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Hemoglobin-based oxygen-carrying blood substitutes
See also Perfluorocarbons
General information
Oxygen carriers can be divided into two classes: hemoglobin-based oxygen carriers, prepared from hemoglobin of human or bovine origin, and synthetic perfluorocarbons (see separate monograph).
Hemoglobin-based oxygen carriers are infusible oxygen-carrying fluids prepared from purified human or animal hemoglobin; they do not need to be refrigerated and cross-matching is unnecessary [ , ]. However, small amounts of residual cell membranes are very toxic. They are used as an alternative to traditional resuscitative fluids such as crystalloids, artificial colloids, and blood [ ]. It is important for the laboratory medicine community to be aware of their effects on routine laboratory testing and the settings in which they might be used [ ].
The characteristics of an ideal emulsion for use as a blood substitute are absence of red cell incompatibility, absence of a risk of transmission of infectious diseases, a long duration of conservation, easy access, and rheological parameters similar to those of blood [ ].
Hemoglobin-based oxygen carriers can provide potential benefits when erythrocytes are unavailable, although in developed countries blood is generally available. Universal compatibility with all blood types, freedom from disease transmission, and prolonged storage must be offset against unexplained biochemical actions and a lack of knowledge regarding the underlying mechanisms of the harms. Adverse reactions include hypertension, dysrhythmias, gastrointestinal problems, pancreatitis, and rises in liver enzyme [ ].
There are three sources of hemoglobin from which oxygen carriers have been developed: human, bovine, and recombinant. Hemoglobin-based oxygen carriers have benefits, such as the lack of pathogen transmission, no need for cross-matching, and increased stability and storage time; however, compared with erythrocyte transfusions, they have a short half-life. Of various hemoglobin-based oxygen carriers, two (Polyheme and Hemopure) have been tested in phase III studies. One product, Hemopure—polymerized hemoglobin of bovine origin—has been licensed for human use in South Africa. The tetrameric hemoglobin easily dissociates in vivo into dimers and monomers that are quickly eliminated by the kidneys. As the administration of tetrameric hemoglobin is associated with renal insufficiency, intermolecular cross-linking of hemoglobin has been performed using different agents to polymerize hemoglobin. Other hemoglobin-based oxygen carriers include conjugated hemoglobin or packed hemoglobin in nanocapsules or lipid vesicles [ ].
General adverse effects and adverse reactions
Reported adverse reactions include myocardial infarction, stroke, acute renal insufficiency, increased arterial blood pressure, methemoglobinemia, increased liver enzymes, and deaths [ ].
Hemoglobin-based oxygen carriers bind endogenous nitric oxide, thereby causing transient hypertension, esophageal dysfunction, and abdominal discomfort. In a phase II study using O-raffinose cross-linked hemoglobin (Hemolink) in patients undergoing coronary artery bypass grafting surgery raised blood pressure, probably caused by binding of O-raffinose cross-linked hemoglobin to nitric oxide, and jaundice were observed [ ]. Jaundice was expected, owing to metabolism of cell-free hemoglobin.
First-generation nanodimension polyhemoglobin (poly-Hb) and bovine polyhemoglobin have been successfully used in phase III clinical trials [ ]. However, these products are merely oxygen carriers with short circulation times, lacking the enzyme activity of red blood cells, and therefore have limited clinical use. The first-generation compounds, prepared from modified tetrameric hemoglobin molecules, were mainly associated with vasoconstriction and renal dysfunction. Clinical trials were stopped because of increased mortality, myocardial infarction, and stroke [ , ].
In 714 patients hypertension, coagulopathy, and myocardial infarction occurred more in those who were given hemoglobin-based oxygen carriers than in the controls [ ]. Although polymerized hemoglobin products appear to have a better safety profile, their safety remains a topic of considerable debate.
Drug studies
Observational studies
Of 55 patients with life-threatening anemia who were treated with HBOC-201, 23 survived and 32 did not [ ]. There were adverse events in 12 patients, of whom six had pre-existing cardiovascular or renal disease, although the events were not attributed directly to HBOC-201 by the treating physician. Myocardial infarction or stroke was reported in four of the non-survivors compared with none of survivors. There was acute renal insufficiency in eight non-survivors and two survivors. The most common non-serious adverse events related to HBOC-201 were increased blood pressure, increased liver enzymes, and methemoglobinemia.
Comparative studies
In a comparison of HBOC-201 and erythrocyte transfusion, the former caused mild platelet dysfunction, which may be caused by reactive oxygen molecules. In blood, there is redox hemostasis as a result of a trans-plasma membrane redox system in platelets. This hemostasis could be impaired by free radicals [ ].
Oxygenated polyethylene glycol-modified hemoglobin (MP4OX) and hydroxyethyl starch 130/0.4 have been compared in 367 patients undergoing primary hip arthroplasty; nausea and hypertension were reported more often in those who were given MP4OX [ ].
Systematic reviews
A meta-analysis of 16 trials involving a total of 3711 patients showed that hemoglobin-based oxygen carriers are associated with a 30% increased risk of death (RR = 1.3; 95% CI = 1.1, 1.6) and a 2.7-fold increased risk of myocardial infarction (RR = 2.7; 95% CI = 1.7, 4.4) [ ], although other authors have debated these results [ ].
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