Author: Mike Darwin

The RhinoChill: A New Way to Cool the Brain Quickly

We scientists are difficult, cranky, and above all, maddeningly frustrating people. Want to turn lead into gold? No problem, we can tell you how to do that, and in fact have even done it already: the only catch is that the cost of such ‘nuclear transmutation’ is many times that of even the most expensive mined gold. You say you want to travel to the moon? Done! That will be ~$80 billion (in 2005 US dollars). Want to increase average life expectancy from ~45 to ~80 years? Your wish is our command, but be mindful, you will, on average, spend the last few of those years as a fleshpot in the sunroom garden of an extended care facility.

And so it has been with an effective treatment for cerebral ischemia-reperfusion injury following cardiac arrest. Thirty years ago, laboratory scientists found a way to ameliorate most (and in many cases all) of the damage that would result from ~15 minutes of cardiac arrest, and what’s more, it was simple! All that is required is that the brain be cooled just 3oC within 15 minutes of the restoration of circulation. The catch? Well, this is surprisingly difficult thing to do because the brain is connected to the body and requires its support in order to survive. And the body, as it turns out, represents an enormous heat sink from which it is very difficult to remove the necessary amount of heat in such short time. Thus, the solution exists and has been proven in the laboratory, but it has been impossible to implement clinically.  This may be about to change as a variety of different cooling technologies, such as cold intravenous saline and external cooling of the head begin to be applied in concert with each other. Separately, they cannot achieve the required 3oC of cooling, but when added together they may allow for such cooling in a way that is both effective and practical to apply in the field.  A newly developed modality that cools the brain via the nasal cavity may provide the technological edge required to achieve the -3oC philosopher’s stone of cerebroprotection.

Read the complete article in PDF here.

Prospects for Mild Therapeutic Hypothermia and Improved CPR in Cardiopulmonary Cerebral Resuscitation

There are two kinds of hypothermia: protective or preservative hypothermia, and therapeutic hypothermia. The former is easy and straightforward to understand for most, clinicians and laymen, alike.  However, therapeutic hypothermia has proved to be a far more difficult idea to communicate, probably because it is so easy to conflate it with protective hypothermia.

Anyone who has had any contact with refrigeration will at once understand the concept of protective hypothermia. Foodstuffs, and other biological materials that are cooled, experience protection against spoilage and decay roughly in proportion to the degree to which they are cooled. A little cooling slows decomposition a bit, and enough cooling will stop it altogether. Again, the temperature-induced decrease in the rate of chemical reaction is a fundamental property of chemistry which is understood intuitively by anyone who lives where it gets cold, or where refrigeration is in use.

By contrast, therapeutic hypothermia does not rely primarily upon the slowing of metabolism or the rate of chemical reactions that occurs as a result of cooling, but rather upon the effects very modest degrees of cooling have on gene activation and signal transduction in mammals. Controlled, mild therapeutic hypothermia (MTH) is generally understood to constitute a reduction in body temperature from ‘normal’ for the species being treated, to 3oC below normal. In the case of humans, this would mean a reduction in body temperature from 37oC to 34oC. Such a modest reduction in temperature results in profound down-regulation of pro-inflammatory cell-signaling pathways and causes the inactivation of genes involved in a multiplicity of deleterious cellular and systemic processes. Similarly, MTH can inhibit apoptosis of brain cells, and slow or halt the downward spiral of excessive metabolic demand by injured cells, causing yet more non-productive hyper-metabolism, and consequently even more cell death. In this article, the biomechanics of MTH are briefly explored, as well as the prospects for improved outcomes in patients who suffer anoxic-ischemic brain injury as a result of cardiac arrest as a result of the rapid application of MTH following the insult.

Read the complete paper in PDF here.

At last, a sure-cold way to sell cryonics with guaranteed success!

A humorous romp through a promising new technique in aesthetic medicine from one cryonicist’s (warped) point of view.

Figure 1: Before cryopreservation (L) and after cryopreservation (R).

As everyone involved in cryonics for more than a fortnight is sadly aware, cryonics doesn’t sell. Indeed, if we were pitching a poke in the eye with a sharp stick, we’d more than likely have more takers than we’ve had trying to ‘market’ cryonics to the public. To see evidence that this is so, you need only wander around a shopping mall on a weekend and observe all the (painfully) stainless steel lacerated and brightly colored needle-pierced flesh sported by the young and trendy and increasing by the old and worn, as well.

Yes, it’s clear; we misread the market, to our lasting detriment.

It’s true that we’ve tried the ‘you’ll be rich when you wake you up line,’ and heaven knows we’ve beaten the ‘you’ll be young and beautiful forever’ line, well, virtually beaten it to death. And while people are certainly interested in great fortune and youth, both of these things share the same unfortunate shortcoming, namely that they are things that people either don’t have but want, or do have and don’t want to lose. As anyone who is really savvy at marketing will tell you, the best way to sell something is to promise (and preferably be able to deliver) that you can get rid of something that people have and really don’t want – something that is ruining the quality of their life, destroying their health, draining their pocketbook and, worst of all, making them really, really ugly.

So, it turns out that for onto 50 years now, we’ve missed the real selling point of cryonics that’s been there all along: IT WILL MAKE YOU THIN! Guaranteed!

Can such a claim be true? Well, surprisingly, the answer would seem to be an almost unqualified, “Yes!”

Recently it’s been discovered that adipocytes, the cells responsible not only for making you fat, but for making you hungry, as well, are particularly susceptible to a phenomenon in cryobiology that has proved a nettlesome (and only recently (partially) overcome) barrier to solid organ cryopreservation: chilling injury. Quite apart from freezing damage due to ice crystals forming, adipocytes are selectively vulnerable to something called ‘chilling injury.’ 1-5 Chilling injury occurs when tissues are cooled to a temperature where the saturated fats that comprise their cell membranes (external and internal) freeze. You see, saturated fat, which is the predominant type of fat in us humans, freezes well above the temperature of water – in fact, it freezes at just below room temperature. That’s why that big gash of fat on the edge of your T-bone steak is stiff and waxy when it is simply refrigerated, and not frozen.

Figure 2: Chilling injury is thought to result from crystallization of cell membrane lipids.

Chilling injury isn’t really well understood. In the days before both cryobiology and indoor heating, humans used to experience a very painful manifestation of it in the form of chilblains – tender swelling and inflammation of the skin due to prolonged cold exposure (without freezing haven taken place). In the realm of organ preservation it is currently thought that chilling injury occurs when cell membranes are exposed to high subzero temperatures (-5oC to -20oC), again, in the absence of freezing.

There is evidence that the lipids (fats) that make up the smooth, lamellar cell membranes undergo crystallization when cells are cooled much below 0 deg C. Since the crystals are hexagonal in shape and have a hole in the middle, this has the effect of creating a pore or hole in the membrane. Cells don’t like that – those holes let all kinds of ions important to cells keeping their proper volume and carrying on their proper metabolic functions leak in and out, as the case may be. This isn’t merely an inconvenience for cells, it’s downright lethal. Without boring you with technical details, it is possible to partially address this state of affairs in organ preservation by adjusting the ‘tonicity’ of the solution bathing the cells: oversimplifying even more, this means by increasing  the concentration of salts to a concentration higher than would normally be present

Figure 3: Contouring of the skin in a pig subjected to brief, subzero cooling of subcutaneous fat.

But, to return to our chilled adipocytes and the promise not only of weight loss, but of a fat-free future; adipocytes are killed, en masse, when their temperature is dropped to between 0 and -7oC. Within a few days of exposure to such temperatures they undergo programmed cell death (apoptosis) and within a couple of months they are phagocytized by the body; and all that ugly and unwanted fat is carted off to be used as fuel by the liver. Now the rub would seem to be that this effect is most pronounced when the temperature of the tissue is cooled to below the freezing point of water and held there – preferably for a period of 10 minutes or longer.

That sounds dire, doesn’t it? What about the skin, the fascia, blood vessels, and the other subcutaneous tissues that will FREEZE (in the very conventional sense of having lots and lots of ice form in them)? Well, the answer, as any long-time experimental cryobiologist will know (even if he won’t tell you) is: pretty much nothing. Way back in the middle of the previous century, a scientist named Audrey Smith and her colleagues at Mill Hill, England found that you could freeze hamsters ‘solid’ – freeze 70+% of the water in their skin and 50% of the water in their bodies – and they would recover from this procedure none the worse for wear. Similarly, those of us who have carelessly handled dry ice for a good part of our lives will tell you that we see parts of our fingertips turn into stiff chalky islands of ice all the time, with the only side effect being a bit of temporary numbness that resolves in a few days to a week – certainly a side effect well worth it to avoid the considerable inconvenience of rummaging around to find a pair of protective gloves.

Figure 4: The Zeltiq Cool Sculpting Cryolipolysis device.

But alas, we scientists (most of us, anyway) are not a very entrepreneurial lot, and so we never thought either of inventing the ZeltiqTM cryolipolysis system, or using ‘the thin-new-you’ as a marketing tool for cryonics.

Yes, that’s right; some very clever folks have found a way to make a huge asset out of a colossal liability – to organ preservationists, anyway. Around 2004 a Minneapolis dermatologist named Brian Zellickson, MD, who specialized in laser and ultrasonic skin rejuvenating procedures, made a not so obvious connection. Both laser and skin ‘face-lifting’ and skin ‘rejuvenation’ procedures rely on the subcutaneous delivery of injuring thermal energy to the tissues of the face, or other treated parts of the body (cellulite of the buttocks and thighs are two other common areas for treatment). These energy sources actually inflict a second degree burn in a patchy and well defined way to the subdermal tissues.

Now this may seem a very counterintuitive thing to do if you are trying to induce ‘rejuvenation’ or ‘lift’ a sagging face. But if you think about it, it makes a great deal of sense. As any burn victim will tell you, one of the most difficult (and painful) parts of recovery is stretching the highly contracted scar tissue that has formed as a result of the burn injury. Indeed, for many patients with serious burns over much of their body, the waxy, rubbery and very constricting scar tissue prevents the return of normal movement, and can lock fingers and even limbs into a very limited range of motion. Many burn victims must do painful stretching exercises on a daily basis to avoid the return of this paralyzing skin (scar) contracture.

And it must be remembered that aged skin – even the skin of the very old – can still do one thing, despite the many abilities it has lost with age, and that thing is to form scar tissue in response to injury. Thus, laser and ultrasonic heating of normal (but aged) skin induces collagen proliferation and large-scale remodeling of the skin. For all the bad things said about scar tissue it is still a remarkable achievement in that it does constitute regenerated tissue. Regenerated tissue which does the minimum that normal skin must do to keep us alive: provide a durable covering that excludes microbial invasion, and prevents loss of body fluids. By injuring the tissue just below the complexly differentiated layer of the dermis (with its hair follicles, sweat glands and highly ordered pigmentation cells) much of the benefit of ‘scarring’ is obtained without the usual downsides.

The injured tissues respond by releasing collagen building cytokines as well as cytokines that result in angiogenesis (new blood vessel formation) and widespread tissue remodeling. And all that newly laid down collagen contracts over time, tightening and lifting the skin – and the face it is embedded in. These techniques may justly be considered much safer versions of the old fashioned chemical face peel, which could be quite effective at erasing wrinkles and achieving facial ‘rejuvenation,’ but was not titrateable and was occasionally highly unpredictable: every once in awhile the result was disastrous burning and accompanying long term scarring and disfiguration of the patient’s face.

St some point Dr. Zellickson seems to have realized that the selective vulnerability of adipocytes to chilling offered the perfect opportunity for a truly non-invasive approach to ‘liposuctioning’ by using the body’s own internal suctioning apparatuses, the phagocytes, to do the job with vastly greater elegance and panache than any surgeon with a trocar and a suction machine could ever hope to do. Thus was invented the Zeltiq Cool SculptTM cryolipolysis machine.6

Figure 5: The cooling head of the Zeltiq devive equipped with ultrasonic imaging equipment and a suction device to induce regional ischemia and hold the tissue against the cooling surface.

The beauty of cryolipolysis is that it is highly titrateable, seems never to result to in excessive injury to, or necrosis of the overlying skin, and yields a smooth and aesthetically pleasing result. Not unjustifiably for this reason it is marketed under the name Cool SculptingTM. The mechanics of the technique are the essence of simplicity. The desired area of superficial tissue to be remodeled is entrained by vacuum in a cooling head equipped with temperature sensors, an ultrasonic imaging device, and a mechanical vibrator. The tissue in the cooling head is sucked against a conductive surface (made evenly conductive by the application of a gel or gel-like dressing to the skin) where heat is extracted from it. The tissue is cooled to a temperature sufficient to induce apoptosis in the adipocytes, while at the same time leaving the overlying skin untouched. The depth of cooling/freezing is monitored by ultrasound imaging and controlled automatically by the Zeltiq device.  At the appropriate point in the cooling process the tissue is subjected to a 5 minute period of mechanical agitation (massage) which helps to exacerbate the chilling injury, perhaps by nucleating the unfrozen fat causing it to freeze.7 When the treatment is over, the device pages an attendant to return to the treatment room and remove it.

The tissue under vacuum is also made ischemic – blood ceases to flow, and this has the dual advantage of speeding the course of the treatment by preventing the blood borne delivery of unwanted heat – and more importantly, by making the cooling more uniform, predictable and reproducible. It also has the effect of superimposing ischemic injury on top of the chilling injury which is something that seems to enhance adipocyte apoptosis. The whole treatment, in terms of actual cooling time, takes about 60 minutes. In the pig work which served as the basis for the human clinical treatments, the duration of treatment was only 10 minutes: but the cooling temperature was also an ‘unnerving’ -7oC. The degree of temporary and fully reversible peripheral nerve damage (that temporary numbness us ‘dry ice handlers’ know so well) was more severe at this temperature, although it resolved in days to a week or two, without exception.

As previously noted, cryolipolysis causes apoptosis of adipocytes and this results in their subsequently being targeted by macrophages that engulf and digest them. This takes time, and immediately after treatment there are no visible changes in the subcutaneous fat. However, three days after treatment, there is microscopic evidence that an inflammatory process initiated by the apoptosis of the adipocytes is underway, as evidenced by an influx of inflammatory cells into the fat of the treated tissues. This inflammatory process matures between seven and fourteen days after treatment; and between fourteen and thirty days post-treatment, phagocytosis of lipids is well underway. Thirty days after treatment the inflammatory process has begun to decline, and by 60 days, the thickness of interlobular septa in the fat tissue has increased. This last effect is very important because it is weakness, or failure of the interlobular fat septae that is responsible for the ugly ‘cottage cheese’ bulging that is cellulite. Three months after the treatment you get the effect you see below on the ‘love handles’ of this fit, and otherwise trim fellow. Thus, it is fair to say that Cool SculptingTM is in no way a misnomer.

Figure 6: Art left is a healthy, fit young male who has persistent accumulation of fat in the form of ‘love handles’ that are resistant to diet and exercise and the same man 3 months after cryolipolysis.

Does cryolipolysis really work? The answer is that it works extremely well for regional remodeling or sculpting of adipose tissue – those pesky love handles, that belly bulge around the navel, that too plump bum, or those cellulite marred thighs. So far it has not been used to try and ablate large masses of fat – although there seems no reason, in principal, why this could not be done using invasive techniques such as pincushioning the fat pannus with chilling probes, as is done with cryoablation in prostate surgery. However, this would be invasive, vastly more expensive, and likely to result in serious side effects.

And that was one of the really interesting things about the research leading up to FDA approval of cryolipolysis: it seems to cause no perturbation in blood lipids, no disturbance of liver function (the organ that has to process all that suddenly available fat) and no global alterations in immune function. It seems to be safe and largely adverse effect free. There is some localized numbness (as is the case in freezing of skin resulting from handling dry ice) but it resolves without incident with a few weeks of the procedure.8

So, all of this makes me wonder, since human tissues tolerate ice formation and respond to it in much the same way as they do to laser or ultrasound ‘rejuvenation’ (depending upon the degree of damage) a logical question is, “would it be possible to use partial freezing of the skin – just enough to provoke the remodeling response – as a method of facial rejuvenation?” It should be safer than a chemical people and it is, like laser and ultrasound therapy, titrateable.

Figure 7: “Gad darn it, this shiny gold stuff keeps getting into the silt I’m tryin to git out of this here river!”

Which returns me to the whole subject of cryonics: fat is very poorly perfused and it seems unlikely that things done to moderate or abolish chilling injury will be nearly so effective for the adipocytes in fat (if it they are effective at all). That means that we might well all come back from our cryogenic naps not only young, via the magic of nanotechnology and stem cell medicine, and rich via the miracle of compound interest (which none other than Albert Einstein once remarked was “the most powerful force in the universe”), but also THIN! For all these years organ cryopreservationists, like Fahy and Wowk, have been panning for the mundane silt of a way around a chilling injury9 all the while discarding the gleaming nuggets of gold that were persistently clogging up their pans.

We cryonicists should not repeat their error and should realize a good thing when we see it. Now, for the first time, we can credibly claim that if you get cryopreserved you’ll come back not only young and rich, but young and rich and beautiful and thin!

Methinks there must be very few in the Western World today, man woman or child, who can resist a product that has all that to offer – and which, by the way, bestows practical immortality in the bargain.

Ok, Ok, maybe we shouldn’t mention that last part about immortality; it might scare the children.

REFERENCES:

1)     Wiandrowski TP, Marshman G. Subcutaneous fat necrosis of the newborn following hypothermia and complicated by pain and hypercalcaemia. Australas J Dermatol 2001;42:207–10.

2)     Diamantis S, Bastek T, Groben P, Morrell D. Subcutaneous fat necrosis in a newborn following icebag application for treatment of supraventricular tachycardia. J Perinatol 2006;26:518–

3)     Lidagoster MI, Cinelli PB, Levee´ EM, Sian CS. Comparison of autologous fat transfer in fresh, refrigerated, and frozen specimens: an animal model. Ann Plast Surg 2000;44:512–5.

4)      Wolter TP, von Heimburg D, Stoffels I, et al. Cryopreservation of mature human adipocytes: in vitro measurement of viability. Ann Plast Surg 2005;55:408–13.

5)      Manstein D, Laubach H, Watanabe K, Farinelli W, Zurakowski D, Anderson RR. Selective cryolysis: a nivel method of noninvasive fat removal. Lasers Surg Med 2008;40:595–604.

6)     Avram MM, Harry RS. Cryolipolysis for subcutaneous fat layer reduction. Lasers Surg Med. 2009 Dec;41(10):703-8. Review. PubMed PMID: 20014262.

7)     Zelickson B, Egbert BM, Preciado J, Allison J, Springer K, Rhoades RW, Manstein D. Cryolipolysis for noninvasive fat cell destruction: initial results from a pig model. Dermatol Surg. 2009 Oct;35(10):1462-70. Epub 2009 Jul 13. PubMed PMID: 19614940.

8)     Coleman SR, Sachdeva K, Egbert BM, Preciado J, Allison J. Clinical efficacy of noninvasive cryolipolysis and its effects on peripheral nerves. Aesthetic Plast Surg. 2009 ul;33(4):482-8. Epub 2009 Mar 19. PubMed PMID: 19296153.

9)     Fahy GM, Wowk B, Wu J, Phan J, Rasch C, Chang A, Zendejas E. Cryopreservation of organs by vitrification: perspectives and recent advances. Cryobiology. 2004 Apr;48(2):157-78.

CPR: A pair of hands aren’t enough

CPR: A Pair of Hands Aren’t Enough: You Also Need a Heart and a Brain

“Anyone, anywhere, can now initiate cardiac resuscitation procedures. All that is needed are two hands.” [Kouwenhoven WB, Jude J, Knickerbocker G. Closed chest cardiac massage. JAMA 1960;173:1064–7.

Sudden Cardiac Arrest

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Figure 1: Mortality from sudden cardiac arrest (SCA) in 2004 as a result of myocardial infarction compared to death from other ‘high profile’ causes of mortality in the US.

Each year in the United States there are ~450,00 deaths from heart attack – myocardial infarction (MI)* with 310,000 of these deaths occurring before the patient reaches the hospital as a result of unsynchronized electrical activity in the heart, ventricular fibrillation, which stops the effective delivery of blood to the body. [2]  This mode of sudden cardiac arrest[1, 2] (SCA) is also responsible for the majority of the 190,000 in-hospital deaths from MI, which typically occur within the first 24 hours following admission.[3]   Especially tragic is that 50% of these deaths occur in persons ~60 years of age or less and thus lose at least a decade of active, productive life.[4]  An estimated additional 20,000 incidents of SCA occur as a result of asphyxiation, drowning, electrocution, and genetic or developmental predisposition to lethal arrhythmias such as Wolf-Parkinson’s White Syndrome, congenital thickening of the interventricular septum, and idiopathic arrhythmic disease and other causes not related to non-atherosclerosis. This latter category of SCA typically occurs in individuals whose mean age is less than 35.[5, 6]

At this time the principal treatments for SCA consist of initiation of manual, ‘bystander’ cardiopulmonary resuscitation, so-called Basic Cardiac Life Support (BCLS or BLS), followed by ‘definitive’ treatment of the arrhythmia beginning with defibrillation and the application of Advanced Cardiac Life Support (ACLS or ALS).[7]

ACLS consists of the application of an algorithm of manual CPR, electrical defibrillation and pharmacologic therapy aimed at restoring a perfusing cardiac rhythm and adequate blood pressure and cardiac output to sustain life until definitive treatment of the underlying cause of the cardiac arrest can be achieved (e.g., coronary revascularization, implantation of an automatic defibrillator, or life-long anti-arrhythmic therapy).

What are the Odds?

Figure 2: Probability of survival as a function of time following cardiac arrest. [8]

Figure 2: Probability of survival as a function of time following cardiac arrest. [8]

As is shown in Figure 3 below, the time to survival without neurological deficit following cardiac arrest in the absence of BCLS declines rapidly following a sigmoid curve with survival without neurological deficit being ~80-90% following 1 minute of arrest time, and less than 10% following 9 minutes of arrest.[8] Put another way, 50% of patients will experience significant morbidity or death following 4 minutes of circulatory arrest (Figure 2).

What is not shown in this graph is that the effect of immediate bystander CPR on survival is negligible in most studies [9,10] with the primary benefit being observed in patients who’s time from the initiation of BCLS to successful cardiac resuscitation was greater than 8 minutes.[11] There is evidence in the literature that morbidity is improved with prompt by-stander CPR [12] providing that EMS response is also rapid, although this remains controversial.[11,13]  A corollary of this is that the overall survival rate following SCA, with or without serious neurological morbidity, ranges between 1% (New York City, NY) [14] to 17% (Seattle, WA).[15] The mean survival (defined as survival to discharge from the hospital) in the United States as a whole is generally agreed to be at best 15%  [16] with ~70% of these patients experiencing lasting neurological morbidity (ranging from ‘mild’ cognitive impairment to total incapacitation in the Persistent Vegetative State (PVS).[17,18,19]

The primary cause of non-survival in patients experiencing SCA is failed cardiac or cerebral resuscitation. Arguably, it is failed cerebral resuscitation, since most underlying causes of refractory cardiac arrest could be treated by ‘bridging’ supportive technologies such as emergency femoral-femoral cardiopulmonary bypass (CPB) until myocardial revascularization and hemodynamic stabilization were achieved.[20] When emergency CPB is applied to patients who are candidates for good neurological outcome, the survival rate is increased.[21, 22, 23, 24] However, these technologies are not typically used on patients who are unsuccessfully resuscitated (restoration of adequate cardiac rhythm and perfusion) because of the justified perception that irreversible brain damage would have occurred during the prolonged period of cardiac arrest or CPR/ACLS.[21]  Similarly, it is for this reason that most attempts to achieve cardiopulmonary resuscitation in hospitalized patients who are not hypothermic or intoxicated with sedative drug(s) are terminated after 15 minutes.[25, 26]

Within medicine it is widely understood that ‘CPR doesn’t really work’ and that if the return of spontaneous circulation (ROSC) is not achieved within ~ 5 minutes of cardiac arrest, the chances for survival are slim, and the chances for survival absent neurological impairment are slimmer still.[8] The principal reasons that conventional CPR is not effective are that it fails to supply an adequate amount of flow at an adequate pressure. Cardiac output (CO) is typically ~1/3rd of the at-rest requirement (~1.5 versus ~4.5 liters per minute), and mean arterial pressure (MAP) is typically 25 mm Hg to 45 mm Hg; well short of the 60 mmHg required to sustain cerebral viability.[27, 28]

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Figure 3: The impact of a delay of 10 min in inducing MHT is a dog model of cardiac arrest followed by 3 min of systemic ischemia, 7 minutes of mechanical CPR and 50 minutes of advanced life support. Hypothermia to 34oC was induced beginning at 10 min post arrest in the early hypothermia group˜ and at 20 min post arrest in the delayed hypothermia group ¢. In the early hypotherrmia group group, 5 of 7 surviving dogs were functionally normal (OPC 1 or 2), 1 had OPC 3, and 1 had OPC 4 (coma) at 96 hours of recovery. Histologically, 4 of 8 dogs in this group were normal (HDS 0), 1 had HDS 16, 1 had 22, and 1 had 98. The only surviving dog in the DH group was functionally normal at 96 hours (OPC 1, NDS 0) with an HDS of score of32 (mild injury) Due to early mortality only two other dogs in the delayed hypothermia group were evaluated histologically and their HDS scores 38 and 45, respectively. Dogs in this study were scored by overall performance categories (OPC; 1=normal, 2=moderate disability, 3=severe disability but conscious, 4=coma, and 5=death) Neurological function and neurological deficit scores (NDS; 0% to 10%=normal, 100%=brain death). [72],[73] Histological damage scores were obtained by neuropathological examination of 19 distcrete brain regions for severity and extent of ischemic neuronal changes, infarcts, and edema. A total brain histological damage score (HDS) >40 represented moderate damage, and HDS >100 represented severe damag.[74] Redrawn from Nozari, A., et al., Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation, 2006. 113(23): p. 2690-6.

The condition of the typical sudden cardiac arrest patient and the circumstances under which he experiences cardiac arrest are far from the ideal of a patient who is a candidate for emergency cardiopulmonary bypass in hospital. The typical SCA patient is middle aged or elderly, often suffering from one or more co-morbidities (diabetes, obesity, COPD, hypertension), and if subjected to prolonged CPR will invariably have impaired gas exchange due accumulation of fluid in both the parenchyma and the air-spaces of the lungs (pulmonary edema with alveolar flooding). This occurs because closed chest CPR quickly causes pulmonary edema.[29, 30]  As previously noted, even when the SCA patient is a ‘good’ candidate for salvage; someone who is relatively young and free of co-morbidities, CPR will likely prove futile due to cerebral ischemia-reperfusion injury and the post-resuscitation syndrome.

Over the past 25 years a vast number of therapeutic interventions have shown great promise in animal models of regional and global cerebral ischemia in the laboratory.[31, 32, 33, 34] In the last 6 years alone, over 1000 experimental papers and over 400 clinical articles on pharmacological neuroprotection have been published.[35, 36] However, with one exception, none of these interventions has been successfully applied clinically despite many attempts. [37, 38, 39, 40, 41, 42, 43, 44] The sole exception to this frustrating debacle has been the introduction of moderate therapeutic hypothermia (MTH) as the standard of care for a select (and very small) minority of SCA patients.[45, 46, 47, 48, 49, 50, 51]

The question thus arises, how good is MTH? Is it, like CPR, just another ‘ritual therapy’ that works well in the laboratory but fails to deliver under the real world conditions of the in-field and clinical environments? And, of potentially great importance to cryonicists is the question of whether techniques being developed for clinical use in SCA have relevance or even merit direct application to the cryonics patient? The answer to those questions will be reviewed here in the near future.

References

1.         American-Heart-Association, Heart Disease and Stroke Statistics – 2008 Update. . 2008, American Heart Association: Dallas, Texas.

2.         de Vreede-Swagemakers, J., et al., Out-of-hospital cardiac arrest in the 1990’s: a population-based study in the Maastricht area on incidence, characteristics and survival. . J Am Coll Cardiol, 1997. 30: p. 1500-5.

3.         American-Heart-Association-and-National-Research-Council, Standards for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). . JJ Amer Med Assoc, 1974. 227(suppl): p. 833-68.

4.         Sakai, A., Sudden deaths among male employees: a six-year epidemiological survey. J Cardiol, 1990. 20: p. 957-61.

5.         Safranek, D., Eisenberg, MS, Larsen, MP., The epidemiology of cardiac arrest in young adults. Ann Emerg Med, 1992. 21: p. 1102-6.

6.         Viskin, S., Belhassen, B., Idiopathic ventricular fibrillation. American Heart Journal, 1990. 120: p. 661 – 671.

7.         Skogvoll, E., et al., Out-of-hospital cardiopulmonary resuscitation: a population-based Norwegian study of incidence and survival. . Eur J Emerg Med, 1999. 6: p. 323-30.

8.         Weale, F., The efficacy of cardiac massage. Lancet, 1960. 1: p. 990-96.

9.         Eisenberg, M., Cardiac Arrest and Resuscitation: A tale of 29 cities. Ann of Emer Med, 1990. 19: p. 179-86.

10.       Kentsch, M., et al., Early prediction of prognosis in out-of-hospital cardiac arrest. Intensive Care Med, 1990. 16: p. 378-83.

11.       Troiano, P., et al., The effect of bystander CPR on neurologic outcome in survivors of prehospital cardiac arrests. Resuscitation, 1989. 17: p. 91-8.

12.       Bossaert, L., Van Hoeyweghen, R., Bystander cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest. The Cerebral Resuscitation Study Group. . Resuscitation, 1989. 17(Suppl): p. S55-69; discussion S199-206.

13.       Stueven, H., et al. , Bystander/first responder CPR: ten years experience in a paramedic system. Ann Emerg Med, 1986. 15: p. 707-10.

14.       Lombardi, G., Gallagher, J, Gennis, P., Outcome of out-of-hospital cardiac arrest in New York City. The Pre- Hospital Arrest Survival Evaluation (PHASE) Study [see comments]. JAMA, 1994. 271: p. 678-83.

15.       McCarthy, M., Looking after your neighbors Seattle-style. Lancet, 1998. 351: p. 732.

16.       Hayward, M., Cardiopulmonary resuscitation: are practitioners being realistic? Br J Nurs, 1999. 8: p. 810-4.

17.       Bengtsson, M., A psychiatric-psychosocial investigation of patients who had survived circulatory arrest. Acta Psychiat Scan, 1969. 45: p. 327.

18.       Roewer, N., Kloss, T, Puschel, K., Long-term result and quality of life following preclinical cardiopulmonary resuscitation. Anasth Intensivther Notfallmed, 1985. 20: p. 244-50.

19.       de Vos, R., Quality of life after cardiopulmonary resuscitation. Resuscitation, 1997. 35: p. 231-6.

20.       Phillips, S., Resuscitation for cardiogenic shock with extracorporeal membrane oxygenation systems. Semin Thorac Cardiovasc Surg, 1994. 6: p. 131-5.

21.       Younger, J., et al., Extracorporeal resuscitation of cardiac arrest [see comments]. Acad Emerg Med, 1999. 6: p. 700-7.

22.       Matsuwaka, R., et al., Emergency percutaneous cardiopulmonary support for patients with cardiac arrest or severe cardiogenic shock. Nippon Kyobu Geka Gakkai Zasshi, 1996. 44: p. 2006-10.

23.       Myerburg, R., Clinical, electrophysiologic, and hemodynamic profiles of patients resuscitated from pre-hospital cardiac arrest. . Amer J Med, 1980. 68: p. 568.

24.       Safar, P., Abramson, NS, Angelos, M, et al., Emergency cardiopulmonary bypass for resuscitation from prolonged cardiac arrest. Am J Emerg Med, 1990. 8: p. 55-67.

25.       Peterson, M., et al., Outcome after cardiopulmonary resuscitation in a medical intensive care unit. Chest, 1991. 100: p. 168-74.

26.       Gener, J., et al., Immediate and 1-year survival after cardiopulmonary resuscitation at an intensive care unit. Med Clin (Barc), 1989. 93: p. 445-8.

27.       Rubertsson, S., et al., Blood flow and perfusion pressure during open-chest versus closed-chest cardiopulmonary resuscitation in pigs. Am J Emerg Med, 1984. 23: p. 568-571.

28.       Bircher, N., Safar, P., Open-chest CPR: An old method whose time has returned. Am J Emerg Med, 1984. 2: p. 568-71.

29.       McDonald, J., Systolic and mean arterial pressures during manual and mechanical CPR in humans. Ann Emerg Med, 1982. 11: p. 292-5.

30.       Ornato, J., et al., Measurement of ventilation during cardiopulmonary resuscitation. Crit Care Med., 1983. 1: p. 79-82.

31.       Kim, H., et al., Amelioration of impaired cerebral metabolism after severe acidotic ischemia by tirilazad post-treatment in dogs. . Stroke, 1996. 27: p. 114-21.

32.       Iwatsuki, N., et al., Hyperbaric oxygen combined with nicardipine administration accelerates neurologic recovery after cerebral ischemia in a canine model. . Crit Care Med, 1994. 22: p. 858-63.

33.       Cervantes, M., Moralı´, G, Letechipı´a-Vallejo, G., Melatonin and ischemia reperfusion injury of the brain. J. Pineal Res, 2008. 45: p. 1-7.

34.       Krep, H., Bernd W, Bottiger, BW, et al., Time course of circulatory and metabolic recovery of cat brain after cardiac arrest assessed by perfusion- and diffusion-weighted imaging and MR-spectroscopy. Resuscitation, 2003. 58: p. 337-348.

35.       DeGraba, T., Pettigrew, C., Why do neroprotectivedrugs work in animals but not in humans? Neurologic Clinics, 2000. 18: p. 475-493.

36.       Ginsberg, M., Adventures in the Pathophysiology of Brain Ischemia: Penumbra, Gene Expression, Neuroprotection. The 2002 Thomas Willis Lecture. Stroke, 2003. 34: p. 214-223.

37.       Cheng, J., Al-Khoury, L, Zivin, JA., Neuroprotection for Ischemic Stroke: Two Decades of Success and Failure. NeuroRX, 2004. 1: p. 36-45.

38.       Roine, R.O., et al., Nimodipine after resuscitation from out-of-hospital ventricular fibrillation. A placebo-controlled, double-blind, randomized trial. JAMA, 1990. 264(24): p. 3171-3177.

39.       Longstreth, W.T., Jr., et al., Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest. Neurology, 2002. 59(4): p. 506-514.

40.       Landau, W.M., et al., Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest. Neurology, 2003. 60(11): p. 1868-1869.

41.       Halstrom, A., Rea, TD, et al., Manual chest compression vs use of an automated chest compression device during resuscitation following out-of-hospital cardiac arrest: a randomized trial. JAMA, 2006. 295: p. 2620-8.

42.       Lafuente-Lafuente, C., Melero-Bascones, M., Active chest compression-decompression for cardiopulmonary resuscitation. Cochrane Database Syst Rev., 2004. (2):CD002751.

43.       Aung, K., Htay, T., Vasopressin for cardiac arrest: a systematic review and meta-analysis. Arch Intern Med, 2005. 10: p. 17-24.

44.       Callaham, M., Madsen, CD, Barton, CW, Saunders, CE, Pointer, J., A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA, 1992. 268: p. 2667-72.

45.       Rincon, F., Mayer, SA., Therapeutic hypothermia for brain injury after cardiac arrest. . Semin Neurol 2006. 26: p. 387-395.

46.       Bernard, S., Gray, TW, Buist, MD, et al., Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med, 2002. 346: p. 557-563.

47.       Liu, L. and M.A. Yenari, Therapeutic hypothermia: neuroprotective mechanisms. Front Biosci, 2007. 12: p. 816-25.

48.       The-Hypothermia-after-Cardiac-Arrest-Study-Group, Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med, 2002. 346: p. 549-556.

49.       Nolan, J., Morley, PT, Vanden Hoek, TL, Hickey, RW., Therapeutic Hypothermia After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Circulation, 2003. 108: p. 118-121.

50.       Arrich, J., Clinical application of mild therapeutic hypothermia after cardiac arrest. Crit Care Med, 2007. 35(4): p. 1041-7.

51.       Sandroni, C., et al., In-hospital cardiac arrest: incidence, prognosis and possible measures to improve survival. Intensive Care Med, 2007. 33(2): p. 237-45.

* The author rejects the conventional designation of ‘sudden cardiac death’ because it is inaccurate; death is, by definition, the irreversible loss of life. Acute cardiac arrest is not death and the nomenclature used to describe it should reflect that fact.

CPR and the breath of death?

And the Lord God formed man of the dust of the ground, and breathed into his nostrils the breath of life; and man became a living soul. Genesis 2:7

For breath is life, and if you breathe well you will live long on earth.  – Sanskrit Proverb

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In the Beginning…

Since the beginning of modern resuscitation over 40 years ago the sequence of interventions, and to a great extent their importance, has been determined by the ABCs of cardiopulmonary resuscitation (CPR): Airway, Breathing and Circulation. [1] Without breath there is no life and the most obviously and easily detected sign that life is fleeing is the absence of breath. What’s more, in many in whom breathing has newly ceased, simply opening the airway, or giving a single rescue breath will restore spontaneous respiration. We are told that breath is life and there is great truth in this saying.

Negative Pressure Ventilation

The physiology of the vertebrate chest is a truly amazing thing and it can take very bright men years to master its implications. One of the hardest concepts for me to grasp was that under normal conditions the pressure inside the pleural space (the space around the lungs) and the mediastinal spaces (the space that surrounds the heart and the great vessels of the chest) is always negative relative to both the atmospheric pressure and the pressure in the rest of the body (more on this later). [2] In other words, there is always a slight vacuum in those parts of the chest. Mostly this is a result of the fact that we breathe using our diaphragms and the muscles of our chest wall to create a low grade vacuum inside the chest into which air rushes via the trachea to fill our lungs.  When we relax those muscles, the natural elasticity, or recoil of the chest wall and diaphragm acts to squeeze the air out [I], and the cycle is then repeated. We thus breathe by means of negative pressure ventilation.

Naturally enough, when medicine began to try to restore breathing when it had ceased, most of the attempts that were made were attempts to simulate the natural process whereby air is moved in and out of the lungs; principally by negative intrathoracic pressure. [3]

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Above: an illustration of the Silvester method of artificial respiration circa 1880. (Silvester HR., A new method of resuscitating still-born children, and of restoring the persons apparently drowned or dead. BMJ 1858;2:576-9.)

Understandably, trying to mimic the complex action of the diaphragm and accessory muscle of the chest wall in normal negative pressure ventilation were difficult, cumbersome and often ineffective.  By 1959 rescue breathing using the mouth-to-mouth technique had become the mandated medical standard. [4]

There is no question that mouth-to-mouth resuscitation is vastly more effective than the medically endorsed methods that preceded it. What’s more, the class of ventilation to which mouth-to-mouth belongs, intermittent positive pressure ventilation (IPPV), has become essentially the only modality for assisting or replacing breathing in humans.  IPPV long ago displaced negative pressure ventilation (NPV) in the form of the iron lung and the cuirass shortly after polio was vanquished in the 1950s.

Below: Polio patients suffering from respiratory paralysis in iron lungs during an epidemic in the early 1950s.

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Below: A contemporary cuirass ventilator; this new breed of machines uses a biphasic approach that employs negative pressure on inspiration and positive pressure assisted exhalation. The Hayek biphasic cuirass ventilator is capable of  delivering higher tidal volumes (negative inspiratory tidal volume and positive expiratory tidal volume),  greatly increased frequency of ‘breaths’ from 6 to 1200CPM, and allows control of the inhalation to exhalation ratio without depending upon the passive recoil of the patient’s chest. Courtesy of United Hayek Medical: http://www.unitedhayek.com/products/mrtx

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While IPPV has many advantages over NPV, it is un-physiologic in one way that turns out to be of crucial importance in the setting of CPR. IPPV dramatically reduces the return flow of blood from the body to heart. The physics and physiology of this are complex, and even the shortest and most lucid tutorials run to many pages of text; often studded with equations and difficult to interpret graphs and charts. Among the many reasons IPPV’s effects are so complex in the human with a beating heart is that the body can respond to changes in venous blood flow, ventricular volume, and so on by dynamically adapting; heart rate can be increased, vascular tone can be altered, and even the amount of fluid retained by the body can be altered. [5]

The Danger of Positive Pressure Ventilation in CPR

For the patient in cardiac arrest none of these adaptive changes is possible. That makes discussion of the problems posed by IPPV much simpler, while at the same time making the adverse consequences more serious and potentially life threatening.

To understand why IPPV is so dangerous in the setting of CPR it is necessary to understand the concept of preload. Most simply, preload can be defined as “the load to which a muscle is subjected before shortening.” If this doesn’t leap out at as a point of great significance it is because this definition needs to be understood in connection with a physiological principle named after the two great physiologists who discovered it, the Frank-Starling Law of the Heart [II]. The Frank-Starling law of the heart (also known as Starling’s law or the Frank-Starling mechanism) states that the greater the volume of blood entering the heart during diastole (the period between cardiac contractions or the end-diastolic volume), the greater the volume of blood ejected during systolic contraction (stroke volume). This may seem pretty obvious: what you put into the heart before it contracts determines what you’ll get out of it after contraction is complete. But, as it turns out, this relationship is rather more complex than simple double entry bookkeeping would suggest.

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Above: Frank-Starling Cardiac Function Curve. Courtesy of Wikimedia Commons.

In the diagram above the Y-axis shows the cardiac output and the X-axis shows right atrial pressure. While the above diagram shows only one line, a classic Frank-Starling plot often shows three separate lines, each roughly the same shape, one atop of each other, to illustrate that shifts on the same line indicate a change in preload, while shifts from one line to another indicate a change in afterload or contractility. This allows the cardiac output to be synchronized with the venous return and with the cardiac output; without depending upon external regulation to make changes. For our purposes this diagram does the job in that it shows that the relationship between venous return from the body to the right heart has a powerful effect not only on how much the blood the heart pumps, but also on the efficiency with which it pumps that blood.

As the heart is increasingly loaded with blood it becomes better and better at pumping it out to the body (up to a point) by contracting more forcefully and emptying the cardiac chambers more completely with each heartbeat. However, as the graph also shows, there is a threshold of filling or stretching of the ventricles beyond which further filling, or preload, causes no further improvement in cardiac output and (not shown) ultimately causes a decrease in pumping efficiency with a corresponding decrease in cardiac output.

Special attention needs to be paid to the Y-axis on the graph because the huge change in cardiac output shown on X-axis happens due to a change in right atrial pressure of just 3 mm Hg, or 4.1 cm H20. [6]

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To put this change in right atrial pressure in context it is only necessary to look at the graphic above to realize that a change in pressure of 3-4 mm Hg is the maximum that occurs over the course of the whole respiratory cycle. Even more importantly, as is also illustrated above, is the seeming impossibility that the pressure inside the pleural mediastinal spaces, the latter of which which contains the heart and the great vessels, is always negative throughout the entire respiratory cycle. Put another way, the areas inside the chest that conduct blood away from and back to the heart always operate under a low vacuum: ~ -6.8 cm H2O during the height of inspiration, and ~ -2.0 cm H2O at the end of exhalation. [7] This continuous negative intrathoracic pressure serves to aid venous (and lymphatic) return from the body to the heart and thus to facilitate preload and optimize cardiac output.

By contrast, a quick glance at the graphic below, which is an actual pleural pressure tracing from a patient undergoing mechanical IPPV, shows that the thoracic viscera, including the vena cavae and right heart, are subjected to positive pressures throughout the respiratory cycle which, at their peak, are typically 30 to 40 times higher than those experienced during normal (negative) pressure breathing! In fact, the situation is even worse than it seems at first glance because not only does the intrathoracic pressure never go to zero (let alone to a negative value), it is deliberately kept positive, in this case by about 8 cm H2O. This is done because in the absence of lung expansion under the influence of the intrathoracic vacuum, the alveoli, the small air sacs of the lungs, begin to collapse and stick to each other. Collapsed alveoli are very difficult to re-open and restore ventilation to. Thus, it is necessary to keep them inflated at the end of exhalation by maintaining some positive pressure in the airways. Since this pressure is applied and maintained at the end of a breath (and between breaths) it is called positive end expiratory pressure, or PEEP, for short. [8]

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Intrapleural pressure tracing of a patient with acute respiratory distress syndrome unergoing intermittent positive pressure mechanical ventilation wih a PEEP of 8 cm H2O

The graphic below shows the effect of only 3 cm of H2O PEEP on blood flow from the head and upper body through the superior vena cava (SVC). Just 3 cm H2O of PEEP reduces superior vena cava (SVC) blood flow by 25%! [9]  A patient with a spontaneously beating heart can (and does) usually compensate for this reduction in return blood flow from the body in many ways, none of which are available to the patient in cardiac arrest.

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The effect of a 3cm H2O water change in PEEP on the flow of venous blood returning to the right heart from the upper body via the superior vena cava. [9]

During conventional closed chest CPR, or in the case of the cryonics patient cardiopulmonary support (CPS), the patient experiences truly massive increases in intrathoracic pressure that last longer and reach extremes never seen in IPPV. The largest and most deleterious source of this pressure results from the physical compression of the thoracic contents during the down-stroke of chest compressions. This raises the intrathoracic pressure to between 80 and 110 cm H2O for roughly 50% of the CPR duty cycle – in other words, the pressure inside the chest is about the same as the normal averaged (mean) blood pressure in a healthy adult for half of the time the patient is undergoing CPR/S! Added to this pressure is the additional pressure of IPPV and the PEEP (usually 5 cm H2O) required to keep the small airways open. The effects of these profoundly un-physiologic pressures on the return of venous blood to the heart and consequently on cardiac output during CPR are devastating. [10]

Overcoming Increased Intrathoracic Pressure and Preserving Cardiac Output

Following the development of active compression decompression CPR (ACD-CPR) by Cohen, et al., in 1992  [11] the critical importance of maintaining negative intrathoracic pressure during the decompression phase of the CPR duty cycle has become increasingly understood. [12, 13, 14]  There is a rapidly growing body of both animal and clinical CPR research documenting improved survival and decreased neurological morbidity when the intrathoracic pressure is kept negative during the decompression (release of chest compression) phase of CPR by the use of inspiratory impedance threshold devices, such as the ResQPod, and ACD-CPR. [15, 17, 18]  An instructive video demonstration of how the ResQPod works can be seen at: http://www.advancedcirculatory.com/

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ResQPod impedance threshold device. Courtesy of Advanced Circulatory systems, Inc. http://www.advancedcirculatory.com/

Similarly, there is accumulating evidence that the increased intrathoracic pressure that results from excessive IPPV during CPR dramatically reduces cardiac output (CO) and causes increased morbidity and mortality. [19, 20, 21].

In 2004, Yannopoulos, et al., reported the development of a device which allows for the continuous application of negative intrathoracic pressure by applying controlled suction to the airway. [22] This device combines an ITD with a vacuum source and a negative pressure regulating valve to maintain an intrathoracic vacuum of between 5 to10 mm Hg (6.8 to 13.6 cm H2O), while allowing IPPV to proceed normally. This device, called the intrathoracic pressure regulator (ITPR) allows IPPV to be delivered as needed during ACD-CPR, while maintaining negative intrathoracic pressure when PPV is not being administered. The device effectively restores the intrathoracic space to its natural state as a low negative pressure (vacuum) chamber; increasing venous return from the body and consequently increasing preload and cardiac output. The ITPR also markedly increases coronary perfusion pressure (CPP) [III] while at the same time decreasing intracranial pressure (ICP). In CPR ICP is typically elevated from the basal value of 12-16 mm Hg to 22-30 mm Hg (as the result of pressure transmission by blood in non-valved veins and by transmission of intrathoracic pressure via the cerebrospinal fluid) further compromising already inadequate cerebral perfusion. [23] Reduction of ICP during CPR has been shown to improve both survival and neurological outcome in an animal model of CPR. [24]

Prototype ITPR (Advanced Circulatory Systems, Inc.) in position in a typical bag-vale resuscitator – ET tube set-up.

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The ITPR has been shown to dramatically improve gas exchange, hemodynamics, cardiac output, vital organ perfusion, and short-term survival during ventricular fibrillation (VF) cardiac arrest in a porcine model of sudden cardiac arrest and CPR. [25] The ITPR is able to not only overcome the high intrathoracic pressures associated with CPR (45 to 55 mmHg or ~61 to 75 cmH20 [26]) but to both create and sustain negative intrathoracic pressure (determined indirectly by measuring the ET tube pressure) continuously during prolonged periods of ITPR-CPR, even in the presence of induced hypovolemia. [27]  In hemorrhaged (hypovolemic) pigs, Yannopoulos, et al., were able to sustain CPP at >15 mm Hg (the accepted threshold for successful defibrillation in human sudden cardiac arrest) and the isovolemic VF animals in the study maintained CPP at >25 mm Hg throughout the full 15 minutes of ITPR-CPR. In both groups, the ETCO2 was consistently maintained above 25 mm Hg, and the 1-hour survival was 100%, as contrasted with 10% in control animals receiving AHA standard CPR (P = 0.0001).

By comparison, after 3 minutes of conventional CPR the control animals had a mean coronary perfusion pressure of less than 15 mm Hg and all had developed pseudo-respiratory alkalosis indicative of the ventilation/perfusion mismatch of standard CPR. [28] Blood gases in VF animals were strikingly preserved during ITPR-CPR; paO2, which was 96±2 mm Hg at baseline, was 214±12.37 mm Hg after 10 min and 198±6.75 mm Hg after 15 min of ITPR-CPR. These findings would seem to suggest that ITPR-CPR may be reducing or eliminating the pulmonary edema that accompanies CPR and the high intrathoracic (and thus pulmonary arterial and venous pressures) generated during CPR.  ITPR is similarly effective at improving both hemodynamics and survival in a swine model of severe hypovolemic hypotension. [29]

The Breath of Death?

However, even with the use of the ITPR, each ventilation transiently raises intrathoracic pressure and decreases CO. In the setting of CPR/S it might be said that each breath is potentially a ‘breath of death’ in terms of its impact on perfusion.

In 2007 the author began experimenting with ways to eliminate tidal ventilation during CPR/S using simple mechanical systems to simulate the lungs and thorax. Based on this preliminary work it appears that it will be possible to eliminate tidal ventilations completely while at the same time maintaining a negative intrathoracic pressure during the non-compression portion of the CPR/S duty cycle. This is possible by the simple expedient of connecting the patient’s airway to a regulated vacuum source while at the same time delivering the desired minute volume of ventilating gas to the carina of the trachea. This scheme is illustrated in the schematic below.

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Above: Experimental implementation of continuous negative pressure ventilation in CPR/S. A conventional endotracheal tube is modified by passing a fenestrated suction catheter down the lumen to the level of the carina through a side opening in the tube through which ventilating gas is continuously delivered at the desired minute ventilation volume. Negative intrathoracic pressure and removal of waste gas is achieved by applying continuous, regulated suction to the 15 mm adapter on the end of the ET tube. Movement of gas to and from the distal airways is achieved by the action of the ACD chest compressor-de-compressor operating at 100 cycles/min on the ventral thorax.

Continuous Non-Tidal Negative Pressure Ventilation

A (negative) airway pressure regulator is attached to the 15 mm connector of a modified endotracheal tube. Continuous negative airway pressure is generated by connecting the airway pressure regulator to a vacuum/suction source. Ventilating gas of the desired composition (i.e., oxygen concentration, therapeutic additives, etc.) is continuously delivered to the patient’s lungs by a ventilation gas delivery catheter that can be advanced or withdrawn through the lumen of the ET tube. The ideal position for the ventilation gas delivery catheter is at the point where the trachea bifurcates into the main-stem bronchi; the carina. Movement of the ventilating gas to the distal airways is achieved by the dynamically varying force on the chest resulting from cardiac compressions, with or without  active decompressions. The desired minute volume is determined by the flow rate of ventilating gas delivered to the carina.

In cases where pulmonary edema is preventing adequate gas exchange and it is deemed necessary to apply positive intrathoracic pressure (at the expense of cardiac output) it is easy to do this by adjusting the pressure on the airway pressure regulator to the desired positive pressure setting; as would be done with the application of positive end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) as is done for the treatment of pulmonary edema by a different means with the Boussignac tube. [30, 31]

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The illustration above shows a possible configuration of a dual-lumen endotracheal tube that would accomplish continuous non-tidal negative pressure ventilation in conjunction with an attached airway pressure control valve.

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Prototype Active Comnpression-Decompression square-wave HLR constructed to the author’s specifications by Michigan Instruments, Inc., of Grand Rapids, MI. The device incorporates a continuous ventilation gas flow meter (red arrow) which allows for delivery of air blended oxygen at the desired oxygen concentration and minute volume.

In 1996 a prototype heart–lung resuscitator capable of delivering non-tidal continuous negative pressure ventilation in conjunction with ACD-square wave-CPR was fabricated by Michigan instruments of Grand Rapids, MI (shown above). Unfortunately, this device was never evaluated in a canine or porcine model of CPR in cardiac arrest. Bench testing with a sophisticated test lung did demonstrate that the unit could deliver adequate minute ventilation while maintaining operator specified negative (or positive) intrathoracic pressure throughout the decompression phase of the CPR/S duty cycle.

If animal research confirms that this mode of ventilation (which is an extension of the ITPR) is both safe and effective it should be possible to apply it to cryonics patients without the years-long wait for regulatory approval. In the case of CPR in the clinical environment, non-tidal continuous negative pressure ventilation using this scheme will likely remain one of the many intriguing and potentially useful ideas in CPR that await another time and place, or perhaps more accurately, a different universe in order to find application.

The End of the Thumper Era?

With clinical advent of ACD-CPR, and the experimental debut of the ITPR and negative intrathoracic pressure CPR delivered via the trachea, it would seem that the days of the Michigan Instruments, Inc. (MII) Thumper CPR devices, which have been the dominant technology used in cryonics transport operations, are over. Despite the very low cost of used Thumper HLRs ($150 to $500 US) the capability of doubling or trebling cardiac output (and sometimes quadrupling cerebral blood flow during CPR) would seem to mandate the expense of either custom fabricated MII equipment, or purchase of a  LUCAS or LUCAS 2 device ($20,000 US).

However, the reality is that the ITPR offers the older generations of conventional CPR machines a new lease on life. The raison d’être for ‘suction cup’ CPR is to create negative intrathoracic pressure by forcefully pulling up on the ventral chest wall between compressions. This method of creating negative intrathoracic pressure was developed as a consequence of the case of a successful resuscitation from cardiac arrest having been carried out by a layman using a lavatory toilet plunger; not as a result of systematic academic or medical laboratory investigation. [32]

It is the principle that is important, and in this case the principle is negative intrathoracic pressure; something that can be applied by surrounding the thorax with a vacuum in a cuirass, or by using a suction cup to decompress the chest wall. Importantly, it can also be accomplished by the ITPR and without the use of complex pneumatic or electromechanical machinery to move a suction cup to and fro. [IV] The ITPR and continuous negative pressure ventilation suggest a number of novel ways that may allow for the continued use of costly first and second generation mechanical CPR equipment – perhaps with even greater efficacy than is possible with the latest generation HLRs. But, alas, that is a subject for another article.

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22) Yannopoulos, D., Nadkarni, VM, McKnite, SH, Rao, A, Kruger, K, Metzger, J, Benditt, D, Lurie,KJ., Intrathoracic pressure regulator during continuous-chest-compression advanced cardiac resuscitation improves vital organ perfusion pressures in a porcine model of cardiac arrest. Circulation, 2005. 112: p. 803-81.

23) Guerci, A., Shi, AY, Levin, H, Tsitlik, J, Weisfeldt, ML, Chandra, N., Transmission of Intrathoracic Pressure to the Intracranial Space during Cardiopulmonary Resuscitation in Dogs. Circ Res, 1985. 56: p. 20-30.

24) Srinivasana, V., Nadkarnia, VA, Yannopoulosb, D, Marinoa, BS, Sigurdssonc, G,  McKnitec, SH, Zookc, M, Bendittc, DG, Lurie, KG., Spontaneous gasping decreases intracranial pressure and improves cerebral perfusion in a pig model of ventricular fibrillation. Resuscitation, 2006. 69: p. 329-334

25) Yannopoulos, D., Nadkarni, VM, McKnite, SH, Rao, A, Kruger, K, Metzger, J, Benditt, D, Lurie,KJ., Intrathoracic pressure regulator during continuous-chest-compression advanced cardiac resuscitation improves vital organ perfusion pressures in a porcine model of cardiac arrest. Circulation, 2005. 112: p. 803-81.

26) Chandra, N.C., et al., Observations of hemodynamics during human cardiopulmonary resuscitation. Crit Care Med, 1990. 18: p. 929-34.

27) Lurie, K., Zielinski, T, Voelckel, W, et al., Augmentation of ventricular preload during treatment of cardiovascular collapse and cardiac arrest. Crit Care Med 2002. 30: p. (Suppl):S162-5.

28) Weil, M., Rackow, EC, Trevino, R, Grundler, W, Falk, JL, Griffel, MI., Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N Engl J Med, 1986. 315: p. 153-156.

29) Sigurdsson, G., Yannopoulos, D, McKnite, S, et al., Lowering of intrathoracic pressure improves blood pressure and survival rates in a porcine model of hemorrhagic shock. Resuscitation, 2006. 68: p. 399-404.

30) Srinivasana, V., Nadkarnia, VA, Yannopoulosb, D, Marinoa, BS, Sigurdssonc, G,  McKnitec, SH, Zookc, M, Bendittc, DG, Lurie, KG., Spontaneous gasping decreases intracranial pressure and improves cerebral perfusion in a pig model of ventricular fibrillation. Resuscitation, 2006. 69: p. 329-334.

31) Weil, M., Rackow, EC, Trevino, R, Grundler, W, Falk, JL, Griffel, MI., Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N Engl J Med, 1986. 315: p. 153-156.

32) Leman P, Greene S, Whelan K, Legassick T., Simple lightweight disposable continuous positive airways pressure mask to effectively treat acute pulmonary oedema: Randomized controlled trial. Emergency Medicine Australasia, 2005. 17 p. 224 – 230.

33) Templier F, Dolveck F, Baer M, Chauvin M, Fletcher D., ‘Boussignac’ continuous positive airway pressure system: practical use in a prehospital medical care unit. Eur J Emerg Med, 2003. 10 P.87-93.

34) Malzer R, Zeiner A, Binder M, Domanovits H, Knappitsch G, Sterz F., Laggner AN. Hemodynamic effects of active compression-decompession after prolonged CPR Resuscitation, Volume 31, Issue 3, Pages 243-253

[I] While most exhalations are passive and do not require muscular  assistance, we do sigh, cough and sometimes forcibly assist air out of our lungs and these instances of assisted exhalation are important to health.

[II] The German Otto Frank and Briton Ernest Starling.

[III] In the setting of resuscitation from cardiac arrest as opposed to CPS in cryonics Transports, the  coronary perfusion pressure during CPR  is the single most important predictor of successful defibrillation and thus of successful  resuscitation.

[IV] It is important to note that this applies only in situations where the chest still possesses its basic structural integrity. In cases of rib fracture or ‘flail chest’ where the thorax has lost its rigidity, only ACD-CPR or the application of an integrated chest compressor and cuirass device would be effective in generating blood flow.

CPR: new standards; new needs

In 2005 the American heart association revised its standards for CPR increasing the number of compressions from 80 cpm to 100 cpm, eliminating pauses for ventilation, and urging that focus be shifted to compressions (perfusion) rather than ventilation. This latter change is more profound than it might seem at first glance. In the past, a central focus (many would argue the central focus) of early ACLS was securing the airway by endotracheal intubation. Intubation is a demanding and skill-intensive task and it tends to absorb not only most of the focus of the rescue effort, but also the attention of the most skilled and experienced personnel on the scene.

As Gordon Ewy has demonstrated, minute ventilation with chest compressions in the presence of an open airway is usually adequate to provide for sufficient gas exchange for the first 6 to 10 minutes of CPR. [1,2]  Indeed, the limiting factor is not a failure of oxygen delivery resulting from the 100 tiny breaths a minute produced by the new AHA standard chest compressions, but rather hypercarbia from progressive accumulation of CO2 due to inadequate alveolar ventilation. This change in the guidelines has meant a refocusing of paramedical attention on perfusion – on chest compressions – and on the way chest compressions are carried out. The new AHA standards call for square wave compressions and emphasize the importance of delivering compressions of adequate force, depth and frequency. [3]

Anyone who has had sustained contact with paramedics (at least in the US) will know that if there is anything paramedics are more enamored of than badges and certifications, it is gadgets. Paramedics (and rightly so) are great users of equipment that makes their work faster, more effective and safer. In a profession where every second counts, anything that can improve speed or efficiency has the potential to translate into additional lives saved. To this end, Zoll (Philips and Laerdal) has introduced the Q-CPR, the first device designed to improve the quality of CPR by providing transducer derived surrogate data which is processed and transformed into verbal instructions which the device gives the EMS personnel.

standards_1

In other words, the Q-CPR measures chest compressions and provides real time verbal feedback during cardiopulmonary resuscitation. This is accomplished using a compression sensor which is placed between the rescuer’s hands and the patient’s sternum where it measures motion and force. Compression rate and depth are presented as a waveform on the monitor and if either the depth or rate drifts outside the target range established by AHA, the Q-CPR provides audible feedback. The sensor tells the EMS personnel to “press harder” or give compressions “more frequently” through verbal commands. Data on the frequency and adequacy of ventilation are collected and analyzed using impedance technology employing sensors built into the adhesive pads placed to deliver the defibrillating shock.  Changes in thoracic impedance are interpreted and displayed as lung volume and ventilation rate on the monitor screen. The Q-CPR is pictured above. As a standalone, this device would likely not have been launched. However, it is available as a ‘value added’ option to Phillips defibrillators and, as such, it has the advantage of being part of the first device, indeed the only definitive device, currently available to restore adequate perfusion and ventilation; the defibrillator. In this case the Phillips HeartStart MRx defibrillator.

Still, this technology does not come cheaply; the Q-CPR add-on retails for $3800. The latest models of the Q-CPR have a miniature LCD screen embedded in the chest sensor enabling the rescuer to see the ‘adequacy’ of his compressions continuously and without interruption.  Preliminary studies indicate that the Q-CPR improves retention of CPR skills via the ongoing verbal feedback the device provides.  Arguably just as importantly, the Q-CPR captures an enormous amount of data about each case, including how well CPR was performed and what courses of treatment are effective. The device not only stores CPR data, but also the complete ECG record and, obviously, a record of all defibrillation attempts. These data are useful not only for post-event debriefing, but will hopefully help to guide the development of more effective treatments, as well.  The Q-CPR weighs about 200 g, adding virtually no weight to the HeartStart MRx.  The module was cleared by FDA earlier this year and is now available for purchase in the U.S.

A useful video review of the Q-CPR system can be seen at:

http://www.youtube.com/watch?v=mZDxZYBneNU&feature=related

As a grimly humorous aside; only a few of us are still alive who hail from the beginnings of ‘practical’ cryonics in the late 1960s. The first HLR used in cryonics was the Westinghouse Iron Heart.

Robert Ettinger with the Iron Heart in 1964

standards_2

The second heart-lung resuscitator used in cryonics (after the Westinghouse Iron Heart) was the Brunswick HLR-50-90 which used a strap-on piston to provide chest compressions. While there are more of us left alive from those days, few of us are still active in cryonics.

standards_3

The HLR-50-90 is shown on Youtube in action with the Q-CPR in a clip entitled ‘Vintage Ambulance Equipment – HLR with MRx.”

http://www.youtube.com/watch?v=FXaFCRr-1ss&feature=related

I should also note that the Brunswick  HLR 50-90 is still being manufactured and sold and is still much cheaper to purchase than competing HLRs. It has been updated by the manufacturer to deliver 2005 AHA compliant CPR, including ventilations: http://www.brunswick-biomedical.com/

Vintage, indeed.

REFERENCES

1. Ewy GA, Kern KB. Recent advances in cardiopulmonary resuscitation: cardiocerebral resuscitation. J Am Coll Cardiol 2009; 53: 149–57.

2. Davis, DP, Cardiocerebral resuscitation: a broader perspective. Journal of the American College of Cardiology 2009; 53: 158-59.

3.2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005; 112: IV-12 – IV-18.

ACD-CPR & the rise of the machine?

If conventional cardiopulmonary support (CPS) in cryonics is difficult to perform adequately, and impossible to sustain for more than brief periods (30-60 min) before exhausting even a 3-man standby team, this is even more the case for active compression-decompression CPS (ACD-CPS) using the ResQPump (formerly the Ambu CardioPump). Even in the conventional medical setting of comparatively brief periods of CPR before defibrillation ACD-CPR is difficult to do, let alone do well. Indeed, if ACD-CPR (in conjunction with an impedance threshold device such as the ResQPod) continues to show superior results in terms of outcome (as it is now doing in recent and ongoing clinical trials) it may be the advance that makes heart-lung resuscitators both medically acceptable and cost effective. There is some evidence that this may actually be happening; while not yet profitable, the LUCAS CPR device is gaining in popularity and continues to be the subject of consistently favourable laboratory and clinical studies.

Currently, mechanical CPS is viewed by paramedical personnel as not just dangerous (i.e., the myth of routinely broken ribs and lacerated lungs and livers) but also as ineffective and, perhaps just as importantly, as a potentially professionally demeaning or threatening piece of technology. In my 30 years of experience interfacing with EMTs and paramedics in both the US and UK regarding mechanical CPR, the most frequent remark I’ve heard is, “I can do better CPR than that machine can.” Since CPR is the most dramatic, and arguably one of the most defining practices in emergency medicine, it is perhaps understandable that many emergency medical system (EMS) personnel will equate replacement of manual CPR as equivalent to replacement of the people who perform it. Many paramedics perceive the heart-lung resuscitator (HLR) as a device that will make high quality CPR something anyone can do ‘with the push of a button.’

1

In reality, deploying and applying even the most automated and technologically sophisticated HLRs will require more skill and expertise on the part of EMS personnel, not less.

Mechanically delivered ACD-CPR is also more effective than conventional mechanical CPR, even when delivered per the new AHA standards. As an example, coronary and cerebral blood flows during LUCAS CPR are improved by 25-30% over those obtained with the Michigan Instruments Thumper HLR.

2

Steen S, Liao Q, Pierre L, Paskevicius A, Sjöberg T. “Evaluation of LUCAS, a new device for automatic mechanical chest compression and active decompression for cardiopulmonary resuscitation.” Resuscitation. 2002; 55: 289-299.

3

Rubertsson S, Karlsten R. “Increased cortical cerebral blood flow with LUCAS, a new device for mechanical chest compressions compared  to standard external compressions during experimental cardiopulmonary resuscitation.” Resuscitation 2005; 65: 357-363

But of even greater interest in the context of cryopatient Transport is the dramatic improvement in the durability of perfusion being demonstrated with ACD-CPR using the LUCAS, as opposed to what can be achieved with conventional CPR. While mean arterial pressure (MAP) and cardiac output (CO) are often adequate to maintain cerebral viability during the first minute or two of chest compressions, they rapidly fall to levels that are inconsistent with survival thereafter. Deterioration of cardiac preload, rapid and progressive loss of chest wall elasticity (and thus recoil) and possibly elevated intrathoracic pressure from ‘auto-PEEP’ (gas trapping at the end of expiration and dynamic hyperinflation of the lungs) all likely contribute to the rapid decay in mean arterial pressure (MAP) and perfusion seen in conventional CPR.

4

ACD-CPR using the LUCAS preserves MAP and perfusion, even during prolonged CPR; in one case up to 240 minutes. The representative waveforms above are from LUCAS CPR performed on 13 patients who experienced cardiac arrest during cardiac catheterization and who underwent CPR for times ranging from 45 to 245 minutes. Mean systolic and diastolic blood pressure were 81±23 and 34±21 mmHg, respectively; pressures fully compatible with preservation of brain viability and long-term survival.

Compressed Gas Bottles & the Autopulse

Aside from the problem of interrupting CPR while HLRs are applied, and the historically complex and clumsy nature of the devices, the other major barrier to the use of mechanical CPR has been the need for a bulky and heavy supply of compressed gas to power the devices. Typically, two E-cylinders containing 640 liters of oxygen or air will run an HLR for only 15 to 20 minutes. This is a major logistic hurdle in conventional emergency medicine which becomes far more serious in the setting of cryopatient Transport. Oxygen (compressed or in chemical form in ‘oxygen generators’ of the type used in commercial jetliners) cannot be transported on commercial aircraft nor shipped by common carrier because of the hazard it represents. As a result, cryonics Standby/Transport teams must find a way to acquire compressed gas immediately upon landing – something that is becoming increasingly difficult since the advent of electrically powered oxygen concentrators which have largely eliminated the need for 24/7 home delivery of oxygen in high pressure cylinders.

One solution to this problem was the development of the Autopulse (Zoll Medical Corporation) which is a battery powered HLR that delivers vest CPR. While vest CPR has been shown to be superior to conventional CPR in some studies, it lacks the ability of ACD-CPR to dramatically reduce intrathoracic pressure and to maintain MAP and CO during long duration CPR. An additional problem with the Autopulse for cryonics is that the device contains the electronics; control circuitry, motors and associated mechanical devices used to power and operate it which are located in the backboard that the patient rests upon.

5

Since cryopatients are immersed in ice water, this means that the device must be extensively re-engineered for this application. Suspended Animation, Inc., of Boynton Beach, FL has reportedly developed such a portable ice bath (PIB) compatible Autopulse which they have patented and plan to market to the cryonics community at a considerable mark-up over the Autopulse’s already high retail price of ~$20,000. Another problem facing the Autopulse is the increasing gap in the quantity and quality of both the published animal and human clinical research between the Autopulse and ACD-ITD-CPR. The strong selling point of the Autopulse has been its ability to operate on compact batteries for up to 20 minutes with the ability to rapidly and easily change out batteries without any interruption in CPR.

I Sing the LUCAS Electric!

A few months ago, LUCAS announced what has certainly been a long and desperately desired advance in HLR technology – in and out of the cryonics community. LUCAS is now marketing the LUCAS 2, which is a completely battery powered version of their pneumatically driven LUCAS 1 machine.

6

This second generation LUCAS uses the basic, the well-proven LUCAS 1 platform, with a number of potentially critical added improvements. In addition to using microprocessor controlled electronic actuators, the device contains a ventilation reminder; with plans to allow interface of the device to a sophisticated, compact ventilator in the near future. Most importantly, the LUCAS 2 operates for 45 minutes on the on the newly available lithium ion polymer (LiPo ) battery technology (with no test-cycles or reconditioning required) and may also be connected to and operated from electrical power points (wall outlets) or car outlets. The battery is neatly integrated in the hood of the HLR and it can easily and rapidly be changed out, making the LUCAS 2 a lightweight and compact device to store and carry (17 kg, complete).

7

Incredibly important to cryonics operations is the fact that the device uses a softer start during the initial adjustment to the patient’s chest, and is much quieter when in operation. This latter consideration is of critical importance in institutional settings where the noise generated by pneumatically driven HLRs has resulted in significant resistance (and even refusal to allow their use in a few cases) on the part of hospital, extended care facility, and hospice administrators. The LUCAS 2 should go a long way towards overcoming this problem since the noise level is actually less than that often encountered when conventional manual CPR is administered.

8

The LUCAS user interface remains very simple with fingertip access to all operating modes and 3-step, 3-button actuation. Delightfully, the LUCAS 2 can operate from wall current (100-240V / 50/60 Hz) or from an automobile car outlet (12-24V); if the engine is running to power the vehicle alternator, the unit can operate from the vehicle power supply indefinitely (or as long as the petrol supply lasts)!

Two useful new respiratory products

Sometime in the 1780s the French scientist Jacques Charles’s noted that  at constant pressure, the volume of a given mass of an ideal gas increases or decreases by the same factor as its temperature on the absolute temperature scale. Or, put more simply, the gas expands as the temperature increases. This is known as Charles’ law which can be written as:

V \propto T\,

where V is the volume of the gas; and T is the absolute temperature. The law can also be usefully expressed as follows:

\frac{V_1}{T_1} = \frac{V_2}{T_2} \qquad \mathrm{or} \qquad \frac {V_2}{V_1} = \frac{T_2}{T_1} \qquad \mathrm{or} \qquad V_1 T_2 = V_2 T_1.

The equation shows that, as absolute temperature increases, the volume of the gas also increases in proportion.

Of course, the converse of this is also true; if you cool a gas it will contract in volume. This bit of physics has surprisingly practical and immediate implications in ultraprofound hypothermia research and, of course, in the transport of cryonics patients.

One of the really nettlesome problems in dog total body washout (TBW) ultraprofound hypothermia research and in cryonics transports is that as the subject cools, the volume of gas in the endotracheal (ET ) tube balloon cuff decreases. It is, in practice, not possible to dynamically monitor and adjust this, so you are left with choice of seriously over-pressurizing the ET tube balloon, or risking aspiration of gastric contents and/or PIB water into the lungs. Even if the tube is over-pressurized to compensate for cooling-induced volume loss of the gas, there is still the substantial risk of air leaking from the balloon and aspiration occurring.   This has been  a very serious problem in our dog work in the past, and it is also a serious problem in medicine. While not a concern in cryonics, over-pressurizing the balloon cuff in clinical situations results in injury to the trachea and can even cause tracheal necrosis. And, of course, balloon pressure should vary dynamically with airway pressure: a pressure that is sufficient to maintain a seal at a low airway pressure will allow gas to leak around the balloon (thus escaping from the lungs) at a high airway pressure. Finally, someone has come up with a brilliant solution to this problem; a device that uses the airway pressure in the ventilation circuit to continually and dynamically adjust the  cuff pressure:

PressureEasy® Cuff Pressure Monitor

javascript:void(window.open('/upload/products/mainImages/pressure-easy.jpg','prodimage' ,config='height=490,width=298,left=10,top=10,scrollbars=no;return false;')) The PressureEasy® Cuff Pressure Controller is designed to continuously monitor tracheal cuff pressure. Its indicator window signals cuff pressure is maintained between 20-30cm/H2O. In addition, the airway pressure auto-feedback feature boosts cuff pressure to ensure proper sealing when high pressures are used during ventilation.

The only device of its kind, the PressureEasy® Cuff Pressure Controller offers several other advantages over traditional methods of cuff pressure control. As a single-patient use device, this cuff pressure controller reduces potential for infection and eliminates sterilization issues with quarantined or isolated patients.

The PressureEasy® Cuff Pressure Controller does away with managing and inventorying of manometers, issues of availability, calibrating, and replacement of reusable manometers.

This device ensures that even over a wide range of temperatures and pressures the seal on the ET cuff balloon, or for that matter, the balloon on any other kind of airway protection device, such as the esophageal gastric tube airway (EGTA), Combitube  or laryngeal mask airway (LMA) remains patent and at the optimum pressure regardless of variations in patient temperature or airway pressure.

I’d also like to note that there is now also a much better alternative to the EasyCap for end tidal CO2 (EtCO2) detection, to monitor the efficacy of CPS: the Stat CO2. I really like this device; it works for 24 hours, it tolerates high humidity environments such as a humidified ventilator circuit, it has a large, easy to read indicator, and it has the truly fantastic feature of allowing you to position it in the breathing circuit  on the heart-lung resuscitator (HLR) or bag-valve resuscitator up to several days before you use it. This is possible because the device has an activation a tab that is removed to activate the device. So, it can be  left in position before use and will remain ready to go until it is needed. The EasyCap rapidly deteriorates as soon as it is removed from its retort packaging, and it has a very short working life (45 minutes in practice) and is completely intolerant of high moisture conditions.

Response to Aschwin de Wolf's 'Evidence Based Cryonics'

In his article entitled ‘Evidence Based Cryonics’ Aschwin de Wolf unassailably argues that: “There is an urgent need to move from extrapolation based cryonics to evidence based cryonics. This will require a comprehensive research program aimed at creating realistic cryonics research models. It will also require vast improvements in the monitoring and evaluation of cryonics cases. The current debate should no longer be between advocates and opponents of standby and stabilization but about what stabilization procedures should be used by cryonics organizations given our current knowledge”.

Unfortunately, much of the rest of what he has to say is incomplete or lacks the necessary context required to allow for a fair and technically sound evaluation. Perhaps the brevity of the blog format was the reason for these shortcomings? In any event, I would like to comment on these remarks and provide a somewhat different perspective on the complex and important issues discussed in ‘Evidence Based Cryonics.’

The best place to start is to define what evidence based medicine is, and then proceed to attempt to describe what might constitute ‘evidenced based cryonics.’ Webster’s New World Medical Dictionary, 3rd Edition (2008) defines evidence-based medicine as, “the judicious use of the best current evidence in making decisions about the care of the individual patient. Evidence-based medicine (EBM) is mean to integrate clinical expertise with the best available research evidence and patient values. EBM was initially proposed by Dr. David Sackett and colleagues at McMasters University in Ontario, Canada.” Having defined what EBM is, the next question is, what constitutes “the best current evidence?”

The United States uses the U.S. Preventive Services Task Force (USPSTF) system for evaluating evidence about the effectiveness of medical interventions. The USPSTF classifies evidence in terms of reliability for use in decision making as follows:

* Level I: Evidence obtained from at least one properly designed randomized controlled trial.

* Level II-1: Evidence obtained from well-designed controlled trials without randomization.

* Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

* Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

* Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

* While beyond the scope of discussion here, it is worth noting (and referencing) the work of Guyatt, et al., and the GRADE Working Group in further defining what constitutes the quality and strength of scientific evidence; a formidable and controversial task (1- 6).

* To anyone knowledgeable in the areas of medicine applicable to human cryopatient stabilization and transport procedures (i.e., resuscitation/reanimatology, ischemia-reperfusion injury, solid organ preservation, deep hypothermic cardiopulmonary bypass and whole animal asanguineous perfusion) it will immediately be apparent that none of the 5 classes of evidence presented above can be directly applied to cryonics cases. Arguably, Level III evidence, the “opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees” might apply were there any acknowledged ‘respected authorities’ in the sphere of cryonics standby, stabilization or transport patient care. Alas, no such authorities, respected or otherwise, are currently ‘acknowledged’ to exist.

Thus, the first statement Aschwin makes in opening his article, “Cryonics patients can greatly benefit from rapid stabilization after pronouncement of legal death,” which he defines as “procedures that aim to rapidly restore blood circulation and drop the patient’s temperature” is itself unsupported by either conventional medical research or by cryonics research or case reporting using EBM criteria. If the information-theorertic criteria, as validated by ultrastructural preservation of the brain (7), or the demonstrated recovery of function of the brain are to be used as the gold standards for determining the efficacy of cryonics stabilization and transport procedures, then there currently exists no EBM quality (scientifically robust) data to support “restoration of blood circulation” following pronouncement of medico-legal death in cryopatients.

More specifically, assuming such an intervention is warranted, the question then becomes,’ under what circumstances and in which patients should it be applied?’ Is the patient with 30 minutes of post-arrest warm ischemia better off with simple external cooling followed by cryoprotective perfusion, as opposed to undergoing in-the-field reperfusion using closed chest cardiopulmonary support? What about the patient with profound peri-arrest hypoperfusion with evidence of failed or inadequate brain perfusion, such as the presence of fixed and unresponsive pupils for many minutes, or even for an hour or more, before cardiac arrest occurs and medico-legal death can be pronounced? At what point in the complex and difficult to quantify spectrum of warm ischemic injury should cardiopulmonary support be withheld? Or, given that the benefits of rapid post arrest cooling are unequivocally supported by Level II-2 and Level II-3 evidence from conventional medicine, should such support be modified to mitigate or prevent oxygen-driven reperfusion injury by carrying out CPS under anoxic conditions, and if so, under what circumstances and by what procedures? We have no rigorous answers to these questions and Aschwin is certainly on-point in calling for well designed, cryonics-appropriate studies to answer these and myriad other questions of great importance.

The problem is, as it has been since the inception of clinical cryonics in 1967, “what, if anything, do we do in the meantime?” Indeed, forty-two years later, we have little direct evidence even that cryoprotective perfusion results in superior conservation of identity-critical information under the real-world conditions encountered by today’s cryopatients than would be the case were they subjected to more timely straight freezing!

Is a patient who has suffered hours of warm ischemia better off simply being rapidly cooled and rendered into the solid state, as opposed to being subjected to 24, 48 or 72 hours of cold ischemia, followed by cryoprotective perfusion and freezing or vitrification? How do we even determine what the ultrastructural condition of a brain is following straight freezing? Freezing in the absence of fairly large amounts of colligative cryoprotectant agent(s) results in the collapse of tissue ultrastructure into dense channels of material, the structural condition of which it is currently not possible to determine by techniques such as transmission electron microscopy. Reaching conclusions based on the post-thaw ultrastructure (or lack thereof) of straight frozen tissue is complicated by the potentially myriad artifacts introduced during rewarming, thawing, fixation and embedding required to image tissue ultrastructure.

Given the extreme resource constraints that have historically been present in cryonics, and the lack of directly applicable mainstream medical research, the answer to the question of ‘what to do’ has been to apply reasoned extrapolation of high quality, peer-reviewed biomedical research to the care of the individual cryonics patient, and where possible, to conduct on-point in-house research to validate such armchair speculation.

It is important to point out that since the inception of cryonics in 1964, until approximately 1976, efforts to establish patient care protocols were a group effort between the then extant cryonics societies. The first of these efforts was organized by Robert Ettinger in 1966 and resulted in the protocol developed by Dante Brunol (8). Beginning in 1972, Fred and Linda Chamberlain, Art Quaife, Greg Fahy, Peter Gouras, M.D., Robert Ettinger, and I engaged in an extensive and largely public effort to reach a consensus about what should constitute a good standard of care for cryonics patients based upon extrapolation (and where feasible) experimental validation of findings in the peer-reviewed biomedical literature. This was done via extensive private correspondence, via publication of findings and recommendations in Manrise Technical Review and The Immortalist, as well as in the form of a detailed procedure manual for administering human cryopreservation entitled Instructions for the Induction of Solid State Hypothermia in Humans published by Fred and Linda Chamberlain and available, in part, on-line at: http://www.lifepact.com/mm/mrm001.htm (Readers interested in obtaining a copy of the full manual, for private use, may contact the author at ).

During the 1980s this effort continued and was both documented and subjected to review by the American Cryonics Society, Trans Time, Alcor and Cryovita Laboratories in the form of detailed technical presentations made at the annual Lake Tahoe Life Extension Conferences hosted by Fred and Linda Chamberlain’s Lake Tahoe Life Extension Festivals from 1979 to 1985[1.] An example of such disclosures is available at: http://www.lifepact.com/tahoe.htm.

In short, these efforts were public, largely collegial, and consisted of a best effort to apply insights from the scientific literature to human cryopatients. Furthermore, both Jerry Leaf and I made a sustained and detailed effort to document, by both presentations and publications, the outcomes achieved in detailed human cryopatient case reports (10-20) and in animal studies of post-cryopreservation ultrastructure, including those designed to reproduce conditions encountered under real-world conditions (21, 22).

These efforts resulted in a number of cryopatient stabilization protocols that incorporated multiple drugs to address the multiple mechanisms of ischemia-reperfusion injury as identified in the literature; an approach which Aschwin describes as administration of “an unorthodox number of medications to protect the brain and prevent impairment of circulation. While there are peer reviewed papers that combine a number of medications, there is no precedent in mainstream medicine or biomedical research in using such a large number of medications (in contemporary cryonics, medications protocol exceeds 12 different drugs and fluids).” This statement deserves further scrutiny.

Are poly-drug approaches to treatment unprecedented in medicine? As an example, let’s consider the case of a hyperkalemic hemodialysis patient who experiences cardiac arrest while preparations are being made for emergency hemodialysis. How many and what kind of medications will this patient likely receive in the setting of refractory cardiac arrest? Per the American Heart Association (AHA) Guidelines the patient will initially receive 1 mg epinephrine IV every 3 to 5 minutes during CPR. This may be substituted (after the first dose) with 40 IU of vasopressin IV. Since the patient is in aystole 1mg atropine IV is also given. Concurrent with the administration of these drugs the patient is given 30,000 IU of sodium heparin to allow for the institution of hemodialysis to definitively reduce the serum potassium level. The patient is given an unsuccessful 360 Joule shock at this point. Point of care evaluation of blood electrolytes discloses blood potassium of 12 mmol/L: a level that is incompatible with the return of spontaneous circulation. A decision is made to administer calcium chloride: 5 mL of 10% solution IV over 2 min and 2 amps (60 mlL) of 50% dextrose in water along with 10 IU regular insulin IV (glucose and insulin facilitate a transient profound cellular uptake of potassium from the interstitial and intravascular spaces). CPR is continued for 8 cycles and the patient is again defibrillated with a resulting non-perfusing rhythm consistent with hyperkalemic cardioplegia. CPR is continued while hemodialysis proceeds. After 4 minutes of hemodialysis a third defibrillation attempt is made with the result being coarse ventricular fibrillation. Following another unsuccessful defibrillation attempt, and confirmation by point of care testing that serum potassium has decreased to 7.8 mmol/L with blood pH at 6.95, 300 mg of amiodarone is given in addition to 1 mEq/kg sodium bicarbonate: by slow IV push; the latter to correct the acidosis that has resulted from prolonged CPR and dialysis with a low pH bicarbonate-acetate dialysate.. Following 5 additional cycles of CPR the patient is successfully defibrillated and recovers with a mild neurological deficit as a consequence of extended, low flow perfusion during CPR.

This patient, undergoing routine resuscitation from hyperkalemia cardiac arrest, has just received 9 discrete drugs, all of them indicated, and all of them within the current guidelines for the treatment of hyperkalemic cardiac arrest (23-24). Interestingly, none of these drugs was administered to ameliorate vital organ ischemia-reperfusion injury. The reason for this is that no such drugs are currently clinically available for this indication.

Similarly, patients undergoing acute fluid resuscitation and initial; treatment for septic shock may receive a dozen or more drugs including pressors, ionotropes, a vasodilator, 2-3 antibiotics, insulin, rAPC, and any ancillary drugs required to facilitate renal replacement therapy or mechanical ventilation (see: http://www.leedspicu.org/Documents/Septic%20shock.pdf). So, it is clearly not the case that, “there is no precedent in mainstream medicine” for a multimodal drug treatment approach to complex illness, since multi-drug interventions constitute the standard of care for resuscitation from both cardiac arrest and septic shock and increasingly serve as the backbone of a wide range of successful cancer chemotherapies.

However, it is the case that, at least until recently, multi-drug interventions in biomedical research to treat cerebral ischemia-reperfusion injury have been virtually nonexistent. This is beginning to change as there is increasing understanding of the complex, multifactorial nature of cerebral ischemia-reperfusion injury. Examples of this are the recent successful work of Buckberg, et al in recovering piglets from 90 minutes of deep hypothermic circulatory arrest using a protocol that employed 5 primary therapeutic drugs (plus leukodepletion using a Leukoguard filter in the arterial line during cardiopulmonary bypass) (25), the work of Liu, et al., demonstrating the effectiveness of a combination of cerebral blood flow promoting drugs and the administration of phenyl-N-tert-butyl-nitrone (a free radical inhibitor) and cyclosporine-A (a mitochondrial poration inhibitor) in improving 24 hour neurological outcome after 8 min of experimental normothermic cardiac arrest in pigs (26) and the work of Gupta, et al., combining melatonin and poly (ADP-ribose) polymerase inhibitors in a rat model of stroke – a study that employed 6 drugs in the most successfully treated group (27).Other research combining multiple drugs and other interventions, such as mild therapeutic hypothermia, have also shown positive results (28, 29).

Aschwin goes on to state, “The only existing justification for using current protocol reflects work done at Critical Care Research (CCR) in the 1990s. Although scattered reports exist about the effectiveness of this protocol in resuscitating dogs from up to 17 minutes of normothermic global ischemia, no detailed (peer reviewed) paper has been published about these experiments “

I do not know what is meant by the term “scattered reports” to describe disclosure of this work and would note that there have been two formal public disclosures, the first in the form of United States Patent 5700828 issued on 12/23/1997, and the second in the form of a public seminar which was subsequently distributed as a videotape: Darwin M, Harris, SB, Russell, SR, O’Farrell, Rasch, C, J, Pengelle, C, Fletcher, M. Routine Resuscitation of Dogs from 15-17 Minutes of Normothermic Ischemia (37.5°C) With Long Term Survival (>6 weeks). In: 21st Century Medicine Seminar on Recent Breakthroughs in Cryobiology and Resuscitation Research, Ontario, CA; 1998.

As the principal investigator on this study, I would be the first to agree that it is both regrettable and unacceptable that it has not been either peer reviewed or published. However, as I do not have access to either the primary or the reduced data from this study, I am personally powerless to remedy this situation. Further, I think it extremely unlikely either that I will be given access to this data, or that the results of this study will be published in any meaningful time frame, if at all, by those at CCR who control the study data.

The question thus arises as to whether the drugs identified in this study are of use, either singly or in combination, in the stabilization of cryonics patients? The only certain way to answer that question is to apply them in well designed animal models that closely approximate the spectrum of real-world conditions under which cryopatients eligible for cardiopulmonary support and pharmacological treatment of ischemia-reperfusion injury present for care. Such studies will take tens of thousands of dollars and several years to complete. So, again, the questions arise, ‘what do we do in the meantime ‘and ‘how do we judge the evidence that we use to justify any interventions we undertake?’

It is not possible to answer these questions without considering the specifics of the work in question. Aschwin states that, “in contemporary cryonics, medications protocol exceeds 12 different drugs and fluids” with the implication that the CCR canine resuscitation series (CRS) research was the source of these 12 drugs/fluids, presumably those described by Aschwin in his January 2007 article Human Cryopreservation Stabilization Medications (http://www.alcor.org/Library/html/stabilizationmeds.html).

In fact, the original CRS protocol included a total of 22 drugs!

o Hemodiluent: defined electrolyte-dextran-40 containing solution
o Hypertensives: 3 primary drugs, 1 secondary drug
o Buffer: tromethamine (THAM), 1 drug
o Antiglycemic: 1 drug
o Free radical inhibitors: 6 drugs
o Excitotoxicity Inhibitors: 3 drugs
o Ca++ Antagonists: 1 drug
o Bradykinin Inhibitor: 1 drug
o Leukotriene Antagonists/Inhibitors: 2 drugs
o COX I&II Inhibitors: 1 drug
o Phospholipase Inhibitor: 1 drug
o Antiplatelet: 1 drug
o PARS Inhibitor: 1 drug
o Metabolic Support: 2 drugs

TOTAL: 22 drugs

Of these, 6 drugs (not including the anticoagulant heparin, the hyperosmotic agent mannitol, the flow promoting agent dextran-40, and the buffer THAM, all of which were previously in use in cryonics) were retained in the protocol licensed by CCR to Alcor and to Suspended Animation, Inc. These drugs are s-methylthiourea (SMT), d-alpha tocopherol (Vitamin E), melatonin, alpha Phenyl t-Butyl Nitrone (PBN), kynurenine, and carprofen. How should the utility of these drugs be judged? The first step in such a process is to determine which patients might benefit based on the available information. By definition, only patients eligible for CPS can be treated, since effective use of all of these drugs requires thorough systemic distribution. Patients with 20 minutes or less of normothermic cardiac arrest are probably the only suitable candidates based on the limited ability of closed chest CPS to generate adequate pressure and flow over increasingly long intervals of cardiac arrest. Beyond this general criterion, it is necessary to consider the evidence for the utility of each drug individually, on the basis not only of the CCR study, but in the context of the published literature.

The patent which first discloses the core drugs used in the CCR protocol was United States Patent 5700828 which was filed on 12/07/1995. This is significant because two of the primary cerebroprotective drugs described in this patent, melatonin and PBN, had not been previously demonstrated to be neuroprotective in cerebral ischemia-reperfusion injury. It was not until 2003 that the first peer-reviewed paper documenting the effectiveness of melatonin in ischemia-reperfusion appeared (30) and not until 1999 that the effectiveness of PBN in cerebral ischemia was documented in the literature (31). Since these papers first appeared a vast literature supporting the effectiveness of melatonin in both focal and global cerebral ischemia-reperfusion injury has appeared, and the PBN analog NXY-059 was demonstrated as effective in a wide range of animal models of cerebral ischemic injury (32)., although the drug failed in a RCT of stroke (33).

The utility of vitamin E, mannitol and of dextran-40 in cerebral ischemia reperfusion injury predate the 1995 patent and are extensively documented in the cerebral resuscitation literature. There are few papers documenting the effectiveness of kynurenine, and no papers supporting the effectiveness of carprofen in cerebral ischemia-reperfusion injury, although there are many papers documenting the utility of other non-steroidal anti-inflammatory and NF-kappa B inhibiting drugs in cerebral resuscitation.

Should any or all of these drugs be applied to cryopatients? Aschwin raises a number of possible contraindications which merit consideration: “The lack of relevant published data to support the administration of large numbers of drugs…in cryonics is not just a matter of risking performing redundant procedures. A lot of time and resources are being spent in cryonics on obtaining and maintaining equipment and supplies for these procedures, in addition to the licensing fees paid to use some of these technologies and the training and recruiting of people to perform them. But perhaps the most troublesome problem is that the preparation and execution of these procedures during actual cryonics cases can seriously interfere with rapid and effective cardiopulmonary support and induction of hypothermia.”

It is clear from the foregoing that Aschwin considers immediate post arrest cooling in the presence of CPS to be an essential element of effective cryopatient stabilization. Unfortunately, the use of CPS in this setting carries with it the risks of return of consciousness (33) as well as the return of ‘signs of life’ such as agonal gasping (34, 35), spontaneous movement (36, 37) and even the return of spontaneous circulation. (38). This implies that the cryopatient undergoing CPS must be protected against these undesirable effects by pharmacological intervention. At a minimum, this means that intravenous (IV) or intraosseous (IO) vascular access must be established and at least 3 drugs must be administered (e.g., an anesthetic, a paralytic, and a cardioplegic). Thus, much of the skill, equipment and added personnel required to administer cerebroprotective drugs to cryopatients are, in fact, a requirement of delivering CPS assisted cooling. When Aschwin writes: “the preparation and execution of these procedures during actual cryonics cases can seriously interfere with rapid and effective cardiopulmonary support and induction of hypothermia” it is not clear what he means? Is it establishing IV or IO access, or the administration of a large number of drugs, or both that constitutes a threat to rapid post-arrest CPS and cooling?

CPS and vascular access must, necessarily, proceed together, with CPS (properly) trumping vascular access where any conflict occurs. It should also be noted that CPS, given in the absence of an effective pressor, and (in most cryopatients) volume expansion, will not achieve perfusion that is effective; either for supplying adequate cerebral blood flow to prevent ongoing ischemic injury, or to facilitate heat exchange. CPS implies not only vascular access and the attendant skills, complexity and hardware, but also the administration of at least half a dozen drugs in order to render it both safe and effective. Given this requirement, what are the additional burdens and costs of delivering cerebroprotective medication?

Currently, melatonin, PBN, vitamin E, and carprofen are combined into a single parenteral product by CCR (Vital-Oxy) which can be administered IV or IO via a stopcock manifold using a pressure infuser. Heparin (anticoagulant), vercuronium (paralytic), magnesium sulfate (cardioplegic) and the first dose of vasopressin (pressor) can similarly be combined to create a single parenteral product shortly before use and may be administered ‘push’ via the stopcock manifold. Dexrtran-40 and mannitol may also be combined into a single parenteral product with a total volume of ~550 mL which can also be given via pressure infuser and the stopcock manifold. Bolus, or continuous doses of vasopressin and THAM (buffer), can be given via the same stopcock manifold using battery operated infusion or syringe pumps.

The broader issue to be addressed is how these multiple medications may be given rapidly, accurately, and with the least use of personnel. Compact, battery operated infusion pumps for in-field use are now available, but they cost a fortune. The same is true of programmable, battery operated syringe pumps. I think the solution to this problem is to computerize it. A laptop computer should already be in use during cryopatient stabilization and transport to acquire data from the patient and it can and should be used to give the meds as well. One simple system for doing this would be to use pressure infusers, and syringes under pressure, with open/close line-clamp solenoids under computer control. Meds would be dispensed by the interval of solenoid opening; push meds would be a full open solenoid, and interval bolus meds would be given by briefly, and for a fixed time, opening the solenoid(s). This is an extremely simple system to implement from both the hardware and software standpoints. A schematic of this type of system is shown below:

darwin_meds

Of course, this presumes that the multidrug approach to cerebroprotection of the cryopatient is economically justified. I would be the first to agree that it is not necessary to pay costly licensing fees to derive most of the benefit from the CRS protocol. It is clear from reviewing the literature that the most widely validated and likely most potent drugs in this protocol (in the context of preventing ultrastructural injury secondary to ischemia-reperfusion injury) are melatonin, PBN[2], and, arguably, vitamin E. These are readily available molecules and may be used by any cryonics organization, absent licensing, on the basis of their documented protective effects in the literature. Other likely useful drugs such as dextran-40, THAM and mannitol have a long history of use in cryonics which predates the CCR research and these drugs may also be used at little cost (Darwin M. Transport Protocol for Cryonic Suspension of Humans, Fourth Edition. 1990, http://www.alcor.org/Library/html/1990manual.html).

In the nearly decade and a half that have elapsed since the CCR canine resuscitation series was undertaken many other promising experimental drugs for the inhibition or moderation of cerebral ischemia-reperfusion injury have emerged. I am in complete agreement with Aschwin that the best way to evaluate the potential utility of these drugs to cryopatients is in animal models that are truly relevant and which simulate the actual condition of cryonics patients who present for stabilization and transport. Such patients are typically suffering from extensive activation of the immune-inflammatory cascade, are often severely dehydrated or fluid overloaded, and invariably suffer from serious disturbances in cerebral microcirculation which begin hours or even days before medico-legal death is pronounced. As a consequence, these patients will typically have pre-arrest ischemic injury which will likely be compounded by post-arrest reperfusion. Evaluation of pharmacological interventions should, and indeed properly must be, carried out in animals models that reflect these facts.

Finally, Aschwin writes: “Even more complexity is introduced when cryonics organizations make an attempt to wash out the blood and substitute it with a universal organ preservation solution. The rationale for this procedure is found in conventional organ preservation and emergency medicine research. The question in organ preservation research is no longer whether hypothermic organs benefit from blood substitution with a synthetic solution, but what the ideal composition of such a solution should be. In emergency medicine research asanguineous hypothermic circulatory arrest is increasingly being investigated to stabilize trauma victims. But it is a major step from these developments to the practice of remote blood washout of ischemic patients with expected transport times of 24 hours or more. At present the only sure benefit of remote blood washout is that it enables more rapid cooling of the patient, a benefit that should not be underestimated. But when liquid ventilation becomes available to cryonics patients, rapid cooling rates will be possible without extracorporeal circulation.”

There can be no argument that blood washout followed by long delays to cryoprotective perfusion is deleterious (as currently practiced) on the basis of both clinical experience with cryopatients and recent unpublished animal research by Fahy, et al., of 21st Century Medicine (39). This practice should probably be abandoned until such time as effective solutions are developed for use in cryopatient transports. The statement that “when liquid ventilation becomes available to cryonics patients, rapid cooling rates will be possible without extracorporeal circulation,” is by no means assured. As the primary inventor of fractional tidal liquid assisted pulmonary cooling (40), I feel it is critical to point out that this technique has been validated only in the setting of healthy animals with spontaneous circulation. The reduced flow state attending external CPS and the typically severely injured lungs of the cryopatient present the twin challenges of greatly reduced blood flow coupled with greatly reduced pulmonary surface area (as a consequence of pre-existing or emergent lung injury; i.e., acute respiratory distress syndrome or acute lung injury resulting from closed chest CPS). which will dramatically reduce the efficacy of heat exchange achievable with this technique.

Once again, as Aschwin correctly notes in the context of pharmacological intervention, it is imperative that modalities developed for application in conventional clinical medicine be validated in the very different setting of the patient presenting for cryopreservation after succumbing to prolonged terminal illness – as well as the added insults of peri- and post-arrest systemic and cerebral ischemia.

REFERENCES:

1. Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ, for the GRADE Working Group. Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-926 or [pdf]
2. Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ; GRADE Working Group. Rating quality of evidence and strength of recommendations: What is “quality of evidence” and why is it important to clinicians? BMJ. 2008 May 3;336(7651):995-8
3. Schünemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE, Williams JW Jr, Kunz R, Craig J, Montori VM, Bossuyt P, Guyatt GH; GRADE Working Group. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008 May 17;336(7653):1106-10
4. Guyatt GH, Oxman AD, Kunz R, Jaeschke R, Helfand M, Liberati A, Vist GE, Schünemann HJ; GRADE working group. Rating quality of evidence and strength of recommendations: Incorporating considerations of resources use into grading recommendations. BMJ. 2008 May 24;336(7654):1170-3
5. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, Schünemann HJ; GRADE Working Group. Rating quality of evidence and strength of recommendations: Going from evidence to recommendations. BMJ. 2008 May 10;336(7652):1049-51
6. Jaeschke R, Guyatt GH, Dellinger P, Schünemann H, Levy MM, Kunz R, Norris S, Bion J; GRADE working group. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive.
BMJ. 2008 Jul 31;337:a744.
7. Merkle RC: The technical feasibility of cryonics. Med Hypotheses. 1992, 39:6-16.
8. Robert F. Nelson & Sandra Stanley: We Froze The First Man, Dell Publishing Company, New York, 1968, pp. 136-56.
9. Leaf, JD, Cryonic suspension of Sam Berkowitz technical report. Long Life Magazine, 3:(2), March/April, 1979, pp. 30-35.
10. Leaf, JD, Case study: K.V.M. suspension, Cryonics, August 1981, pp. 8-18.
11. Leaf, JD, Quaife A, Case study in neurosuspension. Cryonics. 16 November, 1981 pp. 21-28.
12. Leaf, JD, Darwin, M, Hixon, H, Case report: two consecutive suspensions, a comparative study in experimental suspended animation. Cryonics, August 1981, pp. 8-18.
13. Darwin, MG, Leaf, JD, Hixon, HL, Cryonic suspension case report: A-1133, 08 June, 1987, http://www.alcor.org/Library/pdfs/AlcorCaseA1133.pdf.
14. Darwin, MG, Cryonic suspension case report: A-1108, 08May, 1988, unpublished technical case report of the Alcor Life Extension Foundation
15. Darwin, MG, Cryonic suspension case report: A-1165, 08 October, 1988, unpublished technical case report of the Alcor Life Extension Foundation
16. Darwin, MG, Cryonic suspension case report: A-1169, 21 March 1989, unpublished technical case report of the Alcor Life Extension Foundation
17. Darwin, MG, Cryopreservation patient case report: Arlene Francis Fried, A-1049, 06/09/1990, http://www.alcor.org/Library/html/fried.html.
18. Darwin, MG, Cryopreservation case report: Jerome Butler White, 02-05-1994, unpublished, available from the author upon request.
19. Darwin, MG, Cryopreservation case report: Richard Putnam Marsh, 05-06-1994, unpublished, available from the author upon request.
20. Darwin, MG Cryopreservation of James Gallagher CryoCare patient #C-2150, CryoCare Report Number 6, January 1996, and CryoCare Report Number 9, October 1996, http://www.alcor.org/Library/html/casereportC2150.html.
21. Federowicz (Darwin), MG and Leaf JD, Cryoprotective perfusion and freezing of the Ischemic and nonischemic cat. Cryonics, issue 30, p.14, 1983.
22. Federowicz (Darwin), MG and Leaf JD,. The Effects of Cryopreservation on the Cat. Research reported on Cryonet, December 1992.
23. Part 7.2: Management of Cardiac Arrest, Circulation 2005;112;IV-58-IV-66; originally published online Nov 28, 2005, http://circ.ahajournals.org/cgi/content/full/112/24_suppl/IV-58.
24. Alfonzo, AVM, Simpson, K, Deighan, C, Campbell, S, Fox, J. Modifications to advanced life support in renal failure. RESUS-3067; No. of Pages 17, in press.
25. Buckberg, GJ, Deep hypothermic circulatory arrest and global reperfusion injury: Avoidance by making a pump prime reperfusate—A new concept. J Thoracic and Cardiovasc Surg. 2003;125(3); 625-632.
26. Gupta,S, Kaul, CL, Sharma, S. Neuroprotective effect of combination of poly (ADP-ribose) polymerase inhibitor and antioxidant in middle cerebral artery occlusion induced focal ischemia in rats Neurological Research,26;2004:103-107.
27. LIiu, XL, Nozaria, A, Basu, S, Ronquist, G, Rubertsson, S, Wiklund, L. Neurological outcome after experimental cardiopulmonary resuscitation: a result of delayed and potentially treatable neuronal injury? Acta anaesthesiologica scandinavica,46,(5) 2002:.537-546.
28. Schmid-Elsaesser R, Hungerhuber E, Zausinger S, Baethmann A, Reulen HJ. Combination drug therapy and mild hypothermia: A promising treatment strategy for reversible, focal cerebral ischemia. Stroke 1999, 30: 1891–1899
29. Spinnewyn B, Cornet S, Auguet M, Chabrier PE. Synergistic protective effects of antioxidant and nitric oxide synthase inhibitors in transient focal ischemia. J Cereb Blood Flow Metab 1999; 19:139–14.
30. Reiter RJ, Tan DX. Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res. 58:10–19, 2003.
31. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC, Ashwood T,Wasiewski WW, Emeribe U; NXY-059 for the treatment of acute ischemic stroke, N Engl J Med. 2007 Aug 9;357(6):562-71.
32. Siesjö BK, Elmer E, Janelidze S, Keep M, Kristian T, Ouyang,YB et al. Role and mechanisms of secondary mitochondrial failure. Acta Neurochir (Suppl) 1999: 73: 7–13.
33. Darwin, MG, Leaf, JD, Hixon, H, Neuropreservation of Alcor Patient A-1068. http://www.alcor.org/Library/html/casereport8504.html#part2
34. Clark J, Larsen, MP, Culley, LL, Graves, JR, Eisenberg, MS. Incidence of agonal respirations in sudden cardiac arrest. Ann Emerg Med 1992;21(12):1464-7.
35. Rea TD. Agonal respirations during cardiac arrest. Curr Opin Crit Care 2005;11(3):188-91.
36. Jain S, DeGeorgia, M. Brain death-associated reflexes and automatisms. Neurocrit Care 2005;3(2):122-6.
37. Maurino, SJ, Saizar, R,.Bueri.J, Frequency of spinal reflex movements in brain-dead patients. The American Journal of Medicine, 2004, 118(3):311-314;36.
38. Vukmir R, Bircher, N, Radovsky, A, Safar, P. Sodium bicarbonate may improve outcome in dogs with brief or prolonged cardiac arrest. Crit Care Med 1995;23:515-22.
39. Fahy, GM The Whole-Body Vitrification Project at 21st Century Medicine. In the Suspended Animation conference held in Fort Lauderdale, Florida, from May 18th through May 20th May 2007.
40. Federowicz (Darwin), MG, Russell, SR, Harris, SB, Mixed-mode liquid ventilation gas and heat exchange. United States Patent 6,694,977, published 24 February, 2004, http://www.freepatentsonline.com/6694977.html.

ENDNOTES:

[1] The Cryonics Institute declined repeated invitations to participate in these colloquiums.
[2] It is important to note that the PBN used in the CCR study was prepared by dissolving it in boiling water with concurrent microwave heating in the presence of atmospheric oxygen. This is very likely significant because such handling would inevitably create breakdown products of PBN, such as NtBHA and its oxidation product the spin-trap MNP. As Proctor, et al., have pointed out, (Peter H. Proctor and Lynsey P. Tamborello, SAINT-I Worked, But the Neuroprotectant Is Not NXY-059, Stroke 2007 38:e109; published online before print August 23 2007.) it is possible that the failure of NXY-059 in the SAINT-II trial was due to the fact that material used in this trial differed from that used in the successful SAINT-I trial in that it was stabilized and protected against oxidation. It may well be that it is not PBN, per se, that is cerebroprotective, but rather its oxidation and/or break-down products.

Marcelon Johnson dies and is not cryopreserved

For Immediate Release, Friday, 24 January, 2009

Date: 23 January, 2009

Introduction

I have been informed that Marcelon (Marce) Johnson died on 01/21/2009, was cremated, and not cryopreserved.

I understand this information may come as a surprise and as a disturbing shock to many people, especially those who loved and knew Marce, as I did. I thus feel an obligation to explain how this happened and to provide some closure to this story for the many people who helped, or tried to help, avert this catastrophe.

While Marce was alive I was unable to share the full story of what was happening. Now that she is dead and gone I believe it important and the responsible thing to do to relate the story as best I know it.

I do not have access to my records here, so dates precise dates will be missing or supplied later in an amended account (if there is any interest).

A Brief History

Early in January of 1964 a 35-year-old Huntington Beach, California housewife named Marcelon Johnson finished filling out her cryonics paperwork, paid her first cryonic society dues, and dropped her application for a Medic-Alert bracelet in the mail. She had six children and a busy, happy, life which has just gotten better because she now believed, for the first time, that she might never have to die. She had been haunted by the death of her mother who was in her mid-50s when she succumbed to Alzheimers disease. She did not want to die that way, or any other way, for that matter.

Within a year Marcelon Johnson, or Marce as was known to her friends, would become increasingly involved in cryonics. By March of 1967, 3 months after Dr. Bedford began the journey which he continues to this day, Marce Johnson was the Secretary-Treasurer of the Cryonics Society of California (CSC). She opened her home to cryonics meetings and catered them superbly. She answered countless information requests and filled countless orders for books and literature. On October 11, 1974 Marce reluctantly accepted the Presidency of CSC, not suspecting that she had stepped into a nightmare that would go on for almost eight years. Russ Stanley, who had welcomed Marce to her first cryonics meeting on September 30th in 1966, had been frozen (or so it seemed) for 6 years. Two of the other pioneering CSC members whom she had met and befriended were also (presumed) in cryonic suspension at CSCs Cryonic Interment Facility in Chatsworth, CA.

In the 45 years was actively involved in cryonics I have never heard anyone say a bad thing about Marce Johnson. That was an extraordinary achievement for anyone involved in cryonics, but it was made all the more extraordinary by the fact that Marce was the de facto President of CSC when it came to light in 1979 that all of the patients in the Chatsworth facility had been allowed to thaw and decompose. No, Marce had no complicity in that horror beyond that of being loyal and trusting. The very qualities that made Marce an exceptional human beig: her readiness to help, her willingness to trust the words of a friend and colleague, and her quiet and nearly unshakeable loyalty had set her up to be in the crosshairs of the litigation and enmity that followed.

The very public disintegration of CSC was not only financially costly to Marce and her husband Walt (not to mention their 6 children), it was a deep personal humiliation and loss. Three of the people who had welcomed her into cryonics were now gone lost to a gruesome and disgraceful fate. There was no immortality for them; in fact, there was not even the dignity of a decent burial. Many of the people who were cohorts of Marce at that time walked away from cryonics and never looked back and most of them are dead now, or are beyond help in nursing homes, or dependent upon their indifferent children. I have watched as those who died passed, and I have spoken with those who remain, helpless and dying. Chatsworth was not a pretty business.

Marce Johnson did not walk away. She joined Alcor, and at a very bad time for Alcor in 1981. Over the next ten years Marce hosted more Alcor meetings than anyone else has before or since. She and her husband Walt were a dependable source of contributions, and Marce would often make the 2 hour drive (each way) from Huntington Beach to Fullerton to help with various volunteer activities at Alcor. Her gentle, intellectual decency served as a welcome beacon of normality and warmth at cryonics get-togethers that were often marred by partisanship and extremes. Marces home was one of the least conveniently located in Southern California, but the meetings she hosted there were among the best attended.

In 1985 Alcor faced a seemingly insurmountable crisis. For 7 years Alcor had been the guest of Cryovita Laboratories in Fullerton, California. Cryovita was the creation of cryonics pioneer Jerry Leaf and it was a costly drain on Jerry and his family. Jerry not only paid the rent on the facility in Fullerton, he covered all the other operating expenses out of his pocket, including the liability insurance required by the landlord. In the early 1980s the explosion of litigation in California and elsewhere resulted in skyrocketing premiums for basic business liability coverage. By 1985 coverage at any price was no longer available for businesses with a high, or impossible to estimate degree of risk. Alcor, and thus Cryovita, became uninsurable and with that came the inevitable edict from the landlord to vacate the premises.

With the help of a long-time friend of Alcor, Reg Thatcher, a potential solution was identified. A small park of industrial buildings was going to be built in nearby Riverside, California with completion expected in about 10 months. We negotiated with the landlord and began trying to raise the impossible sum of $150,000 plus closing and other costs. We had from April 4th to June 20th, 1986 to do just that a little over two months. At $149,000 we stalled out. All the deep pockets had been tapped and the Life Extension Foundation was locked in a battle with the FDA for its survival, as well as for the personal freedom of Saul Kent and Bill Falloon, both of whom faced decades in prison. Alcor had approximately 100 members in 1986, and finding the additional $5,000 in cash required to cover the closing costs appeared hopeless. As it was, an additional $37,500 had already been pledged to cover the 2-year note carried by the developer. When Marce heard of this situation she quietly opened her and Walts check book and wrote out a check for $5,000.

In the years that followed, Marce was always there for cryonics and it wasnt easy. She and Walt had had to buy life insurance late in life and the premiums were punishing, even for neuro. Sometime around 1997 Marce asked me to meet her for lunch in Huntington Beach. That was an unusual request, but one which I was happy to oblige. It was an unexpectedly emotional and difficult meeting. As we sat in a little Italian restaurant in an anonymous strip mall Marce repeated the story of her mothers death and asked me to promise that I would not abandon her should such a fate befall her. She told me a number of deeply personal things and she asked me to dispose of some unfinished business should I outlive her. It was easy to say yes. Marce was healthy and had every prospect of living many years longer in good health. It takes extraordinary courage to confront not only your own mortality, but also the prospect of closing your life in the darkness of dementia. Nothing in my experience of Marce as a relentlessly positive and optimistic person had prepared me for that meeting.

In 2001 I was alerted by Joan OFarrel of Critical Care Research that Marce seemed both forgetful and inappropriate on the phone (Marce was, as usual, doing volunteer work, this time for Critical Care Research (CCR) and 21st Century Medicine). A call to Walt confirmed Joans suspicions and shortly thereafter Dr. Steve Harris and I visited Marce. Steve did a thorough exam, including an assessment for Alzheimers. Marce did well on this assessment, but Steve suggested she go to the Memory Clinic at UCLA for a more comprehensive evaluation. I tried to call Walt and Marce over the following 2 years and always ended up getting Marces voice on their answering machine. Finally, in 2003 Walt picked up the phone and we talked. I learned that Marce had been placed in a nursing home some months prior, and that she had moderately advanced Alzheimers.

That news was devastating enough, but what followed shook me to the core of my being. Walt told me that Marce no longer had cryonics arrangements and that she was to be cremated. I visited Marce twice in the subsequent months and found her still oriented enough to recognize me and carry on a very basic conversation. From these two visits I learned that Marce still believed she was going to be cryopreserved and that she felt that she had done something wrong, perhaps by getting sick, which had caused her cryonics friends to stop coming to see her. I learned that Saul Kent had been down to see her and Walt and to try to get Walt to reinstate Marces arrangements, but to no avail. Walt had never been a cryonicist and his concern was, understandably, with ensuring that Marce got top quality nursing home care. Walt and Marce were confronted with spend down in the face of monthly nursing home bills of over $5,000. Medicare does not begin to cover these expenses until the patient has $2,000 or less in total assets not even enough for burial. Marces and Walts cryonics insurance policies had been cashed-out and used for her nursing home care.

In the six years that have come and gone since then a number of people have continued to try to find some way to rescue Marce from this situation. Marce did everything right, everything that cryonics organizations asked her to do, including giving them ownership of her policy. Unfortunately, Marce fell ill just as CryoCare was closing down and she never had the opportunity to transfer her arrangements to the Cryonics Institute, or Alcor.

Dave Pizer of the Venturists stepped forward to organize a fund raising effort for Marce. Dave believed, as I did, that the primary obstacle to getting Marce cryopreservation arrangements was money, not any unwillingness on Walts part. days ago Walt confirmed this by consenting to have Marce cryopreserved at CI when the time comes. CI graciously agreed to accept Marce as a member and her future now rests on the ability of the Venturists to raise the $35,000 required to cover CIs costs and to transport Marce to CI from Southern California.

The Rest of the Story

Unfortunately, shortly after the appeal for Marce detailed above was launched, Walt retracted his offer of cooperation and support. When Walt and I spoke about the efforts on Marces behalf he was warm, gracious, and cooperative. Because of the criticality of the matter (Marces potential life or death) I did something I have done only a few times in my adult life: I recorded the conversation between Walt and I without his knowledge. This was a legally permissible action since the call (on my end) was made in Arizona, which has no law prohibiting such recording. When I subsequently called Walt (about 2-weeks later) to set up arrangements for him to sign the CI paperwork in the presence of a notary (Walt had suggested that we do this at his bank, a branch of which was located just around the corner form his home) Walt stated he had changed his mind and that he had decided that Marce should not be cryopreserved and instead would be cremated, in keeping with his, and the rest of her familys wishes. To say that I was both stunned and unprepared for this turn events was an understatement. When I asked to meet with Walt and other concerned members of the family, Walt said that, he had said all he had to say and hung up on me.

After lengthily consultation with Saul Kent, Dave Pizer, and a prominent scientist and cryonicist close to Marce and Walt (including playing the tape recording of the conversation between Walt and I), a decision was made to do the following things:

1) Attempt to arrange a meeting with Walt between Saul Kent and the cryonicist/scientist who had known Marce and Walt since his teenage years in Southern California and who could argue both scientifically, and on the basis of personal knowledge, that cryopreservation was warranted in Marces case and in her condition of advanced Alzheimers disease.

2) Contact Marces most influential (and sympathetic to cryonics) daughter and speak with her in detail about the situation and, if possible, enlist her support in the effort to change Walts decision.

3) No attempt would be made to use the court system or other legal coercive mechanisms to challenge Walts or the familys decision in this matter. Since both Marces husband, her many children, and her other relatives were not supportive of cryonics or were opposed, it was deemed by Saul Kent, and Dave Pizer, that litigation would prove not only fruitless, but possibly counterproductive.

4) Considerations in making the decision not to take coercive action(s) were that Walt was himself dying (he is currently in hospice care) raising the possibility that he might not outlive Marce opening another opportunity to revisit the matter with her children. Other considerations were that there was no funding for such an effort and approaches to several attorneys who might work pro bono (or provide advice gratis), yielded no offers of help and the uniform opinion that litigation would be unsuccessful and costly. [ It probably also should be noted that one similar such effort in the past proved a financially costly failure.]

Saul Kent argued that public disclosure of this turn of events would damage the fundraising effort for Marce and that the most conservative course of action was to proceed with efforts to rescue her until all hope was gone; in other words until she was dead and disposition was completed. Most involved agreed that this was the most conservative course of action to pursue.

This sad outcome has now been realized.

My own heartbreak knowns no words, and although I expected this outcome for many months, it is still difficult to bear.

Marce lived her life without bitterness or anger, and with malice towards none. Those who knew her will understand this and will hopefully also understand that I honor her here by saying simply that I will miss her and that, as is the case with so many others Ive loved and lost, I will neither forget, nor stop looking for ways, however remote in possibility or in time, to somehow recover her.

Information for Contributors

For those who contributed to the effort to help Marce, please contact the Society for Venturism c/o Dave Pizer: or at:

The Venturists

C/O The Creekside Lodge

11255 State Route 69

Mayer Arizona 86333

for information on how to obtain a refund of your contribution, or to reassign it for use by Bill O’Right’s.