Current Topics in Fluid Therapy: Oxyglobin

Summary

Although hemoglobin solutions such as Oxyglobin® (Biopure Corporation) can increase the amount of oxygen carried by blood, they may not effectively deliver oxygen to tissues due to vasoconstriction and reduced cardiac output. Monitoring return of vascular pressures to normal levels as an indicator of adequacy of resuscitation may not be appropriate when vasoactive hemoglobin solutions like Oxyglobin®are administered for the treatment of acute hemorrhagic hypovolemia. The vasoactivity of hemoglobin solutions, however, may prove useful in the treatment of sepsis.

It has been said that all one really needs to know about anesthetic case management can be summarized in the statement that "Air goes in and out, blood goes ‘round and ‘round, and fluids are almost always a good idea". Perianesthetic and intraoperative fluid therapy in veterinary medicine has been extensively reviewed [1-4]. Rather than painting the lily by restating what has already been written on this extensive subject, this chapter will emphasize recent findings concerning the use of oxygen carrying hemoglobin solutions in the perianesthetic period, with particular attention to the issues of vascular reactivity and tissue oxygen delivery.

Oxyglobin® was introduced to the United States veterinary market in 1998; a human version, HBOC-201 is currently undergoing phase 1 and 2 testing. Oxyglobin® is a dark purple, sterile, polyionic colloidal fluid, pH 7.8, based on glutaraldehyde-polymerized, ultrapurified bovine hemoglobin formulated in a modified lactated Ringer’s solution. It contains 13 g/dl of hemoglobin with a P50 of 35 mmHg; the P50 for normal dog hemoglobin is 26 mmHg. The oncotic pressure of Oxyglobin® is similar to that of 5% albumin while the osmolality is similar to that of normal plasma. Polymerization of the bovine hemoglobin tetramer maintains a molecular weight mainly between 65 and 130 kD; this is important in order to prevent breakdown and excretion of hemoglobin dimers with their subsequent renal toxicity. A major advantage of cell-free hemoglobin solutions such as Oxyglobin® is that they lack the antigenic red cell stroma present in whole blood and thus do not require crossmatching prior to infusion. Oxyglobin® is approved by the Food and Drug Administration (FDA) for the treatment of anemia in dogs, but it has been administered on a compassionate basis to many different species including horses, cats, birds, and several exotic species.

Hemoglobin solutions cooperatively bind, carry, and deliver oxygen according to their oxygen binding characteristics. Oxyglobin®distributes within the plasma space and can potentially improve overall oxygen carrying capacity, not only by increasing total hemoglobin concentration in excess of that found in circulating erythrocytes, but also through facilitative transport of oxygen between erythrocytes and tissue and the “near wall excess” phenomenon where plasma containing cell-free hemoglobin is concentrated at the walls of blood vessels. Model simulations in vitro show that a mixture of erythrocytes and 30% extracellular hemoglobin solution can transport oxygen with virtually the same efficiency as pure hemoglobin solutions of the same overall hemoglobin content and more efficiently than erythrocyte suspensions of equivalent hemoglobin concentration [5].

Adequate transport of oxygen to tissues, however, relies on two factors: oxygen content of the arterial blood and distribution of that blood to locations of oxygen consumption. The efficacy of hemoglobin-based solutions may be limited by their vasoactivity. Early cell-free hemoglobin solutions were noted to cause vasoconstriction accompanied by increased systemic and pulmonary blood pressures. Nitric oxide (also known as endothelium-derived relaxing factor) is produced in vascular endothelial cells and is an important factor in the normal regulation of vascular smooth muscle tone. In general, hemoglobin solutions reduce vascular nitric oxide (NO) activity by binding to and inactivating the NO molecule, rather than inhibiting its production [6,7]. The heme moiety preferentially binds NO with an affinity at least 300,000 times greater than that for oxygen [8]. There is considerable evidence to support the hypothesis that the vasoconstrictor effect of hemoglobin is due at least in part to reduced availability of NO [9,10]. Crosslinked purified bovine hemoglobin has also been shown to similarly impair endothelium-dependent relaxation in isolated large canine conduit arteries through the L-arginine-NO pathway [11]. Improved oxygen delivery to tissues may, therefore, not be realized when administering vasoactive hemoglobin solutions such as Oxyglobin®.

One of the first veterinary clinical reports concerning the use of polymerized ultrapure bovine hemoglobin was that of Maxon and coworkers [12]. They administered 2,250 mls of the substance (supplied by Biopure) to a hemorrhaging 75 Kg miniature horse that was instrumented for measurement of cardiac output and vascular resistance. Cardiac output decreased, from 13.7 to 10.1 L/min, while pulmonary arterial pressure increased, from 10 to 40 mmHg, and central venous pressure increased from 1 to 18 mmHg. The authors claimed the reduction in cardiac output was consistent with increased plasma volume and oxygen-carrying capacity of hemoglobin, but acknowledged that hemoglobin-induced vasoconstriction was a possible cause for the increased pulmonary arterial and central venous pressures [12,13].

Findings of impaired oxygen delivery due to reduced cardiac output have since been reported in anesthetized human beings undergoing perioperative hemodilution with Biopure HBOC-201. Thirty minutes following a single dose of 3 ml/Kg of HBOC-201, mean arterial pressure, systemic vascular resistance index, and cardiac index were 149%, 169%, and 75% of their respective preinfusion values; oxygen delivery index and oxygen consumption index were reduced to 79% and 76% of their preinfusion values, while arterial oxygen content and oxygen extraction ratio were unchanged [14]. Because 3 ml/Kg HBOC-201 was not sufficient to augment the oxygen-carrying capacity of circulating blood, the observed cardiac output reduction actually decreased oxygen delivery. In a later study, HBOC-201 at 6.9 ml/Kg and 9.2 ml/Kg (equivalent to 55 to 97 g of hemoglobin) was shown to similarly increase both systemic and pulmonary vascular resistance index and reduce cardiac output; significantly, these changes were not dose-dependent [15]. Although hemodilution with HBOC-201 maintained arterial oxygen content at levels higher than an equivalent volume of hydroxyethyl starch, the advantage of a greater oxygen-carrying capacity was again offset by the increase in systemic vascular resistance and the resulting net decrease in cardiac index and oxygen delivery index. Interestingly, oxygen consumption index was maintained by an increased oxygen extraction ratio.

Similarly, systemic oxygen delivery in anesthetized foxhounds was not improved during isovolemic hemodilution with ultrapurified polymerized bovine hemoglobin over a range of hematocrit values [16]. At a hematocrit of 0.10, arterial oxygen content in hemoglobin-treated dogs was nearly twice that observed in hydroxyethyl starch diluted animals, however this gain in oxygen-carrying capacity was completely negated by a 32 - 40% reduction in cardiac output. Both systemic and pulmonary vascular resistances were noted to increase 30% over baseline, as well. Oxygen delivery was maintained in hemoglobin-treated dogs at a reduced but stable level, as indicated by unchanged total body oxygen consumption and constant mixed venous lactate concentration.

The decrease in oxygen delivery index in the above studies contrasts with results of a study in anesthetized beagle dogs. Isovolemic hemodilution with HBOC-201 to a hematocrit of 0.20 - 0.15 was associated with improved skeletal muscle oxygenation as documented by a 10% increase in PO2, despite a 50% reduction in regional blood flow [17]. The authors speculated that the decrease in regional blood flow was compensated for by a more homogenous distribution of capillary blood flow due to the lower viscosity of the diluted blood, and by enhanced unloading of oxygen from the free hemoglobin. Although similar findings of a 12% increase in normal skeletal muscle PO2 were noted by Hahn et al., following infusion of human hemoglobin A to anesthetized tumor-bearing rats, this was accompanied by a 28% decrease in tumor PO2 [18]. Improvement in skeletal muscle oxygenation following hemoglobin solution administration may be partially due to tissue specific differences in microvascular density and vascular recruitment as well as due to subtle changes in vascular rheology. Acellular hemoglobin solutions are concentration-dependent, oncotically active colloids. Reduced viscosity following cell-free hemoglobin hemodilution has been speculated to improve oxygen delivery to microvascular tissue by improving rheology and flow, with the duration of effect depending on the half-life of the hemoglobin within the circulation[19].

The effect of Biopure HBOC-301 on left ventricular preload, afterload, contractility, and ventricular-arterial coupling has been investigated in chloralose-anesthetized dogs [20]. Cardiac output fell 16-25 percent immediately following the start of HBOC-301 infusion and did not return to baseline values during the 90 min infusion or for 90 min following infusion. Heart rate and dP/dTmax decreased following administration of 30 ml/Kg HBOC-301 while left ventricular end-diastolic and end-systolic pressures, mean arterial pressure, and systemic vascular resistance all increased. Although HBOC-301 produced insignificant changes in load-independent indices of cardiac performance, the collective directional changes in these variables, combined with the observed 56 percent increase in systemic vascular resistance, were considered to be the likely causes for the observed decrease in cardiac output.

The vascular reactivity of hemoglobin solutions may prove useful in the treatment of septicemic hypotension. Symptoms of sepsis arise from a complicated interplay of mediators of cellular function and inflammation caused by the outer cell membrane components of bacteria. Many tissues, including vascular smooth muscle, react to bacterial lipopolysaccharide and cytokines by activating endothelial nitric oxide synthase as well as the de novo synthesis of large amounts of the inducible nitric oxide synthase isoform over a long period of time. NO is believed to be responsible for the sustained vasodilation and critical hypotension accompanied by reduced responsiveness to vasoconstrictor agents in septic shock [21]. Hemoglobin solutions, with their avid binding of the NO molecule, function as scavengers to remove excessive amounts of vascular NO and could therefore be of therapeutic use in the treatment of septic shock. In a rat model of acute endotoxin-induced sepsis, polymerized bovine hemoglobin (Biopure 2), but not nitric oxide synthase inhibition or volume replacement with hydroxyethyl starch, was shown to restore cardiovascular and renal functions [22]. Similar results have been shown in an ovine model of sepsis where an infusion of pyridoxilated hemoglobin polyoxyethylene conjugate was used [23-25].

When should hemoglobin solutions be used clinically? Expensive alternatives to red cells need to be justified by demonstration of efficacy and safety at least equal to blood. This will be extremely difficult to demonstrate in the patient populations most in need of red cell substitutes. Oxyglobin® is currently indicated for treatment of anemia in dogs regardless of cause. In a retrospective analysis, bovine hemoglobin solution was associated with 100 percent mortality in dogs with idiopathic immune-mediated hemolytic anemia [26]. Given the limited number of cases and the poor prognosis associated with this condition, it is difficult to know what role, if any, Oxyglobin®played in the increased risk of death. Observations of gastrointestinal irritability, hypertension, and an unexpectedly high number of deaths in human severe trauma patients recently led to the termination of clinical trials and withdrawal from development of two competing hemoglobin solution formulations [27]. To date, similar clinical trials examining the use of Oxyglobin® in veterinary severe trauma patients have not been published, however, given the effects of Oxyglobin® on oxygen delivery and the cardiovascular system, it is not unreasonable to expect increased morbidity and mortality in this patient group. Currently available hemoglobin solutions, such as Oxyglobin®, may be clinically useful in selected cases but are not miracle drugs. We should temper our expectations until we learn more about their uses and limitations.