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Haemoglobin concentration and mass as determinants of exercise performance and of surgical outcome
Extreme Physiology & Medicinevolume 2, Article number: 33 (2013)
The ability of the cardiorespiratory system (heart, lungs, blood) to deliver oxygento exercising skeletal muscle constrains maximum oxygen consumption,with cardiac output and the concentration of oxygen-carrying haemoglobin ([Hb]) beingkey limiting parameters. Total blood volume (BV) is the sum of the plasma volume (PV)and the total red cell volume. The measured [Hb] is dependent upon the totalcirculating mass of haemoglobin (tHb-mass) and plasma volume (PV). While theproportion of oxygen carried in plasma is trivial (0.3 mL of oxygen per100 mL of plasma), each gram of Hb, contained in red blood cells, binds1.39 mL of oxygen. As a result, the relationship between and tHb-mass is stronger than that observed between and [Hb] or BV. The glycoprotein hormone erythropoietin drives red cell synthesisand, like simple transfusion of packed red blood cells, can increase tHb-mass. Aniron-containing haem group lies at the centre of the Hb molecule and, in situationsof actual or functional iron deficiency, tHb-mass will also rise following ironadministration. However achieved, an increase in tHb-mass also increases circulatingoxygen-carrying capacity, and thus the capacity for aerobic phosphorylation. It isfor such reasons that alterations in and exercise performance are proportional to those in arterial oxygen content andsystemic oxygen transport, a change in tHb-mass of 1 g being associated with a4 mL · min−1 change in.Similarly, increases by approximately 1% for each3 g · L−1 increase in [Hb] over the [Hb]range (120 to 170 g · L−1). Surgery, likeexercise, places substantial metabolic demands on the patient. Whilst subject todebate, oxygen supply at a rate inadequate to prevent muscle anaerobiosis mayunderpin the occurrence of the anaerobic threshold (AT), an important submaximalmarker of cardiorespiratory fitness. Preoperatively, cardiopulmonary exercise testing(CPET) can be used to determine AT and peak exertional oxygen uptake( peak) asmeasures of ability to meet increasing oxygen demands. The degree of surgical insultand the ability to meet the resulting additional postoperative oxygen demand appearto be fundamental determinants of surgical outcome: individuals in whom such abilityis impaired (and thus those with reduced peakand AT) are at greater risk of adverse surgical outcome. This review provides anoverview of the relationships between [Hb], tHb-mass, exercise capacity, and surgicaloutcome and discusses the potential value of assessing tHb-mass over [Hb].
Oxygen (O2) must be transported effectively from the atmosphere to thetissues in order to maintain essential metabolic pathways . The heart, vasculature, and blood function to deliver asufficient supply of O2, as well as metabolic substrate, to the tissues toallow effective resynthesis of adenosine triphosphate (ATP) via the electrontransport chain (ETC.) . Importantly,O2 is the final step in this process acting as the final electronacceptor in the ETC. . Without adequateO2 transfer from the blood to the mitochondria, energy-generatingmechanisms within the mitochondria would come to a halt . At sites with insufficient O2 flow, anaerobicglycolytic metabolism complements ongoing aerobic ATP production, leading to agreater amount of lactic acid .
It is generally accepted that the physiological limits of the Fick equation determinethe maximal rate at which O2 can be transported from the environment tothe mitochondria and utilised to support oxidative phosphorylation, termed themaximal oxygen uptake . This is highlighted in endurance-trained athletes,where O2 transport is the most important limiting factor of,while mitochondrial O2 consumption also limits in untrained individuals .is attained by the simultaneous increase in (SV × HR) and CaO2-CvO2, where is thecardiac output (determined by the stroke volume (SV) and the heart rate (HR)) andCaO2-CvO2 is the arteriovenous oxygen content difference.The ability to increase CaO2-CvO2 depends primarily on thearterial O2 content and haemoglobin concentration [Hb] .
Haemoglobin is an iron-containing globular protein pigment molecule carried withinred blood cells (RBCs) . Haemoglobincarries almost all of the O2 in the blood, with a trivial amount dissolvedin plasma (0.3 mL O2 per 100 mL of plasma) . When fully saturated, assuming a normal [Hb] (e.g.14 g · dL−1 in men) and a constant oxygencapacity of haemoglobin (1.39 mL · g−1),haemoglobin carries nearly 20 mL of O2 per 100 mL of whole blood.
Total haemoglobin mass (tHb-mass) represents the absolute mass of circulatinghaemoglobin in the body, and can now be quickly, safely, cheaply, and reliablymeasured using the optimised carbon monoxide (CO) re-breathing method refined bySchmidt and Prommer . Total blood volume(BV) is the sum of plasma volume (PV) and total red cell volume. The measured [Hb] isdependent upon the total circulating mass of haemoglobin (tHb-mass) and plasma volume(PV). However, the proportion of oxygen carried in plasma is trivial, whilst eachgram of Hb binds 1.39 mL of oxygen. Thus, tHb-mass largely determines bloodO2-carrying capacity. In addition, however, tHb-mass can increase BVvia its impact on erythrocyte volume . Ahigh BV is essential for achieving a high as observed in enduranceathletes [11, 12]. Thus,tHb-mass may be a more sensitive marker of blood O2 carrying capacity thanusing [Hb], and has additional influences (e.g. via impacts on BV) on physicalperformance than [Hb].
This review provides an overview of the relationships between [Hb], tHb-mass,exercise capacity, and surgical outcome, and discusses the potential value ofassessing tHb-mass over [Hb].
Manipulation of haemoglobin concentration and physical performance
The link between the O2-carrying capacity of the blood and indices ofexercise capacity such as has a long history. This section will focus on the effects of elevating and reducing[Hb] on markers of cardiorespiratory fitness.
Elevation of haemoglobin concentration and maximal oxygen consumption
rises when systemic [Hb] is increased by RBC infusion [13–21](Figure 1). and/or exercise endurance have also been shown to increase in circumstances where[Hb] has been elevated by the administration of recombinant human erythropoietin(rhEPO) to healthy individuals [22, 23], athletes [23, 24], haemodialysis patients [25, 26], and patients withheart failure [27, 28], or through the increased Hb synthesis followingadministration of iron supplements .Studies that have failed to find such a relationship between [Hb] and exercisecapacity  may in part be explained by(i) a small quantity of blood being reinfused, (ii) insufficient time for the bodyto adapt its normal [Hb] post venesection, and (iii) inadequate storage of theRBCs . When these factors areappropriately controlled for, elevating [Hb] is shown to increaseand endurance performance . Gledhilland colleagues [31, 32] have postulated that increases by approximately 1% for each3 g · L−1 [Hb] over the [Hb] range (120to 170 g · L−1).
Reduction of haemoglobin concentration and maximal oxygen consumption
Early work by Ekblom and colleagues demonstrated, in four participants, that a 13% reduction in [Hb] (by venesectionof 800 mL of blood) lowered by 10% (from 4.54 to 4.09 L · min−1) with agreater effect on endurance time observed (reduced by 30% from 5.77 to4.04 min). In the same study, an additional four participants underwentsequential venesection of 400, 800, and 1,200 mL of whole blood (at 4-dayintervals) that resulted in a reduction in [Hb] of 10%, 15%, and 18%,respectively. These reductions were mirrored by a stepwise impairment in(6%, 10%, and 16% reduction) and endurance times (13%, 21%, and 30%reduction).
Similar findings have been shown by a number of different authors including Balkeet al. (9% decrease in 1 h after a 500-mL venesection) ,Woodson and colleagues (16% decline in after 34% reduction of [Hb]) ,Kanstrup and Ekblom (9% reduction in and 40% lower endurance time at the intensity eliciting after reducing [Hb] by 11% through the removal of 900 mL blood) and to a lesser extent byRowell et al. (4% decrease in following a 14% decrease in circulating [Hb] after repeated phlebotomies totaling700–1,000 mL over 5 days) .
Change in haemoglobin concentration and anaerobic threshold
Compared to peak or ,less is known about the impact of changes in [Hb] on submaximal markers ofcardiorespiratory fitness such as the AT. The AT represents the highest(or running speed, power output) that can be performed without developing asustained lactic acidosis .
Fritsch and colleagues  reported CPETin 16 young healthy participants before and 2 days after a 450-mL venesectionthat resulted in [Hb] being reduced from 14.5 to13.0 g · dL−1 (not classified as anaemicif using the World Health Organisation recommendations ). The AT was reduced following venesection whenexpressed as a percentage of (pre 68.5% versus post 52%) and as an absolute . Ourlaboratory  has shown an independentassociation between preoperative [Hb] and AT after adjustingvalues for known confounders (age, sex, testing site, operation category,diabetes, creatinine) and performing allometric scaling to remove the influence ofbody size from values.Causality cannot be conferred from these data, but nonetheless demonstrate thatthose patients wiot be conferred from these data, but nonetheless demonstrate thatthose patients with the lowest [Hb] displayed the lowest valuesand vice versa. Data from Japan suggest that the AT is lower in patients with iron deficiency anaemia than innon-athletic controls (AT 15.9 ± 3.3 versus21.3 ± 1.3 mL · kg−1 · min−1,p < 0.01) and responds to increases in [Hb] followingiron supplementation ([Hb] 9.0 ± 1.8 to12.1 ± 0.8 g · dL−1),AT (20.9 ± 6.3 to25.0 ± 8.0 mL · kg−1 · min−1,p < 0.001).
Relationship between tHb-mass, blood volume, and exercise capacity
The relationship between markers of cardiorespiratory fitness and tHb-mass isstronger than that with BV or [Hb] [43, 44]. A high correlation between tHb-mass and(r = 0.97) was observed in the early 1950s by Astrand, where differences in maximalaerobic capacity between adults and children and between men and women were relatedto differences in total haemoglobin (see Figure 2). Thisinitial investigation laid the foundation for much of the subsequent work in relationto tHb-mass and aerobic capacity.
Subsequently, undertaking a meta-analytical approach, Schmidt and Prommer pooled data from 611 subjects.was determined using either an incremental cycle ergometry test or treadmillprotocol, with. values obtained from treadmill exercise adjusted (specificallyreduced) by 7% to account for the greater muscle mass utilised compared to cycling.tHb-mass was measured in all subjects using the CO re-breathing technique. Resultsrevealed a high correlation (r = 0.79) betweenand tHb-mass. A similar close dependency between BV and (r = 0.76) was highlighted, in keeping with early work byConvertino that showed a similar relationship between total BV and(r = 0.78) . Nosignificant dependency of on [Hb] (males r = 0.03, females r = 0.12)or Hct (males r = 0.08, females r = 0.11)was observed.
A number of other cross-sectional studies have demonstrated a strong positiveassociation between and tHb-mass including that by Gore and colleagues  who studied a cohort of trained athletes, female rowers (n =17, r = 0.92, p < 0.0001), male rowers (n = 12,r = 0.79, p < 0.005) and male runners(n = 33, r = 0.48,p = 0.005). Likewise, Heinicke et al.  investigated BV and tHb-mass in elite athletes ofdifferent disciplines (downhill skiing, swimming, running, triathlon, cycling junior,and cycling professional), finding that was significantly related to tHb-mass not only in the whole group but also in allendurance disciplines.
Changes in tHb-mass and exercise capacity
Procedures to increase tHb-mass result in elevated ,whereas the opposite is true when tHb-mass is reduced , highlighting the importance of tHb-mass as a primarydeterminant of by determining O2-carrying capacity.
Elevation of tHb-mass and exercise capacity
When tHb-mass is increased through the use of rhEPO, concomitant increases inhave been reported. Specifically, increased by 6%–7% in 27 recreational athletes after an increase in tHb-massof 7%–12% and both fitness and blood parameters returned to baseline aftercessation of rhEPO . Similarly, arecent study in 19 trained men showed an improved 3,000-m running time trialperformance (11:08 ± 1:15 to10:30 ± 1:07 min/sec, p < 0.001)following 4 weeks of rhEPO administration. This improved performancecoincided with a rhEPO-induced increase in (56.0 ± 6.2 to60.7 ± 5.8 mL · kg−1 · min−1,p < 0.001) and tHb-mass (12.7 ± 1.2 to15.2 ± 1.5 g · kg−1,p < 0.001).
What change in aerobic capacity can we expect for a given change in tHb-mass?Linear regression analysis revealed a change in tHb-mass of1 g · kg−1 was associated with a changein of4.4 mL · kg−1 · min−1(males4.2 mL · kg−1 · min−1,females4.6 mL · kg−1 · min−1)and a change in BV of 1 mL blood per kilogram was related to a change inof0.7 mL · kg−1 · min−1. In 144 male athletes of various specialitieswith absolute values ranging from 1,010 to6,320 mL · min−1 and tHb-mass from 242to 1,453 g, a change in 1 g of haemoglobin was associated with a changein by around 4 mL · min−1. This is the same as reported by Gore andcolleagues  and very similar to thatrecently reported in an excellent review article in this area . Understanding what change in aerobic capacitywe can expect from a change in tHb-mass is important because it allows an accurateprediction of likely improvements in functional capacity as a result of anintervention to improve tHb-mass.
Reduction of tHb-mass and exercise capacity
After 550 mL of whole blood had been withdrawn from 9 moderately trained maleand female athletes, tHb-mass was reduced on average by77 ± 21 g . Thiswas significantly associated with a decline in of 255 ± 130 mL · min−1(1 day post phlebotomy) and was still decreased on day 10(197 ± 116 mL · min−1).The authors commented on a suppression of endurance performance during this periodof lower tHb-mass. tHb-mass has also been shown to be reduced(868 ± 99 to 840 ± 94 g,p = 0.03) following a 30-day detraining period (87% reductionin training hours) with a reciprocal decrease in (4.83 ± 0.29 to4.61 ± 0.41 L · min−1)observed . Given these findings andthat tHb-mass is lower in healthy sedentary individuals than in those who areathletically trained , would sickpatients have a lower tHb-mass by virtue of inactivity? And might the relationshipbetween lower aerobic capacity and poorer operative outcome be in part mediatedthrough a sedentary lifestyle-associated reduction in tHb-mass?
Mechanisms for reduced exercise capacity following haematological changes
A reduction in [Hb] due to a fall in tHb-mass may impair exercise capacity in anumber of ways. Firstly, a reduction in CaO2 will reduce muscleO2 availability (O2 delivery) for the same muscle blood flow. Secondly, muscleO2-diffusing capacity is lower when [Hb] is reduced, which may be relatedto alterations in the intracapillary spacing of erythrocytes or slower dissociationof O2 from [Hb] . Thirdly,pulmonary diffusion is reduced when [Hb] is reduced. Finally, a reduction incirculating BV may also impact aerobic capacity by affecting ventricular preload(diastolic function) via the Frank-Starling mechanism, thus altering SV and[11, 57]. However, it appears that thepredominant mechanism explaining the detrimental impact of reduced [Hb] onand (to a greater extent) exercise endurance is the lowered O2-carryingcapacity of the blood , with [Hb] beingmore important to in the untrained than in trained individuals . This may have significant implications in patientpopulations.
Similar mechanisms may underpin the reduced AT observed when [Hb] is reduced but thisis a much-debated and controversial concept [58, 59]. The AT represents the highest (orrunning speed, power output) that can be performed without developing a sustainedlactic acidosis . When performingexercise above the AT, it is suggested that the metabolic demands of tissues(mitochondria) outstrips O2 supply, and aerobic ATP resynthesis issupplemented by anaerobic metabolism leading to increased lactate production relativeto the rate of glycolysis (i.e. increased lactate/pyruvate ratio) . The AT is therefore an important marker ofcardiorespiratory fitness as it provides an assessment of the ability of thecardiovascular system to supply O2 at a rate adequate to prevent muscleanaerobiosis . A reduced capacity tosupply O2 to actively respiring tissues caused by low [Hb] orcardiovascular disease conditions has the potential to reduce the AT.
Surgical outcome, tHb-mass, and cardiorespiratory fitness
The measurement of tHb-mass (rather than [Hb]) in the clinical setting may haveimportant applications but these remain relatively unexplored. For example, [Hb] mayvary as intravascular fluid shifts as a result of disease states or their treatment,making it a poor index of oxygen-carrying capacity. [Hb] is determined by tHb-massand the total volume of blood. A substantial reduction in oxygen-carrying capacity,related to a low tHb-mass, may thus be masked if PV is contracted, as may be the casein many disease states. Similarly, increases in intravascular volume may depress[Hb], even in the context of a normal tHb-mass. Knowledge of tHb-mass and [Hb] allowscalculation of PV as a separate variable, allowing evaluation of disease-relatedfluid shifts. The degree of surgical blood loss might also be better quantifiedthrough the measurement of tHb-mass than [Hb]. More importantly, perhaps, tHb-massmay represent a more sensitive marker of blood O2 transport capacity than[Hb] in isolation .
Major surgery can be defined as any intervention occurring in a hospital operatingtheatre involving the incision, excision, manipulation, or suturing of tissue,usually requiring regional or general anaesthesia or sedation . The determinants of surgical outcome (morbidityand mortality) are related to an interplay between the health and fitness ofpatients, the number and severity of comorbidities present , and patient age as well as surgery-related factors(emergency or planned, mode, type, and duration). In addition, the systemicinflammatory response caused by hormonal, immunological, and metabolic mediators is essential for effective tissuerepair and healing after surgery. Effective O2 delivery to the tissuesduring the hypermetabolic postoperative period is thought to be a fundamentaldeterminant of surgical outcome [65, 66] with patients who are unable to raise O2delivery to meet the increased requirementmore frequently developing complications [67, 68]. The cause of this uncoupling of O2supply and demand is multifactorial but may be predominantly linked to theinteraction between a patient's existing comorbidities (e.g. cardiac disease,respiratory disease, or indeed any condition that impairs O2 deliveryand/or cardiac output) and the degree of surgical insult .
Impairment in the ability to meet these demands can be determined preoperativelythrough the assessment of exertional peak and AT(by CPET); reductions in both markers of functional capacity are associated with anincreased risk of perioperative morbidity and mortality [70–74]. The original work by Older andcolleagues almost 2 decades ago was the first to highlight the association betweenlow functional capacity by CPET and adverse patient outcome followingnon-cardiopulmonary surgery .Specifically, a reduced cardiorespiratory reserve, typically defined as an AT of lessthan11 mL · kg−1 · min−1being associated with an increased risk of adverse postoperative outcome followingmajor intra-cavity surgery . Similarly,impaired peakhas been shown to predict worse postoperative outcome following major lung resection( peak<20 mL · kg−1 · min−1,<15 mL · kg−1 · min−1) and bariatric surgery ( peak<16 mL · kg−1 · min−1). The reader is referred to anexcellent systematic review in this area covering the role of CPET as a preoperativerisk stratification tool in non-cardiopulmonary surgery for more details.
It is acknowledged that although the response froman exercise test is not directly comparable to that in a postoperative patient,common with exercise, postoperatively in major surgery is high . For example, preoperative resting has been shownto increase from 110 to approximately170 mL · min−1 · m−2[80, 81] indicating a greaterrequirement for O2 following surgery. In this context, tHb-mass may beimportant to surgical outcome due to its role in determining O2 delivery.This may be related to the close linear relationship that exists between tHb-mass,BV, , andaerobic capacity . For example, a high BVis a prerequisite for a high tHb-mass, which in turn impacts upon byelevating venous return and cardiac filling pressures [82, 83]. Because tHb-mass in combinationwith BV also governs [Hb] and therefore oxygen-carrying capacity, the effects oftHb-mass on determining O2 delivery are twofold. Given the closerelationship between tHb-mass and aerobic capacity and the association betweenmarkers of cardiorespiratory fitness ( peak and AT)and surgical outcome, it would seem intuitive that a high tHb-mass may confer asurvival advantage in the perioperative setting. If this is the case, then strategiesaimed at elevating tHb-mass may improve outcome (morbidity and mortality) followingsurgery, but this remains to be confirmed. Given that anaemia is associated with anincreased risk of adverse surgical outcome, it would be surprising if thisrelationship were not maintained for tHb-mass.
Changes in [Hb] and tHb-mass are associated with reciprocal alterations in exercisecapacity proportional to the change in oxygen-carrying capacity of the blood. tHb-massdisplays a stronger relationship with than [Hb] or BV. In the context of surgery, patients with an inability to raise oxygendelivery to meet the increased requirement ofthe perioperative period will more frequently develop complications. Impairment in theability to meet these demands can be determined preoperatively through the assessment ofexertional peak andAT (by CPET), reductions in both markers being associated with an increased risk adversesurgical outcome. Whether differences in tHb-mass are associated with postoperativeoutcome is not known but an interesting question given the high prevalence ofpreoperative anaemia itself being associated with an increased risk of poor outcome. Inaddition, the extent to which postoperative outcomes are dependent upon interactionsbetween [Hb], tHb-mass, and is unknown andwhether strategies to increase tHb-mass result in improved surgical outcome remains tobe clarified.
arteriovenous oxygen content difference
cardiopulmonary exercise testing
total haemoglobin mass
maximal oxygen consumption;
peak oxygen consumption;
arterial oxygen content
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JMO is receiving an Impact PhD Studentship part-funded by VIFOR (INTERNATIONAL) Inc.with a total funding of £32,534 over 3 years. All remaining authors declarethat they have no competing interests.
JMO, HEM, and TR were responsible for drafting and revising the article. All authorsread and approved the final manuscript.