Hemoglobin-based oxygen carriers for reversing hypotension and shock: "NO" way, "NO" how?

E FFORTS to develop a blood substitute, especially for therapy of hemorrhagic shock, have been ongoing. Most clinical trials have focused on hemoglobin-based oxygen carriers (HBOCs) rather than perfluorochemical derivatives. Although HBOCs are purified, synthesized, or modified hemoglobins from human, bovine, or recombinant sources, they most often originate from human senescent blood. Traditional thinking supports the idea that HBOCs may facilitate volume expansion and stabilize shock patients until erythrocytes become available. Unfortunately, it is not that simple. Hemoglobin is an oxygen-carrying transport molecule physiologically contained in erythrocytes and evolutionarily designed as such. However, outside erythrocytes, the molecules function quite differently, with an altered affinity for oxygen in a different milieu of the circulation. Unmodified hemoglobin solutions have different oxygen affinities when outside red cells; the chains have much higher oxygen affinity than do native or cross-linked hemoglobins. As a result, purified hemoglobins have been modified by polymerization, cross-linking, or pegylation to improve oxygen delivery, increase their half-life, and alter their safety profile. The oncotic pressure exerted by these solutions varies widely. Each HBOC has been uniquely modified to improve its oxygen-carrying and -delivery capabilities and contains different amounts of hemoglobin as dosed. However, despite these physiochemical modifications, most HBOCs significantly scavenge nitric oxide (NO). This process is thought to account for many of the adverse effects and outcomes associated with these agents. HBOCs were never intended to have this property. Their use for resuscitation or intraoperative treatment was based on their volume replacement and oxygen-carrying capacity, which is the basis of the current study in ANESTHESIOLOGY. In the endothelium, throughout the vascular arterial bed, NO is important in maintaining vascular tone. Under physiologic conditions and within the erythrocyte membrane, hemoglobin is mostly insulated from the vascular endothelium. However, once released, free hemoglobin and HBOCs are potent NO scavengers. Because of this mechanism, most HBOCs have been shown to cause systemic and pulmonary artery vasoconstriction, though an oxygenated polyethylene glycol–modified hemoglobin molecule (MP4OX [formerly known as Hemospan ]; Sangart, Inc., San Diego, CA) is thought to have enhanced NO synthesis (NOS) as a result of nitrite reductase properties because of -chain cysteine pegylation in the 93 position. Thus, one of the major drawbacks in studying HBOCs for the treatment of hemorrhagic shock is that they avidly bind NO, causing pulmonary and systemic vasoconstriction. The ferric group of iron in hemoglobin is the primary mechanism by which NO is scavenged. This is also why, in part, inhaled NO as used in clinical concentrations has pulmonary artery vasodilating specificity with minimal effects on the systemic vasculature: scavenging occurs via erythrocyte hemoglobin. HBOCs increase pulmonary and systemic blood pressures, that may, in turn, impair autoregulation of vascular flow in organ systems, as demonstrated in animal models. This process may account for adverse events seen clinically with HBOCs. Furthermore, endothelial dysfunction may enhance vasoconstriction, as in the case of patients with atherosclerotic vascular disease. In ANESTHESIOLOGY this month, Olofsson et al. report a clinical study of MP4OX as a low-volume, oxygen-therapeutic agent that is intended to deliver oxygen to ischemic tissue. The authors used this oncotically active agent to prevent hypotensive episodes and also to determine its safety in a surgical setting. Olofsson et al. observed 367 patients from 18 sites in six countries during elective primary hip arthroplasty with spinal anesthesia. Patients were randomized to receive MP4OX or hydroxyethyl starch (HES130/0.4) at induction of spinal anesthesia. A second dose was made available if a predefined drop in systolic blood pressure occurred. The proportion of patients with one or more hypotensive episode(s), the primary endpoint of the study, was significantly lower in the MP4OX group (66.1%) versus HES 130/ 0.4 controls (90.2%). However, when compared with controls, more MP4OX-treated patients experienced adverse events (72.7 vs. 61.4%), including nausea (20.8 vs. 12.0%) and hypertension (4.4 vs. 0.5%). None of the hypertensive adverse events observed occurred during the operative and 6-h postoperative recovery period. Another consistent finding in HBOC studies has been transient elevations in certain laboratory assays, including