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from Cryonics Magazine 2021 2nd Quarter
by Alcor Life Extension Foundation
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Fight Aging
Fight Aging
By Michael Benjamin and Aschwin de Wolf
Introduction
The Alcor Meta-Analysis Project has three distinct objectives: (1) To organize and enter all case data in a comprehensive database; (2) to visually present and publish the data in a format that allows the reader to see trends and patterns; and (3) to identify correlations between specific elements of a case and outcomes.
We present here a selection of case data for the years of 2019 and 2020. This is followed by a more global presentation that covers the period from 2000 to 2020, which roughly coincides with the introduction of vitrification technologies at Alcor.
At this stage in the meta-analysis project, we still confine ourselves to presenting factual data and calculated (or estimated) measures. After completing this project for all Alcor cases, we will move to the next step of identifying trends and correlations.
The magnitude of the project and sheer quantity of data means that some errors are expected in the reporting or interpretation of data. In some cases, detailed data is not available and rough estimates need to be made based on the case data that was available and extrapolation of what we know from other cases. We expect this project to increase in comprehensiveness, accuracy, and actionable information.
2019
There were 11 cases in 2019, 10 Neuro and 1 Whole Body. A local case is defined as a case in the greater Scottsdale, Arizona area.
In some circumstances (like sudden death), an autopsy is ordered. Alcor typically objects to prevent an (invasive) autopsy but is not always successful.
Unattended death cases are cases in which a patient experiences circulatory arrest without medical caregivers or family present. This often happens to older members who live alone.
A straight freeze is a case in which a patient is frozen without any kind of cryoprotection to prevent freezing damage. Straight freezing usually happens in case of long ischemic delays, after autopsy, or when there is a delay in arranging for cryonics arrangements.
Pre-mortem standby refers to cases in which a (professional) standby team was deployed to the patient’s location before pronouncement of legal death. This chart refers to cases in which the complete stabilization medications protocol was administered. This is typically associated with pre-mortem standbys.
In the meta-analysis project cardiopulmonary support (CPS) cases are cases in which chest compressions PLUS ventilation is performed on the patient as part of stabilization procedures. Brief periods of chest compressions to circulate medications are not included in this category.
Medications Administered Full Protocol
Cardiopulmonary Support (Chest Compressions & Ventilation)
Cryoprotective Perfusion Terminal Cryoprotection Concentration Achieved
Cases in which the terminal cryoprotection concentration was achieved are cases in which the full concentration deemed necessary for vitrification to occur was obtained. In patients with prolonged ischemic exposure this target is not always achieved.
Cryoprotective perfusion cases are cases in which a cryoprotectant was delivered to the patient through perfusion of the blood vessels. As a general rule, when there is no cryoprotective perfusion, the case is a straight freeze.
Duration of medication administration refers to the total time it took to administer all the stabilization medications in the full protocol.
Time from arrest to first medication administration is the time between circulatory arrest and administration of the first medication. This can concern the full protocol, abbreviated protocol, or a single medication (like heparin).
Duration of cryoprotective perfusion defined as the total time from the start to the completion (or termination) of cryoprotective perfusion.
Terminal BRIX concentrations are the highest (venous) cryoprotectant concentrations that were achieved in the patient as measured by refractometry. Minor differences in the neuro- and whole-body formulation of the cryoprotectant are reflected in different target concentrations.
S-MIX stands for Standardized Measure of Ischemic Exposure and calculates the total equivalent normothermic ischemic exposure of a patient. The higher the S-MIX, the higher the degree of ischemic exposure of a patient.
In the S-MIX histograms all cases are divided into 6 different categories ranging from least ischemia to most ischemia.
0 = CNV achieved in whole brain 1 = Between 75% and 100% of brain at CNV 2 = Between 50% and 75% of brain at CNV 3 = Between 25 and 50% of brain at CNV 4 = Between 0 and 25% of brain at CNV 5 = Straight freeze
The CT cryoprotection concentration score is an estimation of the amount of brain area with concentrations of the cryoprotectant to inhibit ice formation.
The CT cryoprotection concentration score histogram shows the number of cases in each concentration score.
2020
There were 6 cases total in 2020, 4 Neuro and 2 Whole Body.
Cardiopulmonary Support (Chest Compressions & Ventilation)
Terminal Cryoprotection Concentration Achieved
2000 – 2020
141 Cases
Terminal Cryoprotection Concentration Achieved
Alcor Case Metrics: Scope and Comments
By Aschwin de Wolf and Michael Benjamin
The Alcor meta-analysis projects collects and organizes case data for all patients. It is easy to lose track of the bigger picture. To show readers the progress that has been made to date, we present here the first series of case metrics for the years 20002020. This cut-off point was chosen because the in year 2000 Alcor started perfusing its patients with a vitrification solution (initially, only neuro).
Selecting a number of case metrics out of many possible metrics raises the question why these metrics and not others. At this point we simply claim that we consider these metrics the most important for evaluating the quality of care at Alcor. Whether to omit, add, or refine some of our metrics is something that we will learn from feedback.
One of the biggest concerns about publication of these metrics is that without knowing the specific context of a case it is difficult to establish whether a “poor” outcome (or trend) is something that was beyond Alcor’s control or not. This topic was discussed in quite some detail at Alcor’s SST Committee meetings. A consensus emerged that while some external events and decisions can sharply reduce Alcor’s ability to provide optimal care given specific policies, ultimately it will be beneficial to treat all bad outcomes as something that is within Alcor’s responsibility to improve. For example, at first sight it seems that an event such as an unattended death of an elderly member who lives alone is not something Alcor can greatly influence. Upon further reflection, this is not the case if we consider that Alcor can allocate resources to providing a daily check-in service for such members, as Alcor has now started doing. If we find that most out-of-state cases show a significant amount of ice formation in CT scans, renewed efforts can be made to provide members with incentives to relocate to Arizona when terminally ill. Another effort could entail providing more field cryoprotections when we consider transport times to the facility too long. In the short run, some events that transpire during a case seem to be beyond Alcor’s control, but in the long run Alcor can design and implement policies to reduce the frequency of those events. One of the reasons for doing the meta-analysis project is that it will more easily identify opportunities for new or enhanced policies to produce substantial improvements.
Fundamentally, the two most important metrics to assess the quality of a cryonics case are ischemia and ice formation. In an ideal case, ischemia is equal to zero and ice formation is equal to zero. Most other technical case metrics can be reviewed in light of these benchmarks. If and when Alcor would consistently deliver on these metrics (which is not yet the case), finer criteria can be added such as viability assays of brain tissue samples after cryoprotection. The series of metrics that we present here have been divided between presenting the metrics for each case for the years 2019 (the year the meta-analysis started) and 2020. We do not intend to publish such detailed annual metrics prior to the year that the meta-analysis project started but all that data is available to us and used for year-to-year comparisons.
Quantitative presentation of case metrics presents a number of challenges that need resolution. We can only briefly review a few of them here:
Median vs mean
One thing that became quite clear to us during the creation of these case metrics is that in most cases presenting the average can lead to poor information quality due to extreme outliers. To use a specific, real-world, example, the case in which Alcor prevailed in a court order against a family to have a patient exhumed after months of delay and litigation produced an equivalent normothermic ischemia time (S-MIX) so large that calculating the average for that year would have showed an extremely high S-MIX value, even if all other cases had low S-MIX values. Such a number would not tell us much about Alcor’s general effectiveness to mitigate ischemia through standby and stabilization.
Quantification of ice formation in the brain
Since Alcor started CT scanning its neuropatients a wealth of visual information has become available to determine the degree of successful cryoprotection of the brain. The different colors for cryoprotectant concentration and ice formation shown in the CT scan images gives us a reasonably good estimate of how much of the brain has vitrified. Ideally, software can be developed to quantify these results with precision. At this stage we simply rank the concentration of cryoprotectant achieved in the brain on a scale from 0-5, with 0 representing no areas with sub-vitrification concentrations and 5 being a straight freeze. The reason to represent the best outcome by 0 is motivated by the fact that 0 also represents the best outcome in the ischemia S-MIX metric, which allows us to correlate them. It is important to understand here that a CT scan does not allow us to exactly quantify ice formation because the degree of ice formation cannot be simply inferred from knowing the concentration of a vitrification solution in a specific area.
Precision
In many cryonics cases, comprehensive data is not available for every single procedure. Sometimes data is only available in
intervals, and in other cases data was not collected at all. Faced with missing or incomplete data we face a challenge. Either we simply report this as “not available”, or we make our best estimate. The meta-analysis project uses both approaches. For example, if the scribe sheets do not show evidence of ventilation during CPS, we will not assume that it happened because it is in Alcor’s protocol. On the other hand, if we do not have detailed temperature data for a patient but know when the person died and when cooling started, we can estimate the typical temperature decrease of a patient based on models and empirical data in the literature and other cryonics cases. In other words, we generally do not assume that something happened without data to corroborate it but when we know something must have happened (the lowering of the temperature of a patient), we use our best calculations. One important question in the metaanalysis project is how much precision we should aim for. As discussed in the article about implementing the S-MIX, the ideal manner to calculate this measure is to use all temperature data available. This does not mean, however, that until the measure is calculated in this manner it cannot yield powerful insights. Since the meta-analysis is such a huge project, we consider it important not to get bogged down in pursuing precision at the cost of progress. What we hope is that over time the precision of our data and models will continue to improve.
Local cases
Only about 25% of all Alcor cases are “local” cases. This means that the overwhelming majority of patients sustain a significant amount of cold ischemia during transport to the facility. In recent years, a growing number of these local cases have been “field cryoprotections” which, in ideal circumstances, eliminates the difference in ischemic exposure time between local and nonlocal cases.
Unattended deaths
Unattended deaths are almost invariably associated with poorer outcomes due to extensive normothermic ischemia and/ or autopsy. For the last two years the number of such cases has increased, relative to its historical average. Preventing unattended deaths has recently been identified as one of the most important priorities for improving case outcomes. Pre-mortem standby
For the years 2000-2020 only 50% of Alcor members received pre-mortem standby. By definition, unattended (sudden) deaths do not receive pre-mortem standby and there are also many cases in which Alcor, or a contractor, arrives after circulatory arrest has occurred. This number shows the limitations of a centralized SST deployment system.
S-MIX
The S-MIX (Standardized Measure of Ischemic Exposure) for a typical patient is around 5 hours of normothermic ischemia. An S-MIX <1 hour of normothermic ischemia has only been achieved in 4 cases during the 2000-2020 period. A case with a <1 hour S-MIX typically entails ultra-rapid stabilization, ventilation during CPS, and continued metabolic support during washout.
Terminal cryoprotection concentration achieved
Complete equilibration of the brain (or whole-body) with cryoprotectant is achieved in 50% of all Alcor cases. It is important to emphasize that this does not mean that in all those cases the brain completely vitrifies. Refractive index measurements concern the brain (or whole-body) at a global level and can co-exist with ischemia-induced regional perfusion impairment.
CT Cryoprotectant Concentration Score
As of writing, there are no CT scans of Alcor patients that show unambiguous visual evidence of the concentration necessary for vitrification in all areas of the brain, although there are a number of scans that appear close to this goal (typically these are ultra-rapid response local cases and/or field cryoprotections after “dying with dignity”). More than 50% of Alcor (neuro) cases show concentrations below what is deemed necessary for vitrification in more than half of the brain.
Implementing the S-MIX
By Aschwin de Wolf
In the 4th quarter issue of Cryonics magazine Michael Perry and Aschwin de Wolf wrote the first exposition of a measure to calculate the estimated total time of equivalent normal body temperature ischemic exposure for a cryonics patient. Because it weights time spent at higher body temperature more than time spent at a lower temperature, this measure provides a more precise measure of ischemic exposure than just calculating the total time between circulatory arrest and the start of cryogenic cooling. This measure also allows for a “discount” when metabolic support is provided through ventilation. In an ideal scenario metabolic support would be provided throughout all parts of the procedure, producing an S-MIX value of zero (or close to it). In the metrics provided here the S-MIX is calculated by dividing the total ischemic time in segments, ideally corresponding to distinct procedures (cardiopulmonary support, surgery, blood washout etc.) which allows applying discounts to parts of the case where metabolic support was available. In practice, this approach can only be an approximation because there can be (brief) interruptions of metabolic support and the efficiency of ventilation can vary. To simplify matters we assumed a metabolic discount of 50% when ventilation was performed during CPS.
In the segmental approach we calculate the S-MIX for a given temperature decrease between a start and end time of a procedure (for example, cardiopulmonary support). It should be noted that this approach is a simplification because the cooling rate from the start to the end of a segment is not identical. To remedy this, we calculate a segment under the assumption of Newtonian cooling in which the cooling rate decreases as the difference between the cooling medium and patient temperature decreases. An even more precise calculation would use all the actual measured temperature data available for a case. This is an approach we aim to implement later in the meta-analysis project, which will allow us to compare both approaches. One of the challenges with this approach is that comprehensive temperature data is only available for a few select cases.
How to incorporate metabolic support in the S-MIX is a complicated issue. In our first exposition we allow for a 50% discount in the S-MIX if ventilation is provided during cardiopulmonary support. If this is followed by oxygenation during washout we give a 100% discount. This approach is open to several objections. Giving a 50% discount for ventilation is somewhat of an arbitrary number meant to reflect the lower cerebral perfusion pressure that can be obtained by (mechanical) chest compressions. Whether this number is reasonable is difficult to determine without doing cerebral oxygenation measurements in the patient, or at least modelling various scenarios in a research model. Another complication arises when a higher metabolic discount is allowed for oxygenation during washout (and cryoprotectant perfusion). One might argue that the dissolved oxygen in washout solutions and cryoprotectants will provide adequate oxygenation of the brain, even in the absence of actual oxygenation. So far we have assumed that oxygenation is always beneficial for the patient without considering the possibility that for some patients oxygenation will actually be detrimental. This topic is mostly unexplored in a typical cryonics context and requires more experimental investigation as well.
The typical cryonics patient may have accumulated (regional) metabolic deficits during the agonal phase as well. This is not taken into account in the way the S-MIX is currently calculated. The most obvious reason for this is because we know so little of the metabolic state of the brain in the typical cryopatient.
In principle, the S-MIX can be calculated for any temperature. At this point, we calculate the S-MIX for all procedures up to the point that cryogenic cooling starts (typically around 0 °C). In principle, the S-MIX can be calculated for sub-zero temperatures but in practice this adds little additional value because the time spent at subzero temperatures before solidification is so short that very little equivalent normothermic exposure time is incurred. The only relevant exception to this concerns storage at dry ice temperature, which can occur as a temporary low-temperature storage measure (for example, when cryonics arrangements still need to be finalized) or after field cryoprotection. The table below shows the S-MIX for storage at dry ice temperature (-78°C), based on Q10=2.
Exposure, in days S-MIX in minutes 1 0.50 2 0.99 3 1.49 7 3.48 14 6.96 31 15.41 62 30.83 186 92.49
As can be seen, even storing a patient at dry ice temperature for half a year “only” generates an equivalent normothermic ischemic exposure of about 1.5 hours. This estimate is likely to be on the conservative side given that the patient is either frozen or has a highly viscous vitrification solution in his system, which
inhibits most or all diffusion-based biochemistry. One positive consequence of these calculations is that it can support the practice of holding a patient on dry ice for extensive periods when long-term cryogenic storage arrangements are being arranged.
Unlike a straightforward task like calculating the duration of a procedure (for example, cryoprotectant perfusion) the S-MIX is a good-effort approximation of the degree of ischemia in a patient’s brain. One thing we hope to do in the later stages of the Alcor meta-analysis project is to experimentally model and validate some of the assumptions made in the S-MIX calculations. We will also seek to correlate the S-MIX of a patient with CT scan results to further understand and quantify the relationship between ischemic exposure and the quality of cryoprotection. Like the meta-analysis project itself, the development, validation, and refinement of a quantitative ischemia measure is a work-in-progress that evolves as we learn more.
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MEMORY BOX ...now!
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No one knows better than you what you will want to have with you.
Alcor makes available to every member and patient, without charge, one acid free Memory Box about the size of a standard banker’s box (H10” x W12” x L15”) for memorabilia to be stored underground at a commercial storage site called Underground Vaults and Storage (UGVS) in Kansas. Additional Boxes are a one-time charge of $250 each for perpetual storage.
Some of the most popular items that have been placed into storage are such things as letters, cards, photographs, diaries, journals, notebooks, books, clippings, army records, directories, recipes, video tapes, cassettes, medical records, fl ash drives, and external drives.
If you would like to begin working on your own Memory Box, or perhaps contribute items to a Box for an Alcor Member already in stasis, or if you have any questions, please contact Linda Chamberlain at linda.chamberlain@alcor.org.
Attempts to Establish a Cryonics Community
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