Alternatives to Transfusion: A Case Report and Brief History of Artificial Oxygen Carriers

Sara Emily Bachert, MD; Prerna Dogra, MD; Leonard I. Boral, MD

Disclosures

Am J Clin Pathol. 2020;153(3):287-293. 

In This Article

Perfluorocarbons

As the name suggests, perfluorocarbons (PFCs) are chemically inert compounds derived from cyclic or straight-chain hydrocarbons with hydrogen atoms replaced primarily by fluoride atoms. PFCs do not carry gases but rather act as excellent solvents. Because of their decreased surface tension and intramolecular action, PFCs have an essentially unlimited ability to absorb gases. In addition, PFCs are hydrophobic, so they must be emulsified for intravenous use.[4]

The biggest theoretical advantage to PFCs is their small size. The median size of PFCs is less than 0.2 μm.[4] For comparison, RBCs have a diameter of 6.0 to 8.0 μm. Therefore, these special artificial oxygen carriers can bypass obstructions (mainly vascular thromboses) that RBCs cannot. Thus, oxygen could be delivered downstream to ischemic tissues to help prolong vitality while the vascular blockage is being resolved. On a related note, their small size is also important for clearance of the fluorocarbon particles from the body. PFCs are cleared from the bloodstream by the reticuloendothelial system (RES) with larger particles being phagocytized first. The particles then diffuse across the cell membranes from the RES organs (spleen and liver, primarily) back into the circulation, where they are taken up by circulating lipid carriers. The particles are then eventually excreted though the alveoli and expelled out of the body through the lungs.[5]

PFCs are unique in their oxygen-carrying capacity because their oxygen dissociation curve is linear. Since the perfluorochemicals have to be emulsified, their oxygen delivery is much less efficacious than that of pure liquids. For example, Fluosol-DA could deliver only 0.4 mL oxygen per 100 mL when a patient was breathing room air. For comparison, unaltered Hb normally carries 1.34 mL oxygen per gram.[1] However, when the amount of supplemental oxygen is increased (up to FiO2 = 1.0), the oxygen delivery capacity of PFCs approaches that of whole blood.[3] As a result of this phenomenon, patients receiving these agents require high concentrations of supplemental oxygen. The use of exogenous high-flow oxygen then becomes a balance of managing oxygen toxicity while still maximizing the capabilities of PFCs to deliver oxygen.

One of the first PFCs to be developed was Fluosol-DA. It contained perfluorodecalin and perfluorotripropylamine with Pluronic-68 and egg yolk phospholipid as emulsifying agents. It achieved FDA approval in 1989 as an oxygen-carrying adjunct for perfusion of ischemic tissues in the setting of percutaneous transluminal coronary artery balloon angioplasty.[6] However, just 5 years later, in 1994, Fluosol-DA was withdrawn from the market primarily because of a lack of commercial success. The product had to be frozen for shipping and storage and then thawed and reconstituted before use. There were other problems with the product, including marginal efficacy (as discussed above), short half-life (t1/2 = 7.5 and 22 hours for 4- and 6-g/kg doses, respectively), and adverse effects such as acute complement activation by the Pluronic F-68 emulsifier.[5–7]

After Fluosol-DA, multiple second-generation agents were developed, including Oxygent, Perftoran, Oxycyte, and Oxyfluor. These products had three main improvements from the first-generation attempts: (1) they used natural phospholipids as emulsifiers instead of the water-soluble F-68, (2) they could be stored without freezing, and (3) they contained two to four times larger PFC contents per emulsion.[6,7] Unfortunately, these products all caused similar side effects, such as flu-like symptoms and hepatomegaly because of cytokine-mediated effects and platelet sequestration. Ultimately, PFCs were unable to achieve success as oxygen carriers, and none are commercially available in the United States today. However, they remain an attractive theoretical option primarily because mass production would be cost-effective. In particular, developing countries, where the demand for blood is high but storage conditions are poor, could benefit from these products.[6]

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