hu, MD, DABAe

aCentre for Transfusion Research, Clinical Epidemiology Program, Ottawa Health Research Institute,

University of Ottawa, 501 Smyth Road, Ottawa, Ontario K1H 8L6, CanadabClinical Epidemiology Unit, Room 1812-H, Ottawa General Hospital, 501 Smyth Road, Ottawa,

Ontario K1H 8L6, CanadacDepartment of Anesthesiology, Centre Hospitalo-Universitaire Brugmann-Hopital Universitaire

des Enfants Reine Fabiola, 4 Place Van Gehuchten, B-1020, Bruxelles, BelgiumdDepartment of Physiology, University of Toronto, 223 Dunview Avenue,

Toronto, Ontario M2N 4H9, CanadaeDepartment of Anesthesiology, Northwestern Memorial Hospital, Feinberg School of Medicine,

Northwestern University, 251 E. Huron Street, F5-704, Chicago, IL 60611, USA

Many of the physiological concepts in oxygen (O2) transport and use were

described in the early part of the 20th century and are still widely accepted [1]. In

1920, Barcroft [2] noted that tissue oxygenation was a function of hemoglobin

concentration, oxygenation of blood by the lungs, and the cardiac output to deliver

a supply of oxygenated blood to the tissues. Similarly, many of the principles

underlying the transfer of O2 from the microcirculation to the mitochondria have

been established and also have stood the test of time [1]. This article describes

some of the basic principles of O2 transport that have been studied extensively

and published in text books and review articles [1,3–5]. It emphasizes the physi-

ological consequences of anemia to provide information relevant to red cell trans-

fusion decisions.

The following questions underscore much of this article. First, does the evi-

dence from physiological studies suggest an optimal hemoglobin level in most

anemic patients or in patients with specific diseases? Second, are certain patients

at increased risk from the physiological consequences of anemia?

0749-0704/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.ccc.2004.01.001

Dr. Hebert is an Ontario Ministry of Health Career Scientist.

* Corresponding author. Centre for Transfusion Research, Clinical Epidemiology Program, Ot-

tawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

E-mail address: [email protected] (P.C. Hebert).

P.C. Hebert et al / Crit Care Clin 20 (2004) 187–212188

Overview of oxygen transport

Hemoglobin is a complex molecule consisting of four globin moieties, each

incorporating an iron-containing heme ring where oxygen may bind. The O2

carrying capacity of hemoglobin or binding affinity to O2, is represented graphi-

cally by a sinusoidal relationship between the hemoglobin saturation and the

partial pressure of oxygen (pO2). This relationship, referred to as the oxyhemo-

globin dissociation curve, enables efficient loading in the lungs at high pO2s

and efficient unloading in the tissues at low pO2 values (Fig. 1). Hemoglobin’s

O2 binding affinity (the degree to which O2 molecules saturate the hemoglobin

binding sites at a given pO2), however, may be altered by various disease states

and may play a significant adaptive role in response to anemia.

The amount of O2 delivered, either to the whole body or to specific organs,

is the product of blood flow and arterial O2 content. For the whole body, O2

delivery (DO2) is the product of total blood flow or cardiac output (CO) and

arterial O2 content (CaO2). Thus, the equation reads: DO2 = CO � CaO2.

When breathing ambient air under normal conditions, O2 present in arterial

blood essentially is transported by hemoglobin, which is nearly fully saturated,

while the remainder is dissolved in plasma water. The negligible amount of

dissolved O2 is directly proportional to the partial pressure and may be calculated

by multiplying pO2 by a constant (k = 0.00301), termed the solubility coefficient.

0 25 50 75 100 125 150

Hemoglobin (g/L)

0

5

10

15

Car

diac

Out

put (

L/m

in)

Fig. 1. Effects of hemoglobin concentration on cardiac output. The series of curves illustrate how

cardiac output will increase as hemoglobin concentration decreases. The solid curve describes the

increase in healthy adult. The top dashed line shows how the cardiac output response may be

accentuated in a young athlete, while the lower dashed line might correspond to someone with poor

cardiovascular function.

P.C. Hebert et al / Crit Care Clin 20 (2004) 187–212 189

Thus, under most circumstances, arterial O2 content may be approximated from

the portion bound to hemoglobin using the equation:

CaO2ðin mL/LÞ ¼ % Sat� 1:39 ðmL/gÞ � ½Hb� ðg/LÞ

If one substitutes CaO2 from the second equation into the first, then:

DO2 ¼ CO� ð% Sat� 1:39� ½Hb�Þ

Where, CO equals cardiac output in L per minute, % Sat equals hemoglobin O2

saturation in percentage, [Hb] equals hemoglobin concentration in g/L, and 1.39

is the hemoglobin binding constant (ie, 1.39 mL of O2 will bind to 1 g of hemo-

globin when fully saturated).

Cardiac output, a measure of blood flow to the entire body, is the other

major determinant of O2 delivery. It may be quantified by multiplying the stroke

volume (the difference between end diastolic volume and end systolic volume in

liters) and heart rate (in beats per minute). Stroke volume is influenced by preload

(end diastolic volume), afterload (the arterial pressure and resistance encountered

during each ventricular ejection), and contractility (the force generated during

each contraction). Cardiac work or energy expended by the heart is directly

proportional to the heart rate, the change in pressure (arterial minus left ven-

tricular pressure), and volume (ejection fraction) during a cardiac cycle [6–11].

Thus, for a given blood pressure, increasing cardiac output will increase myo-

cardial O2 consumption or for a given cardiac output. O2 consumption also will

increase with increased blood pressure. A tight coupling of myocardial O2 sup-

ply to O2 demand is regulated by metabolic byproducts such as adenosine [12].

Tissue hypoxia (and anoxia) will occur if O2 delivery is decreased to a

level where tissues no longer have enough O2 to meet their metabolic demands.

From the first and third equations, it is apparent that tissue hypoxia may be

caused by decreased O2 delivery caused by decreases in hemoglobin concen-

tration (anemic hypoxia), cardiac output (stagnant hypoxia), or hemoglobin satu-

ration (hypoxic hypoxia). Each of the determinants of DO2 has substantial

physiologic reserves, thereby enabling the human body to adapt to significant

increases in O2 requirements or decreases in one of the determinants of DO2

as a result of various diseases.

In health, the amount of O2 delivered to the whole body exceeds resting

O2 requirements by a factor of two- to fourfold. For example, if a hemoglobin

level of 150 g/L, an oxygen saturation (% Sat) of 99%, and cardiac output of

5 L per minute are assumed, then O2 delivery will be 1032 mL per minute. At

rest, the amount of O2 required or consumed by the whole body will range from

200 to 300 mL per minute. An isolated decrease in hemoglobin concentration

to 100 g/L will result in an O2 delivery of 688 mL per minute. Despite this

33% decrease in DO2, there remains a twofold excess of DO2 as compared with

O2 consumption. A further drop in hemoglobin concentration to 50 g/L with all

other parameters, including cardiac output, remaining constant, however, will

decrease O2 delivery to a critical level of 342 mL per minute. Under stable

experimental conditions, this dramatic decrease O2 delivery would not affect


O2 consumption. Below a critical level or threshold of O2 (DO2crit), however,

O2 consumption will decrease with further decreases in hemoglobin concentra-

tions (and decreased DO2). There is therefore a biphasic relationship between

DO2 and consumption (Fig. 2): a DO2-independent portion of the relationship

above a threshold value (DO2crit) where O2 consumption is independent of

DO2 and a delivery or supply-dependent portion, where O2 delivery is related

linearly to O2 consumption. The latter portion of this relationship below the

DO2crit indicates the presence of tissue hypoxia. Laboratory and clinical studies

have attempted to determine DO2crit. The most rigorous clinical study [13]

found a threshold value of 4 mL per minute/kg, while other clinical and labora-

tory studies found value in the range of 8 mL per minute/kg [14–16]. The

DO2crit or the anaerobic threshold is unlikely to be a single fixed value but will

vary substantially depending on such factors as basal metabolic rate, the specific

organ or tissue, some disease states, and perhaps complex factors such as a pa-

tient’s age or genetic make-up.

After blood is oxygenated, it is distributed to all organs and tissues through

the arterial tree into the microcirculation. Organ blood flow is controlled by

arterial tone in medium-sized vessels, primarily responsive to changes in auto-

nomic stimulation and the release of locally generated vasodilating substances.

Within organ systems, red cells are carried into the microcirculation, where

O2 is released to the tissues through a thin-walled capillary network. Once

released, O2 diffuses through the interstitial space, finally finding its way into

the cell and mitochondria to be used in cellular respiration. Each of these

0 25 50 75 100 125

pO2 (mmHg)

0

20

40

60

80

100

% S

atur

atio

n of

Hem

oglo

bin

Right shifted

Lower pH

Left shifted

Higher temperature

Increased 2,3- DPG

Higher pH

Lower temperature

Decreased 2,3- DPG

Fig. 2. O2 consumption to O2 delivery relationship. The solid line demonstrates the biphasic rela-

tionship between O2 consumption and O2 delivery. The dashed line illustrates the postulated changes

in the relationship with diseases such as sepsis and ARDS. The anaerobic threshold is shifted to the

right, suggesting that patients require increased levels of O2 delivery to avoid ongoing ischemic

damage to vital organs.


physiologic mechanisms may be altered in disease states. There are additional

adaptive changes in the microcirculation enhancing DO2 in anemic states [1].

Adaptation to anemia and transfusions

In anemia, O2 carrying capacity is decreased, but tissue oxygenation is pre-

served at hemoglobin levels well below 100 g/L. Following the development

of anemia, adaptive changes include a shift in the oxyhemoglobin dissociation

curve and hemodynamic and microcirculatory alterations. The shift to the right

of the oxyhemoglobin dissociation curve in anemia is primarily the result of

increased synthesis of 2,3-DPG in red cells [17–30]. This rightward shift

enables more O2 to be released to the tissues at a given pO2, offsetting the effect

of reduced O2 carrying capacity of the blood. In vitro studies also have

demonstrated rightward shifts in the oxyhemoglobin dissociation curve with

decreases in temperature and pH [31]. Although clinically important shifts have

been documented in several studies, measurements of hemoglobin O2 saturation

generally are performed on arterial specimens processed at standardized tem-

peratures and pH. Therefore, current measurement techniques will not reflect

O2 binding affinity in the patient’s microcirculatory environment, potentially

affected by temperature, pH, and several disease processes. The Bohr effect

[31,32] determines the shift in the oxyhemoglobin dissociation curve caused by

carbon dioxide (CO2) entering or leaving the blood. At tissue level, CO2 enters

blood, causing the pH to decrease (acidosis), and the oxyhemoglobin dissociation

curve shifts to the right, facilitating the release of O2 from hemoglobin. The

reverse change at the lungs results in alkalosis with a leftward shift of the

oxyhemoglobin dissociation curve, enhancing the affinity of hemoglobin for

O2. The Bohr effect is unlikely to have important clinical consequences [31,32],

however, as a 0.6 change in pH is required to modify the p50 by 10 mm Hg.

Several hemodynamic alterations also occur following the development of

anemia. The most important determinant of cardiovascular response is the pa-

tient’s volume status, or more specifically, left ventricular preload. The combined

effect of hypovolemia and anemia often occur as a result of blood loss. Acute

anemia thus may cause tissue hypoxia or anoxia through decreased blood flow

(stagnant hypoxia) and decreased O2 carrying capacity (anemic hypoxia) [1,3–5].

The body primarily attempts to preserve DO2 to vital organs through increased

myocardial contractility and heart rate and increased arterial and venous vascular

tone mediated through increased sympathetic tone. In addition, central and

regional reflexes redistribute organ blood flow. The adrenergic system plays an

important role in altering blood flow to and within specific organs. The renin–

angiotensin–aldosterone hormone system also is stimulated to retain water and

sodium. Losses ranging from 5% to 15% in blood volume result in variable

increases in resting heart rate and diastolic blood pressure measures. Orthostatic

hypotension is often a sensitive indicator of relatively small losses in blood

volume that are not sufficient to cause a marked blood pressure fall. Larger losses


will result in progressive increases in heart rate and decreases in arterial blood

pressure accompanied by evidence of end organ hypoperfusion. The increased

sympathetic tone diverts an ever decreasing global blood flow or cardiac output

away from the splanchnic, skeletal, and skin circulation toward the coronary and

cerebral circulation. Once vital organ systems such as the kidneys, the central

nervous system and the heart are affected, the patient is considered in hypovolemic

shock. Although the American College of Surgeons’ Committee on Trauma [33]

has categorized the cardiovascular and systemic response to acute blood loss

according to degrees of blood loss, many of these responses are modified by

patient characteristics such as age, comorbid illnesses, pre-existing volume status

and hemoglobin values, the use of medications having cardiac (ie, beta blockers)

or peripheral vascular effects (ie, antihypertensives), and the rapidity of blood loss.

The compensatory changes in cardiac output have been the most thoroughly

studied cardiovascular consequence of normovolemic anemia. When intravascular

volume is stable or increased following the development of anemia (as opposed

to hypovolemic anemia and shock), increases in cardiac output have been reported

consistently. Indeed, an inverse relationship between hemoglobin levels (or

hematocrit) and cardiac output has been established in well-controlled laboratory

studies [34–40] (Fig. 3). Similar clinical observations were made in the peri-

operative setting [41–48] and in chronic anemia [34,49–51]. The strength of

inferences from clinical studies, however, is limited by confounding factors aris-

0 200 400 600 800 1000 1200

O2 delivery (ml/min)

0

100

200

300

400

500

O2

cons

umpt

ion

(ml/m

in)

Anaerobic threshold

Fig. 3. Oxyhemoglobin dissociation curve. The solid line represents oxygen binding affinity to the

hemoglobin molecule under standard temperatures (37�C) and pH (7.4). The dashed lines represent

hypothetical shifts in the curve. A rightward shift may be related to increased 2,3-DPG levels or

decreased temperature or pH. A shift to the left will result from decreased 2,3-DPG or increased tem-

perature or pH.


ing from major comorbid illnesses such as cardiac disease, a lack of appropriate

control patient, and significant weaknesses in study design (Table 1). Researchers

also have attempted to determine the level of anemia at which cardiac output

begins to rise. Reported thresholds for this phenomenon identified in primary

clinical and laboratory studies has ranged from 70 to 120 g/L [34,35,52–55].

Two major mechanisms are thought to modulate the physiological processes

underlying the increased cardiac output during normovolemic anemia; they are

reduced blood viscosity and increased sympathetic stimulation of the cardiovas-

Table 1

Inferences drawn from the published literature

Strength of inference

Oxyhemoglobin dissociation curve

Anemia is associated with a shift the oxyhemoglobin curve to the

right because of increased 213 DPG levels.

Strong

Anemia causes clinically significant rightward shifts in the

oxyhemoglobin curve because of the Bohr effect.

Weak

The shift in the oxyhemoglobin curve has been established in many

forms of anemia (excluding hemoglobinopathies).

Moderate

The shift in the oxyhemoglobin curve has been established in a

number of human diseases.

Weak

Cardiac output

Cardiac output increases with increasing degrees of

normovolemic anemia.

Strong

Increased cardiac output in normovolemic anemia is mainly a result of

increased stroke volume.

Strong

The contribution of increased heart rate to the increase in cardiac

output following normovolemic anemia is variable.

Strong

Other hemodynamic alteration

Changes in blood viscosity result in many of the hemodynamic

changes in normovolemic anemia.

Strong

Normovolemic anemia results in increased sympathetic activity. Strong

Normovolemic anemia causes increased myocardial contractility. Moderate

Normovolemic anemia causes a decrease in systemic vascular resistance. Strong

Normovolemic anemia results in a redistribution of cardiac output

towards the heart and brain and away from the splanchnic circulation.

Strong

Maximal global O2 delivery occurs at hemoglobin values of

100 to 110 g/L.

Moderate

Global O2 delivery declines above and below hemoglobin values of

100 to 160 g/L.

Moderate

Coronary and cerebral blood flow

Coronary blood flow is increased during anemia. Strong

Cerebral blood flow is increased during anemia. Strong

Coronary artery disease in the presence of moderate degrees of anemia

(hemoglobin values below 90 g/L) results in impaired left ventrical

contractility or ischemia.

Strong

Moderate anemia does not aggravate cerebral ischemia in patients with

cerebrovascular disease.

Strong


cular effectors [1,38,56–58]. Blood viscosity exerts major effects on preload

and afterload, two of the major determinants of cardiac output [56,59,60], while

sympathetic stimulation primarily increases the two other determinants, heart rate

and contractility. As opposed to hypovolemic anemia, the effects of blood visco-

sity appear to predominate in this setting [59–61].

There are complex interactions between blood flow, blood viscosity, and

cardiac output. In vessels, blood flow alters blood viscosity, and in turn, blood

viscosity modulates cardiac output. Under experimental conditions in rigid hol-

low cylinders, blood flow is related directly to the diameter and the pressure

difference between the ends of the cylinder, and inversely related to its length

and the blood viscosity (Poiseuille–Hagen Law) [1,56,57]. Blood is not a New-

tonian fluid (ie, its viscosity will change according to blood flow velocity). Thus,

viscosity is highest in postcapillary venules where flow is the lowest, and

viscosity is lowest in the aorta where flow is highest. In postcapillary venules,

there is a disproportionate decrease in blood viscosity as anemia worsens, and as

a consequence, venous return is increased significantly. If cardiac function is

normal, the increase in venous return or (left) ventricular preload will be the

most important determinant of the increase in cardiac output during normo-

volemic anemia. Interestingly, if viscosity is maintained during anemia using

colloidal solutions of known high viscosity other than red cells, these cardiovas-

cular effects are attenuated [59]. Decreased (left) ventricular afterload, another

cardiac consequence of decreased blood viscosity, also may be an important

mechanism for the increase in cardiac output as anemia worsens [59].

Investigators [38,53,59,60,62–64] not only have observed changes in vis-

cosity but also have noted alterations in sympathetic stimulation. Reviews and

guidelines indicate that anemia also results in an increase in heart rate [35,56,65].

This physiologic response is thought to be mediated predominantly through aor-

tic chemoreceptors [38,58] and release of catecholamines [38,39,62,66,67].

Primary laboratory studies [67,68] and studies of perioperative normovolemic

hemodilution [41–43] and chronic anemia [49,50], however, have not demon-

strated consistently significant increases in heart rate following moderate degrees

of anemia. From a detailed review by Spahn et al [56], there appeared to be some

differences in species responses and differences between awake and anesthetized

patients. In three poorly controlled studies in children, there were conflicting

results as to whether the increase in cardiac output is mostly a consequence of

increased heart rate [50,69] or stroke volume [70]. In summary, the increase in

cardiac output is more dependent on stroke volume and to a lesser extent on heart

rate in most clinical settings. If indeed increased heart rate does occur from

normovolemic anemia, one of its major consequences will be to affect coronary

blood flow adversely by decreasing diastole, the time when the left ventricular

myocardium is perfused [71,72].

The sympathetic stimulation also may result in increased cardiac output

through enhanced myocardial contractility [73,74] and increased venomotor tone

[38,75]. The effects of anemia on left ventricular contractility in isolation have

not been determined clearly, given the complex changes in preload, afterload, and


heart rate. Only one before-and-after hemodilution study used load independent

measures to document increased left ventricular contractility [74]. Chapler and

Cain [38] have summarized several well-controlled studies indicating that veno-

motor tone is increased and that it results from stimulation of the aortic chemo-

receptors. If sympathetic stimulation is significant in the specific clinical setting,

then contractility will be enhanced from stimulation of the beta-adrenergic re-

ceptors [56,62,64,73].

Under experimental laboratory conditions, several investigators [66,76–80]

have observed significant increases in coronary blood flow directly related to the

degree of normovolemic anemia. In addition, these same studies do not appear

to demonstrate significant shifts in the distribution of coronary flow between

endocardium and epicardium in a normal coronary circulation during moderate

degrees of anemia. Further, significant alterations in flow distribution between

major organs following acute hemodilution also have been documented [35,38,

61,68,76,80–84]. Disproportionate increases in coronary and cerebral blood flow

were noted while simultaneously observing decreases in blood flow to the splanch-

nic circulation. The interaction between anemia and cardiac disease in general, and

coronary artery disease (CAD) specifically are described subsequently.

The inverse relationship between cardiac output and hemoglobin levels has led

investigators to determine the hemoglobin level that maximizes O2 transport.

Richardson and Guyton [85], evaluating the effects of hematocrit on cardiac

performance in a canine model, established optimal O2 transport to occur be-

tween hematocrit values of 40% to 60%. Others determined maximum DO2 to be

in the lower end of the range, at a hematocrit value of 40% to 45% (132 to 150 g/

L) [76,80,86]. One of the most widely quoted studies addressing this topic from

Messmer et al [55], however, found that optimal O2 transport occurred at hema-

tocrit values of 30% (hemoglobin = 100 g/L). Unfortunately, global indices of

optimal DO2 will mask any differences in blood flow between specific organs

[61,66,87,88]. In addition, attempting to identify a single optimal hemoglobin

that maximizes DO2 neglects to consider the large number of factors interfering

with adaptive mechanisms when dealing with anything other than healthy young

patients with anemia.

Will the transfusion of allogeneic red cells reverse any adaptive response to

acute or chronic normovolemic anemia? Given that O2 carrying capacity is not

impaired in the red cell storage process and that blood viscosity is restored fol-

lowing a transfusion, the cardiovascular consequences will be reversed, assuming

there has been no irreversible ischemic damage. The storage process alters the

red cells properties, however, which, in turn may impair flow and O2 release

from hemoglobin [17,22] in the microcirculation.

Microcirculatory effects of anemia and red cell transfusions

At the level of the microcirculation, different mechanisms potentially could

increase the amount of O2 supplied to tissues within capillary networks. In a


model of the microcirculation proposed by Krogh [89,90], O2 supply to the

tissues may be enhanced through recruitment of previously closed capillaries,

increased capillary flow, and increased O2 extraction from existing capillaries.

The degree of anemia, the specific tissue bed, and a variety of disease processes

all may impact on microcirculatory blood flow [1,91,92]. As the degree

hemodilution becomes more pronounced, and hemoglobin values decrease, blood

viscosity decreases disproportionately in capillary networks. This results in pro-

gressive increases in flow velocities of red cells through capillary beds and

proportionate decreases in the time red cells spend in capillaries (eg, decreased

transit times) [93]. With moderate degrees of anemia, the increased red cell flow

velocities may increase the amount of O2 supplied to tissues [1]. During profound

anemia, however, the transit times may be so brief so as to interfere with the

diffusion of O2 to the tissues [94]. Indeed, increases in flow velocities may be one

of the important reasons for the onset of anaerobic metabolism. Other mecha-

nisms could contribute to an improvement of DO2 at the tissue levels. A decrease

in precapillary O2 loss, caused by a reduction in red blood cell residence time

combined with a decreased diffusional exchange [92]. An increase in the ratio of

microcirculatory to systemic hematocrit also has been demonstrated, relayed to

the complex interaction between axially migrating red blood cells (Fahraeus

effect) and the heterogeneous nature of the capillary network [95]. All these

mechanisms allow tissue oxygen extraction capabilities to improve as demon-

strated in experimental models of hemorrhagic and endotoxic shock [96,97].

Although the effect of hemoglobin levels (hematocrit) on systemic O2 trans-

port in the central circulation have been studied, it remains unclear how raised

hematocrit levels influence DO2 in the microcirculation [98–100]. Until recently,

few interpretable studies were published in this area because of the difficulty in

obtaining in situ measurements of blood viscosity, microcirculatory flow, DO2,

and cellular respiration [101]. Messmer et al [93,100,102,103] have suggested

microcirculatory stasis and impaired DO2 to the tissues may be related directly to

changes in hematocrit. They theorized that normovolemic hemodilution improves

microcirculatory flow and DO2. Other authors have suggested that hematocrit

has limited effects on microcirculatory flow [104,105].

Transfused red cells also may have properties that differ from their in vivo

counterparts. There are several age-related changes that occur in stored red cells.

Characteristically, older packed red cell (PRC) units have lower levels of 2,3-DPG,

a small molecule that alters hemoglobin’s affinity for O2 [17,22,35,68,106–112].

Low levels of 2,3-DPG induce a leftward shift in the oxyhemoglobin dissocia-

tion curve, which may impede delivery of O2 to the tissues. In addition, storage

of red cells may decrease red cell membrane deformability [113,114] through

alterations in cell membrane characteristics. As a consequence, transfused red

cells may impair flow in the microcirculation [115] and may have a limited ability

to release O2 to tissues.

There are reports [114,116–119] suggesting that disease processes such as

sepsis also impair red cell deformability. In conjunction with significant systemic

microcirculatory dysfunction, the decrease in red cell deformability may affect


tissue DO2 dramatically in sepsis and septic shock [114,116–118]. Therefore,

there is evidence that suggests PRC transfusions increase systemic DO2 but

may have adverse effects on microcirculatory flow.

Interaction between pathophysiologic processes and anemia

Several disease processes affecting either the entire body or specific organs

potentially limit adaptive responses, thereby making patients more vulnerable

to the effects of anemia. Specifically, heart, lung, and cerebrovascular diseases

have been proposed to increase the risk of adverse consequences from anemia

[35,120,121]. Age, severity of illness, and therapeutic interventions also may

affect adaptive mechanisms.

The heart, and more specifically the left ventricle, may be particularly prone to

adverse consequences following anemia. This is because the myocardium

consumes 60% to 75% (extraction ratio) of all O2 delivered to the coronary cir-

culation [66,76–80,86,122]. Such an elevated extraction ratio is unique to the

coronary circulation. As a result, DO2 to the myocardium can increase only by

increasing blood flow [86,123]. Moreover, most of left ventricular perfusion is

restricted to the diastolic period, and any shortening of the duration of diastole

(eg, tachycardia) constrains blood flow. Laboratory studies have investigated

the effects of normovolemic anemia on the coronary circulation [39,77,80,86,

122–126]. There appears to be minimal consequences from anemia with he-

moglobin levels in the range of 70 g/L, if the coronary circulation is normal

[40,74,77,86,123,127]. Myocardial dysfunction and ischemia, however, either

occur at a higher hemoglobin concentration or are more significant in anemic

animal models with moderate to high grade coronary stenoses, when compared

with controls with normal coronary arteries [122,124–129].

The clinical data do not appear to be as consistent. Several clinical studies

in patients with CAD undergoing normovolemic hemodilution have not reported

any increase in cardiac complications or silent ischemia during ECG monitoring

[47,130–132]. In addition, a retrospective analysis involving 224 patients

undergoing coronary artery bypass graft (CABG) surgery was not able to

demonstrate any significant association between the level of hemoglobin and

coronary sinus lactate levels (a measure of coronary ischemia) [133]. In two recent

cohort studies, moderate anemia was tolerated poorly in perioperative [134] and

critically ill patients [135] with cardiovascular disease, confirming observations

made in the laboratory. Anemia also may result in significant increases in

morbidity and mortality in patients with other cardiac pathologies, including heart

failure and valvular heart disease [128], presumably because of the greater burden

of the adaptive increase in cardiac output.

During normovolemic anemia, cerebral blood flow increases as hemoglo-

bin values decrease. Investigators have observed increases ranging from 50% to

500% of baseline values in two laboratory studies [136–142] and in one human

study [143]. Increased cerebral blood flow occurs because of overall increases

Table 2

Eighteen studies examining O2 delivery, O2 consumption, and lactate before and after red cell transfusion

Author and

year published Study population

Number of

patients

Amount transfused

(units)

Changes in measurements of post-transfusion

" HgB " DO2 " VO2 # Lactate Comments

Ronco, et al

[170] (1990)

PCP pneumonia 5 1.5 U Yes Yes Yes NA All patients had lactate

at baseline.

Thermodilution used for

DO2/VO2 measurements.

Fenwick, et al

[171] (1990)

ARDS 24 1.5 U Yes Yes No No Normal lactate (n = 1)

was compared with high

lactate (n = 13) group.

Yes Yes No Yes Hemodilution catheter

used for all measurements.

Significant increases

observed in VO2 in

response to transfusion in

high lactate group.

Ronco, et al

[172] (1991)

ARDS 17 1.5 U Yes Yes No NA Normal lactate (n = 7) was

compared to high lactate

group (n = 10).

No relationship observed

between VO2 and DO2

when VO2 directly measured

with expired gases.

Shah, et al

[173] (1982)

Post-trauma 8 1 or 2 U Yes No No NA 1 RBC unit (n = 5) or

2 units (n = 3) were given

to patients.



P.C.Hebert

etal/Crit

Care

Clin

20(2004)187–212

198

Steffes, et al

[174] (1991)

Postoperative +

Post trauma

21 1–2 U Yes Yes Yes No There were 27

measurements sets in

21 patients.


DO2 and VO2 measurements.

Increased lactate values did

not predict VO2 response.

Babineau, et al

[165] (1992)

Postoperative 31 328±9 ml Yes Yes No NA 32 of 33 transfusions were

single units.



58% of transfusions did

not increase VO2.

Gilbert, et al

[175] (1988)

Septic 17 4 20 g/L Yes Yes No No There were 33 measurement

sets in 31 patients.

10 of 17 patients had

increased lactate.

VO2 significantly increased

in high group only.

Dietrich, et al

[176] (1990)

Medical shock

(septic/cardiac)

32 577 mL Yes Yes No No There were 36 measurement

sets in 32 patients.

No change observed in VO2

after transfusion.



(continued on next page)

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Table 2 (continued )

Author and

year published Study population

Number of

patients

Amount transfused

(units)

Changes in measurements of post-transfusion

" HgB " DO2 " VO2 # Lactate Comments

Conrad, et al

[177] (1990)

Septic shock 19 4 30 g/L Yes Yes No No Normal lactate (n = 8)

compared to high lactate

(n = 11) group.

No increase observed in

VO2 with transfusion in

either group.



Marik, et al

[113] (1993)

Septic 23 3 U Yes Yes No No DO2 measured independently

of VO2.

Using gastric tonometry,

patients receiving old red

cells developed evidence

of gastric ischemia.

Lorento, et al

[178] (1993)

Septic 16 2 U Yes Yes No NA Dobutamine significantly

increased VO2 while red

cells did not.



Mink, et al

[179] (1990)

Septic shock

2 mo – 6 y

8 8–10 mL/kg

� 1–2 h

Yes Yes No NA In pediatric patients, VO2

did not increase with

red cells.


DO2, VO2 measurements.

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Lucking, et al

[180] (1990)

Septic shock

4 mo – 15 y

7 10–15 mL/kg

� 1–3 h

Yes Yes Yes NA There were 8 measruement

sets in 7 patients.



Silverman, et al

(1992) [181]

Septic shock

21–88 y

21 2 U Yes Yes No No RBC transfusion decreased

pHia when in 7 patients

when measurement sets

were initially normal.



Gramm et al

(1996) [182]

Septic shock

46 ± 3 y

19 2 U Yes No No NA RBC transfusion was

associated with heart decrease.



Fernandes et al

2001 [183]

Septic shock

18–80 y

10 1 U Yes No No No No effect of RBC

transfusion on pHi observed.

VO2 measured independently

of VO2.

Kahn et al

1986 [184]

Acute respiratory

failure

15 7–10 mL/kg Yes No No NA Pulmonary venous admixture

increased with transfusion.



Casutt et al

1999 [185]

Postoperative

32–81 y

67 368 ± 10 mL Yes Yes No NA There were 170 measurements

in 67 patients.



4 = increment.

Abbreviations: A DO2, increased O2 delivery; A VO2, increased O2 consumption; pHi; intramucosal gastric pH; A NA, not available.a Authors only indicated average hemoglobin change not number of units transfused.

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in cardiac output, which is diverted preferentially to the cerebral circulation. Also,

as DO2 begins to decrease, cerebral tissues are able to increase the amount of

O2 extracted from blood. The increase in global cerebral blood flow combined

with the possibility of improved flow characteristics across vascular stenoses

(improved rheology of blood because of decreased viscosity) prompted a number

of laboratory and clinical [144–149] studies investigating hemodilution as a

therapy for acute ischemic stroke [140,142,144,150–152]. The laboratory studies

suggest that moderate degrees of anemia alone rarely should result in or worsen

cerebral ischemia. As a therapy in acute ischemic stoke, however, all randomized

clinical trials did not find any overall improvement in clinical outcomes. There

are several factors including the degree of hemodilution, the type of fluid used

for volume expansion and the volume status (preload), and the extent of the

cerebrovascular disease that potentially modify global or regional cerebral blood

flow during anemia [153,154]. Thus, cerebrovascular disease does not appear to

predispose patients to significant ill consequences from anemia.

Changes in DO2 to the brain during normovolemic anemia (either increases

or decreases in blood flow) do not affect various forms of cerebral pathologies

uniformly. For instance, patients with raised intracranial pressure from traumatic

brain injury may be adversely affected by increased cerebral blood flow. Fol-

lowing subarachnoid hemorrhage, mild degrees of normovolemic or hypervolemic

anemia may improve overall DO2 during cerebral vasospasm by improving

cerebral blood flow through decreased viscosity [155–158]. The effects of mod-

erate to severe anemia have not been assessed in laboratory or clinical studies. A

study from Weiskopf and colleagues [159] in healthy volunteers showing that

anemia to a hemoglobin concentration of 50 to 60 g/L is associated with subtle but

significant cognitive function defects, that can be reversed by autologous blood

retransfusion or by high inspired FiO2.

One of the major consequences of diverting the cardiac output toward the

coronary and cerebral circulation during normovolemic anemia is a shunting away

from other organs including the kidneys and bowel. Critically ill patients affected

by a wide variety of pathologic processes, may be adversely affected by this

redistribution of cardiac output away from the mesenteric circulation [5,15,

160,161]. Critical illness also may tax many of the body’s adaptive responses.

Specifically, cardiac performance may be impaired [162,163] or already maxi-

mally responding to increased metabolic demands. Pathologic processes affecting

the microcirculation, particularly prevalent in this population, also may affect

the patient’s response to anemia and transfusions.

Red cell transfusions and oxygen kinetics

The authors identified 18 studies (Table 2) evaluating the impact of red cell

transfusions on O2 kinetics. Although hemoglobin concentration increased sig-

nificantly in all the studies, DO2 did not increase in four of them. Despite the

administration of 1 to 3 packed red blood cell units, cardiac output did not change


or even tended to decrease. In the 14 studies that showed an increase in systemic

DO2, only five reported an increase in systemic O2 consumption. Blood lactate

levels were not predictive of O2 consumption changes given that only two of the

eight studies evaluating patients with increased lactate concentration reported an

increase in O2 consumption. The lack of change in O2 consumption reflects either

methodologic errors [164] or patients with no O2 debt rather than an indication

that red cells were unnecessary as suggested by one of the studies [165]. Even

though several clinical trials [166–168] have attempted to define optimal levels

of DO2, there is no consensus as to which patients are most likely to benefit

and which intervention or approach is superior (ie, fluids, red cells, inotropic

agents, or a combination of these interventions). The results of a recent meta-

analysis suggest that optimizing DO2 may be of greater benefit in perioperative

patients [169]. All experimental protocols maintained hemoglobin values

greater than 100 g/L, however, and therefore did not compare various red cell

transfusion strategies.

Summary

The most important adaptive responses from a physiological stance involved

the cardiovascular system, consisting in particular of elevation of the cardiac

output and its redistribution to favor the coronary and cerebral circulations, at the

expense of the splanchnic vascular beds. The evidence regarding these physio-

logical responses, especially in experimental studies that permit the control of

many variables, is particularly powerful and convincing. On the other hand, there

is a remarkable lack, in quality and quantity, of clinical studies addressing how

normal physiological adaptive responses may be affected by a variety of diseases

and conditions that often accompany and may complicate anemia, and interactions

with other such compounding variables as age and different patient populations.

For these reasons, it is not possible to offer guidelines on how to increase,

maintain, or even to determine optimal DO2 in high-risk patients and how best

transfusion strategies might be used under these conditions.

From the brief review of physiological principles and the strong consensus in

the literature, it is evident that cardiac function must be a central consideration in

decisions regarding transfusion in anemia, because of the critical role it plays

in assuring adequate oxygen supply of all vital tissues. Particular attention should

be paid to the possible presence of CAD or incipient or cardiac failure, as these

conditions may require careful transfusions to improve DO2 at levels that may not

necessitate such interventions when cardiac disease is absent. Although the

cerebral circulation also serves an obligate aerobic organ unable to tolerate sig-

nificant hypoxia, there is little convincing evidence to support the notion that

cerebral ischemia is aggravated by anemia and that this can be prevented by

improved DO2 through rapid correction of anemia. Consequently, the arguments

favoring transfusions in the presence of ischemic heart disease do not appear

to apply to occlusive cerebrovascular disease.


Because firm evidence is lacking on the interactions of concurrent diseases

and anemia in various patient populations, understanding of the physiological

consequences of anemia, and of the diseases concerned, is useful but not fully

sufficient to provide firm and rational guidance to transfusion practice in specific

complex clinical instances. A good deal of clinical and experimental investigation

is required to support fully rational and comprehensive guidelines. In the mean-

time, prudent and conservative management, based on awareness of risks and

sound understanding of the normal and pathological physiology, must remain the

guiding principle.

Acknowledgments

We are grateful to the Canadian Medical Association Expert Working Group

for Guidelines on Transfusion of Red Cells and Plasma in Adults and Children

for their support and assistance in preparing the original manuscript and to

Dr. Claudio Martin for his meticulous review of the original manuscript published

in the Canadian Medical Association Journal.

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Physiologic aspects of anemia