X-Message-Number: 7220
From: Brian Wowk <>
Date: Tue, 26 Nov 1996 12:01:30 -0600
Subject: Cryonics Quality Control

Tim Freeman notes on CryoNet that Steve Harris suggested at least

CPK-BB
A-V O2
lactate
temp descent data

be published for all cryonics patients, and goes on to query whether or not
CryoCare and/or BPI are collecting or publishing such data on their patients.
Tim further wonders what the response of others is to Steve's assertion that
this data should be gathered and reported.

Mike Darwin no longer routinely participates on CryoNet or sci.cryonics.
However, he was kind enough to answer my inquiry about Steve's suggestions,
BPI procedures, and the rationale for their use.  Below is a summary of his
remarks.

The need for generating feedback in the care delivered to cryopatients is 
indeed important.  Some of the specfic markers Dr. Harris mentions are 
especially important in determining the quality of the care an organization's 
cryopatients are receiving.  However, the remarks as they stand could use 
more qualification and elaboration, just as Tim Freeman suggests.

Corrections first: CPK-BB is a brain specific isoenzyme of creatine 
phosphokinase (CK) which is released from brain tissue which is injured 
(ruptured or leaky cell membranes).  However, its use in evaluating the 
status of ischemic injury to cryopatients is minimal.  The reasons for 
this are that:

1) The blood brain barrier typically remains intact after even severe global
ischemic insults and CK-BB levels do not rise in clinical or experimental
ischemia until many hours after reperfusion following an ischemic insult 
(i.e. cardiac arrest) or in other words until the barrier is compromised.  
For this reason CK-BB levels are not used clinically to evaluate the degree 
of neurological injury to humans following global cerebral ischemia.

CK-BB levels do rise in the days following stroke, and elevated CK-BB may 
be of utility in determining the differential diagnosis in stroke, brain 
trauma and in certain neurodegenerative diseases.

2) The typical cryonics patient is so massively injured that total CK levels
exceed 3000 IU/L and not frequently exceed 6000 IU/L even with 3-fold or 
4-fold dilution. Skeletal muscle and cardiac muscle also have CK in their 
cells and these isoenzymes are released from injured muscle in massive 
amounts. Such very high total CK levels render CK-BB isoenzyme determination 
problematic with conventional clinical techniques.

3) BB isoenzyme level evaluation is very costly and is not very reliable.

4) In animal models of ischemic injury simulating that likely to be 
experienced by cryopatients (conducted  at 21st Century Medicine and BPI) 
cerebrospinal levels of CK-BB correlate well with total CK levels.  Thus, 
total CK is probably a reasonably good marker for overall injury in most 
cases (but not in all patients; exceptions being cases where there is 
antemortem injury to muscle or brain).

In addition to total CK levels, LDH levels (total, not isoenzyme) are 
probably the other most useful indicator of overall injury from ischemia.  
LDH is an enzyme present in most body cells and its presence in elevated 
levels in serum has been found to correlate well with the quality of 
transport (resuscitation, medication, cooling...) a cryopatient receives.

Serum lactate levels are sensitive indicators of the degree of antemortem
ischemic injury as well as a good indicator of the efficacy or lack thereof 
of post arrest cardiopulmonary support.  Lactate is a product of anerobic 
(i.e., oxygen-less) metabolism and thus, if oxygen delivery is inadequate 
serum lactate levels will rise.  Serum lactate levels are measured when it 
is possible to do so.  However, serum for lacate evaluation must be 
separated from blood _immediately_after collection and frozen on dry ice 
unless it is to be analyzed on site.  The logistics of this have limited 
its application in the past.  In the case of CryoCare patient James Gallagher 
lactate levels were measured, and BPI has in-field lactate monitoring 
equipment.  Availability of personnel during a given transport will be the 
major determinig factor in whether or not lactate levels are measured.  
Cost of the test is modest (about $2.00 per determination).

In all of the above discussion of serum markers of the efficacy of transport 
it is important to point out the importance of _baselines_ in allowing 
meaningful conclusions to be drawn.  If a patient has a CK of 3500 IU/L due 
to a crushing injury to a limb before transport begins, then the significance 
of serum CK and LDH levels must be considered in light of where they 
_started from_.   It is critically important to obtain samples for analysis 
at intervals during the entire cryopreservation procedure and if at all 
possible at least one baseline sample at the start of transport.  It is 
highly desirable (and often possible) to obtain antemortem and/or agonal 
samples which document the degree of injury the patient is sustaining 
during the dying process (i.e., terminal shock).  Many patients who present 
for cryopreservation have sustained massive ischemic injury due to 
antemortem (agonal) hypoperfusion (ischemia) many hours before cardiac
arrest occurs and legal death is pronounced.

A-V O2 data is very useful during cryoprotective perfusion and documents 
that the patient has at least some metabolic activity going on at that 
point in the procedure.  This is important feedback because it can provide 
useful information ruling out catastrophic errors of the following kinds:

1) Exposure of the patient to an iatrogenic source of injury which causes
massive cellular or metabolic damage.  For instance, failure of a heat 
exchanger or oxygenator might allow cooling water or disinfectant chemicals 
to enter the patient's circulation.  In one instance lithium hypochlorite 
(bleach) entered a perfusion circuit.  A-VO2 monitoring during transport 
and/or cryoprotective perfusion would allow for an asessment as to the 
biological consequences of such an adverse event.

2) A kinked line into the oxygenator or some other interruption of oxygen 
supply during perfusion can rapidly be detected in this way.  Mike once 
saw a dog die on bypass because the perfusionist rolled a wheel of his 
stool onto the oxygen line supplying the oxygenator. With cryonics 
patients there is only one way to tell if you are oxygenating your 
patient: measure it!

3) Oxygen consumption and CO2 generation during transport and cryoprotective
perfusion provides critical feedback about the efficacy of the equipment and
procedures used.  

BPI routinely measures arterial and venous blood gases and electrolytes 
during cryoprotective perfusion and these values have been reported for 
ACS and CryoCare patients cryopreserved by BPI with most case histories 
having been posted to CryoNet.

BPI has in-field capability for continuously monitoring arterial and venous
blood gases and pH during extracorporeal (heart-lung bypass) support using 
the Sarns 3M CDI in-line blood gas system.  BPI owns 5 of these systems and 
now packs one in the Remote Standby Kit as well as in the ambulance.  The 
CDI system was used for the first time on Jim Gallagher.  This data was not 
reported graphically in the case history because time on bypass before 
washout was brief and parameters were within desirable ranges.  This data 
can be posted if anyone is interested.

A-V O2 data during CPR is very problematic to collect because it:

1) Requires that an arterial line be rapidly placed (for obtaining arterial
blood samples) which is difficult under field conditions.

2)Requires a central venous line be placed to obtain central venous blood
samples for the venous oxygen determination.  This is less difficult, 
however, the ability to place a central venous line for sample taking 
implies the ability to place a a central venous line with fiberoptic 
oxygen saturation monitoring capability allowing for evaluation of central 
venous oxygen saturation SvO2.  This yeilds even more useful real-time 
information than isolated A-V O2 measurements (see discussion below).

Of more use (because they are more practically achieveable!) are 
measurements of patients' oxygen saturation (SO2), central venous oxygen 
saturation (SvO2), and end tidal CO2 concentration (EtCO2).

EtCO2 is useful because if blood is not being circulated and/or if the 
lungs are not functioning properly during CPR then carbon dioxide generated 
in the tissues cannot be removed by the lungs. EtCO2 is thus a very 
sensitive indicator of the efficacy of CPR.

If an evaluation of the patient indicates inadequate perfusion 
(the end-tidal CO2 concentration is equal to or less than 0.5%) at the 
start of CPR, attempts should be made to identify the problem(s) and 
correct it.  At least 3% CO2 is preferred; 2% is the minimum acceptable.  
If acceptable EtCO2s are not beig achieved then steps can be taken to find 
out why and attempt to correct the situation.

As previously mentioned, a very useful tool for evaluating the effectiveness 
of cardiopulmonary support during transport is SvO2 monotoring. Recently, BPI 
has obtained a number of monitors and fiber-optic central venous catheters 
which allow for continuous evaluation of venous oxygen saturation (SvO2) as 
well as central venous pressure, temperature, and other physiologic 
parameters.  Continuous SvO2  monitoring is achieved by passing a special 
fiber-optic catheter through a large vein (in cryopatients, the external 
jugular) distally into the superior or inferior vena cava.  The fiber-optic 
catheter contains three optical channels. One channel is for conducting the 
infrared beam to the tip of the catheter where it is passed through a layer 
of blood flowing over the catheter tip.  The other two optical channels 
conduct the light signal back to the monitor where the measurement is made.  
The principle of operation is much the same as that employed in pulse 
oximetery, except in this case the signal is a "clean" one since it is 
entirely venous blood which is being evaluated as opposed to the mixed 
signal from arterial, capillary and venous blood obtained from conventional 
pulse oximetery.  

This is a particularly valuable technology for use in evaluating the 
efficacy of CPR because, unlike oxygen saturation obtained from pulse 
oximetery (SaO2), the SvO2 indicates the degree of oxygen saturation of 
the blood after it has passed through the tissues.  Normally, SvO2  on 
room air (FiO2  =21%) in a healthy human is in the range of 60-80%, with 
75% being the normal value at rest. This is in contrast to the 95-99% 
oxygen saturation which is normal for arterial blood.  Thus, the SvO2 
represents an indirect measurement of the amount of oxygen extracted from 
the arterial blood.  In the agonal period immediately prior to cardiac 
arrest SvO2  can drop to levels as low as 10-20%.  For practical purposes, 
however, SvO2  levels of 40% or below signal major physiologic 
decompensation, and levels of  30% or below are rapidly lethal. 
In CPR it is desirable to raise SvO2  to at least 40% and preferably to
60-70% or higher.

An obvious question is why must the SvO2 level be greater than zero?  
Indeed, why must SvO2 be at as high as 40-50% for the patient to even 
survive?  The answer is complex and involves consideration of basic 
physiology including the oxygen-hemoglobin disassociation curve and the 
mechanics of oxygen delivery to the mitochondria, a full discussion of 
which is beyond the scope of this post.  A very simplified explanation will 
be provided here.  The partial pressure of oxygen in blood leaving the 
lungs is in the range of 75 to 120 mmHg.  Due to all kinds of 
"inefficiencies" every step of the way along the oxygen delivery process, 
only 1 to 3 mmHg of PO2 actually reaches the mitochondria inside the cells 
where it is needed to allow for aerobic metabolism.  Some oxygen is not 
delivered because hemoglobin cannot unload 100% of the oxygen bound to it.
Still more is lost in diffusing from the red cells to the capillary membrane.  
More still is lost in crossing the barriers represented by the capillary and
cell membranes, and cytoplasm. Finally, a further loss is incurred in 
crossing the mitochondrial membrane. So, what starts out as typically over 
100 mmHg of PO2  sent on its way to the mitochondria from the lungs ends up 
resulting in delivery of only 1-3 mmHg!

Thus, in order for the mitochondria to get the required 1-3 mmHg  of PO2 
under normal conditions, the PO2  of capillary blood has to be 40 mmHg and 
this translates to an oxygen  saturation reading of about 70%.  While a 
very low capillary PO2  can cause the hemogolobin to unload more oxygen, 
and the heart can speed up the rate of pumping to deliver more red cells 
per unit of time, it is simply not possible for sufficient oxygen pressure 
to be present to get the 1-3 mmHg of PO2  into the cells when capillary 
blood PO2  falls to 20 mmHg or below26.  A PO2  of 20 mmHg equals an SvO2  
of 30%.  This is why an SvO2  of 30% is not compatible with life, and why 
all of the oxygen cannot be removed from the arterial blood with any 
possibility of the patient's metabolic needs being met. 
	
The above discussion should make clear the utility of SvO2  measurements 
in CPR.  Even if SaO2  is 80%, this is not a valid  indicator of the 
adequacy of tissue perfusion if SvO2  is 20%.  Clearly, what is happening 
in such a situation is that virtually all of the available oxygen is being 
removed from the blood.  SvO2  thus tells us about the real perfusion and 
metabolic status of the patient.  For instance, in a patient with severe 
anemia (hematocrit of 10%) the true SaO2 may well be 95% on room air and 
the pulse oximeter may show a reading of 90% saturation.  This reflects the 
fact that nearly all of the hemoglobin in the red cells is loaded with 
oxygen.  But this is very misleading in this situation, for, while all of 
the cells are carrying their full capacity of oxygen, there are far too few 
of them to deliver the volume of oxygen required by the tissues.

Despite its obvious utility, SvO2 measurement, due its invasiveness and the
need for sophisticated hardware, may not seem a very practical tool for use 
in cryonics transports.  Certainly, in many remote standby and emergent 
transport situations its application would not be practical.  However, in 
patients where the terminal course allows for meticulous preparation, and 
in particular in patients in whom it will be necessary to establish IV 
access (i.e., no Hickman or other large bore venous line in place at the 
time of cardiac arrest) insertion of an SvO2  catheter will not be an 
inconvenience since it will be necessary to place a central line to 
facilitate administration of transport medications and draw samples for 
subsequent laboratory evaluation.

An SvO2 catheter is ideal for administering medications in the setting of
cryopatient transport because it delivers medications to the central 
circulation where they will be rapidly diluted (avoiding damaging high 
local concentrations) and optimally placed for rapid distribution to all 
the tissues.  An added advantage is the presence of multiple lumens in the 
catheter, allowing for simultaneous administration of different medications, 
as well as the simultaneous administration of medications that would be 
incompatible (cause a precipitate or be inactivated or altered undesirably) 
if they were administered at the same time through the same line.

Since placement of a large bore central line will frequently be necessary 
in approximately one-third of home hospice cryopatients based on past 
experience, placement of a line with SvO2  capability becomes 
not only practical, but extremely desirable.

SVO2 is thus the "gold standard" indicator for the adequacy of perfusion 
during transport.

Temperature descent is a critical indicator of the quality of transport
operations, and of the cryopreservation process as a whole.  Organizations 
who's optimally transported patients are cooling at a rate 0.1 degrees C 
per minute or less are experiencing a lot of unnecessary ischemic injury.  
Under good circumstances (transport team on site) cooling rates during the 
first 10 minutes of CPR of 0.5 to 1.0 degrees C per minute should be 
achieveable.  Graphic data for CryoCare patient Jim Gallagher showing 
temperature descent during transport and dry ice cooling are in press 
right now and will be published in the next issue of CryoCare Report 
(Issue #9).

Organizations that don't publish such data with each case or make such 
data available upon request simply cannot be relied on to be delivering 
this standard of care. Organizations which do not collect such data are 
quite simply delivering grossly inadequate care.

The use of such feedback tools has lead BPI to develop more and more 
effecient methods of cooling and oxygenating patients and has sensitized 
CryoCare and BPI personnel to the tremendous problem of ischemic (shock) 
injury to the patient during the agonal period.  This in turn has lead to 
the development of antemortem "premedication" strategies which are aimed 
at reducing ischemic injury by loading the patient with protective drugs 
before the dying process begins.

Similarly, careful evaluation of the cooling rates being achieved with
cryopatients over the years has lead to the development of the portable 
ice bath and SQUID (at Alcor) and more recently to chilled liquid
ventilation and peritoneal and colonic lavage (at BPI); the combination of
which allowed Jim Gallagher to be cooled at a rate of over 1.0 degrees C
per minute. 

Even more exciting developments are underway.

The first part of the Gallagher technical case history was reported in  
BPI Tech Brief #18 (CRYOMSG #5966 and  
http://www.cryocare.org/cryocare/bpi/tech18b.txt)

***************************************************************************
Brian Wowk          CryoCare Foundation               1-800-TOP-CARE
President           Human Cryopreservation Services   
   http://www.cryocare.org/cryocare/

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