Liquid breathing

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'Liquid breathing' is a form of respiration in which a normally air-breathing organism breathes an oxygen rich liquid (usually a perfluorocarbon), rather than breathing air. It is used for medical treatment and could some day find use in deep diving and space travel. Liquid breathing is sometimes called fluid breathing, but this is misleading because both liquids and gases are fluids.

Contents 1 The early experiments 2 Later developments 3 Methods of application 3.1 Total liquid ventilation 3.2 Partial liquid ventilation 3.3 PFC vapor 3.4 Aerosol-PFC 4 Potential uses 4.1 Diving 4.2 Medical treatment 4.3 Space travel 5 Acknowledgement 6 Fiction 7 References 8 See also 9 External links

[edit] The early experiments

In the mid-1960s Dr. J. Kylstra, a physiologist at the University at Buffalo, realized that salt solutions could be saturated with oxygen at high pressures. In a US Navy recompression chamber, Kylstra experimented to see if mice could move the saline solution in and out of their lungs, while extracting enough oxygen from the fluid to survive. The mice and rats could breathe the liquid (he could keep the animals alive for up to 18 hours), but carbon dioxide was not removed fast enough from the system, and quickly built up to near-toxic levels. This had to be fixed before liquid breathing could be used in humans.

In 1966 Dr. Leland Clark and Dr. Golan experimented on liquid breathing in mice. Oxygen and carbon dioxide are very soluble in fluorocarbon liquids such as freon. Leland Clark realized that, if the alveoli of the lungs can draw oxygen out of the liquid and unload carbon dioxide into the liquid, these fluorocarbons should support respiration of animals. Testing first on anesthetized mice, he temporarily paralyzed each mouse and put a tube down its trachea, inflating a cuff inside the airway to provide a seal and ensure that no air entered the lungs, and no solution leaked out.^[1]

After bubbling oxygen through the fluorocarbon, the oxygenated liquid was pumped into the animals' lungs, and recirculated at about 6 cycles of inhalation and exhalation per minute. Most of the animals who were kept in the liquid for up to an hour survived for several weeks after their removal, before eventually succumbing to lung damage. Necropsies uniformly revealed that the lungs appeared congested when collapsed but normal when inflated.

As in Kylstra's studies, Clark had problems due to the size of the animals' airways. The tiny size limited the amount of liquid that could get into the lungs. For that and other reasons, carbon dioxide tended to build up in the system and could not be removed fast enough. Dr. Clark discovered that the length of time the mice could survive in the liquid was directly related to the fluorocarbon's temperature: the colder the liquid, the lower the respiration rate, which prevented carbon dioxide buildup. The only way was to induce hypothermia in the animals. This technique seemed to give him the most success, as one animal survived over 20 hours breathing liquid at 18ºC.

All animals in the earliest studies suffered lung damage, but whether that was due to toxic impurities in the fluorocarbon, chemical interaction of the fluorocarbon with the lung, or some unknown effect, was undetermined. This mystery of the lung damage, and the problem of carbon dioxide elimination, and the body tissues tending to retain the fluorocarbon, would have to be solved before the process could be attempted on human subjects. Also, perfluorocarbon is denser and more viscous than air. This increases resistance and thus the effort needed to breathe.

[edit] Later developments

During later years, the techniques of liquid breathing were constantly refined and improved. The survival rate of all the tested animals in recent years has been very high, thanks mainly to improvements in carbon dioxide elimination. Current liquids used can dissolve over 65 ml of oxygen and 228 ml of carbon dioxide per 100 ml perfluorocarbon. By the early 1990s this procedure was developed:-

1. The animal was anesthetized with intravenous sodium thiopental.
2. The animal was put on its back. A tube was placed down its airway, ready for the liquid breathing medium.
3. A blood sample was taken. The temperature of the liquid was adjusted correspondingly. It was no longer necessary to make the animals hypothermic.
4. The perfluorocarbon was instilled into the animal's lungs through the tube.
5. A floor-mounted 3-litre reservoir was filled with the perfluorocarbon. The liquid was driven by a pump through a series of machines which warmed and oxygenated the liquid and took the carbon dioxide out of it. The liquid flowed through a tube into a 3-way pneumatic valve which directed flow to the animal. A computer controlled the respiration (18 ml of fluid per second), pumping the liquid into the animal's lungs, then back out again to the reservoir, at a rate of about 6 complete respirations per minute.
6. At the end of the test, the animal was tilted for about 15 seconds and the perfluorocarbon was allowed to drain from the lungs. This can be seen in the film The Abyss where Ensign Monk drained the liquid out of the rat's lungs: in the filming, the rat genuinely breathed liquid.

These tests of the early 90s were successful: dogs could be kept alive in the perfluorcarbon medium for about 2 hours; after removal the dogs were usually slightly hypoxic, but returned to normal after a few days. When the animals were necropsied, the typical findings were mild oedema and some hemorrhaging, clearly an improvement over the lung damage of earlier tests.

[edit] Methods of application

Despite recent advances in liquid ventilation, a standard mode of application of perfluorocarbon (PFC) has not been established yet.

[edit] Total liquid ventilation

Although total liquid ventilation (TLV) with completely liquid filled lungs is beneficial, the necessity for a liquid filled tube system that contains pumps and heater and membrane oxygenator to deliver and remove tidal volume aliquots of conditioned perfluorocarbon to the lungs is of great disadvantage.

[edit] Partial liquid ventilation

In contrast, partial liquid ventilation (PLV) can be applied using standard ventilators connected with gas filled standard respirator systems, delivering tidal volumes of oxygen-air mixture to perfluorocarbon filled lungs.

The influence of PLV on oxygenation, carbon dioxide removal and lung mechanics has been investigated in several animal studies using different models of lung injury. Clinical applications of PLV have been reported in patients with acute respiratory distress syndrome (ARDS), meconium aspiration syndrome, congenital diaphragmatic hernia and respiratory distress syndrome (RDS) of neonates. PLV requires extreme respiratory care, because the ventilatory setting is determined by the perfluorocarbon filled lung. Profound expertise is mandatory to perform and maintain filling of the lung with perfluorocarbon to functional residual capacity (FRC). Disruption of PLV immediately deteriorates gas exchange. Incomplete filling of the lung has been shown to be less effective than filling the lung to functional residual capacity volume. Severe adverse events affecting gas exchange and pulmonary circulation limit the use of PLV.

New application modes for PFC have been developed^[2].

[edit] PFC vapor

Vaporization of perfluorohexane with two anesthetic vaporizers calibrated for perfluorohexane has been shown to improve gas exchange in oleic acid induced lung injury in sheep ^[3]. Predominantly PFCs with high vapor pressure are suitable for vaporization.

[edit] Aerosol-PFC

With aerosolized perfluorooctane, significant improvement of oxygenation and pulmonary mechanics was shown in adult sheep with oleic acid-induced lung injury. In surfactant-depleted piglets, persistent improvement of gas exchange and lung mechanics was demonstrated with Aerosol-PFC ^[4]. The aerosol device is of decisive importance for the efficacy of PFC aerosolization, as aerosolization of PF5080 (a less purified FC77) has been shown to be ineffective using a different aerosol device in surfactant-depleted rabbits (Kelly). Partial liquid ventilation and Aerosol-PFC reduced pulmonary inflammatory response ^[5].

[edit] Potential uses

[edit] Diving

In diving, the pressure inside the lungs must effectively equal the pressure outside the body, otherwise the lungs collapse. Mathematically speaking, if the diver is f feet (or m meters) deep, and the air pressure at the water surface is p bar (usually p = 1, but less at high-altitude lakes such as Lake Titicaca), he must breathe fluid at a pressure of f/33+p = m/10+p bar.

Since external and internal pressures must be equal, the required gas pressure increases with depth to match the increased external water pressure, rising to around 13 bar at 400 feet (120m), and around 500 bar on the oceans' abyssal plains. These high pressures may have adverse effects on the body, especially when quickly released (as in a too-rapid return to the surface), including air emboli and nitrogen narcosis and decompression sickness (colloquially known as "the bends"). (Diving mammals, as well as free-diving humans who dive to great depths on a single breath, have little or no problem with decompression sickness despite their rapid return to the surface, since a single breath of gas does not contain enough total nitrogen to cause tissue bubbles on decompression. In very deep-diving mammals and deep free-diving humans, the lungs almost completely collapse).

One solution is a rigid articulated diving suit, but these are bulky and clumsy. A more moderate option to deal with narcosis is to breathe heliox or trimix, in which some or all of the nitrogen is replaced by helium. However, this option does not deal with the problem of bubbles and decompression sickness, because helium dissolves in tissues and causes bubbles when pressures are released, just like nitrogen does.

Liquid breathing provides a third option. With liquid in the lungs, the pressure within the diver's lungs could accommodate changes in the pressure of the surrounding water without the huge gas partial pressure exposures required when the lungs are filled with gas. Liquid breathing would not result in the saturation of body tissues with high pressure nitrogen or helium that occurs with the use of non-liquids, thus would reduce or remove the need for slow decompression. (This technology was dramatized in James Cameron's 1989 film The Abyss.)

A significant problem, however, arises from the required density of the liquid and the corresponding reduction in its ability to remove CO₂. All uses of liquid breathing for diving must involve total liquid ventilation (see above). Total liquid ventilation, however, has difficulty moving enough fluid to carry away CO₂, because no matter how great the total pressure is, the amount of partial CO₂ gas pressure available to dissolve CO₂ into the breathing liquid can never be much more than the pressure at which CO₂ exists in the blood (about 40 mm of mercury (Torr)).

At these pressures, most fluorocarbon liquids require about 70 mL/kg minute-ventilation volumes of liquid (about 5 L/min for a 70 kg adult) to remove enough CO₂ for normal resting metabolism.^[6] This is a great deal of fluid to move, particularly as it is about 1.8 times as dense as water; any activity on the diver's part which increases CO₂ production would increase this figure, which is at the limits of realistic flow rates in liquid breathing.^[7][8] It seems unlikely that a person would move 10 liters/min of fluorocarbon liquid without assistance from a mechanical ventilator, so "free breathing" may be unlikely.

[edit] Medical treatment

The first medical use of liquid breathing was treatment of premature babies and adults with acute respiratory distress syndrome (ARDS) in the 1990s. Liquid breathing was used in clinical trials after the development by Alliance Pharmaceuticals of the fluorochemical perfluorooctyl bromide, or perflubron for short. Useful as an emulsified blood substitute and for liquid ventilation, perflubron (under Alliance Pharmaceutical's brand name LiquiVent) is poured directly into the lungs of patients with acute respiratory failure (caused by infection, severe burns, inhalation of toxic substances, and premature birth), whose air sacs have collapsed. Once inside the lungs, perflubron enables collapsed alveoli (air sacs) to open and permits a more efficient transport of oxygen and carbon dioxide.

All blood that flows out from the heart to the rest of the body first must go through the lungs, where it picks up oxygen and gets rid of carbon dioxide. If the lungs do not function properly, as is common in premature infants with respiratory distress syndrome, the lungs become stiff and collapse, and the infants must be put on ventilators. A study, led by Dr. Corrinne Leach of the University at Buffalo, tested 13 infants on ventilators who were born prematurely with respiratory distress syndrome. The infants were at risk of dying because they could not produce a natural surfactant that stops the lungs from collapsing from surface tension. They were at risk of severe and permanent lung damage from the force of the ventilators that were inflating their lungs. Their lungs were filled with perflubron which would let the air sacs of the lungs open and permit breathing. The perflubron let the lungs inflate with less pressure and let oxygen pass through the lungs and into the blood stream and carbon dioxide out more efficiently and with less stress. This was successful.

The 13 premature infants received partial liquid ventilation for 24 to 76 hours; they were weaned back to gas ventilation without difficulties or adverse side effects, and 11 of the 13 showed significant improvement in lung functioning. Six of the infants eventually died, but of causes apparently unrelated to the liquid ventilation.^[9]

Clinical trials with premature infants, children and adults were conducted. Since the safety of the procedure and the effectiveness were apparent from an early stage, the US Food and Drug Administration (FDA) gave the product "fast track" status (meaning an accelerated review of the product, designed to get it to the public as quickly as is safely possible) due to its life-saving potential. Clinical trials showed that using perflubron with ordinary ventilators improved outcomes as much as using high frequency oscillating ventilation (HFOV). But because perflubron was not better than HFOV, the FDA did not approve perflubron, and Alliance is no longer pursuing the partial liquid ventilation application. Whether perflubron would improve outcomes when used with HFOV remains an open question.

In 1996 Mike Darwin and Dr. Steven B. Harris proposed using cold liquid ventilation with perfluorocarbon to quickly lower the body temperature of victims of cardiac arrest and other brain trauma to allow the brain to better recover.^[10] The technology came to be called gas/liquid ventilation (GLV), and was shown able to achieve a cooling rate of 0.5 degrees Celsius per minute in large animals.^[11] It has not yet been tried in humans.

[edit] Space travel

Liquid immersion provides a way to reduce the physical stress of G forces. Forces applied to fluids are distributed as omnidirectional pressures. Because liquids are (virtually) incompressible, they do not change density under high acceleration such as performed in aerial maneuvers or space travel. A person immersed in liquid of the same density as tissue has acceleration forces distributed around the body, rather than applied at a single point such as a seat or harness straps. This principle is used in the Libelle G-suit, which allows aircraft pilots to remain conscious and functioning at more than 10 G acceleration by surrounding them with water in a rigid suit.

Acceleration protection by liquid immersion is limited by the differential density of body tissues and immersion fluid, limiting the utility of this method to about 15 to 20 G^[12] Extending acceleration protection beyond 20 G requires filling the lungs with fluid of density similar to water. An astronaut totally immersed in liquid, with liquid inside all body cavities, will feel little effect from extreme G forces because the forces on a liquid are distributed equally, and in all directions simultaneously. However effects will be felt because of density differences between different body tissues, so an upper acceleration limit still exists.

Author Joe Haldeman, in his "Forever War" series, describes fluid being introduced into all 7 natural orifices in the human body, and one surgically-added connection, through which the thoracic cavity would be filled and drained. In such a situtation, the fluid in the lungs would have to be pumped in and out to provide an inspiration/expiration cycle (total liquid ventilation). Alternatively blood could be oxygenated extracorporeally while lungs remained full of passive fluid, although this is not really liquid breathing.

Liquid breathing for acceleration protection may never be practical because of the difficulty of finding a suitable breathing medium of similar density to water that is compatible with lung tissue. Perfluorocarbon fluids are twice as dense as water, hence unsuitable for this application.

Around 1970, liquid breathing found its way into fiction, in alien spacesuits in the Gerry Anderson UFO series, which enabled a spaceman to withstand extreme acceleration forces.

[edit] Acknowledgement

Taken, with permission, from: Fluid Breathing, and afterwards edited.

[edit] Fiction

• The James Cameron film The Abyss features a character using liquid breathing to dive thousands of feet without compressing. The Abyss also has a scene with a rat actually being submerged and breathing fluorocarbon liquid in real life.
• In the Anime series Neon Genesis Evangelion, the EVA pilots use liquid breathing when they are inside their robotic-like machines.

[edit] References

[edit] See also

• Mechanical ventilation
• Breathing gas

[edit] External links

• Alliance Pharmaceutical Corp
• Here, Breathe This Liquid