Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes. In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10–42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants. Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78–1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68–1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints. Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10–42 days before elective major abdominal surgery. UK National Institute of Health Research Health Technology Assessment Program.

Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P=0.04 for noninferiority). Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.)

In practice, clinicians generally consider anemia (circulating hemoglobin concentration < 120 g.l-1 in non-pregnant females and < 130 g.l-1 in males) as due to impaired hemoglobin synthesis or increased erythrocyte loss or destruction. Rarely is a rise in plasma volume relative to circulating total hemoglobin mass considered as a cause. But does this matter? We explored this issue in patients, using the optimized carbon-monoxide rebreathing method to measure hemoglobin concentration and thereby calculate plasma volume in healthy volunteers, surgical patients, and those with inflammatory bowel disease, chronic liver disease or heart failure. We studied 109 participants. Hemoglobin mass correlated well with its concentration in the healthy, surgical and inflammatory bowel disease groups (r= 0.687-0.871, p< 0.001). However, they were poorly related in liver disease (r= 0.410, p= 0.11) and heart failure patients (r= 0.312, p= 0.16). Here, hemoglobin mass explained little of the variance in its concentration (adjusted R2= 0.109 and 0.052; p= 0.11 and 0.16), whilst plasma volume did (R2 change 0.724 and 0.805 in heart and liver disease respectively, p<0.0001). Exemplar patients with identical (normal or raised) total hemoglobin masses were diagnosed as profoundly anemic (or not) depending on differences in plasma volume that had not been measured or even considered as a cause. The traditional inference that anemia generally reflects hemoglobin deficiency may be misleading, potentially resulting in inappropriate tests and therapeutic interventions to address ‘hemoglobin deficiency not plasma volume excess. Measurement of total hemoglobin mass and plasma volume is now simple, cheap and safe, and its more routine use advocated.

The ability of the cardiorespiratory system (heart, lungs, blood) to deliver oxygento exercising skeletal muscle constrains maximum oxygen consumption$\left({\dot{\mathrm{V}}\mathrm{O}}_{2\max }\right)$,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 ${\dot{\mathrm{V}}\mathrm{O}}_{2\max }$and tHb-mass is stronger than that observed between ${\dot{\mathrm{V}}\mathrm{O}}_{2\max }$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 ${\dot{\mathrm{V}}\mathrm{O}}_{2\max }$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${\dot{\mathrm{V}}\mathrm{O}}_{2\max }$.Similarly, ${\dot{\mathrm{V}}\mathrm{O}}_{2\max }$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(${\dot{\mathrm{V}}\mathrm{O}}_2$ 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 ${\dot{\mathrm{V}}\mathrm{O}}_2$ 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].