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Canadian Journal of Anesthesia 47:150-154 (2000)
© Canadian Anesthesiologists' Society, 2000
Reports of Investigation

Accuracy of carboxyhemoglobin dilution method for the measurement of circulating blood volume

Satoshi Ohki, MD*, Fumio Kunimoto, MD{dagger}, Yukitaka Isa, MD{dagger}, Hideaki Obata, MD{ddagger}, Susumu Ishikawa, MD*, Tetsuya Koyano, MD*, Noboru Oriuchi, MD§, Fumio Goto, MD{ddagger} and Yasuo Morishita, MD*

* From the Second Department of Surgery,
{dagger} Intensive Care Unit,
{ddagger} Department of Anaesthesiology and Reanimatology and
§ Department of Nuclear Medicine, Gunma University School of Medicine, Maebashi, Gunma, Japan.

Satoshi Ohki MD, Second Department of Surgery, Gunma University School of Medicine, 3-39-15, Showa-Machi, Maebashi, Gunma 371-8511, Japan. Phone/Fax: 81-27-220-8245; E-mail: ohkisato{at}akagi.sb.gunma-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: The management of circulating blood volume (BVc) is crucial in intensive care unit (ICU) patients. The purpose of this study was to verify the accuracy and precision of the carbon monoxide-labeled hemoglobin (CO-Hb) dilution method (CO method) by comparing it with the 51Cr-labeled erythrocyte dilution method (51Cr method) for the measurement of BVc.

Methods: A prospective study was performed in 18 patients who underwent coronary artery bypass grafting (CABG) under mild hypothermic cardiopulmonary bypass (CPB). The BVc was measured by both the CO method and the 51Cr method at 24 hr after ICU admission in order to verify the accuracy and precision of the CO method. Paired data were assessed in absolute terms, and percentage errors were calculated by the degree of agreement.

Results: Small mean differences and standard deviations between the CO method and the 51Cr method (–70.2 ± 184.8 mL) and small percentage errors (–0.49 ± 1.29%) indicated the accuracy and precision of the CO method, and a close correlation was observed (r=0.97).

Conclusion: The CO method can measure BVc with a similar degree of accuracy as the 51Cr method. It is simple, repeatable and safe without the risk of exposure to radioactivity in the ICU.


   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
ASSESSMENT of circulating blood volume (BVc) is essential in the management of intensive care unit (ICU) patients. The BVc has been estimated by indirect means such as arterial blood pressure, heart rate, central venous pressure (CVP), or pulmonary capillary wedge pressure (PCWP), but these parameters do not correlate with values obtained by direct measurement.1 Radioactive methods have been accepted as a reliable measurement for direct determination of BVc. However, such methods involve risk of exposure to radioactivity and, for this reason, repeated measurements are not available to ICU patients. The carbon monoxide-labeled hemoglobin (CO-Hb) dilution method (CO method) has been introduced for the measurement of BVc.2,3 The clinical usefulness of the CO method for BVc measurement was reported as both simple and safe with no risk of exposure to radioactivity.4 Obata et al.5 reported the highly predictive value of BVc measurement using the CO method in an animal hemorrhagic model. However, the CO method has not been widely accepted as a method for BVc measurement. In this study, we simultaneously measured BVc using the 51Cr method as well as the CO method and verified the accuracy and precision of the CO method by comparing the values obtained from the CO method with those obtained from the 51Cr method which is widely accepted as a standard method for BVc measurement.


   Patients and methods
TOP
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
The protocol was approved by the Gunma University Ethical Committee for Human Research. A total of 18 patients (11 male, 7 female) who underwent coronary artery bypass grafting (CABG) and were admitted to the ICU of Gunma University Hospital from April 1997 to March 1998 were included in this study. The day before surgery, patients were fully informed of the purposes of the study and the procedures involved, and written consent was obtained.

Patients with 1) renal, hepatic or gastrointestinal disease, 2) left ventricular ejection fraction (LVEF) < 40%, as determined by preoperative echocardiography, 3) low cardiac output syndrome (LOS) with cardiac index < 2.5 Lmin–1m–2, 4) or postoperative bleeding > 500 mL for six hours after admission to the ICU were excluded from this study. Anesthesia was induced with 12-20 µgkg–1 fentanyl, 0.4-1.0 mgkg–1 midazolam and 0.1 mgkg–1 vecuronium and maintained by additional doses of fentanyl. Isoflurane (0.5-1.0%) was administered according to the hemodynamic response to surgical procedure. After induction of anesthesia, a pulmonary artery catheter (744H-7.5 F; Baxter Healthcare Corp., Irvine, CA) was floated into the pulmonary artery via the right internal jugular vein for hemodynamic monitoring. Non-pulsatile, mild hypothermic cardiopulmonary bypass (CPB) was conducted in a standard manner using a membrane oxygenator including a heat exchanger (AFFINITY, AVECOR Cardiovascular Inc. Plymouth, MN) and roller pump (TOW NOK, Tonokura Ika Kogyo Co., Ltd., Tokyo, Japan). Rectal temperature was maintained at 28 to 30°C in all patients.

All patients were given a low dose of catecholamines (# 3 µgkg–1min–1 dopamine and # 3 µgkg–1min–1 dobutamine, 1 µgkg–1min–1 diltiazem and 0.5-1 µgkg–1min–1 nitroglycerin after surgery. No patients received blood transfusion but each received 476 ± 96 mL albumin 4% during the study period. In all patients, the endotracheal tubes were extubated 24 hr after ICU admission. The postoperative course was uneventful in all patients with no episodes of low cardiac output syndrome or major complications.

Measurement of BVc
The BVc was measured by the CO method at 24 hr after ICU admission. At 24 hr, BVc was also measured by the 51Cr method to verify the accuracy and precision of the CO method.

The CO method
After the baseline measurement of hemoglobin level (Hbb) and CO-Hb concentration (CO-Hbb ), 100 mL blood was drawn from an arterial line into a sterile bag containing 15 mL of a citrate solution. Then, CO gas was insufflated into the bag through a bacterial filter. After insufflation and agitation three times, the oximeter indicated CO-Hb concentration (CO-Hbi) > 97%, hemoglobin concentrations (Hbi) were measured simultaneously and the indicator volume (Vi) of CO saturated blood was reinfused into a central vein. Two 1.0 mL arterial blood samples were drawn at 5, 10, 15, 20 and 30 min after reinfusion in order to measure CO-Hb concentration in the circulating blood. After the reinfusion of the indicator, several distinct dilution phases were observed: early circulation, a mixing phase and a major dilution phase.6 In this study, the major dilution phase was achieved within 5-10 min. Thus, we excluded the data at five minutes in our calculation. The mean CO-Hb concentration obtained from the two samples at each point were plotted on a semilogarithmic graph against time in minutes and the zero time value (CO-Hbz) was obtained by the extrapolation of an exponential decay curve. Blood hemoglobin and CO-Hb concentrations were measured with a blood gas analyzer with oximetry (ABL520, Radiometer, Copenhagen, Denmark). The PaO2 values were controlled between 90 and 120 mmHg and the PaCO2 between 35 and 45 mmHg in all patients. The BVc was calculated using the following equation;**

(1)

The 51Cr method
At 24 hr after ICU admission, BVc was measured by both the CO method and the 51Cr method to verify the accuracy and precision of the CO method. Blood volume was measured using the standard 51Cr method with modification.7,8 Initially, 20 mL of arterial blood was drawn using a heparin-coated syringe. Erythrocytes were collected by centrifugation and labelled with 100 µCi of [51Cr] sodium chromate (Daiichi Radioisotope Laboratories Ltd.,Tokyo, Japan) by incubation for 20 min at room temperature. After being centrifuged and washed in saline, the 51Cr-labelled erythrocytes were suspended in saline to create an original volume of 20 mL and the 51Cr radioactivity of the aliquot (100 µL) of this suspension was measured. Following injection of 20 mL 51Cr-labelled erythrocytes suspension, three samples of 0.5 mL arterial blood were drawn at 30 min for measurement of 51Cr radioactivity in the circulating blood, and the mean value was obtained.

Statistical analysis
The analysis of agreement was based on a method proposed by Bland and Altman9 for comparing two methods of evaluation of the same parameter. The differences between the CO method and the 51Cr method were plotted against the average of the two methods. Bias and precision were evaluated using the mean and standard deviation (SD) of the differences between the CO method and the 51Cr method. Bias measures systematic error between the methods, and precision quantifies the random error or variability. The limits of agreement were defined as the mean difference ± 2SD. To determine whether the differences between the methods depend on BVc in absolute terms, the percentage difference [100 x (difference in BVc between the methods) / (mean of BVc by the two methods)] was calculated and plotted against the average of the two methods.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
The characteristics of the patients, aortic cross-clamp and CPB time are shown in Table IGo and hemodynamic status before BVc measurement are shown in Table IIGo.


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  		TABLE I Patient characteristics and surgical data ( mean ± SD ( range ) )
 

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  		TABLE II Hemodynamic status before BVc measurement (mean ± SD)
 
Regression analysis revealed a correlation between values obtained from the CO and 51Cr method (Y = 0.98X+22.0, r=0.97) (Figure 1Go). As shown in Figure 2Go, the mean difference and standard deviations were : –70.2 ± 184.8 mL and percentage errors were –0.49 ± 1.29% (Figure 3Go). The CO-Hb concentration after the infusion of carbon monoxide saturated blood ranged from 2.1% to 5.0%. There was no sign of CO intoxication, such as headache and nausea, nor any major complications due to the reinfusion of blood, such as pulmonary infarction or infection.



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  		FIGURE 1 The BVc measurement with the CO method plotted against their simultaneous measurements with the 51Cr method.

 


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  		FIGURE 2 Difference in circulating blood volume measured by the CO method and the 51Cr method (CO–51Cr) plotted against their respective means. The horizontal lines indicate the mean and the mean ± 2 SD. Bias = –70.2 ± 184.8 mL (mean ± SD).

 


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  		FIGURE 3 Percentage difference in circulating blood volume measured by the CO method and the 51Cr method against their respective means.

Percentage difference = 100 x (CO–51Cr) / (CO+51Cr)x0.5. The horizontal lines indicate the mean and the mean ± 2 SD. Bias =–0.49 ± 1.29% (mean ± SD).

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The 51Cr method has been used as a standard method for the measurement of BVc.7,8 However, the 51Cr method has several drawbacks in clinical use: 1) difficulty in repeated measurement due to the long half-life (27.8 dy), 2) a risk of exposure to radioactivity and 3) a complicated measurement procedure. On the other hand, BVc measurement using the CO method is simple, repeatable and safe. The only equipment necessary for measurement is a CO-oximeter. Dissociation of carbon monoxide could be facilitated by the inhalation of pure oxygen. It is generally considered that CO-Hb concentration < 10% is harmless and causes no clinical symptoms,4,10 however, the highest CO-Hb concentration predicted < 5 % in this study.

Nomof et al.7 reported that BVc measured using the CO-rebreathing method was 16% larger than with the 51Cr method, as some CO was located in the extravascular space and some was excreted, metabolized or leaked. Christensen et al.11 reported on the CO-rebreathing method using a to-and-fro system, and analysed CO kinetics using a computer simulation. They used a special system was designed by Water's Co. to avoid CO leakage. However, in our method, special instruments and computer analysis were not necessary.

Several methods for BVc measurement have been reported recently. Sugimoto et al.12 reported a method for continuous measurement of BVc using 51Cr in rats. Throughout their experiment there was no change in erythrocyte volume and therefore changes in blood volume were calculated continuously from changes in the radioactivity of 51Cr in BVc. If there is bleeding, their method could not be used to calculate BVc. Hoeft et al.13 reported a different method for measuring blood volume using indocyanine green (ICG). However, blood ICG concentration is influenced by hepatic clearance, distribution of ICG, cardiac output and circulation time. A two-compartment model of circulation is required for an adequate fit of the data.

There are some disadvantages in using tracer dilution methods. Although the major dilution phase is achieved within 10 min in humans, it is prolonged by circulatory dysfunction.6 In this study, patients with low LVEF of < 40% by preoperative echocardiography and LOS with cardiac index of < 2.5 Lmin–1m–2 after ICU admission were excluded. In patients with circulatory dysfunction, more frequent examination of CO-Hb concentration is required to confirm the achievement of the dilution phase. The CO method has several advantages over other methods because it requires only a brief time for labeling and allows rapid and repeated measurement with a CO-oximeter in the ICU. Further, the CO method avoids use of a radioactive tracer.

We verified the accuracy and precision of the CO method by the analysis of agreement proposed by Bland and Altman9 comparing the CO method with the 51Cr method. Our results showed a close relationship between values obtained by these two method (r = 0.97). The difference in BVc measured by the two methods (bias) was –70.2 ± 184.8 mL and the percentage of errors were –0.49 ± 1.29%. Obata et al.5 reported the accuracy of the CO method in a rabbit hemorrhage model. Our study confirmed the accuracy and precision of the CO method in humans.

We conclude that the CO method can measure BVc with the same degree of accuracy as the 51Cr method. There was no sign of CO intoxication, nor any major complications due to the reinfusion of blood. It is simple, repeatable and safe without the risk of exposure to radioactivity in the ICU.

Accepted for publication November 8, 1999.


   References
TOP
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 Shippy CR, Appel PL, Shoemaker WC. Reliability of clinical monitoring to assess blood volume in critically ill patients. Crit Care Med 1984; 12: 107–12.[Medline]

2 Sjöstrand T. A method for the determination of the total haemoglobin content of the body. Acta Physiol Scand 1948; 16: 211–31.

3 Fogh-Andersen N, Thomsen JK, Foldager K, Siggaard-Andersen O. pH effect on the COHb absorption spectrum: importance for calibration of the OSM3 and measurement of circulating hemoglobin and blood volume. Scand J Clin Lab Invest 1990; 50(Suppl203): 247–52.[Medline]

4 Fukui M, Shigemi K. Determination of single and repeated red cell volumes by the indicator dilution method using carbon monoxide as the indicator. Crit Care Med 1989; 17: 1199–202.[Medline]

5 Obata H, Goto F, Nara T, et al. High predictive value of red cell volume measurement using carboxy-haemoglobin in a rabbit model of haemorrhage. Br J Anaesth 1998; 81: 940–4.[Abstract/Free Full Text]

6 Moore FD, Hartsuck JM, Zollinger RM Jr, Johnson JE. Reference models for clinical studies by isotope dilution. Ann Surg 1968; 168: 671–700.[Medline]

7 Nomof N, Hopper J Jr, Brown E, Scott K, Wennesland R. Simultaneous determinations of the total volume of red blood cells by use of carbon monoxide and chromium51 in healthy and diseased human subjects. J Clin Invest 1954; 33: 1382–7.

8 A report by the international committee for standardization in hematology (ICSH): panel on diagnostic applications of radioisotopes in haematology. Standard techniques for the measurement of Red-Cell and plasma volume. Br J Haematol 1973; 25: 801–14.[Medline]

9 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307–10.[Medline]

10 Okada Y, Tyuma I, Ueda Y, Sugimoto T. Effect of carbon monoxide on equilibrium between oxygen and hemoglobin. Am J Physiol 1976; 230: 471–5.[Abstract/Free Full Text]

11 Christensen P, Rasmussen JW, Henneberg SW. Accuracy of new bedside method for estimation of circulating blood volume. Crit Care Med 1993; 21: 1535–40.[Medline]

12 Sugimoto E, Shigemi K, Okuno T, Yawata T, Morimoto T. Effect of ANP on circulating blood volume. Am J Physiol 1989; 257: R127–31.[Abstract/Free Full Text]

13 Hoeft A, Schorn B, Weyland A, et al. Bedside assessment of intravascular volume status in patients undergoing coronary bypass surgery Anesthesiology 1994; 81: 76–86.[Medline]




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