Date: Sat, 23 Mar 1996 16:32:36 -0500 (EST) Liquid Ventilation: A Bypass On The Way to Bypass by Mike Darwin Introduction: The Problem One of the most frustrating problems in cryonics is the limitation that the procedure cannot start until legal death has been pronounced. Even the recent Circuit Court decision ruling on the legality of assisted suicide does not alter the situation in this regard; whatever the "cause" and whatever the "mode" of death, cardio-respiratory arrest, legal death, _must_ have occurred before cryopreservation procedures can begin. There are, additionally, some reasons why, at least for the foreseeable future, cryonics organizations and their clients may want it to remain this way. Chief amongst these reasons is the regulatory burden associated with procedures that would be considered under the "aegis" of medicine. Any procedure done on a patient before legal death would certainly be considered a medical procedure -- even if such a procedure were to result in the patient's death. An unfortunate corollary of this is that the full weight and force of the medical-industrial-regulatory-complex would come to bear on that part of the cryopreservation process carried out before legal death is pronounced. In effect, this would be tantamount to a prohibition on the use of these procedures. Thus, patients confronting cryopreservation are still faced with the necessity of experiencing a period of cardio- respiratory arrest before the procedure can begin, and this situation is unlikely to change in the foreseeable future. In practical terms what this means is the following: 1) All cryonics patients will experience some period of interruption of blood flow to their brains (cerebral ischemia). 2) Methods used to restore blood flow and oxygenation must not result in return of spontaneous cardiac or respiratory activity in effect reversig clinical and thus _legal_ death. 3) Currently, the best methods available for restoring blood flow after legal death that meet the criteria set forth in 2) above, are either very poor at restoring adequate circulation (CPR) or require a significant time-delay to implement (cardiopulmonary bypass; i.e., use of a blood pump and "artificial lung" to move and oxygenate blood). Of course, in many cases the patient will not be experiencing legal death under the controlled conditions allowed for in the scenario of medically assisted suicide many cryonicists envision as ideal. Many patients will not choose active euthanasia, or will not be candidates for it (i.e., it will not be at all certain that the outcome of their medical crisis is a terminal one until such time as heartbeat and breathing cease, and resuscitation attempts are deemed futile or fail). Many patients, even those dying or known to be at high risk of dying, will experience sudden de compensations and die with little or no opportunity for complex preparations (both in terms of personnel and equipment) for cardiopulmonary bypass. The Most Desired Solution to The Problem Ideally, what is needed is a way to restore circulation and breathing in such patients _acutely_; immediately after pronouncement of legal death, in an efficient manner, which allows for cooling, oxygenation and blood circulation at rates of efficiency achievable with bypass, in a simple, straightforward and inexpensive way. To put it another way, we need a way to provide rapid cooling and circulatory support in cryopatients that can be applied by anyone with paramedic-level, or perhaps EMT-level training, with not much added training needed beyond that required to use the equipment currently used to achieve these ends during the transport of today's cryopatients (i.e., mechanical CPR using Thumper). This is a tall order, and one which has occupied significant BPI and 21st research effort for the past two years. The solution to this problem would, of course, result not only in tremendous potential benefit to cryopatients, but also to many other people who experience sudden cardiac death from heart attack, electrocution, drowning, and other causes, and who could similarly benefit from rapid induction of hypothermia _and_ efficient CPR. A little over two years ago, Mike Darwin came up with an idea that had the promise to solve this problem. It would have all the necessary elements discussed above, and then some. It would be: *Easy to apply, requiring far less highly skilled personnel than are needed for bypass *Technically less demanding, requiring _fewer_ total personnel than bypass *Effective at achieving a rate of heat exchange in the brain comparable to or _better_ than that achievable with bypass *Effective at achieving good gas exchange even patients with severe lung disease/injury (pulmonary edema, Adult Respiratory Distress Syndrome (ARDS), space occupying lesions of the lungs such as tumor, etc.) *More effective than conventional closed-chest CPR at delivering good good flow *Relatively inexpensive to use While this technology would not replace bypass in ideal scenarios of patient transport, it could as a minimum act as a far more efficient bridge to it than do conventional transport techniques, and in those cases where bypass was not possible, this modality _would_ be available to insure rapid cooling and allow for prompt transport of the patient either to a facility where blood washout was possible, or to the facilities of the cryonics organization for definitive stabilization (cryoprotective perfusion and cryopreservation). Well, what is this idea, how workable is it, and how soon will be available? The answer to the first two questions is comparatively easy and straightforward, the answer to the third question is a little less definite. The Idea The idea for this technology came about from making the following simple observations: 1) _All_ of the blood that flows out from the heart to the various organs of the body flows through the lungs first, where it is oxygenated and carbon dioxide is removed. 2) The lungs are soft, compliant sacks which are easily compressed during CPR and act to absorb a lot of the mechanical energy or "pumping" force exerted during the downstroke of compression on the chest. 3) Air, oxygen, and other gases make terrible heat exchange media; since they are roughly a thousand times less dense than water, they will remove heat at only roughly one thousandth the rate! 4) The surface area of the pulmonary alveoli and bronchi is very large, roughly the size of a tennis court. The Solution to the Problem With a little further thought it becomes apparent that the thing to do is _get rid of the gas_ in the lungs and replace it with fluid. Preferably a fluid that could deliver oxygen and carbon dioxide as well as or better than air--or even high concentration oxygen. It would also be desirable if this fluid were nontoxic, and if it were not soluble in water, or in fats, so that it would not get into the tissues. It should also be a reasonably good heat transfer medium. Ideally, it should be possible to fill large mammals' lungs with this fluid (such as dogs) and have them recover uneventfully after being ventilated with it for an extended period of time. To summarize, the _simple_ answer to the problem of efficient gas exchange, rapid cooling, and improved hemodynamics during CPR is _liquid ventilation._ Initially, when we began this work, we started with hemoglobin solutions. There were many problems with this approach which neither time nor space will permit discussion of here; and we knew such problems would occur. The important thing was that this early work (conducted starting two years ago) established the feasibility of liquid ventilation in achieving the rates of cooling and increase in mean arterial pressure and cardiac output in CPR that were needed for both cryonics and non cryonics applications. We then looked to perflurodecalin and mixtures of other flurocarbons such as FX-80, the breathing medium used by Leland Clark and his associates in the late 1960's. Clark and his colleagues were able to briefly keep mice alive, submerged and breathing in FX-80 until they died from exhaustion from the increased work of breathing _and hypothermia_ (the liquid was not heated). However, the physical characteristics of this agent including its viscosity, spreading coefficient, and gas transfer capabilities (as well as problems with its toxicity) made it an unacceptable choice. A great deal of time and effort has been focused on developing a suitable working fluid and developing a usable, simple technique for applying total liquid ventilation in the setting of cryonics transport. These problems have now largely been solved. A proprietary working fluid that results in long term survival of animals ventilated with it has been found by BPI and 21st Century Medicine. Just as importantly, a way of using this fluid has been developed. Two ways in fact. The one which will be discussed here is simple, straightforward and, we believe, very elegant. It is called sweep flow total liquid ventilation (SFTLV). It works as follows. A large tube is placed in the patient's windpipe (trachea) by either endotracheal intubation (passage of the tube down the mouth and into the trachea past the vocal cords) or preferably by tracheotomy (wherein the trachea is surgically opened through the skin of the neck and a tube placed directly in it). The tube used for liquid ventilation using this technique differs from a conventional tracheal tube in several ways. First, it is a double-lumen tube; in other words one tube inside the other. The "inside" tube extends beyond the tip of the "outside" tube by about 15 mm. Second, the lower 2/3rds of the outside tube has numerous holes or fenestrations in it, from the point where the end of the tube is positioned (at a level just above the location where the trachea divides into the two main-stem bronchi [the carina]) to the point on the outer tube where a balloon is inflated to prevent the liquid ventilating medium from escaping in any space between the tube and the trachea. The smaller, inner tube is connected to a reservoir-pump-oxygenator-heat exchanger assembly (the liquid ventilator) and carries oxygenated and chilled liquid breathing media down the tube where it is delivered into the trachea at a point just above that of the carina. The larger outer tube picks up the fluid from the trachea and returns it (under gravity or pump assisted flow) to the reservoir. (See Illustrations 1 and 2). When this system was first developed we were focused on mimicking the normal process of breathing: inspiration and expiration. We soon found this problematic. While it was possible to successfully meet the gas exchange demands of an animal in this fashion, we were limited on our ability to carry out heat exchange, and the control of inhalation and exhalation of the liquid was demanding and equipment- intensive. Due to the very high viscosity of liquid, as compared to air or other gases, we were constrained to limit the number of ventilations to no more than 5 to 7 per minute (normal is 12 for air) and the total flow rate of liquid in and out of the lungs to no more than 2000 ml/min for an average adult (65 kg) (a comparable normal tidal volume in air would be about 4200 ml/min). While these tidal liquid volumes and ventilation frequencies provide adequate gas exchange, they limit us undesirably on heat exchange. This is particularly the case because the liquid breathing medium we are using, CryoVent (TM, BPI) carries only aboutone half of the amount of heat per unit volume as does water. The solution to this problem was to use a "sweep flow" system, wherein CryoVent is continuously pumped into the trachea at relatively high flows (about 4-6 liters per minute) and continuously returned to the oxygenator-heat- exchanger. Movement or exchange of chilled, oxygen rich CryoVent from the large aiways (the trachea and bronchi) to the small airways (the alveoli) where gas and heat exchange takes place is achieved by the use of Active Compression Decompression CPR (ACD-CPR) (with or without a high impulse component to the wave of force delivered to the chest on downstroke). Thus, each up stroke of the suction-cup plunger on the ACD-CPR machine pulls chilled oxygen rich liquid into the alveoli of the patient's lungs (See Illustration 3) This means, in effect, that the patient is ventilated not once every 5 chest compressions with gas as in conventional CPR, or once every 12-14 compressions with conventional "tidal- volume" (inspiration-expiration) liquid ventilation, but rather _after, or rather during, each upstroke and downstroke of CPR!_ Thus, the large airways serve as a reservoir, or sump, of chilled, oxygenated fluid which is rapidly changed out during each upstroke and down stroke of ACD-CPR. The sump is kept "fresh" by the fast flow or "sweep" of chilled oxygenated CryoVent through the large airways. This system is highly effective at facilitating rapid cooling and good gas exchange even when used without external (ice water immersion) cooling and colonic and peritoneal lavage with cold solutions. It is _much_ more effective when combined with them. Indeed, we anticipate being able to achieve cerebral cortical cooling rates in the average adult male (65 kg) of 1.5 to 2.0 C/min! The solubility of oxygen in CryoVent at both 0 C and 25 C is approximately 50 ml/100 ml.. The solubility of carbon dioxide is over three times that of oxygen at room temperature; 170 ml/100 ml of CryoVent, and roughly four times that of oxygen at 0 C; or, 200 ml/100 ml of CryoVent. The use of the sweep flow system greatly improves the rate of heat exchange, indeed, even the CryoVent liquid _not_ moved in and out of the alveoli still contributes powerfully to heat exchange by cooling the large airways and the rich supply of blood which flows both into and out of the lungs adjacent to them (the hilar arteries and veins). The efficacy of ACD-CPR at circulating blood is also greatly increased due to the vast reduction in lung compliance associated with replacing the normally present gas with liquid. The underlying biomechanics of this is shown in Illustration 4, where the compliance curve for both the air and CryoVent filled lung are shown. As can be seen, air is far more compliant than CryoVent and the lung thus dissipates energy, or "compresses" when it is squeezed, decreasing the pressure or pumping force delivered to the heart and large blood vessels of the chest, the so called "thoracic pump" of CPR. As in the film THE ABYSS, the answer is to replace the gas with liquid, albeit for different reasons. The solution is just that simple. Unexpected Benefits An unexpected benefit of CryoVent was its ability to rapidly and effectively restore gas exchange in the wet edematous lung. On X-ray, it first appeared as though CryoVent was reversing pulmonary edema and re-inflating liquid filled lung within minutes of being given down the endotracheal tube! It took us quite a little while to understand what was happening. The clue came from the pioneering work of an Italian Intensivist by the name of Gattinoni (Anesthesiology 1991;74:15-29). What Gattinoni discovered was that when patients were turned prone the "water-logged" or consolidated "dependent" part of the lung quickly moved from the lower lobes on the posterior side, to the newly dependent anterior part of the lung lobes. This quick reappearance of consolidated lung occurred too rapidly to be explained by a shift of water through the airspaces, or through the tissue itself (i.e., migration of fluid between the cells from "high" to "low" areas). As it turns out, the dependent areas of the lung are collapsed, and appear fluid laden not because they have more fluid in them, but because they have less gas. By carefully calculating the Hounsfield number for each cubic centimeter of lung tissue, Gattinoni showed that the lung water content did not vary significantly from the consolidated to the non consolidated area in edematous lung. Water content in edematous lung did however, differ radically from that of normal lung. The consolidation of the lower lobes, or the most dependent part of the lung occurs as a result of the increased weight and thus the increased pressure exerted by the water-logged lung sitting atop the equally water-logged dependent lung. Normal lung tissue is very light and weighs alomost nothing. Injured lung is dense with fluid and the weight of this fluid filled tissue exceeds the ability of the gas pressure and the mechanical strength of the small airsacs (the alveoli) to resist it. Thus, the alveoli in the dependent lung collapse and the lung takes on its wet, liver- like appearance. It is doubly unfortunate that most of the blood flow to the lung in the prone position is to those very same dependent lobes that are water-logged and whose alveoli are collapsed and inaccessible to gas exchange. Thus, _most_ of the blood leaving the heart goes through lung where no gas exchange is possible and proceeds to be distributed to the tissues without oxygenation and without removal of carbon dioxide. This phenomenon is known as ventilation/perfusion mismatch, or V/Q mismatch for short. Because CryoVent is about 1.8 times the density of water, it rapidly re inflates these collapsed dependent alveoli and "recruits" them to gas exchange and heat exchange. In fact, CryoVent opens up consolidated edematous lung within 10 minutes of administration! CryoVent has other advantages as well; it displaces alveolar mucus and fluid and stops these fluids from acting as cesspools of free radical and proteolytic enzyme activity: CryoVent will not support either biologically meaningful free radical chemistry or catabolic biochemistry. CryoVent is as inert as liquid teflon. One other advantage not at first appreciated: nitric oxide is readily soluble in CryoVent. Nitric oxide is not to be confused with _nitrous_ oxide (so-called laughing gas used in dental anesthesia). Rather, nitric oxide is a powerful blood vessel dilator and is currently being used to selectively up regulate blood flow through areas of lung which _are_ being ventilated with gas by addition of nitric oxide in the ppm range to the breathing gas in patients with severe ARDS to correct V/Q mismatch. We are currently getting the capability of nitric oxide administration and it should be feasible to use nitric oxide in combination with CryoVent to more quickly and _selectively_ improve blood flow to lung tissue which CryoVent reaches. The Problems with the Solution So, as we said before, the solution is just that simple: ventilate with liquid. Unfortunately, _life_ is never quite that simple. CryoVent is definitely ready to move from the laboratory and into the field for clinical application to human cryopreservation patients. How soon will this happen? Well, that is a more difficult question to answer. Currently we are hopeful that this technology will be ready for implementation within the next 60 to 90 days. Most of the hardware exists or is under construction. The working fluid is being produced now. What we are waiting on is for _all_ of these elements to fall into place. We expect to take delivery on our first in-field Thumpers capable of delivering the kind of CPR we need in about 60-90 days. We have a similar timetable for obtaining 20 liters of CryoVent. We have a prototype ventilator now, but it has not been refined into the compact and easy to transport unit that we would like. Indeed, THAT is one of our weakest links; rapid and cost-effective implementation of final, "user ready" hardware for sweep-flow liquid ventilation. This will not be an easy task. Many of the normal benchmarks used to monitor the efficacy of CPR (such as end tidal CO2 measurement) are rendered inapplicable by sweep-flow liquid ventilation. Indeed, just the engineering of the system into a compact, easy to use system will take many months. But, we are on our way. In the meantime, we should shortly have the capability to apply this technology using bulkier equipment, and we will certainly be able to apply a unique variant of it which requires almost no equipment and little expertise, but which is not as effective at achieving good heat exchange. The nice thing about CryoVent is that it stable indefinitely at room temperature. It will not expire, go bad or need to be restocked, except after use. We apologize for not telling you about this sooner, but as we said, life is never that simple. We have been in the process of patenting CryoVent and related technology. If its any comfort, it has been very hard for us to keep this secret. We are excited about this technology and we think it is about to revolutionize cryopatient transport. Our patent work is in, and the time for disclosure is right since CryoVent will soon be applied to BPI client patients. In fact, we sincerely hope to have CryoVent and sweep flow total liquid ventilation available for the next patient BPI cryopreserves. Wish us luck!