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 can be confusing because both liquids and gases can be called fluids.
Methods of application
Despite recent advances in liquid ventilation, a standard mode of application of perfluorocarbon (PFC) has not been established yet.
Total liquid ventilation
Although total liquid ventilation (TLV) with completely liquid filled lungs is beneficial, the necessity for the 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 a disadvantage with regard to gas ventilation. One research group led by Thomas H. Shaffer has maintained that with the use of microprocessors and new technology, it is possible to maintain better control of respiratory variables such as liquid functional residual capacity and tidal volume during TLV, than with gas ventilation. [1][2][3][4].
[edit] Partial liquid ventilation
In contrast, partial liquid ventilation (PLV) is a technique in which a PFC is instilled into the lung to a volume approximating functional residual capacity (approximately 40% of TLC (Total Lung Capacity)). Conventional mechanical ventilation delivers tidal volume breaths on top of this. This mode of liquid ventilation is technically more viable than total liquid ventilation as it can utilise technology currently in place in neonatal intensive care units (NICU) worldwide.
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[5] 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. In order to correctly and effectively conduct PLV, it is essential to (1) properly dose a patient to a specific lung volume (10-15 ml/kg)to recruit alveolar volume and (2) redose the lung with PFC liquid (1-2 ml/kg/hr) to oppose PFC evaporation from the lung. If PFC liquid is not maitained in the lung, PLV can not effectively protect the lung from biophysical forces associated with the gas ventilator.
New application modes for PFC have been developed[6].
[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 [7]. Predominantly PFCs with high vapor pressure are suitable for vaporization.
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 [8]. 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 [9].
Summary of clinical uses
At present all modes of liquid ventilation remain experimental. PLV has been used in only a small number of patients worldwide. The technique is currently only employed in specialist centers usually as part of a randomized controlled trial. With the accumulation of evidence supporting the safety and efficacy of liquid ventilation it is probable that it will become an important technology for the future treatment of patients in respiratory distress.
Potential uses
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 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 high viscosity 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 liquid 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.[10] This is a great deal of fluid to move, particularly as liquids are generally more viscous than gases, (for example water is about 56 times the viscosity of air). Any increase in the diver's metabolic activity also increases CO2 production and the breathing rate, which is already at the limits of realistic flow rates in liquid breathing.[11][12] 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.
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 administered via an endotracheal tube (ETT) directly into the lungs of patients with acute respiratory failure (caused by infection, severe burns, inhalation of toxic substances, and premature birth), whose alveoli have collapsed. Once instilled, perflubron acts in two principal ways to improve gas exchange in the lung. Firstly, the gas-liquid interface present in the ordinary lung is replaced with a liquid-liquid interface allowing for more efficient transfer of Oxygen and Carbon dioxide. Furthermore, a liquid positive end expiratory pressure or "PEEP" is exerted which forces open previously closed regions of the lung creating a more homogenously respiring lung.
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.[13] 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.[14] It has not yet been tried in humans.
Pediatric medicine
The most promising area for the use of liquid ventilation is in the field of pediatric medicine. Current methods of positive-pressure ventilation can contribute to the development of lung disease in pre-term neonates, leading to diseases such as bronchopulmonary dysplasia. Liquid ventilation removes many of the high pressure gradients responsible for this damage. Furthermore, Perfluorocarbons have been demonstrated to reduce lung inflammation, improve ventilation-perfusion mismatch and to provide a novel route for the pulmonary administration of drugs. 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.
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 a new type of G-suit called 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[15] 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.
Around 1970, liquid breathing found its way into television, in alien spacesuits in the Gerry Anderson UFO series, which enabled a spaceman to withstand extreme acceleration forces.
Author Joe Haldeman, in his science fiction novel The Forever War, 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 situation, 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.
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