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/ Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=7220