Cardiopulmonary exercise testing before and after intravenous iron in preoperative patients: a prospective clinical study.

BACKGROUND: Anemia is associated with impaired physical performance and adverse perioperative outcomes. Iron-deficiency anemia is increasingly treated with intravenous iron before elective surgery. We explored the relationship between exercise capacity, anemia, and total hemoglobin mass (tHb-mass) and the response to intravenous iron in anemic patients prior to surgery. METHODS: A prospective clinical study was undertaken in patients having routine cardiopulmonary exercise testing (CPET) with a hemoglobin concentration ([Hb]) < 130 g.l-1 and iron deficiency/depletion. Patients underwent CPET and tHb-mass measurements before and a minimum of 14 days after receiving intravenous (i.v.) Ferric derisomaltose (Monofer®) at the baseline visit. Comparative analysis of hematological and CPET variables was performed pre and post-iron treatment. RESULTS: Twenty-six subjects were recruited, of whom 6 withdrew prior to study completion. The remaining 20 (9 [45%] male; mean ± SD age 68 ± 10 years) were assessed 25 ± 7 days between baseline and the final visit. Following i.v. iron, increases were seen in [Hb] (mean ± SD) from 109 ± 14 to 116 ± 12 g l-1 (mean rise 6.4% or 7.3 g l-1, p = < 0.0001, 95% CI 4.5-10.1); tHb-mass from 497 ± 134 to 546 ± 139 g (mean rise 9.3% or 49 g, p = < 0.0001, 95% CI 29.4-69.2). Oxygen consumption at anerobic threshold ([Formula: see text] O2 AT) did not change (9.1 ± 1.7 to 9.8 ± 2.5 ml kg-1 min-1, p = 0.09, 95% CI - 0.13 - 1.3). Peak oxygen consumption ([Formula: see text] O2 peak) increased from 15.2 ± 4.1 to 16 ± 4.4 ml.kg.-1 min-1, p = 0.02, 95% CI 0.2-1.8) and peak work rate increased from 93 [67-112] watts to 96 [68-122] watts (p = 0.02, 95% CI 1.3-10.8). CONCLUSION: Preoperative administration of intravenous iron to iron-deficient/deplete anemic patients is associated with increases in [Hb], tHb-mass, peak oxygen consumption, and peak work rate. Further appropriately powered prospective studies are required to ascertain whether improvements in tHb-mass and performance in turn lead to reductions in perioperative morbidity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT 033 46213.

A carbon monoxide 'single breath' method to measure total haemoglobin mass: a feasibility study.

NEW FINDINGS: What is the central question of this study? Is it possible to modify the CO-rebreathing method to acquire reliable measurements of haemoglobin mass in ventilated patients? What is the main finding and its importance? A 'single breath' of CO with a subsequent 30 s breath hold provides almost as exact a measure of haemoglobin mass as the established optimized CO-rebreathing method when applied to healthy subjects. The modified method has now to be checked in ventilated patients before it can be used to quantify the contributions of blood loss and of dilution to the severity of anaemia. ABSTRACT: Anaemia is defined by the concentration of haemoglobin (Hb). However, this value is dependent upon both the total circulating haemoglobin mass (tHb-mass) and the plasma volume (PV) - neither of which is routinely measured. Carbon monoxide (CO)-rebreathing methods have been successfully used to determine both PV and tHb-mass in various populations. However, these methods are not yet suitable for ventilated patients. This study aimed to modify the CO-rebreathing procedure such that a single inhalation of a CO bolus would enable its use in ventilated patients. Eleven healthy volunteers performed four CO-rebreathing tests in a randomized order, inhaling an identical CO volume. In two tests, CO was rebreathed for 2 min (optimized CO rebreathing; oCOR), and in the other two tests, a single inhalation of a CO bolus was conducted with a subsequent breath hold of 15 s (Procnew 15s) or 30 s (Procnew 30s). Subsequently, the CO volume in the exhaled air was continuously determined for 20 min. The amount of CO exhaled after 7 and 20 min was respectively 3.1 ± 0.3 and 5.9 ± 1.1 ml for oCOR, 8.7 ± 3.6 and 12.0 ± 4.4 ml for Procnew 15s and 5.1 ± 2.0 and 8.4 ±2.6 ml for Procnew 30s. tHb-mass was 843 ± 293 g determined by oCOR, 821 ± 288 g determined by Procnew 15s (difference: P < 0.05) and 849 ± 311 g determined by Procnew 30s. Bland-Altman plots demonstrated slightly lower tHb-mass values for Procnew 15s compared with oCOR (-21.8 ± 15.3 g) and similar values for Procnew 30s. In healthy volunteers, a single inhalation of a CO bolus, preferably followed by a 30 s breath hold, can be used to determine tHb-mass. These results must now be validated for ventilated patients.

Application of the optimized carbon monoxide rebreathing method for the measurement of total haemoglobin mass in chronic liver disease.

BACKGROUND: Anemia is common in liver cirrhosis. This generally infers a fall in total hemoglobin mass (tHb-mass). However, hemoglobin concentration ([Hb]) may fall due to an expansion in plasma volume (PV). The "optimized carbon monoxide rebreathing method" (oCOR) measures tHb-mass directly and PV (indirectly using hematocrit). It relies upon carboxyhemoglobin (COHb) distribution throughout the entire circulation. In healthy subjects, such distribution is complete within 6-8 min. Given the altered circulatory dynamics in cirrhosis, we sought in this pilot study, to assess whether this was true in cirrhosis. The primary aim was to ascertain if the standard timings for the oCOR were applicable to patients with chronic liver disease and cirrhosis. The secondary aim was to explore the applicability of standard CO dosing methodologies to this patient population. METHODS: Sixteen patients with chronic liver parenchymal disease were studied. However, tHb-mass was determined using the standard oCOR technique before elective paracentesis. Three subjects had an inadequate COHb% rise. In the remaining 13 (11 male), mean ± standard deviation (SD) age was 52 ± 13.8 years, body mass 79.1 ± 11.4 kg, height 175 ± 6.8 cm. To these, mean ± SD dose of carbon monoxide (CO) gas administered was 0.73 ± 0.13 ml/kg COHb values at baseline, 6 and 8 min (and "7-min value") were compared to those at 10, 12, 15 and 20 min after CO rebreathing. RESULTS: The "7-min value" for median COHb% (IQR) of 6.30% (6.21%-7.47%) did not differ significantly from those at subsequent time points (8 min: 6.30% (6.21%-7.47%), 10 min: 6.33% (6.00%-7.50%), 12 min: 6.33% (5.90%-7.40%), 15 min: 6.37% (5.80%-7.33%), 20 min: 6.27% (5.70%-7.20%)). Mean difference in calculated tHb-mass between minute 7 and minute 20 was only 4.1 g, or 0.6%, p = .68. No subjects reported any adverse effects. CONCLUSIONS: The oCOR method can be safely used to measure tHb-mass in patients with chronic liver disease and ascites, without adjustment of blood sample timings. Further work might refine and validate appropriate dosing regimens.

Replicating measurements of total hemoglobin mass (tHb-mass) within a single day: precision of measurement; feasibility and safety of using oxygen to expedite carbon monoxide clearance.

Hemoglobin concentration ([Hb]) is a function of total hemoglobin mass (tHb-mass) and plasma volume. [Hb] may fall by dilution due to plasma volume expansion and changes in the perioperative period may therefore correlate poorly with blood loss. A simple, reliable, repeatable way to measure plasma volume and tHb-mass would have substantial clinical utility. The "optimized carbon monoxide re-breathing method" (oCOR) meets these criteria. However, it is recommended that a minimum of 12 h (when breathing room air) is left between repeat measurements. Twenty-four subjects underwent 3 days of testing. Two oCOR tests were performed (T1 and T2), 3 h apart, with a different CO clearance method employed between tests aiming to keep the carboxyhemoglobin level below 10%. The primary aim was to ascertain whether tHb-mass testing could be safely repeated within 3 h if carboxyhemoglobin levels were actively reduced by breathing supplemental oxygen (PROCA ). Secondary aims were to compare two other clearance methods; moderate exercise (PROCB ), or a combination of the two (PROCC ). Finally, the reliability of the oCOR method was assessed. Mean (SD) tHb-mass was 807.9 ± (189.7 g) (for T1 on day 1). PROCA lowered the carboxyhemoglobin level from the end of T1 (mean 6.64%) to the start of T2 (mean 2.95%) by a mean absolute value of 3.69%. For PROCB and PROCC the mean absolute decreases in carboxyhemoglobin were 4.00% and 4.31%, respectively. The fall in carboxyhemoglobin between T1 and T2 was greatest in PROCC ; this was statistically significantly lower than that of PROCA (P = 0.0039) and PROCB (P = 0.0289). The test-retest reliability for the measurement of total hemoglobin mass was good with a mean typical error (TE) of 2.0%. The oCOR method is safe and can be repeated within 3 h when carbon monoxide is suitably cleared between tests. Using oxygen therapy alone adequately achieves this.

Hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia.

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, measuring hemoglobin concentration, total hemoglobin mass (optimized carbon monoxide rebreathing method) and thereby calculating 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 is advocated.