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Anesth Analg 2005;100:912-920 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000146960.79532.DB
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Abstract |
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We assessed the systemic effects of exchanges with blood or hemoglobin (Hb) raffimer under conditions of critical oxygen delivery (Do2crit). We compared Do2crit in animals receiving Hb-based oxygen carrier (HBOC; HemolinkTM), fresh blood (collected <24 h), or stored blood (10 days) before hemodilution. Rats were randomized to control, blood, or HBOC isovolemic exchange. Oxygen consumption was measured by using expired gas (
o2a) and blood (o2b) samples, whereas whole-body oxygen delivery (Do2) was calculated from cardiac output and arterial oxygen content. After exchange, rats were subjected to stepwise isovolemic hemodilution. Blood pressure, gases, acid-base status, glucose, Hb oxygen saturation, heart rate, and total peripheral resistance were also measured. We found that 1) HBOC-treated rats showed an increased mean arterial blood pressure and total peripheral resistance throughout the hemodilution, 2) Do2crit calculated with o2a or o2b gave identical results, 3) Do2crit was not different between animals receiving blood and those receiving HBOC, 4) the terminal Hb concentration (1.8 ± 0.1 g/dL) and Do2 (5 ± 1 mL · min–1 · kg–1) were similar for all animals, and 5) most oxygen transport and biochemical variables changed similarly during hemodilution. The data suggest that tolerance to Do2crit is not altered by 50% replacement of native Hb by stored blood or Hb raffimer. |
Introduction |
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Studies of transfusion and oxygen therapeutics using relevant animal models can be used to evaluate oxygen delivery, transport, and utilization. These studies are key to evaluating the efficacy of stored blood and of hemoglobin (Hb)-based oxygen carriers (HBOCs). The ability of transfused red blood cells (RBCs) to flow and to release oxygen is affected by alterations due to storage (1–3), and HBOCs are anticipated to be efficient alternatives to RBC transfusions. However, Stowell et al. (4) pointed out recently that the effects of different HBOCs on systemic hemodynamics are "not yet possible to predict."
At normal or high levels of systemic oxygen delivery (Do2), oxygen consumption (o2) is independent of Do2. However, o2 decreases in a supply-dependent phase when Do2 is below a level known as "critical Do2" (Do2crit). Because Do2crit is an important marker of the transition to anaerobic metabolism (5–7), it has been considered the ultimate physiological threshold to the manifestation of tissue hypoxia and shock (6). Although Do2crit does not seem to be affected by the method used to decrease Do2 (8), hemodilution is often used to experimentally study critical conditions of Do2 and to obtain Do2crit.
Hb raffimer (HemolinkTM; Hemosol Inc., Toronto, ON, Canada) is a polymerized human Hb that has been successfully used in clinical trials, but there is little information on its ability to provide adequate oxygenation under critical conditions. Similarly, the response of animals transfused with stored RBCs under these conditions has not been studied. We hypothesized that if transfused Hb has similar behavior in vivo compared with native Hb, then transfused animals should be able to tolerate decreases in Do2 caused by hemodilution. We tested this hypothesis by comparing the levels of Do2crit in transfused animals subjected to hemodilution. Changes in systemic variables associated with a 50% exchange transfusion with stored blood (equivalent to 42 days for humans) and with HBOC were measured during hemodilution.
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Methods |
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This study was approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University. Twenty-nine male Sprague-Dawley rats weighing 432 ± 5 g (mean ± sem) were housed for a 1-wk adaptation period and were then instrumented under anesthesia with a mixture of ketamine and acepromazine, followed by an IV infusion (0.24–0.36 mg · kg–1 · h–1) of alfaxalone/alfadolone acetate. The left femoral artery was used to continuously measure arterial blood pressure (AP). A jugular cannula, advanced to the entrance of the right atrium, was used to collect central venous blood and to record central venous blood pressure. The right femoral artery was used for blood exchange and blood sampling. The core temperature was maintained at 36.5°C–37.0°C by using an electric blanket. Rats were subjected to tracheostomy and were ventilated by a pressure-controlled ventilator with 95% oxygen in the inspired gas. Positive inspiratory pressure and ventilatory frequency were adjusted to set the baseline arterial Pco2 at 35 ± 5 mm Hg and were not changed thereafter. To monitor minute ventilation volume (
e), the expiratory limb was connected to a heated pneumotach and to oxygen and CO2 analyzers (O2100C and CO2100C modules; Biopac Systems, Goleta, CA) by means of water-absorbing Nafion (perfluorosulfonic acid copolymer) tubing. Individually calibrated pumps continuously sampled mixed expired gas to the analyzers. Gas sensors were calibrated daily at measured flow rates with gas standards. Pancuronium (0.5 mg · kg–1 · h–1) and Hespan (6% hetastarch; 5 mL · kg–1 · h–1) were infused IV. After a sternotomy, a transit-time ultrasonic flowprobe was positioned around the ascending aorta and connected to a flowmeter. The thorax was left open during the experiment. Paired arterial and venous samples (0.1 mL each) were collected at various time points by using heparinized glass capillaries. Blood Po2, Pco2, and chemistry were measured with a blood gas analyzer. Total Hb concentration, methemoglobin, and Hb oxygen saturation were measured with a cooximeter adjusted for the rat’s Hb absorption spectra (OSM3; Radiometer, Copenhagen, Denmark). An additional 0.06-mL sample was withdrawn for hematocrit determination. All blood samples were replaced by equal volumes of Hespan.
Hespan was used as a hydration fluid and for hemodilutions. HBOC (Hb raffimer; Hemolink) is a polymerized human Hb crosslinked with oxidized trisaccharide o-raffinose and formulated in lactated Ringer’s solution. The characteristics of this HBOC and its manufacturing process have been described in detail elsewhere (9). For use in this study, it was stored in sterile plastic syringes under nitrogen at –70°C and was defrosted 1 h before infusion.
A separate group of Sprague-Dawley rats was used exclusively to collect blood. Blood was withdrawn under sterile conditions from the exposed carotid artery of anesthetized rats into 20-mL sterile syringes containing 2 mL of citrate-phosphate-dextrose solution with adenine (CPD-A; Sigma Chemical, St. Louis, MO). The blood was centrifuged, stored as packed cells (60%–70% hematocrit) in neonatal unit storage bags at 4°C, and maintained for the appropriate length of time (<24 h for fresh blood and 10.5 days for aged blood). Before injection, packed cells were diluted with normal saline to the same Hb concentration as the HBOC (9.5–10 g/dL). Before administration, all solutions were warmed to room temperature and subjected to the analyses described previously.
Animals were heparinized (260 U/kg body weight), and, after at least 20 min of stabilization, two sets of baseline measurements were made. For isovolemic blood exchange, rats were randomly allocated to experimental groups in which isovolemic exchange was performed with fresh blood (n = 13), stored blood (n = 8), or HBOC (n = 8). At the end of the baseline period, animals were subjected to the exchange procedure (rate, 1 mL/min) with 1 of the 3 solutions. Ten minutes after the end of the exchange, one set of measurements was performed. For progressive stepwise hemodilution, to decrease Do2, animals were subjected to 10–14 isovolemic hemodilutions (0.5–1 mL/min) of 3–8 mL/kg. Typically, higher rates and exchange volumes were used in the first five or six steps and slowly decreased as lower values of Hb were achieved. Blood was withdrawn from the femoral artery with a syringe pump, and Hespan was infused through the femoral vein. Five minutes after completion of each dilution, one set of measurements was collected. The time interval between data-collection periods averaged 14 min. The dilution protocol was followed until a terminal stage was reached such that cardiac output (CO) and AP were no longer constant from the beginning to the end of the data-collection period. Typically, the animals died shortly after this terminal stage. A subgroup (n = 5) of the rats receiving fresh blood were used as controls for the hemodilution procedure. These rats were subjected to all surgical procedures (including exchange with fresh blood) except for hemodilution. Animals that needed to be killed early received a pentobarbital overdose of 100 mg/kg IV.
Outputs from the pressure amplifiers, aortic flowmeter, pneumotach, and gas analyzers were connected to a computer for continuous online data acquisition at 500 Hz. Systolic (SBP), diastolic (DBP), pulse, and mean arterial blood pressures (MAP) were calculated from the AP signal. Heart rate (HR) was calculated from the flowmeter signal. CO and mean e were estimated from the aortic flow and pneumotach signals, respectively. Mean stroke volume was calculated as CO/HR. Cardiac index (CI) and stroke index (SI) were computed by dividing the variables by body mass. Mean stroke work was calculated as SI x MAP. Total peripheral resistance (TPR) was calculated as (MAP – central venous blood pressure)/CI. Cardiac contractility was estimated by using the maximum value of the first derivative of aortic flow with respect to time (dF/dtmax). Offline calculations were based on 1-min segments of the digitized signals, taken as close as possible to the blood-collection time points. Global o2 was calculated from blood samples (o2b) and from expired oxygen concentrations (o2a). o2a was calculated as o2a = e (Fio2 – Feo2), where Fio2 and Feo2 are the fractions of inspired and expired oxygen, respectively. o2b was calculated by the product of CI and the difference between arterial (Cao2) and venous oxygen contents. Whole-animal Do2 was computed as the product of Cao2 and CI. Accordingly, 2 oxygen-extraction ratios (O2ER) were computed: O2ERa = o2a/Do2 and O2ERb = o2b/Do2. Do2crit was determined in each animal from plots of o2 against Do2, as described previously (10). In brief, for each rat, o2 was plotted against Do2, and regression lines were fitted to the delivery-dependent and delivery-independent portions of the o2/Do2 curve. The Do2 at which these two regression lines intersected indicated the Do2crit.
Values are reported as mean ± sem. Differences among groups were analyzed with one-way analysis of variance. When a significant F-value was encountered, post hoc analyses were performed between groups by using Bonferroni’s correction for multiple comparisons. Although some data are presented as percentage change from baseline (for clarity), the statistical tests were performed with the original, absolute values. The P values correspond to two-tailed tests with significance set at 0.05.
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Results |
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Control animals subjected to all procedures except hemodilution showed relatively stable physiological variables throughout the experimental period of 5 h and maintained high oxygen saturation and Po2. Values of Do2 and
o2 did not differ by >30% from the baseline measurements. The animals subjected to transfusion were divided into groups according to the fluid tested: HBOC (H), fresh (F), and stored (S) blood. Baseline values for systemic variables were within physiological limits and were similar for all groups of animals. The biochemical analysis of the fluids used for exchange obtained just before injection showed that stored blood and HBOC had significantly higher lactate levels than fresh blood. MetHb levels of HBOC were always less than 5%. The exchange volumes were similar for all animals (30.6 ± 0.3 mL/kg), and the time to complete the exchange averaged 13.2 ± 0.2 min. After exchange, arterial Pco2 was higher in HBOC-treated rats, whereas venous Pco2 was higher in blood-treated animals. The acidosis after blood infusion was characterized by a highly significant (P < 0.001) decrease in pH for all rats and by decreased base excess (BE) and bicarbonate with a simultaneous increase in lactate. The hyperglycemic response of blood-treated animals contrasted with the hypoglycemia observed in HBOC-treated rats. Mean ventilation (250 ± 9 mL/min) did not change after exchange. Figure 1, A and B, presents hemodynamic and cardiac data from transfused animals. Animals receiving HBOC showed significant increases in MAP that started within 1 min after the beginning of the transfusion and that gradually decreased over the following hour. Conversely, blood-treated animals showed hypotension that also gradually subsided over the following hour. Despite the increased MAP and TPR, animals receiving HBOC presented a better cardiac performance than animals receiving blood, as expressed by comparatively higher values for all variables except HR. The difference between HBOC-treated and blood-treated animals was particularly striking for SW, reflecting the cumulative effects of higher CI and MAP. Figure 1, C and D, presents oxygenation data from transfused animals. HBOC-treated animals showed less pronounced decreases in Do2 and venous Hb oxygen saturation than rats receiving blood. Regarding Do2, the difference between rats receiving blood and those receiving HBOC was mainly due to the difference in CI (Fig. 1A). No change in the baseline level of O2ER (0.30 ± 0.05) was observed for HBOC-treated animals, whereas blood-treated rats showed significant increases in O2ER—to 0.49 ± 0.05 and 0.38 ± 0.06, respectively. Most of the effects shown in Figure 1 were still present 25 min later, after the first step of hemodilution was concluded.
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The number of hemodilution steps and the total volume of Hespan used were similar for all animals, averaging 13 ± 1 and 64.1 ± 2.2 mL/kg, respectively. Figure 2A–C illustrates that each isovolemic exchange led to progressively lower Hb and Do2 and followed similar time courses. Measurements made after the last dilution step showed that, before death, all animals presented the same Hb concentration (1.8 ± 0.1 g/dL). These measurements also revealed a "terminal" Do2 of 5.0 ± 0.6 mL · min–1 · kg–1, 4.5 ± 0.4 mL · min–1 · kg–1, and 5.9 ± 0.6 mL · min–1 · kg–1 for Groups F, H, and S, respectively. The decrease in Do2 led to changes in systemic variables that were qualitatively and quantitatively similar for all animals, as illustrated in Figure 2D for the increase in lactate during hemodilution as a function of Do2. In all animals, the main change occurred after Do2 reached 10 mL · min–1 · kg–1, although HBOC-treated animals died with higher levels of lactate.
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, n = 129) and from 8 rats that received stored blood (
, n = 124) before hemodilution. HBOC = hemoglobin-based oxygen carrier.
The Do2crit was determined with o2b and o2a. Regardless of the method used, similar values of Do2crit were found for animals from all groups (Table 1). In many cases, the data could not be adequately fitted by two crossing regression lines, and an inflection point could not be found in a given o2/Do2 relationship. Therefore, the number of Do2crit determinations is different for various groups in Table 1. Because the systemic variables presented relatively stable values when Do2 was above Do2crit, these values were averaged to represent means during aerobic conditions. Systemic variables were also averaged when Do2 was below Do2crit to represent means during anaerobic conditions. This approach helped to organize and analyze a wealth of data while still preserving the focus of studying systemic variables under conditions of Do2crit. The overall Do2crit averaged 10.0 mL · min–1 · kg–1, and the sd was 2.5 mL · min–1 · kg–1. This sd was used to organize >9000 measurements obtained from 24 animals. Data in Tables 2–4 are grouped into three hemodilution levels according to the o2/Do2 relationship: above Do2crit or Do2 independent (Do2 >12.5 mL · min–1 · kg–1), close to Do2crit (Do2 of 7.5–12.5 mL · min–1 · kg–1), and below Do2crit or Do2 dependent (Do2 <7.5 mL · min–1 · kg–1).
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The arterial oxygen content levels were similar for all animals, averaging 8.1 ± 0.4, 3.9 ± 0.2, and 2.5 ± 0.1 mL/dL for each hemodilution level, respectively. Likewise, venous oxygen content averaged 5.4 ± 0.4, 1.8 ± 0.1, and 0.9 ± 0.1 mL/dL. Table 2 presents data on oxygenation variables averaged over the three Do2 ranges defined previously. As expected, HBOC-treated rats showed a significantly lower arterial Hb oxygen saturation throughout the hemodilution because of the characteristic Hb oxygen-dissociation curve of the Hb raffimer (9). Otherwise, changes were similar for all animals.
Hemodynamic and cardiac data from hemodiluted animals are shown in Table 3. Because of the particular cardiovascular responses of animals receiving HBOC, prehemodilution values of these rats were different from those of animals receiving blood. Although the trend during hemodilution was similar for all animals, HBOC-treated animals presented higher MAP, DBP, SBP, and TPR throughout the hemodilution.
Table 4 shows data on changes in blood electrolytes and glucose. Biochemical values of arterial blood also reflected similar responses to hemodilution for animals from all groups. Similar values were found for venous blood.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We investigated physiological variables describing biochemical and oxygen transport patterns in animals subjected to a stepwise hemodilution until death. Our hypothesis was that 50% replacement of native Hb by HBOC or by stored blood would not alter the ability of animals to respond to decreases in Do2. The main findings were that 1) Do2crit was not different between animals receiving blood or HBOC, 2) terminal Hb concentration and Do2 were similar for all animals, and 3) most oxygen transport and biochemical variables changed similarly during hemodilution.
A stable preparation was developed to investigate >60 different systemic variables, and a protocol of several hemodilution steps was chosen to obtain enough Do2 values to adequately estimate Do2crit and to evaluate the efficacy of transfused Hb in carrying oxygen. Although previous studies examined systemic variables during hemodilution (8,11,12), this is the first study to specifically address Do2crit levels after transfusion with stored blood and Hb raffimer, with fresh blood as a control. In addition, these three transfusion fluids have never been compared with one another with respect to so many systemic variables, including Do2. These fluids have clinical importance because stored blood and HBOC may be important options to increase oxygen-carrying capacity in surgical and acute trauma settings.
Analysis, performed before injection, of the fluids used for exchange showed higher metHb levels in HBOC than in transfused blood, but the level was still less than 5%. In addition, circulating MetHb levels after exchange were consistently less than 3% in all animals. These levels probably did not significantly alter the ability of these solutions to deliver oxygen (13).
Rats subjected to exchange with HBOC showed pronounced hypertension (increased afterload) with increased CO. Although ventricular dP/dt was not measured, other indices of cardiac performance (Fig. 1) were suggestive of increased contractility. Because HBOC is less viscous than whole blood and because hematocrit was decreased, most of the observed cardiac effects may have been due to decreased blood viscosity. However, the Hb raffimer may have had some inotropic action. These findings suggest that the increase in MAP with this HBOC did not negatively affect cardiac performance in this experimental model. In contrast, blood-treated animals showed markedly decreased cardiac performance and hypotension. The cause for this effect is unknown, but it may be partially due to the composition of the stored blood. The blood used in the rats of Groups F and S always had a lower pH than normal blood, and this might have negatively affected cardiac performance. Blood preservation with CPD-A results in progressively lower pH, as observed in this and in previous (14) studies. CPD-A-preserved blood chelates calcium (15), which will decrease myocardial contractility. However, it is unclear to what extent acute differences in cardiac function with this animal model are clinically relevant in human transfusion versus the use of HBOC. In addition, acidosis results in a decreased concentration of 2,3-diphosphoglycerate in RBCs and in less delivery of oxygen to the tissues (14).
Overall Do2 has been previously measured with CO and Cao2, whereas overall body metabolism was evaluated with o2 by using CO and the arteriovenous oxygen content difference (16–18). In the current study, whole-body Do2 and o2 were also measured by using this approach. A common criticism in experiments dealing with the o2/Do2 relationship is that both variables depend on the CO measurement. Therefore, o2 was also measured by a CO-independent method. Although estimations using blood samples (o2b) and expired gas (o2a) led to similar Do2crit values, an inflection point was more often found when o2a was used.
Do2crit (the level at which o2 becomes dependent on Do2) is an important benchmark in the response of the organism to changes in oxygen availability. The average Do2crit (10 mL · kg–1 · min–1; equivalent to Hb 3 g/dL, as shown in Fig. 2C) was similar to the value reported for dogs (8) and was not different for animals treated with Hb raffimer or blood. However, the fact that this HBOC maintains Do2 in conditions where the oxygen unloading by Hb is optimized for RBCs (low Po2, high Pco2, and low pH) indicates that even in critical physiological conditions, the administration of Hb raffimer did not compromise Do2 when compared with blood. This concept is further corroborated by the findings of similar levels of pH, BE, bicarbonate, and Pco2 in HBOC-treated rats and animals receiving blood when Do2 was less than Do2crit. In addition, changes in venous Po2 and venous Hb oxygen saturation were similar among animals from all groups. Mixed venous Po2 has been used as a marker of tissue oxygenation at a whole-body level (11,19,20). As reported previously (11), venous Po2 and venous Hb oxygen saturation decreased with hemodilution in our study, and the mean venous Po2 at Do2crit was less than the value reported for dogs (8).
The sustained increase in TPR for HBOC-treated animals during hemodilution resulted from higher MAP and lower CI at all Do2 levels. Hypertension has been also observed in humans (21) and in experimental animals (22,23) after HBOC administration. The mechanism of this hypertension is not fully understood but is thought to be related to the nitric oxide-scavenging activity by Hb, inhibition of endothelial cell-relaxing factors (4,24,25), and autoregulation (26). Whatever the cause, animals showed nearly normal MAP, whereas Do2 levels were well below Do2crit. Vasoconstriction could also cause changes in the microvascular distribution of oxygen (27), although compromised tissue oxygenation is not always associated with the pressor effects of Hb (26,28–30). Previous studies have shown that HBOC-induced vasoconstriction may reduce CO (4,31). This increase in afterload might explain the lower CI, SI, and dF/dtmax found in HBOC-treated rats during hemodilution.
In summary, our studies showed that HBOC-treated animals presented systemic responses to hemodilution comparable to those of animals that received blood. At each Do2 level, differences among groups in most physiologic variables were small, but the overall pattern of changes was consistent as Do2 decreased. The results suggest that tolerance to Do2crit is not altered by 50% replacement of native Hb by stored blood or Hb raffimer.
The authors are indebted to Drs. Michael Shannon and George Biro for their insight in the development of the model and data analysis. The authors are also grateful to Dr. Jiepei Zhu for excellent support in the initial phase of the work; to Brian Berger for expert assistance in the methodology; to Dr. Penny Reynolds, Ben Pierce, and Leonardo Somera III, who assisted in the data analysis; and to Biopac Systems technical support for consultation for the data acquisition and analysis.
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Footnotes |
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Supported in part by a grant from Hemosol.
Accepted for publication September 16, 2004.
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