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Anesth Analg 2001;92:609-614
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

A Novel Approach to Measuring Circulating Blood Volume: The Use of a Hemoglobin-Based Oxygen Carrier in a Rabbit Model

Jonathan S. Jahr, MD*, Fedor Lurie, MD, PhD*, Side Xi, PhD{dagger}, Mohammad Golkaryeh, MD*, Olga Kuznetsova, MD*, Ravjeet Kullar, and Bernd Driessen, DVM, PhD{ddagger}

Departments of *Anesthesiology and Pain Medicine and {dagger}Pediatrics, University of California-Davis, Sacramento, California; and {ddagger}Department of Clinical Studies, New Bolton Center, University of Pennsylvania, Kennett Square, Pennsylvania

Address correspondence and reprint requests to J. S. Jahr, MD, Department of Anesthesiology, UC Davis Medical Center, 4150 V St., Ste. 1200, Sacramento, CA 95817.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Hemoglobin-based oxygen carriers (HBOC) may be ideal for monitoring circulating plasma volume (CV-P) and circulating blood volume (CV-B). We used an HBOC (Hemoglobin glutamer-200 [bovine], Oxyglobin®; Biopure, Cambridge, MA) as an indicator for relative CV-B in the rabbit model. Accuracy of the technique was determined by comparison with the Evans blue dye (EBD) dilution technique in 19 anesthetized female New Zealand rabbits weighing 2.0 to 10.6 kg. The measurements were performed at baseline, after hemorrhage (1/3 of CV-B), normovolemic hemodilution (replacement of 1/3 CV-B by Hextend®; Abbot Laboratories, North Chicago, IL), and hypervolemic hemodilution (additional infusion of Hextend® in a volume equal to 1/3 of CV-B). Hemoglobin concentration was measured by using a HemoCue® photometer (HemoCue AB, Angelholm, Sweden). EBD concentration was analyzed by using linear regression to estimate Time 0 concentration; Time 0 was defined as EBD injection time. The difference between CV-P values determined by EBD and HBOC dilution was independent from the magnitude of the CV-P value. The relative bias was 1.29 mL, and the precision (one SD) was 2.82 mL. The difference did not reach statistical significance.

Implications: Circulating plasma and blood volumes can be accurately estimated by plasma hemoglobin concentration measurements by using hemoglobin-based oxygen carrier infusion.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Restoration of adequate circulating volume is an important goal in management of critically ill patients (1). Circulating blood volume (CV-B) changes are routinely estimated from hemodynamic variables (systemic arterial pressure, central venous pressure, pulmonary artery occlusion pressure), hematocrit (Hct), and urine output. Changes in these variables correlate with blood volume (BV) changes, but they do not allow for calculation of an absolute value of CV-B. Furthermore, estimation of CV-B by using the listed variables in critically ill patients may lead to inappropriate pharmacological support (2). Hemoglobin-based oxygen carriers (HBOC) seem to be superior candidates for the optimal resuscitation fluid because of oxygen-carrying capacity and volume replacement (3). Three HBOCs are under United States Food and Drug Administration (FDA) Phase III clinical trials for use in humans. One of the HBOCs (Hemoglobin glutamer-200 [bovine], Oxyglobin®; Biopure, Cambridge, MA) has been FDA approved for the treatment of anemia in dogs (4). HBOCs are ultrapurified, polymerized, and/or crosslinked hemoglobin solutions; in addition to providing oxygen transport, they act as volume expanders and vasoconstrictors (5). This combination of properties makes it important to monitor CV-B when HBOC is infused to avoid both insufficient volume restoration and overload.

The standard direct measurement of CV-B is the indicator dilution method (6). The indicators used include radioisotope-labeled agents, dyes, and carbon monoxide (1,6,7). These methods can be time consuming and expensive and may require specialized laboratory support. Conversely, HBOCs are hemoglobin solutions circulating in plasma that are easily and accurately identifiable and measurable with standard equipment, such as a Hct centrifuge and a point-of-care hemometer (8–11).

The half-life of HBOCs, such as Hemoglobin glutamer-200 (bovine) exceeds 20 hours (4). If a blood sample is drawn within a few circulation times of HBOC administration, there will be very little sequestration in the reticuloendothelial system, which would occur over a longer period of time. All these properties of stroma-free hemoglobin make it possible to use HBOC itself as an indicator in a dilution method. This application of HBOC has not been reported in the literature.

The aim of this study was to investigate the use of Hemoglobin glutamer-200 (bovine), as an indicator for circulating plasma volume (CV-P) and CV-B measurements. The accuracy of this technique was determined by comparison with the Evans blue dye (EBD) dilution technique in rabbits.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The procedures and experimental design were approved by the Animal Care and Use Committee of the University of California, Davis and were conducted in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animal Care" prepared by the Institute of Laboratory Animal Resources. Nineteen female New Zealand rabbits were sedated with acetylpromazine (0.1 mg/kg IM), and anesthetized with ketamine (10 mg/kg IM). Fifteen animals had a body weight of 2.0 to 2.6 kg (mean 2.2 ± 0.2 kg). To test circulating volumes over a wider range, a separate group of four animals with a body weight of 9.5 to 10.6 kg (mean 9.9 ± 0.5 kg) was included in the study.

IV catheters (InsyteTM 22- or 24-gauge; Becton Dickinson, Sandy, UT), flushed with preservative free 0.9% saline, were placed in the left or right ear marginal vein and artery. The rabbits were placed on a table and were breathing room air spontaneously, with a warming blanket at 37°C underneath them and covered with clear plastic to maintain body temperature.

All animals were assigned to one of four groups. In Group 1 (five rabbits, body weight 2.2–2.6 kg) and Group 2 (four rabbits, body weight 9.5–10.6 kg) only baseline values of CV-P and CV-B were determined by using both techniques (EBD and HBOC dilution).

In Groups 3 and 4 (five rabbits per group), after baseline values for CV-P and CV-B were determined, 1/3 of the CV-B (31.6 ± 2.1 mL) was withdrawn through the arterial catheter for 10 min. CV-P and CV-B determinations were performed in each animal immediately after blood withdrawal (posthemorrhage values). Volume resuscitation was then performed in both groups. In Group 3, Hextend® solution (6% hetastarch in lactated Ringer’s solution, Abbot Laboratories, North Chicago, IL) was infused in a volume equal to the blood withdrawn. In Group 4, the same volume (31.6 ± 2.1 mL) of Hemoglobin glutamer-200 (bovine) (Oxyglobin®, Biopure, Cambridge, MA) was infused followed by CV-P and CV-B measurements. The procedure described for Group 3 was interpreted as normovolemic hemodilution, and the procedure described for Group 4 had the specific aim to test a large dose of Hemoglobin glutamer-200 (bovine) for the indicator dilution technique. In both Groups 3 and 4, an additional volume of Hextend® equal to 1/3 of the CV-B (31.6 ± 2.1 mL) was infused, and measurements of CV-P and CV-B were repeated immediately after the infusion to simulate hypervolemic hemodilution and severe anemia in the Control group. The time interval between the first (baseline) sample and the last sample withdrawn did not exceed 60 min.

In summary, comparative measurements of CV-P and CV-B by using EBD and Hemoglobin glutamer-200 (bovine) as indicators were conducted under the following conditions:

  1. 1. Using small dose of Hemoglobin glutamer-200 (bovine).
  2. a. Baseline (normovolemic) animals with body weight of approximately 2 kg (in 15 animals).
  3. b. Baseline (normovolemic) animals with body weight of approximately 10 kg (in 4 animals).
  4. c. Posthemorrhage (in 10 animals).
  5. d. Normovolemic hemodilution (in 5 animals).
  6. e. Hypervolemic/anemic hemodilution (in 5 animals).
  7. 2. Using a large dose of Hemoglobin glutamer-200 (bovine).
  8. a. Normovolemic hemodilution (in 5 animals).
  9. b. Hypervolemic/anemic hemodilution (in 5 animals).

Samples of arterial blood were collected at baseline (before the indicator injection), 1, 2, and 5 min after the Hemoglobin glutamer-200 (bovine) injection, and 1, 2, and 5 min after the EBD injection. Two millileters of 13 g/dL solution of Hemoglobin glutamer-200 (bovine) was rapidly administered IV. EBD (5 mg/mL solution in preservative-free normal saline) was injected immediately after the last arterial blood sample was collected. The injected volume of EBD solution was calculated to deliver a dose of 0.05 mg/mL of predicted plasma volume. After Hemoglobin glutamer-200 (bovine) was used for volume replacement, the infused volume was used for CV-P calculations. Samples were collected by using the same scheme. For all repeated measurements, the sample of arterial blood was collected just before the indicator injection. The concentration of the indicator in this sample was used as a baseline for subsequent measurements. EBD concentration was determined by means of a spectrophotometric assay: 0.1 mL of the plasma of each blood sample was placed into a 1-mL spectrophotometer cuvette and diluted 10:1 in pH 9.0 phosphate buffer to minimize the effect of hemoglobin on the measured spectra (Shimadzu UV160A; Shimadzu Co., Kyoto, Japan). The absorbance was read at 650 nm, and the concentration of dye was calculated from the standard curve of EBD solution in plasma of the baseline sample. The background reading for turbidity and presence of hemoglobin was corrected with the plasma of the baseline sample (8). Dye concentration per optical density unit was measured by using a standard solution of EBD in plasma of the baseline sample. The hemoglobin concentration was measured in the supernatant plasma harvested from the Hct capillary tubes, with a HemoCue®; Hemoglobin Photometer (HemoCue AB, Angelholm, Sweden). This device is highly accurate for plasma hemoglobin measurements after HBOC infusion (9–10).

CV-P and CV-B were determined as follows: measurements of indicator concentrations at 1, 2, and 5 min after the injection were analyzed by using linear regression to extrapolate Time 0 concentration (C0); Time 0 was defined as the time of the EBD injection. The following equation (8) was used for CV-P calculations: CV-P = (Ci x Vi)/C0, where Ci and Vi are the indicator concentration and volume injected. Estimated BV was calculated from measured plasma volume and Hct as CV-B = CV-P/(1 - Hct), where Hct is expressed as a fraction.

We did not correct calculations for trapping factor or for F-cell ratio. Those factors remained the same for each of the studied animals and thus did not influence the correlation between two investigated techniques. The Hct was measured in each blood sample. Hct values obtained from samples 5 min after the Hemoglobin glutamer-200 (bovine) injection and 1 min after the EBD injection were used for CV-B calculations. The hemoglobin concentration was measured in each package of Hemoglobin glutamer-200 (bovine) and was identical among different packages (13 g/dL).

The independence of the between-methods differ-ences and the size of the measurements were tested by plotting the difference (CV-P Hemoglobin glutamer-200 [bovine] - CV-P EBD) against the means ([CV-P Hemoglobin glutamer-200 {bovine} + CV-P EBD]/2). The relative bias was defined as a mean of the difference. The precision was defined as standard deviation (SD) of the differences. The hypothesis of zero bias was examined by paired t-test (12). A P value < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The values of CV-P measured by both methods at baseline were within the normal physiological range: 53.5 ± 2.6 mL/kg [normal for female New Zealand rabbits are 53.8 ± 5.2 mL/kg (13–16)]. The Hct values ranged between 0.37 and 0.42 with a mean (± SD) of 0.39 ± 0.16. The bias and precision of HBOC versus EBD measurements were constant across the range of BV tested ( Fig. 1). The mean of the bias was 1.29 mL, and the precision was 2.82 mL. The difference never exceeded the 95% probability level (Fig. 1). The test of the hypothesis of zero bias with paired t-test indicated P > 0.05; thus, results of two methods did not differ significantly.



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  		Figure 1. Difference between values of the circulating plasma volume (CV-P) measured with Evans Blue Dye (EBD) and Hemoglobin glutamer-200 (bovine, Hb glutamer-200) dilution techniques. The difference (CV-P Hb glutamer 200 versus CV-P Evans Blue) is plotted against the mean ([CV-P Hb glutamer-200 + CV-P Evans Blue]/2). Horizontal lines indicate the range of two standard deviations (SD).

 
We were not able to detect any significant difference between CV-P values measured with either technique (EBD versus HBOC) under all tested conditions: posthemorrhagic, normovolemic hemodilution, hypervolemic/anemic hemodilution, and using a large dose of Hemoglobin glutamer-200 (bovine) (see Table 1 and Fig. 2).


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  		Table 1. Circulating Plasma Volume (CV-P) and Circulating Blood Volume (CV-B) Measured with Evans Blue Dye (EBD) and Hemoglobin Glutamer-200 (Bovine, Hb Glutamer-200 = HBOC) Dilution Techniques
 


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  		Figure 2. Circulating plasma volume (CV-P) in mL measured with Evans Blue Dye (EBD) and Hemoglobin glutamer-200 (bovine, Hb glutamer-200 [HBOC]) dilution techniques. Data represent mean values ± SDs of CV-P measurements as determined under four different conditions: baseline (normovolemia), posthemorrhage (withdrawal of 1/3 of CV-B), postresuscitation (replacement of 1/3 of CV-B with equal volume of Hb glutamer-200)), and hypervolemic hemodilution (additional infusion of 6% hetastarch solution equal to 1/3 of CV-B).

 
Determinations of CV-B revealed larger differences between the two methods than determinations of CV-P. The mean difference was 2.36 mL and the precision was 3.41 mL. The difference was independent of the volume value and exceeded 95% probability level in one case ( Fig. 3). Despite this, the difference did not achieve statistical significance (P > 0.05).



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  		Figure 3. Difference between values of the circulating blood volume (CV-B) measured with Evans Blue Dye (EBD) and Hemoglobin glutamer-200 (bovine, Hb glutamer-200 [HBOC) dilution techniques. The difference (CV-B Hb glutamer-200 versus CV-B Evans Blue) is plotted against the mean ([CV-B Hb glutamer-200 + CV-B Evans Blue]/2). Horizontal lines indicate the range of two standard deviations.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Use of HBOC makes restoration of adequate circulating volume more challenging. One of the potential effects of polymerized hemoglobin is the expansion of CV-B caused by oncotic effects (5,8). Another effect of HBOCs is vasoconstriction likely the result of nitric oxide scavenging (15), stimulation of {alpha}-adrenergic receptors (17), and changes in tissue oxygenation (18). These effects may lead to cardiovascular changes, which make use of hemodynamic indicators for CV-B estimation questionable.

Direct measurement of CV-B by using labeled red cell isotope or carbon monoxide (1,19) might be erroneous when a significant volume of stroma-free hemoglobin is infused. However, plasma compartment-labeled dilution techniques can be time consuming and cost prohibitive (1). Moreover, the presence of stroma-free hemoglobin makes it more difficult to detect any dye and accurately measure its concentration in plasma.

This study examined the possibility of using HBOC itself as an indicator for direct CV-P measurements. When HBOC is infused, the infused volume and hemoglobin concentration are known, if quantified within minutes of infusion. Measurement of the plasma hemoglobin concentration is routine for patients receiving HBOC solutions, is not expensive, and does not require additional time or equipment.

We compared measurements of CV-P and CV-B determined by Hemoglobin glutamer-200 (bovine) and EBD dilution techniques and demonstrated good correlation between the two methods. One of the potential pitfalls of this comparison was a change of colloid oncotic pressure during the experiment because of the high colloid oncotic pressure of the HBOC used (Hemoglobin glutamer-200 [bovine] has a colloid oncotic pressure of 41.6 mm Hg). The two indicators were used consecutively in the same animal. The time interval between the Hemoglobin glutamer-200 (bovine) injection and the EBD injection was five minutes. Neither Hct nor hemoglobin concentration changed significantly during this interval, thus excluding a relevant volume expansion during the time of the measurements. However, to eliminate the plasma expansion influence, linear regression analysis was applied for both techniques to extrapolate to the same time point (the time of the EBD injection). Our data demonstrate significant agreement between the two methods of CV-P measurements ( Fig. 4).



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  		Figure 4. Correlation between measurements of circulating plasma volume (CV-P) by using Evans blue dye (EBD) and Hemoglobin glutamer-200 (bovine; Hb glutamer-200 [HBOC]) in all groups. The Pearson coefficient of correlation is given.

 
The influence of high colloid oncotic pressure on the accuracy of the CV-P measurements should increase when a large dose of HBOC is infused. In clinical practice, HBOC and other colloid solutions may be infused simultaneously, which then confounds CV-P calculations based on measurements of initial concentration and volume of HBOC. We therefore studied the correlation between the two techniques of CV-P measurements in animals with one third of the CV-B replaced by using either a 6% hetastarch solution (Group 3) or Hemoglobin glutamer-200 (bovine; Group 4). In both groups, replacement of one third of CV-B did not affect the agreement between the two techniques of CV-P measurements.

We conclude that CV-P and CV-B may be accurately estimated by using plasma hemoglobin concentration measurements after HBOC infusion.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Dingley J, Foex BA, Swart M, et al. Blood volume determination by the carbon monoxide method using a new delivery system: accuracy in critically ill humans and precision in an animal model. Crit Care Med 1999; 27: 2435–41.[Web of Science][Medline]
  2. Hinds C, Watson D. Manipulating hemodynamics and oxygen transport in critically ill patients. N Engl J Med 1995; 333: 1074–5.[Free Full Text]
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  4. Food and Drug Administration. 21CFR522.1125 Hemoglobin glutamer-200 (bovine). 63 Federal Register 11598, Mar 1998:10.
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  6. International committee for standardization in haematology. Recommended methods for the measurement of red cell and plasma volume. J Nucl Med 1980; 21: 793–800.[Free Full Text]
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  8. Migita R, Gonzales A, Gonzales ML, et al. Blood volume and cardiac index in rats after exchange transfusion with hemoglobin-based oxygen carriers. J Appl Physiol 1997; 82: 1995–2002.[Abstract/Free Full Text]
  9. Jahr JS, Lurie F, Driessen B, et al. An ultrapurified, polymerized, hemoglobin-based oxygen carrier (HBOC): validation of the oxygen saturation measurements from the i-STAT Portable Clinical Analyzer, NOVA CO-Oximeter and a blood gas analyzer in a canine model. Clin Lab Sci 2000; 13: 173–9.
  10. Lurie F, Jahr JS, Davis J, et al. Reliability of plasma hemoglobin concentration measurement using the HemoCue®, a point of care hemoglobin photometer, after infusions of a hemoglobin-based oxygen carrier (HBOC) [abstract]. Anesthesiology 2000; 93: A408.
  11. Lurie F, Jahr JS, Driessen B, et al. Oxygen saturation measurements in canine blood after Hemoglobin glutamer-200 (bovine) (HBOC) infusion: in-vitro validation of the Nova Co-oximeter. Vet Clin Pathol. In press.
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Accepted for publication November 16, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press