Chapter 186

### INTRODUCTION

No blood substitutes are available in the United States today. However, many substances have been synthesized and studied over the years in an attempt to mimic the oxygen carrying capacity of hemoglobin, including several products that are in phase II and III trials in the United States. Products under development lack many of the ideal properties of a synthetic oxygen carrier (Table 186-1).

TABLE 186-1Ideal Characteristics of Blood Substitute

### HEMOGLOBIN-BASED OXYGEN CARRIERS

The majority of synthetic oxygen carriers aim to alter or encapsulate actual human hemoglobin molecules to take advantage of its cooperative binding. Unfortunately, free hemoglobin molecules in solution have many shortcomings as an oxygen carrier:

1. Rapid renal excretion—Normally, the 64 kDa hemoglobin molecule is filtered by the glomerulus and does not cause tubular damage. However, these molecules often degrade into 32 kDa dimers that bypass glomerular filtration and cause renal tubular damage. In addition, these dimers lose the cooperative binding effect of the hemoglobin tetramer. They have a much higher p50 for oxygen and release O2 only at very low oxygen concentrations.

2. Reduced P50—Free hemoglobin in plasma has a lower P50 than hemoglobin contained in RBCs. Functionally, the difference can be thought of as a left shift in the hemoglobin dissociation curve, where free hemoglobin “holds more tightly” to oxygen at a given O2 tension and will only release O2 if the O2 tension is very low. Hemoglobin contained in RBCs has a P50 of 26-28 mm Hg. Hemoglobin-based oxygen carriers (HBOCs) have reduced P50 of 10-16 mm Hg. Hemoglobin dimers, which are spontaneous split products of free hemoglobin, lose the cooperative binding properties of the hemoglobin tetramer. These dimers have a hemoglobin dissociation curve similar to that of myoglobin, and will only release oxygen at O2 tensions as low as 5 mm Hg.

3. Nitrous oxide scavenging—Hemoglobin contained in RBCs is a known nitrous oxide (NO) scavenger, so it is not surprising that HBOCs exhibit NO binding capacity. However, HBOCs free in plasma are free to cross through the vascular endothelium, allowing them to bind a greater amount of NO. Nitrous oxide scavenging leads to vasoconstriction and subsequent hypertension and pulmonary hypertension, so this is a major drawback of HBOCs. Nitrous oxide present at the endothelium mediates smooth muscle relaxation by preventing the conversion of pro-endothelin to endothelin, which is a potent vasoconstrictor. The NO scavenging with HBOCs causes increased levels of endothelin. Many other side effects of HBOCs can be linked to NO scavenging. Reported side effects of HBOC administration include esophageal spasm, abdominal discomfort, ...

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