- Email: [email protected]
Anaemia
C H A P T E R 2 3
Anaemia KEY POINTS ■ Anaemia has little effect on pulmonary gas exchange but decreases oxygen carriage in the arterial blood in direct proportion to the reduction in haemoglobin concentration. ■ Mechanisms that compensate for the reduced oxygen delivery include increased cardiac output, increased tissue oxygen extraction and a right shift of the oxyhaemoglobin dissociation curve. ■ Older patients or those with poor cardiac reserve compensate less well when anaemic.
Anaemia is a widespread pathophysiological disorder that interferes with oxygen transport to the tissues. A quarter of the world’s population are anaemic, with women and children being more affected, particularly in poorer countries.1 In high-income countries it has a varied aetiology, including iron deficiency, chronic haemorrhage and end-stage renal failure. However, in low- and middle-income countries anaemia is endemic as a result of dietary deficiencies and infection with parasites such as hookworm and malaria. Anaemia per se has no major direct effects on pulmonary function. Arterial Po2 and saturation should remain within the normal range in uncomplicated anaemia, and the crucial effect is on the arterial oxygen content and therefore oxygen delivery. Important compensatory changes are increased cardiac output, greater oxygen extraction from the arterial blood and to a lesser extent the small rightward displacement of the oxyhaemoglobin dissociation curve. However, there are limits to these adaptations, which define the minimal tolerable haemoglobin concentration, and also the exercise limits attainable with various degrees of severity of anaemia. Physiological aspects of blood transfusion and blood substitutes are discussed on page 186.
PULMONARY FUNCTION Gas Exchange Alveolar Po2 is determined by dry barometric pressure, inspired oxygen concentration and the ratio of oxygen consumption to alveolar ventilation (page 131). Assuming that the first two are unchanged, and with good evidence that the latter two factors are unaffected in the resting state by anaemia down to a haemoglobin concentration of at least 50 g.l−1 (see later), then there is no reason why alveolar Po2 or Pco2 should be affected by uncomplicated anaemia down to this level. The increased cardiac output (see later discussion) will cause a small reduction in pulmonary capillary transit time which, together with the reduced mass of haemoglobin in the pulmonary capillaries, causes a modest decrease in diffusing capacity (page 144). However, such is the reserve in the capacity of pulmonary capillary blood to reach equilibrium with the alveolar gas (see Fig. 8.2) that it is highly unlikely that this would have any measurable effect on the alveolar/ end-pulmonary capillary Po2 gradient, which in the normal subject is believed to be negligible. Thus pulmonary end-capillary Po2 should also be normal in anaemia. Continuing down the cascade of oxygen partial pressures from ambient air to the site of use in the tissues, the next step is the gradient in Po2 between pulmonary end-capillary blood and mixed arterial blood. The Po2 gradient at this stage is caused by shunting and the perfusion of relatively underventilated alveoli. There is no evidence that these factors are altered in anaemia, and arterial Po2 should therefore be normal. Because the peripheral chemoreceptors are stimulated by reduction in arterial Po2 and not arterial oxygen content (page 61), then there should be no stimulation of respiration unless the degree of hypoxia is sufficient to cause anaerobic metabolism and lactacidosis.
Haemoglobin Dissociation Curve It is well established that red blood cell 2,3-diphosphoglycerate levels are increased in anaemia (page 183), typical changes being from 335
336
PART 2 Applied Physiology
a normal value of 5 mmol.l−1 to around 7 mmol. l−1 at a haemoglobin concentration of 60 g.l−1. This results in an increase in P50 from 3.6 to 4.0 kPa (27–30 mm Hg). This rightward shift of the dissociation curve would have a negligible effect on arterial saturation, which has indeed been reported to be normal in anaemia. The rightward shift will, however, increase the Po2 at which oxygen is unloaded in the tissues, mitigating to a small extent the effects of reduction in oxygen delivery so far as tissue Po2 is concerned.
Normal values give an oxygen delivery of approximately 1000 ml.min−1, which is about four times the normal resting oxygen consumption of 250 ml.min−1. Extraction of oxygen from the arterial blood is thus 25% and this accords with an arterial saturation of 97% and mixed venous saturation of 72%. If the small quantity of dissolved oxygen (0.3 ml.dl−1) is ignored, then oxygen delivery is seen to be proportional to the product of cardiac output, haemoglobin concentration and arterial oxygen saturation. There is, of course, negligible scope for any compensatory increase in saturation in a patient with uncomplicated anaemia at sea level.
Arterial Oxygen Content Although the arterial oxygen saturation usually remains normal in anaemia, the oxygen content of the arterial blood will be reduced in approximate proportion to the decrease in haemoglobin concentration. Arterial oxygen content can be expressed as follows:
Effect of Anaemia on Cardiac Output Equation (3) shows that, if other factors remain the same, a reduction in haemoglobin concentration will result in a proportionate reduction in oxygen delivery. Thus a haemoglobin con centration of 75 g.l−1, with unchanged cardiac output, would halve delivery to give a resting value of 500 ml.min−1, which would be approaching the likely critical value. However, patients with quite severe anaemia usually show little evidence of hypoxia at rest and, furthermore, achieve surprisingly good levels of exercise. Because arterial saturation cannot be increased, full compensation can be achieved only by a reciprocal relationship between cardiac output and haemoglobin concentration. Thus if haemoglobin concentration is halved, maintenance of normal delivery will require a doubling of cardiac output. Full compensation may not occur, but fortunately a reduction in haemoglobin concentration is usually accompanied by some increase in cardiac output.
CaO2 = ([ Hb ] × SaO2 × 1.39) + 0.3 g.dl −1 % 100 ml.g −1 ml.dl −1 ml.dl −1 e.g. 20 = (14.7 × 0.97 × 1.39) + 0.3 [1] where CaO2 is arterial oxygen content, [Hb] is haemoglobin concentration, SaO2 is arterial oxygen saturation, 1.39 is the combining power of haemoglobin with oxygen (page 179) and 0.3 is dissolved oxygen at normal arterial Po2.
OXYGEN DELIVERY The important concept of oxygen delivery D O 2 is considered in detail on page 192. It is defined and CaO . as the product of cardiac output (Q) 2 D O 2
=
Q
× Ca O 2 ml.min 1.min −1 ml.dl −1 e.g. 1050 = 5.25 × 20 −1
Acute Anaemia
[2]
(the right-hand side is multiplied by a scaling factor of 10 to account for the differing units of volume). Combining Equations (1) and (2): D O2 = Q × {([ Hb ]) × SaO2 × 1.39) + 0.3} ml.min −1 1.min −1 g.dl −1 % 100 ml.g −1 ml.dl −1 e.g. 1050 = 5.25 × {(14.7 × 0.97 × 1.39) + 0.3}
[3]
(the right-hand side is again multiplied by a scaling factor of 10).
Early studies of cardiac output and anaemia involved measurement of cardiovascular parameters in patients before and after treatment for uncomplicated anaemia.2 Cardiac output was significantly greater before the patients’ haemoglobin concentration increased from 59 to 109 g.l−1. There was, however, a negative correlation between age and cardiac index in the anaemic state, reflecting the relative inability of the older patient to compensate. More recent studies have involved deliberately reducing the haemoglobin concentration isovolaemically in volunteers and patients.3-5 One of these studies reduced the haemoglobin concentration from 131 to 50 g.l−1, and the effects of this on the
23 Anaemia
A
D 78
2500
76 2000
Svo2(%)
SVRI (dyne.s.cm–5.m2)
337
1500
74 72 70
1000
40
60
80 100 120 Haemoglobin (g.l–1)
68
140
60
80 100 120 Haemoglobin (g.l–1)
140
40
60
80 100 120 Haemoglobin (g.l–1)
140
E
6
5 Vo2 (ml.kg–1.min–1)
5 4 3
4
3
•
Cardiac index (l.min–1.m–2)
B
40
2
40
60
80 100 120 Haemoglobin (g.l–1)
140
40
60
80 100 120 Haemoglobin (g.l–1)
140
C
2
14
12
•
Do2 (ml.kg–1.min–1)
16
10
FIG. 23.1 ■ Cardiovascular changes in response to acute isovolaemic reduction of mean haemoglobin concentration from 131 to 50 g.l−1 in healthy volunteers. (A) Systemic vascular resistance index (SVRI) falls in direct proportion to hemoglobin (Hb) concentration as blood viscosity decreases; (B) cardiac index doubles when Hb has fallen to 50 g.l−1; (C) oxygen delivery (D O2) remains mostly unchanged until Hb is less than 80 g.l−1; (D) mixed venous oxygen saturation (Sv O2 ) is approximately maintained until Hb is less than 60 g.l−1; (E) oxygen consumption is maintained despite the fall in D O2 by increasing oxygen extraction, hence the fall in Sv O2 . (After reference 4.)
cardiovascular system are shown in Figure 23.1.4 In these healthy volunteers the predictable linear relationship between cardiac index and haemoglobin concentration can easily be seen (Fig. 23.1, B). The increase in cardiac output seen in response to acute anaemia is much less in anaesthetized patients.5 The mechanism underlying the increase in cardiac output is not clear, but results from increases in both stroke volume and heart rate.4 Likely explanations for these changes include
reduced cardiac afterload due to lowered blood viscosity (Fig. 23.1, A) and increased preload due to greater venous return secondary to increased tone in capacitance vessels.6 Chronic Anaemia In one study of isovolaemic reduction of haemoglobin concentration, down to a mean value of 100 g.l−1, the anaemia was then maintained at the same level for 14 days.3 Immediately after
PART 2 Applied Physiology
induction of anaemia there was a marked increase in cardiac output (55%), but this decreased to only 17% above control levels after 14 days.
The Influence of Cardiac Output on Oxygen Delivery After the acute reduction of haemoglobin concentration in healthy subjects,3,4 cardiac output increases sufficiently to maintain near-normal oxygen delivery with moderate anaemia (Hb 100 g.l−1)3 but with more severe acute anaemia (Hb 50 g.l−1) oxygen delivery may not be maintained (Fig. 23.1, C) and mixed venous oxygen saturation falls (Fig. 23.1, D).4 However, in prolonged anaemia (2 weeks), the increase in cardiac output (only 17%) is insufficient to maintain oxygen delivery, which decreases to 27% below control values.3 Similarly, in a study of anaemic patients,2 oxygen delivery was reduced in proportion to the degree of anaemia. Without an increase in cardiac output it is likely that a haemoglobin concentration of 60 to 80 g.l−1 would be a significant physiological challenge. It is clear that the ability of the cardiovascular system to respond to anaemia with an increase in cardiac output is an essential aspect of accommodation to anaemia, and this is less effective in anaesthetized patients, the elderly or other subjects with reduced cardiac reserve. Relationship between Oxygen Delivery and Consumption The relationship between oxygen delivery and consumption has been considered on page 193 et seq. When oxygen delivery is reduced, for whatever reason, oxygen consumption is at first maintained at its normal value, but with increasing oxygen extraction and therefore decreasing mixed venous saturation. Below a ‘critical’ value for oxygen delivery, oxygen consumption decreases as a function of delivery and is usually accompanied by evidence of hypoxia, such as increased lactate in peripheral blood. Values for critical oxygen delivery depend on the pathophysiological state of the patient and vary from one condition to another. It has not been clearly established what is the critical level of oxygen delivery in uncomplicated anaemia in humans. Studies of acutely induced anaemia have found no evidence of reduced oxygen consumption (Fig. 23.1, E) or tissue hypoxia even at a haemoglobin concentration of 50 g.l−1.4 In volunteers maintained at a haemoglobin concentration of 100 g.l−1 for 14 days, oxygen delivery decreased from about 1200 to 900 ml.min−1 whereas oxygen consumption
remained virtually unchanged.3 Similarly, a study of treated anaemic patients found no increase in oxygen consumption when haemoglobin concentration was increased from a mean value of 60 to 110 g.l−1.2 Thus these patients with longterm anaemia seemed to have all remained above the critical value for oxygen delivery down to haemoglobin values of about 60 g.l−1.
ANAEMIA AND EXERCISE Maintenance of constant oxygen consumption in the face of reduced delivery can only be achieved at the expense of a reduction in mixed venous saturation, as a result of increased extraction of oxygen from the arterial blood. This has been clearly demonstrated in both acute (Fig. 23.1, D) and sustained anaemia.3 A reduction in the oxygen content of mixed venous blood curtails the ability of the anaemic patient to encroach on a useful reserve of oxygen, which is an important response to exercise. Reduction of haemoglobin to 100 g.l−1 resulted in a curtailment of oxygen consumption attained at maximal exercise from the control values of 3.01 l.min−1 (normalized to 70 kg body weight) down to 2.53 l.min−1 in the acute stage, and 2.15 l.min−1 after 14 days of sustained anaemia (Fig. 23.2).3 The increase in cardiac output required for the same increase in oxygen consumption was greater in the anaemic state, and cardiac output at maximal oxygen consumption was slightly less than under control conditions. Maximal exercise in the anaemic state resulted in a reduction of mixed venous (23) Maximal exercise (12) –1 ) .l (g 0 –1 ) 0 1 g.l ( b H 53 ia b1 m H e a ol An ntr Co
20 Cardiac output (l.min–1)
338
15
10 (70) 5
(78) Resting 0
1 2 Oxygen consumption (I.min–1) (STPD)
3
FIG. 23.2 ■ Cardiac output as a function of oxygen consumption during rest and maximal exercise under control and isovolaemic anaemic conditions. Numbers in parentheses indicate mean mixed venous oxygen saturation. (Redrawn from reference 3 on the assumption that mean weight of the subjects was 70 kg, by permission of the author, and the editors and publishers of Journal of Applied Physiology.)
23 Anaemia
oxygen saturation to the exceptionally low value of 12%, compared with control values of 23% during maximal exercise with a normal haemoglobin concentration. Brisk walking on level ground normally requires an oxygen consumption of about 1 l.min−1 and a cardiac output of about 10 l.min−1. At a haemoglobin level of 50 g.l−1, this would require a cardiac output of about 20 l.min−1 to permit an oxygen consumption of 1 l.min−1 with a satisfactory residual level of mixed venous oxygen saturation. It will be clear that, at this degree of anaemia, cardiac function is a critical factor determining the mobility of a patient. Exercise tolerance may be limited by either respiratory or circulatory capacity. In uncomplicated anaemia, there is no reason to implicate respiratory limitation, and exercise tolerance is, therefore, to a first approximation, governed by the remaining factors in the oxygen delivery Equation (3). On the assumption that the maximal sustainable cardiac output is only marginally affected by anaemia, it is to be expected that exercise tolerance will be reduced in direct proportion to the haemoglobin concentration. Available evidence supports this hypothesis (Fig. 23.3). Using Haemoglobin to Enhance Athletic Performance The corollary of the preceding description is the question of improving athletic performance by increasing haemoglobin concentration above the normal range. This used to be achieved by removal of blood for replacement of red cells
Harvard step test score
80 70
High average
60
Low average
50
Poor
40 30 20 10 0
0
50 100 Haemoglobin (g.l–1)
150
FIG. 23.3 ■ Relationship between capacity for exercise and haemoglobin concentration. (After reference 7 by permission of the authors, and the editor and publishers of Clinics in Haematology.)
339
after a few weeks when the subject has already partially restored his haemoglobin concentration, a procedure known as blood doping. The same effect is now much more conveniently achieved by the administration of erythropoietin. Studies of trained athletes in this area are notoriously difficult, and it is easy to confuse the effects of changes in blood volume and haemoglobin concentration. However, the strategy is effective. For example, in a well-controlled study of highly trained runners,8 in which a mean haemoglobin concentration of 167 g.l−1 was attained, there were significant increases in maximal oxygen uptake from 4.85 to 5.10 l.min−1.
WHAT IS THE OPTIMAL HAEMOGLOBIN CONCENTRATION IN THE CLINICAL SETTING?9,10 Evolution has resulted in a haemoglobin concentration of 130 to 160 g.l−1 presumably for sound biological reasons, and this value must represent the best compromise between oxygen carriage, cardiac output and blood viscosity. For many years a haemoglobin concentration of over 100 g.l−1 was regarded as acceptable. At this level, cardiac output increases are modest and though exercise tolerance may be reduced this is unlikely to trouble the patient. There is evidence that much lower values will be acceptable in some circumstances. Jehovah’s Witnesses, whose religious beliefs prevent them from consenting to blood transfusion, frequently undergo major surgery and survival is reported following haemoglobin values of less than 30 g.l−1, albeit with substantial cardiovascular and respiratory support. Studies of these patients11 indicate that perioperative death is uncommon if haemoglobin concentration remains greater than 50 g.l−1. There is also a suggestion that low haemoglobin values may actually be beneficial, with lowered blood viscosity improving blood flow through diseased vessels and so increasing tissue oxygenation, though the role of this effect in patients is unknown. However, blood transfusion has always been, and currently remains, a hazardous and financially costly procedure,9 so in recent years there have been many studies addressing the haemoglobin level below which a blood transfusion should be used, the transfusion trigger (TT). The studies compared restrictive TTs (70–90 g.l−1) with liberal TTs (100–120 g.l−1) and found the restrictive strategies to be at least equivalent, if not better, than liberal ones in a variety of clinical settings including intensive care, cardiothoracic and orthopaedic surgery
340
PART 2 Applied Physiology
and gastrointestinal haemorrhage. Transfusion trigger values recommended by a variety of expert bodies worldwide are now all in the range of 60 to 80 g.l−1, though these may not be applicable to patients with ischaemic heart disease, and higher values are needed if there is clinical evidence of inadequate tissue oxygenation.9 The organ that limits the acceptable degree of anaemia is inevitably the heart, where oxygen extraction is normally in excess of 50%. Increased oxygen extraction as a compensatory mechanism is therefore limited, and coronary blood flow must increase to facilitate the greater oxygen requirement of a raised cardiac output. Thus any patient with impaired coronary blood supply will be considerably less tolerant of anaemia than those with normal coronary arteries, as recognized in the previous recommendations. Chronic renal failure leads to a lack of renal erythropoietin release and severe symptomatic anaemia results, with patients commonly having haemoglobin levels of less than 80 g.dl−1. The availability of erythropoiesis-stimulating agents12 has allowed partial correction of anaemia in many patients, leading to a substantial improvement in quality of life for most. There is, however, debate about the optimal target haemoglobin concentration.13 There is good evidence that the chronic severe anaemia associated with renal disease commonly leads to cardiac complications. Unfortunately, there is also some evidence that correction of haemoglobin to normal values is associated with increased cardiac complications in these patients, and a
value of around 115 g.l−1 seems to be the safest compromise.12,13 REFERENCES 1. Balarajan Y, Ramakrishnan U, Özaltin E, et al. Anaemia in low-income and middle-income countries. Lancet. 2011;378:2123-2135. 2. Duke M, Abelmann WH. The hemodynamic response to chronic anemia. Circulation. 1969;39:503-515. 3. Woodson RD, Wills RE, Lenfant C. Effect of acute and established anemia on O2 transport at rest, submaximal and maximal work. J Appl Physiol. 1978;44:36-43. 4. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998;279:217-221. 5. Ickx BE, Rigolet M, Van der Linden PJ. Cardiovascular and metabolic response to acute normovolemic anemia. Anesthesiology. 2000;93:1011-1016. 6. Chapler CK, Cain SM. The physiologic reserve in oxygen carrying capacity: studies in experimental haemodilution. Can J Physiol Pharmacol. 1986;64:7-12. 7. Viteri FE, Torun B. Anaemia and physical work capacity. Clin Hematol. 1974;3:609-626. 8. Buick FJ, Gledhill N, Froese AB, et al. Effect of induced erythrocythemia on aerobic work capacity. J Appl Physiol. 1980;48:636-642. 9. Goodnough LT, Murphy M. Do liberal blood transfusions cause more harm than good? BMJ. 2014;349:g6897. 10. Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet. 2013;381: 1845-1854. 11. Viele MK, Weiskopf RB. What can we learn about the need for transfusion from patients who refuse blood? The experience with Jehovah’s Witnesses. Transfusion. 1994;34:396-401. 12. Drüeke TB. Anemia treatment in patients with chronic kidney disease. N Engl J Med. 2013;368:387-389. 13. Phrommintikul A, Haas SJ, Elsik M, et al. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369:381-388.
CHAPTER 23 ANAEMIA • Anaemia has no effect on pulmonary function but significantly affects oxygen delivery to the tissues. Increased cardiac output in response to anaemia decreases the transit time of red blood cells through the pulmonary capillary, but this does not impede their oxygenation. • Red blood cell 2,3-diphosphoglycerate concentration is increased in anaemia, causing a right shift of the oxyhaemoglobin dissociation curve which facilitates unloading of oxygen in the tissues. • Arterial oxygen content is reduced in proportion to the reduced haemoglobin level. Cardiac output therefore increases, probably in response to reduced afterload from the lower blood viscosity. Above haemoglobin values of 100 g.l−1 these two physiological changes are approximately balanced, and oxygen delivery is maintained. Below this level, oxygen delivery begins to fall, and
23 Anaemia 340.e1
oxygen extraction must increase to maintain tissue oxygenation. Oxygen consumption therefore remains unchanged until anaemia is very severe. Elderly patients, or any patients with heart disease, cannot mount a suitably robust increase in cardiac output to compensate, and so have more clinical manifestations of anaemia. Exercise tolerance is greatly reduced by anaemia because of a limited ability to further increase cardiac output to deliver the required extra oxygen. • The optimal haemoglobin concentration to maintain in clinical practice is controversial. There are considerable costs and complications of using blood transfusions, and recent studies in intensive care, some forms of surgery and with gastrointestinal haemorrhage suggest that blood transfusions should not be used until haemoglobin values are in the range of 60 to 80 g.l−1. Patients with signs of inadequate tissue oxygenation or with ischaemic heart disease may need a haemoglobin level higher than 80 g.l−1.
Anaemia KEY POINTS ■ Anaemia has little effect on pulmonary gas exchange but decreases oxygen carriage in the arterial blood in direct proportion to the reduction in haemoglobin concentration. ■ Mechanisms that compensate for the reduced oxygen delivery include increased cardiac output, increased tissue oxygen extraction and a right shift of the oxyhaemoglobin dissociation curve. ■ Older patients or those with poor cardiac reserve compensate less well when anaemic.
Anaemia is a widespread pathophysiological disorder that interferes with oxygen transport to the tissues. A quarter of the world’s population are anaemic, with women and children being more affected, particularly in poorer countries.1 In high-income countries it has a varied aetiology, including iron deficiency, chronic haemorrhage and end-stage renal failure. However, in low- and middle-income countries anaemia is endemic as a result of dietary deficiencies and infection with parasites such as hookworm and malaria. Anaemia per se has no major direct effects on pulmonary function. Arterial Po2 and saturation should remain within the normal range in uncomplicated anaemia, and the crucial effect is on the arterial oxygen content and therefore oxygen delivery. Important compensatory changes are increased cardiac output, greater oxygen extraction from the arterial blood and to a lesser extent the small rightward displacement of the oxyhaemoglobin dissociation curve. However, there are limits to these adaptations, which define the minimal tolerable haemoglobin concentration, and also the exercise limits attainable with various degrees of severity of anaemia. Physiological aspects of blood transfusion and blood substitutes are discussed on page 186.
PULMONARY FUNCTION Gas Exchange Alveolar Po2 is determined by dry barometric pressure, inspired oxygen concentration and the ratio of oxygen consumption to alveolar ventilation (page 131). Assuming that the first two are unchanged, and with good evidence that the latter two factors are unaffected in the resting state by anaemia down to a haemoglobin concentration of at least 50 g.l−1 (see later), then there is no reason why alveolar Po2 or Pco2 should be affected by uncomplicated anaemia down to this level. The increased cardiac output (see later discussion) will cause a small reduction in pulmonary capillary transit time which, together with the reduced mass of haemoglobin in the pulmonary capillaries, causes a modest decrease in diffusing capacity (page 144). However, such is the reserve in the capacity of pulmonary capillary blood to reach equilibrium with the alveolar gas (see Fig. 8.2) that it is highly unlikely that this would have any measurable effect on the alveolar/ end-pulmonary capillary Po2 gradient, which in the normal subject is believed to be negligible. Thus pulmonary end-capillary Po2 should also be normal in anaemia. Continuing down the cascade of oxygen partial pressures from ambient air to the site of use in the tissues, the next step is the gradient in Po2 between pulmonary end-capillary blood and mixed arterial blood. The Po2 gradient at this stage is caused by shunting and the perfusion of relatively underventilated alveoli. There is no evidence that these factors are altered in anaemia, and arterial Po2 should therefore be normal. Because the peripheral chemoreceptors are stimulated by reduction in arterial Po2 and not arterial oxygen content (page 61), then there should be no stimulation of respiration unless the degree of hypoxia is sufficient to cause anaerobic metabolism and lactacidosis.
Haemoglobin Dissociation Curve It is well established that red blood cell 2,3-diphosphoglycerate levels are increased in anaemia (page 183), typical changes being from 335
336
PART 2 Applied Physiology
a normal value of 5 mmol.l−1 to around 7 mmol. l−1 at a haemoglobin concentration of 60 g.l−1. This results in an increase in P50 from 3.6 to 4.0 kPa (27–30 mm Hg). This rightward shift of the dissociation curve would have a negligible effect on arterial saturation, which has indeed been reported to be normal in anaemia. The rightward shift will, however, increase the Po2 at which oxygen is unloaded in the tissues, mitigating to a small extent the effects of reduction in oxygen delivery so far as tissue Po2 is concerned.
Normal values give an oxygen delivery of approximately 1000 ml.min−1, which is about four times the normal resting oxygen consumption of 250 ml.min−1. Extraction of oxygen from the arterial blood is thus 25% and this accords with an arterial saturation of 97% and mixed venous saturation of 72%. If the small quantity of dissolved oxygen (0.3 ml.dl−1) is ignored, then oxygen delivery is seen to be proportional to the product of cardiac output, haemoglobin concentration and arterial oxygen saturation. There is, of course, negligible scope for any compensatory increase in saturation in a patient with uncomplicated anaemia at sea level.
Arterial Oxygen Content Although the arterial oxygen saturation usually remains normal in anaemia, the oxygen content of the arterial blood will be reduced in approximate proportion to the decrease in haemoglobin concentration. Arterial oxygen content can be expressed as follows:
Effect of Anaemia on Cardiac Output Equation (3) shows that, if other factors remain the same, a reduction in haemoglobin concentration will result in a proportionate reduction in oxygen delivery. Thus a haemoglobin con centration of 75 g.l−1, with unchanged cardiac output, would halve delivery to give a resting value of 500 ml.min−1, which would be approaching the likely critical value. However, patients with quite severe anaemia usually show little evidence of hypoxia at rest and, furthermore, achieve surprisingly good levels of exercise. Because arterial saturation cannot be increased, full compensation can be achieved only by a reciprocal relationship between cardiac output and haemoglobin concentration. Thus if haemoglobin concentration is halved, maintenance of normal delivery will require a doubling of cardiac output. Full compensation may not occur, but fortunately a reduction in haemoglobin concentration is usually accompanied by some increase in cardiac output.
CaO2 = ([ Hb ] × SaO2 × 1.39) + 0.3 g.dl −1 % 100 ml.g −1 ml.dl −1 ml.dl −1 e.g. 20 = (14.7 × 0.97 × 1.39) + 0.3 [1] where CaO2 is arterial oxygen content, [Hb] is haemoglobin concentration, SaO2 is arterial oxygen saturation, 1.39 is the combining power of haemoglobin with oxygen (page 179) and 0.3 is dissolved oxygen at normal arterial Po2.
OXYGEN DELIVERY The important concept of oxygen delivery D O 2 is considered in detail on page 192. It is defined and CaO . as the product of cardiac output (Q) 2 D O 2
=
Q
× Ca O 2 ml.min 1.min −1 ml.dl −1 e.g. 1050 = 5.25 × 20 −1
Acute Anaemia
[2]
(the right-hand side is multiplied by a scaling factor of 10 to account for the differing units of volume). Combining Equations (1) and (2): D O2 = Q × {([ Hb ]) × SaO2 × 1.39) + 0.3} ml.min −1 1.min −1 g.dl −1 % 100 ml.g −1 ml.dl −1 e.g. 1050 = 5.25 × {(14.7 × 0.97 × 1.39) + 0.3}
[3]
(the right-hand side is again multiplied by a scaling factor of 10).
Early studies of cardiac output and anaemia involved measurement of cardiovascular parameters in patients before and after treatment for uncomplicated anaemia.2 Cardiac output was significantly greater before the patients’ haemoglobin concentration increased from 59 to 109 g.l−1. There was, however, a negative correlation between age and cardiac index in the anaemic state, reflecting the relative inability of the older patient to compensate. More recent studies have involved deliberately reducing the haemoglobin concentration isovolaemically in volunteers and patients.3-5 One of these studies reduced the haemoglobin concentration from 131 to 50 g.l−1, and the effects of this on the
23 Anaemia
A
D 78
2500
76 2000
Svo2(%)
SVRI (dyne.s.cm–5.m2)
337
1500
74 72 70
1000
40
60
80 100 120 Haemoglobin (g.l–1)
68
140
60
80 100 120 Haemoglobin (g.l–1)
140
40
60
80 100 120 Haemoglobin (g.l–1)
140
E
6
5 Vo2 (ml.kg–1.min–1)
5 4 3
4
3
•
Cardiac index (l.min–1.m–2)
B
40
2
40
60
80 100 120 Haemoglobin (g.l–1)
140
40
60
80 100 120 Haemoglobin (g.l–1)
140
C
2
14
12
•
Do2 (ml.kg–1.min–1)
16
10
FIG. 23.1 ■ Cardiovascular changes in response to acute isovolaemic reduction of mean haemoglobin concentration from 131 to 50 g.l−1 in healthy volunteers. (A) Systemic vascular resistance index (SVRI) falls in direct proportion to hemoglobin (Hb) concentration as blood viscosity decreases; (B) cardiac index doubles when Hb has fallen to 50 g.l−1; (C) oxygen delivery (D O2) remains mostly unchanged until Hb is less than 80 g.l−1; (D) mixed venous oxygen saturation (Sv O2 ) is approximately maintained until Hb is less than 60 g.l−1; (E) oxygen consumption is maintained despite the fall in D O2 by increasing oxygen extraction, hence the fall in Sv O2 . (After reference 4.)
cardiovascular system are shown in Figure 23.1.4 In these healthy volunteers the predictable linear relationship between cardiac index and haemoglobin concentration can easily be seen (Fig. 23.1, B). The increase in cardiac output seen in response to acute anaemia is much less in anaesthetized patients.5 The mechanism underlying the increase in cardiac output is not clear, but results from increases in both stroke volume and heart rate.4 Likely explanations for these changes include
reduced cardiac afterload due to lowered blood viscosity (Fig. 23.1, A) and increased preload due to greater venous return secondary to increased tone in capacitance vessels.6 Chronic Anaemia In one study of isovolaemic reduction of haemoglobin concentration, down to a mean value of 100 g.l−1, the anaemia was then maintained at the same level for 14 days.3 Immediately after
PART 2 Applied Physiology
induction of anaemia there was a marked increase in cardiac output (55%), but this decreased to only 17% above control levels after 14 days.
The Influence of Cardiac Output on Oxygen Delivery After the acute reduction of haemoglobin concentration in healthy subjects,3,4 cardiac output increases sufficiently to maintain near-normal oxygen delivery with moderate anaemia (Hb 100 g.l−1)3 but with more severe acute anaemia (Hb 50 g.l−1) oxygen delivery may not be maintained (Fig. 23.1, C) and mixed venous oxygen saturation falls (Fig. 23.1, D).4 However, in prolonged anaemia (2 weeks), the increase in cardiac output (only 17%) is insufficient to maintain oxygen delivery, which decreases to 27% below control values.3 Similarly, in a study of anaemic patients,2 oxygen delivery was reduced in proportion to the degree of anaemia. Without an increase in cardiac output it is likely that a haemoglobin concentration of 60 to 80 g.l−1 would be a significant physiological challenge. It is clear that the ability of the cardiovascular system to respond to anaemia with an increase in cardiac output is an essential aspect of accommodation to anaemia, and this is less effective in anaesthetized patients, the elderly or other subjects with reduced cardiac reserve. Relationship between Oxygen Delivery and Consumption The relationship between oxygen delivery and consumption has been considered on page 193 et seq. When oxygen delivery is reduced, for whatever reason, oxygen consumption is at first maintained at its normal value, but with increasing oxygen extraction and therefore decreasing mixed venous saturation. Below a ‘critical’ value for oxygen delivery, oxygen consumption decreases as a function of delivery and is usually accompanied by evidence of hypoxia, such as increased lactate in peripheral blood. Values for critical oxygen delivery depend on the pathophysiological state of the patient and vary from one condition to another. It has not been clearly established what is the critical level of oxygen delivery in uncomplicated anaemia in humans. Studies of acutely induced anaemia have found no evidence of reduced oxygen consumption (Fig. 23.1, E) or tissue hypoxia even at a haemoglobin concentration of 50 g.l−1.4 In volunteers maintained at a haemoglobin concentration of 100 g.l−1 for 14 days, oxygen delivery decreased from about 1200 to 900 ml.min−1 whereas oxygen consumption
remained virtually unchanged.3 Similarly, a study of treated anaemic patients found no increase in oxygen consumption when haemoglobin concentration was increased from a mean value of 60 to 110 g.l−1.2 Thus these patients with longterm anaemia seemed to have all remained above the critical value for oxygen delivery down to haemoglobin values of about 60 g.l−1.
ANAEMIA AND EXERCISE Maintenance of constant oxygen consumption in the face of reduced delivery can only be achieved at the expense of a reduction in mixed venous saturation, as a result of increased extraction of oxygen from the arterial blood. This has been clearly demonstrated in both acute (Fig. 23.1, D) and sustained anaemia.3 A reduction in the oxygen content of mixed venous blood curtails the ability of the anaemic patient to encroach on a useful reserve of oxygen, which is an important response to exercise. Reduction of haemoglobin to 100 g.l−1 resulted in a curtailment of oxygen consumption attained at maximal exercise from the control values of 3.01 l.min−1 (normalized to 70 kg body weight) down to 2.53 l.min−1 in the acute stage, and 2.15 l.min−1 after 14 days of sustained anaemia (Fig. 23.2).3 The increase in cardiac output required for the same increase in oxygen consumption was greater in the anaemic state, and cardiac output at maximal oxygen consumption was slightly less than under control conditions. Maximal exercise in the anaemic state resulted in a reduction of mixed venous (23) Maximal exercise (12) –1 ) .l (g 0 –1 ) 0 1 g.l ( b H 53 ia b1 m H e a ol An ntr Co
20 Cardiac output (l.min–1)
338
15
10 (70) 5
(78) Resting 0
1 2 Oxygen consumption (I.min–1) (STPD)
3
FIG. 23.2 ■ Cardiac output as a function of oxygen consumption during rest and maximal exercise under control and isovolaemic anaemic conditions. Numbers in parentheses indicate mean mixed venous oxygen saturation. (Redrawn from reference 3 on the assumption that mean weight of the subjects was 70 kg, by permission of the author, and the editors and publishers of Journal of Applied Physiology.)
23 Anaemia
oxygen saturation to the exceptionally low value of 12%, compared with control values of 23% during maximal exercise with a normal haemoglobin concentration. Brisk walking on level ground normally requires an oxygen consumption of about 1 l.min−1 and a cardiac output of about 10 l.min−1. At a haemoglobin level of 50 g.l−1, this would require a cardiac output of about 20 l.min−1 to permit an oxygen consumption of 1 l.min−1 with a satisfactory residual level of mixed venous oxygen saturation. It will be clear that, at this degree of anaemia, cardiac function is a critical factor determining the mobility of a patient. Exercise tolerance may be limited by either respiratory or circulatory capacity. In uncomplicated anaemia, there is no reason to implicate respiratory limitation, and exercise tolerance is, therefore, to a first approximation, governed by the remaining factors in the oxygen delivery Equation (3). On the assumption that the maximal sustainable cardiac output is only marginally affected by anaemia, it is to be expected that exercise tolerance will be reduced in direct proportion to the haemoglobin concentration. Available evidence supports this hypothesis (Fig. 23.3). Using Haemoglobin to Enhance Athletic Performance The corollary of the preceding description is the question of improving athletic performance by increasing haemoglobin concentration above the normal range. This used to be achieved by removal of blood for replacement of red cells
Harvard step test score
80 70
High average
60
Low average
50
Poor
40 30 20 10 0
0
50 100 Haemoglobin (g.l–1)
150
FIG. 23.3 ■ Relationship between capacity for exercise and haemoglobin concentration. (After reference 7 by permission of the authors, and the editor and publishers of Clinics in Haematology.)
339
after a few weeks when the subject has already partially restored his haemoglobin concentration, a procedure known as blood doping. The same effect is now much more conveniently achieved by the administration of erythropoietin. Studies of trained athletes in this area are notoriously difficult, and it is easy to confuse the effects of changes in blood volume and haemoglobin concentration. However, the strategy is effective. For example, in a well-controlled study of highly trained runners,8 in which a mean haemoglobin concentration of 167 g.l−1 was attained, there were significant increases in maximal oxygen uptake from 4.85 to 5.10 l.min−1.
WHAT IS THE OPTIMAL HAEMOGLOBIN CONCENTRATION IN THE CLINICAL SETTING?9,10 Evolution has resulted in a haemoglobin concentration of 130 to 160 g.l−1 presumably for sound biological reasons, and this value must represent the best compromise between oxygen carriage, cardiac output and blood viscosity. For many years a haemoglobin concentration of over 100 g.l−1 was regarded as acceptable. At this level, cardiac output increases are modest and though exercise tolerance may be reduced this is unlikely to trouble the patient. There is evidence that much lower values will be acceptable in some circumstances. Jehovah’s Witnesses, whose religious beliefs prevent them from consenting to blood transfusion, frequently undergo major surgery and survival is reported following haemoglobin values of less than 30 g.l−1, albeit with substantial cardiovascular and respiratory support. Studies of these patients11 indicate that perioperative death is uncommon if haemoglobin concentration remains greater than 50 g.l−1. There is also a suggestion that low haemoglobin values may actually be beneficial, with lowered blood viscosity improving blood flow through diseased vessels and so increasing tissue oxygenation, though the role of this effect in patients is unknown. However, blood transfusion has always been, and currently remains, a hazardous and financially costly procedure,9 so in recent years there have been many studies addressing the haemoglobin level below which a blood transfusion should be used, the transfusion trigger (TT). The studies compared restrictive TTs (70–90 g.l−1) with liberal TTs (100–120 g.l−1) and found the restrictive strategies to be at least equivalent, if not better, than liberal ones in a variety of clinical settings including intensive care, cardiothoracic and orthopaedic surgery
340
PART 2 Applied Physiology
and gastrointestinal haemorrhage. Transfusion trigger values recommended by a variety of expert bodies worldwide are now all in the range of 60 to 80 g.l−1, though these may not be applicable to patients with ischaemic heart disease, and higher values are needed if there is clinical evidence of inadequate tissue oxygenation.9 The organ that limits the acceptable degree of anaemia is inevitably the heart, where oxygen extraction is normally in excess of 50%. Increased oxygen extraction as a compensatory mechanism is therefore limited, and coronary blood flow must increase to facilitate the greater oxygen requirement of a raised cardiac output. Thus any patient with impaired coronary blood supply will be considerably less tolerant of anaemia than those with normal coronary arteries, as recognized in the previous recommendations. Chronic renal failure leads to a lack of renal erythropoietin release and severe symptomatic anaemia results, with patients commonly having haemoglobin levels of less than 80 g.dl−1. The availability of erythropoiesis-stimulating agents12 has allowed partial correction of anaemia in many patients, leading to a substantial improvement in quality of life for most. There is, however, debate about the optimal target haemoglobin concentration.13 There is good evidence that the chronic severe anaemia associated with renal disease commonly leads to cardiac complications. Unfortunately, there is also some evidence that correction of haemoglobin to normal values is associated with increased cardiac complications in these patients, and a
value of around 115 g.l−1 seems to be the safest compromise.12,13 REFERENCES 1. Balarajan Y, Ramakrishnan U, Özaltin E, et al. Anaemia in low-income and middle-income countries. Lancet. 2011;378:2123-2135. 2. Duke M, Abelmann WH. The hemodynamic response to chronic anemia. Circulation. 1969;39:503-515. 3. Woodson RD, Wills RE, Lenfant C. Effect of acute and established anemia on O2 transport at rest, submaximal and maximal work. J Appl Physiol. 1978;44:36-43. 4. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998;279:217-221. 5. Ickx BE, Rigolet M, Van der Linden PJ. Cardiovascular and metabolic response to acute normovolemic anemia. Anesthesiology. 2000;93:1011-1016. 6. Chapler CK, Cain SM. The physiologic reserve in oxygen carrying capacity: studies in experimental haemodilution. Can J Physiol Pharmacol. 1986;64:7-12. 7. Viteri FE, Torun B. Anaemia and physical work capacity. Clin Hematol. 1974;3:609-626. 8. Buick FJ, Gledhill N, Froese AB, et al. Effect of induced erythrocythemia on aerobic work capacity. J Appl Physiol. 1980;48:636-642. 9. Goodnough LT, Murphy M. Do liberal blood transfusions cause more harm than good? BMJ. 2014;349:g6897. 10. Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet. 2013;381: 1845-1854. 11. Viele MK, Weiskopf RB. What can we learn about the need for transfusion from patients who refuse blood? The experience with Jehovah’s Witnesses. Transfusion. 1994;34:396-401. 12. Drüeke TB. Anemia treatment in patients with chronic kidney disease. N Engl J Med. 2013;368:387-389. 13. Phrommintikul A, Haas SJ, Elsik M, et al. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369:381-388.
CHAPTER 23 ANAEMIA • Anaemia has no effect on pulmonary function but significantly affects oxygen delivery to the tissues. Increased cardiac output in response to anaemia decreases the transit time of red blood cells through the pulmonary capillary, but this does not impede their oxygenation. • Red blood cell 2,3-diphosphoglycerate concentration is increased in anaemia, causing a right shift of the oxyhaemoglobin dissociation curve which facilitates unloading of oxygen in the tissues. • Arterial oxygen content is reduced in proportion to the reduced haemoglobin level. Cardiac output therefore increases, probably in response to reduced afterload from the lower blood viscosity. Above haemoglobin values of 100 g.l−1 these two physiological changes are approximately balanced, and oxygen delivery is maintained. Below this level, oxygen delivery begins to fall, and
23 Anaemia 340.e1
oxygen extraction must increase to maintain tissue oxygenation. Oxygen consumption therefore remains unchanged until anaemia is very severe. Elderly patients, or any patients with heart disease, cannot mount a suitably robust increase in cardiac output to compensate, and so have more clinical manifestations of anaemia. Exercise tolerance is greatly reduced by anaemia because of a limited ability to further increase cardiac output to deliver the required extra oxygen. • The optimal haemoglobin concentration to maintain in clinical practice is controversial. There are considerable costs and complications of using blood transfusions, and recent studies in intensive care, some forms of surgery and with gastrointestinal haemorrhage suggest that blood transfusions should not be used until haemoglobin values are in the range of 60 to 80 g.l−1. Patients with signs of inadequate tissue oxygenation or with ischaemic heart disease may need a haemoglobin level higher than 80 g.l−1.