In the 1960's, researchers discovered that there could be an alternative method for supporting injured lungs. They found that mice whose lungs were filled with an oxygenated saline solution could survive for several hours. Further uses with oxygenated silicone oils had some success, but were later found to be toxic.
Liquid ventilation is accomplished through a liquid called perfluorocarbon (PFC). Leland C. Clark, Jr. and Frank Gollan published an article in 1966 about their experiment with fluorocarbon. They discovered that oxygen and carbon dioxide are very soluble in certain silicone oils and fluorocarbon liquids. Experimenting with mice and cats, it was found that these liquids would support the animals' respirations. What was strange was that the mice and cats that breathed the silicone oil died shortly after returning to breathing normal air, while those that remained in the fluorocarbon survive for weeks. The cats proved to have excellent arterial oxygenation, but there was a problem with carbon dioxide elimination. The most significant discovery that resulted from this period of time was the potential for the use of these perfluorochemical liquids.
Studies of total (tidal) liquid ventilation were first performed in treatments of several premature babies in 1989. These studies showed improvement in patients' lung compliance and gas exchange, but could not be pursued further due to the lack of technology to provide an applicable liquid ventilator system. Also at that time there was not a pharmaceutical-grade PFC available.
Partial liquid ventilation would not be possible without this remarkable chemical known as perfluorocarbon (PFC). These liquids are clear, colorless, odorless, nonconducting, and nonflammable. They are approximately twice as dense as water, and are capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide). PFCs are generally very chemically stable compounds that are not metabolized in body tissues. PFCs require a high FIO2 to maintain high oxygen concentrations within the fluid. It is only the carrier of oxygen and carbon dioxide. PFCs do not produce the gases.
Chemistry of PFC
Perfluorcarbons (PFCs), fluorocarbons, or perfluorochemicals (terms which can be used interchangeably) are formally derived from hydrocarbons by replacing all the hydrogen atoms with fluorine atoms.
First synthesized in the 1920s, PFCs were developed for industry in the 1940s as part of the Manhattan project. Liquid PFCs are uniquely characterized by very high intramolecular bonding and very low intermolecular forces. The C-F bond is the strongest single bond encountered in organic chemistry, and its strength is further increased when several fluorine atoms are present on the same carbon atom. The presence of fluorine even reinforces the C-C bonds. PFCs are taken from fluorinating organic compounds. This altered chemical is fairly stable with some varying physical properties. Those physical properties include vapor pressure, density, and viscosity. PFCs may stay in the body for some time but not affect any functions. After a few years they are completely excreted from the body. PFCs are lipid soluble, but they are totally insoluble in water. This may be the reason that they remain in the body for longer periods of time.
PFCs are used in a variety of industries. They are used in paints to make them spread easier and in textile manufacturing as a fabric protectant. PFCs are also being used as blood substitutes and radiological imaging agents.
One PFC that is being used in the FDA clinical trials of liquid ventilation therapy is Perflubron or "LiquiVent®" by Alliance Pharmaceutical Corporation.
Perflubron has several unique characteristics that make it very efficient in ventilation and oxygenation.
- Perflubron is an excellent medium to carry respiratory gases. PFC at one atmosphere of pressure can carry 20 times as much oxygen than saline.
- It can be used as a surfactant product in premature infants, or in patients with ARDS or lung injury. In an ARDS patient, surface tension in the lung is noted to be 67 to 75 dynes/cm. In a lung with perflubron, the surface tension is only 18 dynes/cm which helps prevent alveolar collapse and reduces alveolar opening pressures.
- It will spread uniformly and quickly throughout the lungs when being used for treatment of ARDS or as a surfactant. It does this because of its chemical make up.
- PFCs are almost twice as dense as water. It will tend to circulate in dependant areas and those areas where gas exchange is most diminished. This characteristic is useful in the removal of foreign bodies or pulmonary edema.
- The components of PFCs are not taken up by the body but evaporated by the lungs. Continuous administration may be necessary to maintain an adequate dosage. This is allowable because it does not break down into toxic metabolites like high concentrations of gaseous oxygen.
From these unique characteristics of LiquiVent®, there are many potential benefits that can be gained from its administration. It can,
- Improve gas exchange
- Wash out debris
- Open atelectatic areas by recruitment, increasing total lung capacity
- Act as a surfactant
- Reduce injury to the lung caused by excessive ventilator pressures
- Decrease chance of oxygen toxicity
- Decrease inflammation in the lung
- Decrease pulmonary blood flow to injured lung areas creating better oxygenation.
Radiology images have shown dramatic changes with the administration of perflubron. Before the initiation of PFCs, the CXR will take the appearance of the initial problem. (e.g. Respiratory Distress Syndrome (RDS) in infants will have the ground glass appearance, air bronchograms, low volumes, and bell shaped chest). During PLV the CXR becomes completely radiopaque. The amount of opacification increases with the amount of lung tissue being ventilated. The Anterior-posterior CXR can then be scored from 0-5 on the amount of lung opacification.
- 5 represents complete opacification of the lungs with no air alveolograms or air bronchograms distal to the main bronchi
- 4 represents 67%-99% opacification
- 3 represents 33%-66% opacification
- 2 represents 10%-32% opacification
- 1 represents minimal or less than 10 % opacification of the lung with perflubron
- 0 is defined as no detecable perflubron
This scoring occurs until the PFCs are discontinued and they evaporate from the lung. Then the CXR will take the appearance of a normal lung or show the underlying disease.
A similar scoring system is in place for lateral CXR. The AP dimension is divided into three compartments of equal width: anterior, middle, and posterior. Again the 0-5 scale is applied to each compartment. Perflubron located outside of the lungs would be noted, and the symmetry of right and left perflubron distribution would also be noted.