From: Mike Darwin <75120.575@compuserve.com>
Subject: BPI TECH BRIEF #19, Liquid Ventilation
Date: 01 Apr 1996

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Date: Sat, 23 Mar 1996 16:32:36 -0500 (EST)
From: Mike Darwin <75120.575@compuserve.com>
Subject: BPI TECH BRIEF #19, Liquid Ventilation

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!