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© 2001 International Anesthesia Research Society
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Abstract |
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We investigated the ability of hemoglobin-based oxygen carrying solutions (HBOCs) to alleviate fetal hypoxemia from maternal hemorrhage. Fifteen pregnant ewes (132-day gestational age) were hemorrhaged 20 mL/kg over 1 h; they were randomized to receive 20 mL/kg IV of HBOC, hetastarch (HTS), or autologous blood (BLD) (n = 5 each) over 30 min and were monitored for 2 h. Hemorrhage significantly (P
0.05) decreased maternal mean blood pressure (from 98 to 48 mm Hg, median), arterial oxygen content (from 12.2 to 11.1 mL/dL), and fetal arterial oxygen content (from 8.1 to 3.9 mL/dL). Fluid replacement restored maternal blood pressure in all groups, although maternal oxygen content immediately returned to baseline only after BLD or HBOC. Maternal oxygen saturation decreased after HBOC (from 98% to 88%). Fetal oxygen content rapidly returned to baseline with either BLD (7.1 mL/dL) or HBOC (8.0 mL/dL) but was never restored with HTS (4.7 mL/dL), and, 60 min after fluid replacement, it was higher with HBOC (8.3 mL/dL) than with HTS (4.7 mL/dL). Fetal plasma-free hemoglobin did not change after HBOC. In conclusion, maternal fluid replacement with HBOC or BLD effectively restored fetal oxygenation, primarily by restoring maternal oxygen content, whereas HTS did not.
Implications: Hemoglobin solutions eliminate many limitations of blood transfusions. Ourresults show that fluid replacement with either blood or a hemoglobinsolution, compared with hetastarch, restored fetal oxygenation in pregnantewes after hemorrhage. If applicable to women, these results suggest apotential for the use of hemoglobin solutions in obstetrics.
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Introduction |
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Hemorrhage is associated with 25% of pregnancy-related maternal deaths (1). Although blood transfusions are indicated for peripartum hemorrhage, compatible blood is often unavailable, or there are religious or moral objections to its administration. Furthermore, there are risks, especially the transmission of infectious diseases, associated with the use of homologous blood products (2,3). Crystalloid and colloid fluids may deleteriously reduce oxygen delivery and promote systemic and pulmonary edema (4,5). These concerns have prompted the development of hemoglobin-based oxygen-carrying (HBOC) solutions for use as red cell substitutes.
The effects of the maternal administration of polymerized bovine hemoglobin solutions on the fetus have not been reported. Differences in formulation of these solutions (e.g., molecular size and the degree of polymerization) may cause differences in their pharmacodynamic and pharmacokinetic properties (6–8), making it difficult to predict their fetal effects. For example, some solutions cause increases in systemic and pulmonary arterial pressures (6,9–11) and coronary (8) and cerebral vasoconstriction (12). If uterine blood vessels also vasoconstrict, the usefulness of a hemoglobin solution in pregnant patients may be limited because uterine blood flow and oxygen delivery to the fetus may be diminished. Published data indicate that generalized vasoconstriction does not occur consistently with these fluids (13). Fetal oxygenation might still be adequate, regardless of the maternal cardiovascular response, because polymerized bovine hemoglobin delivers more oxygen to tissues than does homologous whole blood (14–18).
By using a standard sheep model of maternal hemorrhage to produce fetal hypoxemia (19), fetal cardiopulmonary variables were compared after maternal fluid replacement with equivalent volumes of a specific glutaraldehyde-polymerized bovine hemoglobin solution (HBOC), synthetic colloid (hetastarch; HTS), or autologous blood transfusion (BLD). Our primary interest was to obtain preliminary data determining whether or not HBOC provided a benefit over traditional, commonly used colloid. BLD was compared as the standard fluid replacement fluid for hemorrhage. We hypothesized that the three solutions would equivalently restore maternal hemodynamic and cardiopulmonary variables. We also hypothesized that, for hypoxemic fetuses, HBOC would improve fetal condition, including oxygenation, better than HTS.
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Methods |
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Cornell University’s Animal Care and Use Committee approved all procedures. Sixty-kilogram body weight Rambouillet ewes (n = 16, initially) of 128–133 days’ gestational age had food and water withdrawn 24 and 12 h, respectively, before surgical instrumentation. They were premedicated with ketamine HCl (20 mg/kg) and glycopyrrolate (0.02 mg/kg) IM and maintained with halothane anesthesia. Instrumentation consisted of two maternal jugular venous catheters (for hemorrhage and for fluid and drug administration), one maternal carotid artery catheter (for blood pressure monitoring and blood sampling), a 6-mm uterine artery ultrasonic velocity flowprobe and a 4-mm umbilical artery flowprobe (Transonic Systems Inc., Ithaca, NY), and a fetal carotid artery and left femoral artery catheter (for blood sampling and blood pressure monitoring). An amniotic cavity catheter permitted correction of fetal blood pressures for changes in maternal position and uterine contractions.
After surgery, ewes received phenylbutazone (0.5 g by mouth, twice a day) for postsurgical analgesia and antibiotic therapy (1.5 g IV ampicillin twice a day). Catheter patency was maintained by constant heparinized saline infusion (25 U/mL, 12 mL/day).
Three to five days after surgery, the sheep underwent a single-day study with four phases: baseline (30 min), hemorrhage (60 min), fluid replacement (30 min), and postfluid replacement (120 min).
After baseline recordings, ewes were hemorrhaged four times (5 mL/kg over 10 min), with 5 min between hemorrhages. The 20 mL/kg total hemorrhage volume mimicked intermittent maternal bleeding from conditions such as placental abruption or placenta praevia. Ewes then were randomized into three groups and received 20 mL/kg IV of BLD (n = 5), HTS (6%; Du Pont Pharmaceuticals, Wilmington, DE; n = 6), or HBOC (130 gm/L, Oxyglobin Solution®; Biopure Corporation, Cambridge, MA; n = 5) over 30 min. These doses of HTS and HBOC were estimated to provide similar blood volume expansion for the study duration on the basis of similar oncotic pressures of 35 and 31 mm Hg (20), respectively, and on similar elimination half-lives of 30–40 h (21,22). HTS, often used clinically, was selected because earlier studies already provided some comparisons between it and HBOC (7,11,15,18). During the 2-h postfluid replacement period, no additional intervention took place. The most salient differences in the effects of fluid replacement were predicted to occur within the first 30 min, and the additional time provided an opportunity to evaluate the acute effect of these changes. Ewes were killed with sodium pentobarbital. Necropsies were performed to obtain fetal weights and to verify catheter and flowprobe placement.
The total volume of hemorrhaged maternal blood and the number of fetal deaths were measured. Maternal blood pressure transducers were zeroed at the ewe’s thoracic inlet, and fetal blood pressures were corrected by subtraction of amniotic pressures. Maternal and fetal systemic arterial blood pressures, heart rates, amniotic pressures, and uterine and umbilical artery blood flows were measured continuously. At the end of baseline, hemorrhage, and fluid replacement, and at the end of each hour of the postfluid replacement period, maternal and fetal arterial blood samples were obtained for arterial pH, blood gas tensions, hemoglobin concentration, hematocrit, oxygen saturation, and arterial oxygen content (CaO2) measurement. These blood samples also were used to measure sodium, potassium, chloride, ionized calcium, and glucose concentrations. Maternal and fetal free-plasma hemoglobin concentrations were measured by using aliquots of blood from the HBOC sheep at these time points.
Blood gas tensions, pH, electrolytes, and glucose were measured with an ABL System 600/605 (Radiometer Medical A/S, Copenhagen, Denmark) immediately after each blood sample. Hemoglobin concentration and percentage of oxygen saturation were measured with an automated hemoximeter (OSM2 Hemoximeter®; Radiometer Medical A/S) calibrated for sheep hemoglobin. Hematocrit was determined by microcentrifugation. Total blood and free plasma hemoglobin concentrations were measured with an automated ß-hemoglobin photometer (HemoCue®; HemoCue AB, Helsingborg, Sweden). Oxygen content was measured with an oxygen-specific fuel cell (LexO2Con–K; Hospex Fiberoptics, Chestnut Hill, MA). In five animals in which the oxygen-specific fuel cell was unavailable, oxygen content was calculated by using the following equation:
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where [Hb] = total blood hemoglobin concentration, SaO2 = arterial oxygen saturation, and PaO2 = arterial partial pressure of oxygen. The constant 1.31 is the oxygen-binding capacity of hemoglobin (23).
The calculated oxygen content values and the measured values for those sheep (n = 11) in which both measurements were possible were compared. This comparison indicated that the source of these values could be ignored.
Data were skewed, and therefore nonparametric statistical tests were used (24). A significant P value was set at 0.05. To demonstrate adequacy of the model, comparisons of hemorrhage measurements back to baseline measurements within groups were done for all ewes or fetuses combined, with Wilcoxon’s signed rank test. Within-group comparisons after fluid replacement back to baseline were performed by using Wilcoxon’s signed rank test with Bonferroni’s correction (individual P 0.033 for significance). Between-group comparisons during baseline and hemorrhage were done by using the Kruskal-Wallis test. If even a tendency toward a significant difference (P 0.10) was detected between groups at either baseline or hemorrhage, then the percentage of change from baseline was used for that variable for all future comparisons. Percentage of change from baseline was used for maternal CaO2, hemoglobin concentration, hematocrit, PaO2, and fetal hemoglobin concentration. Comparisons after fluid replacement were made only between the HBOC group and either BLD or HTS (comparisons were not made between HTS and BLD) by using Wilcoxon’s ranked sum test with Bonferroni’s correction (individual P 0.025 for significance). All comparisons were two-tailed except for variables in which results could be predicted (e.g., maternal hemoglobin) or were known from previous models (e.g., fetal response to maternal hemorrhage) (19). Data are reported as median (range).
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Results |
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No differences were detected in the descriptive statistics of the treatment groups (Table 1). Maternal and fetal electrolytes were within the normal range throughout, and there were no differences between groups (data not shown). One HTS fetus died during hemorrhage. This lamb and ewe were eliminated from the study. All remaining fetuses (n = 15) survived through the fluid replacement period.
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Maternal hemorrhage created the expected hypotension (Fig. 1) and decreased maternal hemoglobin concentration, hematocrit, oxygen content, uterine blood flow, and uterine oxygen delivery (Figs. 1and 2, Table 2). These changes had consequential effects on fetal oxygenation, including a decrease in fetal PaO2, SaO2, and oxygen content (Fig. 3). Maternal hemorrhage resulted in no change in maternal blood gas measurements, but a fetal mixed acidosis developed (Tables 2 and 3).
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Maternal systemic blood pressure was restored in all groups, with HBOC ewes having a blood pressure more than baseline (Fig. 1). Maternal oxygen content was restored immediately after both BLD and HBOC, but with HTS, it was not restored until 120 min after fluid replacement. At 60 min after fluid replacement, maternal oxygen content after HTS was less than after HBOC (Fig. 2). As expected on the basis of fluid characteristics, changes in oxygen content coincided with changes in total hemoglobin concentration. The maternal total hemoglobin concentrations returned to baseline after either HBOC or BLD but remained decreased after HTS (Fig. 2). The maternal hematocrit returned to baseline after BLD but remained decreased after either HBOC or HTS (Table 2). The HBOC hematocrits were less than the BLD hematocrits (Table 2). Maternal oxygen saturation after HBOC was lower compared with baseline and compared with both HTS and BLD at all times (Table 2). Uterine blood flow and oxygen delivery returned to baseline for HBOC and BLD ewes (Fig. 1). Because of technical failures, there were insufficient numbers to evaluate the HTS group.
After maternal fluid replacement, fetal CaO2 was restored for up to 1 h with BLD and at least 2 h after HBOC (Fig. 3). Fetal CaO2 was never restored after HTS and was significantly less than HBOC at 60 min after fluid replacement (Fig. 3). Similarly, fetal PaO2 and oxygen saturation were restored after BLD or HBOC, but not after HTS (Fig. 3). At 60 min after fluid replacement, oxygen saturation was more with HBOC than either BLD or HTS. Furthermore, fetal oxygen saturation remained at baseline values after HBOC but decreased below baseline by 120 min after BLD.
After fluid replacement, fetal metabolic acidosis persisted in all groups for up to an hour before returning to baseline (Table 3). For the HTS fetuses, the persistent acidosis was caused both by decreased base excess and by slight hypercapnia (Table 3).
Other fetal variables did not change (Table 3). As predicted if HBOC did not cross the placenta, free plasma hemoglobin concentrations in HBOC fetuses did not change. The median concentration was 0.1 g/dL (0.1–0.2 g/dL) at baseline, 0.1 g/dL (0.0–0.4 g/dL) after hemorrhage, and 0.1 g/dL (0.0–0.1 g/dL), 0.0 g/dL (0.0–0.1 g/dL), and 0.1 g/dL (0.0–0.1 g/dL) at the end of fluid replacement and during the 1- and 2-h postfluid replacement periods, respectively.
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Discussion |
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The HBOC used, Oxyglobin Solution, is a glutaraldehyde-polymerized bovine hemoglobin solution licensed for veterinary use in dogs in the United States and Europe. Its counterpart, Hemopure® (Biopure, Cambridge, MA), is being evaluated for human use. These HBOCs are compatible with all species and blood types, thus eliminating transfusion risks and removing the need for compatibility testing (20,21). They have produced normovolemic hemodilution and treated hemorrhage or hemolytic anemia in several species (7,10,18), including humans (7,11,16–19). Although their effects in pregnancy have never been investigated, their combined colloidal properties and unique oxygen-carrying capacity suggest that they might be useful in some obstetric emergencies, e.g., placental abruption or placenta praevia.
This study obtained preliminary data on fetal oxygenation measurements to introduce the potential for using HBOC in the treatment of acute hemorrhage during pregnancy. We used equivalent volumes of the treatments because this was the simplest method of obtaining an initial comparison. Other fluid replacement end points, such as filling pressure, blood pressure, or cardiac index, were not chosen because the direct cardiovascular effects of HBOC are not clearly defined, even in nonpregnant animals. Similarly, because data suggest that the amount of oxygen delivered per gram of hemoglobin is three to four times more with HBOC than with BLD, another purported limitation of our study is that we did not deliver an equivalent amount of oxygen-carrying capacity to the ewe. However, our primary interest in fetal oxygenation was in comparison with the colloid HTS and, to administer equivalent oxygen-carrying capacity of BLC and HBOC, the volumes would have been vastly different and would have made any comparison with HTS impossible. Thus, because all the fluids were colloids, the assumption was made that the administration of equivalent volumes would result in a similar initial maternal blood volume expansion. Thus, results should be interpreted while realizing that equivalent volumes of fluid replacement fluid were administered and acknowledging that because of this, not all maternal variables could be resuscitated to a standard end point simultaneously.
This model of maternal hemorrhage was chosen because although it results in minimal metabolic changes to the ewe, it produces acute fetal hypoxemia and acidemia (19). The fetus is more profoundly affected than the ewe because of its limited ability to compensate for decreased maternal oxygen content and uterine blood flow, which combine to produce a severe decrease in oxygen delivery to the fetus. Although the fetus can partially compensate by redistributing its blood and decreasing unnecessary oxygen use, these responses are limited (19,25). The degree of fetal distress in this model is further indicated by the 6% fetal mortality. As expected, only mild differences were observed in the maternal response to the type of fluid replacement. However, fluid replacement with either BLD or HBOC compared with colloid solution conferred a beneficial effect on fetal oxygenation and acid-base variables.
Because there was no free hemoglobin in the plasma of the HBOC fetuses, fetal changes were caused by the effects of fluid replacement on the dam and not placental transfer of the HBOC. Whether or not other HBOCs cross the placenta or this HBOC would cross the placenta in nonepitheliochorial placentae species (i.e., humans) is unknown.
For all groups, decreases in fetal PaO2, oxygen saturation, and CaO2 during hemorrhage paralleled decreases in maternal CaO2, uterine blood flow, and uterine oxygen delivery. After maternal fluid replacement, only BLD and HBOC fetuses had a restoration of fetal oxygen variables, and these paralleled increases in maternal oxygen content, uterine blood flow, and uterine oxygen delivery. Maternal oxygen content in the HTS group was restored by 120 min, but fetal oxygen variables were still decreased. Thus, although adequate maternal oxygen content is one of the principal mechanisms for maintaining fetal oxygen variables, other factors, such as uterine blood flow, also play a vital role. The ultimate effect of decreased fetal oxygen content in the HTS group could not be determined from this study because there was no difference in acute fetal mortality.
It is interesting to note that the oxygen saturation in HBOC fetuses was temporarily increased over that of BLD or HTS fetuses. Differences in the kinetics of oxygen delivery with HBOC may account for this difference, despite apparently similar rates of uterine oxygen delivery in the BLD and HBOC ewes. HBOC delivers three times more oxygen on a gram-for-gram basis compared with equal amounts of hemoglobin stored in red blood cells (14–16). Previous data demonstrate improved tissue oxygenation in muscles with HBOC compared with red blood cells. This is thought to be an increased efficiency of oxygen delivery and change in blood viscosity and velocity (17,18). This latter mechanism is indirectly supported in our study by the tendency for uterine blood flow to consistently be increased in HBOC ewes compared with BLD ewes. Improved pulmonary diffusion capacity of oxygen, up to 20% above baseline, has also been reported after HBOC administration (17). Therefore, it is possible that fetal oxygenation may improve in animals receiving HBOC as compared with a colloid (the HTS group had less oxygen content and oxygen saturation) and autologous fresh whole BLD (the BLD group had less oxygen saturation).
All solutions restored maternal hemodynamic measurements to at least baseline values, although maternal blood pressure after HBOC was higher than baseline. Previous reports suggest that HBOCs cause an increase in blood pressure by increasing systemic vascular resistance through platelet-activating factor (9), nitric oxide scavenging (13), adrenergic- or endothelin- related mechanisms (6), or effects on calcium-channel function (6). However, HBOCs also increase plasma colloidal osmotic pressure (20). Thus, we cannot discount the subsequent acute translocation of interstitial fluid into the vascular compartment that might contribute to increased maternal blood pressures. Irrespective of the mechanism behind these changes, normalization of uterine blood flow and uterine oxygen delivery is the most important variable for the fetus. Because uterine blow returned to baseline with the HBOC ewes and there was no difference between the HBOC and BLD groups after fluid replacement, uterine vascular resistance does not seem to increase selectively after HBOC.
Overall, changes in maternal CaO2 paralleled changes in maternal hemoglobin concentrations. In BLD ewes, the restoration of CaO2 was associated with replenishment of cell-associated hemoglobin. In contrast, HBOC restored oxygen content by increasing free-plasma hemoglobin (20–22) and thus caused the expected decreased hematocrit. HTS, providing neither cell-associated nor free hemoglobin, caused a decrease in hemoglobin and hematocrit, and thus oxygen content.
Maternal arterial oxygen saturation was decreased in HBOC ewes. This was expected and was attributed to differences in the hemoglobin dissociation curves between whole red cells and free bovine hemoglobin (7,14). Nevertheless, CaO2 was maintained in these animals, apparently because of the increase in plasma-free hemoglobin.
In this ovine model of acute hemorrhage, initial maternal fluid replacement with HBOC restored fetal oxygenation similarly to a blood transfusion, whereas fetal oxygenation was not restored with standard colloid fluid replacement. These preliminary results suggest a potential for the use of hemoglobin solutions in obstetrics and support the need for additional investigations.
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Acknowledgments |
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Supported, in part, by the United States Department of Agriculture Hatch Act, Cornell Veterinary College Consolidated Research Grant, and National Institutes of Health grant HD 21350.
The authors acknowledge Biopure Corporation (Cambridge, MA) for the supply of HBOC-301 (Oxyglobin Solution).
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