CHRONOSPHERE

By Mike Darwin

External Cooling Using the Portable Ice Bath (PIB)

Early in 1995, the PIB was redesigned so that it would be collapsible, easily air transportable and extremely rugged. Since that time there have been many designs for PIBs executed around the world. The PIB design shown here can be assembled by one person in approximately 10 minutes. The lightweight aluminum construction means that it can be easily transported in a standard automobile trunk or as passenger luggage by air (both before and after patient use). This PIB was also designed to be small enough and easy enough to break down and re-deploy, so that it can be used in commercial air ambulances for air transport of patients while cardiopulmonary support or other interventions requiring access to the patient are underway.

Assembling the PIB

The PIB may be assembled using the following procedure:

1)   Unfold the Roller Base and lay out the components of the PIB in an organized fashion to make sure all parts are present:

Quantity            Item

1         Folding Frame

1         Roller Base

1         Vinyl Liner

2         IV Pole

8         Locking Pins

4         Attaching (Cotter) Pin assembly for securing Roller Base to Folding Frame

1         Cotter Pin for securing the Locking Bars on the underside of the Folding Frame

1         Privacy Cover

1         Records & Supplies Holster (at foot)

1         Portable Oxygen Pack Holder (POP) (and Medications Tray)

2         Heavy duty plastic tarpaulins

2)    Unfold the Folding Frame into its fully deployed configuration and insert the 8 Locking Pins (with rings on the top) into the four holes on each side of the center portion (top and bottom) of the middle section of the Folding Frame.

3)    Open the Roller Base and slide the locking bars on the underside of the Roller Base Plate into position. Secure the locking bars with the Cotter Pin.

4)    Orient the Roller Base to the Folding Frame properly. The top surface of the Roller Base and the inside of the Folding Frame are labeled “Head” and “Foot” with matching, brightly colored tape.

5)    Tilt the Roller Base so that it will fit inside the Folding Frame and the square aluminum channel on the bottom of the Folding Frame lines up with the square tubing stock of the Roller Base Plate.

6)    Push the channel on the Folding Frame up onto the bar-stock of the Roller Base.

7)    Insert the Attaching Pins into the holes on the bottom of the Roller Base.

8)    Position the Thumper Board of the MII-HLR in the correct position on the top end surface of the Roller Base.

9)    Correctly align the Vinyl Liner with the Folding Frame and secure it to the Folding Frame by mating the male and female Velcro.

10)  Insert the IV Pole into the hole in the aluminum tubing of the Folding Frame in the position most convenient as dictated by the needs of the patient (location of the IV site, position of personnel, etc.).

11)  Attach the Records and Supplies Holsters to the head end of the Folding Frame.

12)  Place the Portable Oxygen Pack (POP) Holder over the lower 1/4th of the top of the PIB and rest the POP on it.

Figure 24: An essential accessory to the PIB is a combination E oxygen cylinder carrier and medications/instrument tray. Early in CPS the tray may be used to hold Transport medications. Once the medications have been administered the tray can be flipped over to allow racking and safe transport of the high pressure oxygen cylinders driving the heart-lung resuscitator (HLR).

A Visual Guide to Assembly of the PIB

A:  Components of the Portable Ice Bath (PIB) prior to assembly.

B:  Accessory Bag containing Locking and Attaching Pins, Allen wrenches and spare parts.

C: The Folding Frame in the collapsed configuration.

D: Open the Folding Frame by pulling apart the two endplates.

E: Fully expand the Folding Frame and make it rigid by inserting the eight locking pins.

F: Rigidify the Roller Base by sliding the Locking Bars across the hinge of the Roller Base.

G: Secure the Locking Bars in position by placing the Cotter Pin into the securing bracket

H. Insert the Roller base into the Folding Frame and snap the metal channel of the Roller Base onto the metal tubing of the Folding Frame.

I: Secure the Folding Frame to the Roller Base with the four Attaching Cotter Pins. Be sure to have the locking end of the Cotter Pin point to the inside of the Roller Base.

J: It is critically important that the eight Locking Pins be inserted into the Folding Frame both at the top and the bottom of the center section of the Folding Frame. Be sure to double check for proper placement of all pins prior to covering the Folding Frame with the Vinyl Liner.

K: The Roller Base with the Folding Frame Attached should look like this after assembly.

L: Place the Thumper Board onto the Roller Base being sure to anchor it into position using the Velcro on the Thumper Board and Roller Base.

M: Unfold the Vinyl Liner inside the Folding Frame on the Roller Base.

N:  Anchor the top of the Vinyl Liner to the Folding Frame using the Velcro on the lip of the Liner and the top of the square tubing of the Folding Frame.

O: Insert the IV Pole into any of the four positions on the Folding Frame as convenience dictates.

P: The fully assembled PIB shown without the POP/Medications Tray or the Records and Supplies Holster.

Initiating External Cooling with the PIB

Preparation of the PIB for Use

Figure 25: The PIB in use during a patient transport from a hospital in Northern California.

Upon arriving at the site where Transport is to take place the PIB should be assembled per the instructions above and, if time permits, the liner should be carefully inspected for punctures. A repair kit is included with the liner and will affect water tight repairs in ~30 minutes.

If transport is to be undertaken in a home, or in a room where there is carpeting, the heavy duty tarpaulins should be used to cover the carpeting in the work area. Use duct tape to secure the tarps to the carpeting to avoid creation of a trip hazard from folds that will develop in the tarps if they are left unsecured.

Once a place to store the PIB has been secured until the patient is pronounced the PIB should be fully outfitted with all ancillary equipment needed for induction of hypothermia, as well as with all equipment and supplies that will be immediately required to facilitate stabilization of the patient.

The dorsal cooling blanket should be positioned in the bottom of the PIB and connected to the pump that supplies cold water to the surface convective cooling device (SCCD) as well as to the cooling blanket.

If space is constrained, as it usually is in a hospital or extended care facility (ECF), ancillary equipment and supplies may be stored inside the PIB and the entire assembly covered with a sheet to avoid attracting attention, reduce the risk of pilferage of equipment and supplies, and protect the PIB and its contents from dust and fluids as shown in Figure 26.

Figure 26: At left, the PIB set-up for Transport in hospital with ancillary equipment in position. At right the PIB adjacent to ice in coolers, the medications kit (light green box) and other required supplies. The PIB is covered with a Nylon sheet to protect its contents and avoid attracting attention.

As soon as legal death is pronounced, remove all clothing from the patient such as hospital gowns, undergarments, and anti-embolism stockings. The most expedient and practical way to remove clothing is to cut it off using bandage scissors or the Super Scissors contained in the RSK.  The patient’s genitals must remain covered at all times during transport and external cooling.  The genitals may be covered with a towel or small disposable drape sheet. This is an important gesture of respect and is not just a courtesy to the patient and personnel who may come in contact with the patient; it is also the law in many states. Failure to offer this respect can result in civil prosecution.

The combination fecal retention device (FRD), thermocouple probe, and colonic lavage tube should be inserted into the rectum and inflated with 30 mL of air. Easy passage of the FRD should be facilitated by lubricating it with surgical jelly before insertion (do not use oil based lubricants, including silicone lubricants, as they will destroy the retention balloon). The FRD will allow for immediate determination of the patient’s temperature, either at the time of pronouncement, or whenever Transport is permitted to begin. The FRD may also be used to irrigate the colon with cold electrolyte balanced physiologic solution (do not use water!). This will render further rectal temperature readings inaccurate, but the tradeoff in terms of speeding cooling is well worth it. Step by step instructions for insertion of the FRD and colonic irrigation are given in Colonic Lavage Cooling, below.

As soon as possible after legal death is pronounced, the patient should be rapidly transferred to the PIB and the HLR applied (manual CPR should only be used as a bridge between the time legal death is pronounced and the time it takes to organize transfer of the patient into the PIB if transfer to the PIB cannot be carried out immediately). Once the patient is positioned in the PIB and mechanical CPR has been started, the patient should be packed in ice from head to foot.  The PIB, which uses crushed ice in direct contact with the patient’s skin, will more than double the rate of cooling that can be achieved with ice-filled plastic bags. The PIB is many times more effective at reducing patient core temperature than simple air cooling such as is achieved by placing the patient in a refrigerated morgue or “reefer” unit.

Figure 27: 300 mL Vindicator quaternary ammonium disinfectant should be added to the heat exchange water in the PIB to kill the most common transmissible human pathogens.

Concurrent with the addition of ice to the PIB, 5 gallons of water containing 300 ml of Vindicator Disinfectant (10% didecyl dimethyl ammonium chloride and 6.76% n-alkyl [C₁₄ 50%, C₁₂ 40%, C₁₆ 10%] dimethyl benzyl ammonium chloride) should be added to the PIB as a microbicide.^[158] The combination of quaternary ammonium compounds present in Vindicator is effective at killing the pathogens listed in in the box below. Because of the low temperature in the PIB, microbial kill times will be longer, and it may take as long as 5 minutes after disinfectant is added until the microbial burden in the PIB water is reduced or eliminated. Quaternary ammonium compounds have very low toxicity and are generally not irritating to the oral mucosa or the conjunctiva. Used in the proper concentrations these compounds are safe for use with disposable stainless steel heat exchangers, such as those incorporated into combination hollow fiber oxygenator-heat exchanger devices used in cardiopulmonary bypass. Quaternary ammonium compounds should not be used with aluminum blood heat exchangers.

Pathogens killed by Vindicator Disinfectant Vindicator Disinfectant  is effective against: BACTERIA: Psuedomonas aeruginosa, Staphylococcus aureus , Salmonella choleraesus, Acinetobacter calcoaceticus, Bordetella bronchispetica, Chlaymydia psittaci, Enterobacter aerogenes, Enterobacter cloacae, Enterococcus faecalis, (Vancomycin Resistant), Escherichia coli, Fusabacteria necrophorum, Klebsiella pneumonia, Leoginella pneumonia, Listeria monocytogones, Pasturella multcoccidia, Proteus mirabilis, Proteus vulgaris, Salmonella enteritidias, Salmonella typhi, Salmonella typhimurim, Serratia marcensens, Shigella flexneri, Shigella sonnei, Staphylococcus aureus – Methcillin resistant (MRSA), Staphylococcus aureus – Vancomycin resistant, Staphylococcus epidermis, Streptococcus faecalis, Streptococcus pyogenes. VIRUSES: Adenovirus Type 4, Hepatitis A virus, Hebatitis B virus, Hepatis C virus, Herpes Simplex Type I virus, Herpes Simplex Type II virus, Human Corona virus, HIV-1 (AIDS) virus, Influenza Hong Kong, Vaccinia, Rubella, SARS associated Coronavirus, Respiratory Syncitial virus. ANIMAL VIRUSES: Avian polyomavirus, Canine distemper, Feline leukemia, Feline picornavirus, Infectious bovine rhinotracheitis, Avian infectious bronchitis, Pseudorabies, Rabies, Transmissible gastroenteritis. FUNGI: Aspergilus niger, Candida albicans, Tricchyton mentagrophytes.[1]

 

 

 

 

 

CAUTION: Do not place ice in the PIB before the patient is transferred into it, as the presence of ice (particularly if an MII-HLR is being used) will make proper application of the HLR impossible. Exercise care to avoid wetting the piston of MII-HLR units as it will cause the piston to “lock-up” and the unit to stop cycling!

Figure 28: The Fecal Retention Device (FRD) consists of a rigid, fenestrated tube with a tough silicone rubber balloon near the tip. The FRD is outfitted with a Cu⁺⁺/C thermocouple probe to allow for immediate determination of the patient’s core temperature at the time Transport begins. The silastic balloon is inflated with 50 mL of air to hold the FRD in place and prevent leakage of feces into the refrigerating water of the PIB. The FRD tube is covered with a caplug, but this may be removed and the tube connected to a closed cold physiologic solution irrigation set-up to facilitate more rapid induction of hypothermia.

The Surface Convection Cooling Device (SCCD)

Figure 29: Current implementation of the Surface Convective Cooling Device (SCCD). For use where there is no AC power, or in situations where the patient will have to be immediately relocated following the start of CPS, an Atwood self-contained battery operated marine bilge pump should be used. The SCCD above uses 4 circular diffusers to distribute cold water over the patient’s body and a Head Ice Positioner (HIP) to hold ice around the patient’s head. The HIP is also supplied with cold water from the SCCD pump and has a diffuser which may be placed on the patient’s forehead to deliver chilled water to cool the forebrain.

One of the principal barriers to efficient external cooling is the existence of “boundary layers” of insulating water which become established around the patient in the PIB. Anyone who has ever been on a camping trip and had the frustrating experience of trying to melt snow for drinking water will immediately understand this phenomenon. In the center of the kettle will be a mass of snow surrounded by tepid water while the water near the wall of the pot is boiling. Only by  stirring can such boundary layers be disrupted and efficient heat exchange achieved. One solution to this boundary-layer problem was the development by Fred Chamberlain, and consisted of a circulating pump and ice water distribution assembly that can be used in the PIB.^[156]

This device, known as the Surface Convective Cooling Device (SCCD), exists in a variety of implementations. It’s most basic implementation consists of a 40 GPM (gallons per minute) output, lightweight, mains powered (AC) submersible sump pump, which is connected to a manifold of hoses and small sprinkler heads (Figure 33 ). The hosing and sprinkler heads – using quick disconnects – snap rapidly into any desired configuration. Sprinkler heads may be positioned so that a fast moving stream of ice cold water can be directed over the patient’s head, as well as to other key heat exchange areas, such as the axilla and groin. Alternative designs which employ a rigid tubing manifold with slotted cooling “fingers” have also been developed. However they operate, the principle remains the same: to rapidly move large adequate volumes of chilled water over the surface of the patient.

Figure 30: Close up of one of the four cold water diffuser rings used in the SCCD.

Three shortcomings of these SCCD designs is that they do not uniformly sheet or film water over the surface of the patient’s body, they do not reliably apply stirred cold water to the patient’s head, and finally, they generate splashes and aerosols that may transmit infectious disease. This has become a particular concern with the advent of multi-resistant Staphylococcus aureus (MRSA).^{[159], [160]} Most in-hospital Staph infections are now MRSA and other, even more dangerous strains of antibiotic resistant organisms are on the way.^[161]

A solution to these problems has come in the form of a more efficient SCCD which is more easily and rapidly applied. It consists of modified diffusers consisting of 4 rugged plastic rings with perforations positioned and immobilized inside two wire-reinforced fabric frames. The side of the frame that is placed facing the surface of the patient is made of an open-mesh nylon fabric that allows the free flow of water (Figures 31-32 ). The opposite side of the fabric frame is comprised of a solid fabric panel to reduce the risk of water spraying or splashing from the PIB onto staff caring for the patient.

Figure 31: Above, A) cross-linked Dacron polyester wool blanket, B) Cold water delivery control valve for the HIP, C) insulating plastic covered foam mattress, D) HLR backboard.

These two frames holding the cold water diffusers are then placed atop a blanket consisting 2” thick cross-linked Dacron polyester wool which serves as a spreading medium for the cold water over the patient’s body (Figure 32). The entire assembly is then covered with a very thin sheet of nylon tricot or Dacron polyester fabric.

Figure 32: Cutaway looking “up” from the surface of the patient showing the relationship between the fabric frame, cold water diffusers and the Dacron wool cold water dispersing mat or spreading blanket. This assembly is covered with a nylon tricot or Dacron polyester fabric sheet to prevent splashing and aerosolization of the PIB water.

Using the SCCD

Instructions for use of both types of the SCCD are included here because a number of the older-style garden hose type units are still present in BPI field kits. Additionally, it is easy to quickly assemble a garden hose style SCCD from parts readily available at any hardware store. For these reasons instructions on use of both versions are given here.

The SCCD is simple in design and extremely easy to apply. Once the patient is in the PIB and packed in ice, add enough water to the PIB to fill it to a depth of at least 2–3 inches, typically 5-10 gallons (20-40 liters) of water. Position the SCCD pump inside the PIP at the foot end, either between the patient’s feet or to one side of them as shown in Figure 31. Snap the distribution tubing onto the pump and position the sprinkler heads as appropriate. A recommended pattern of positioning for the garden hose style SCCD is 2 sprinklers each at the head, neck, groin and axilla.

Figure 33: Garden hose style SCCD fabricated from garden hose, garden hose quick disconnects and valving and garden hose sprinkler heads; all obtainable at most hardware and home supply centers. The pump can be either a 110VAC powered submersible sump pump, or an Atwood fully submersible battery powered bilge pump powered by 4 “D-cell” batteries.

Figure 34: Two views of the garden hose style SCCD in use.

New SCCD

The new SCCD, as previously noted, uses two fabric frames containing 4 cold water diffusers. These fabric frames are connected to a cold water supply line. Connect the cold water supply line to the quick disconnect on the water circulating pump. Place the Head Ice Positioner (HIP; see discussion, below) at the head end of the PIB and connect the cold water supply line to the disperser inside the HIP. Ensure that the drain valve on the HIP is closed.

Figure 35: The Head Ice Positioner is designed to keep refrigerant in constant contact with the patient’s head. This can be accomplished with crushed or shaved ice or by a constant flow of chilled (~0^oC) water flowing over the patient’s head. The HIP is equipped with a cold water disperser connected to SCCD pump allowing water to build up in the HIP and overflow from drain holes in the side of the container to return to the PIB.

Figure 36: Relationship between patient the HIP and the PIB. Care must be taken to ensure that heat exchange water does not enter the patient’s nose or mouth.

Once the patient is in position inside the PIB (ensure that the patient’s head is properly positioned inside the HIP and that it does not interfere with ventilation) cover the patient with the Dacron wool cold water dispersing mat, and then place both fabric frames containing the cold water dispersers atop the mat; one adjacent to the AC-DC cup of the HLR, and the other over the lower abdomen and legs. Activate the circulating pump and insure that water is flowing freely from all four dispersers and that water is exhausting from the HIP around the patient’s neck, or from the overflow holes on the side of the HIP (Figure 35). Take care that the water level in the HIP is not high enough to enter the patient’s oropharynx.

Until a few years ago, the only pumps to drive the SCCD were either AC sump pumps, or 12 volt powered marine bilge pumps. While compact and lightweight, marine bilge pumps required lead-acid batteries which may not be transported by air. Attwood Marine now markets the Attwood Waterbuster™ pump, which is a self contained, fully submersible pump that runs up to 5 hours on three alkaline D batteries. It delivers a 200 gph flow at a head of 40” and measures only 6-3/8″ high x 5-1/4″ diameter. This pump is currently replacing the AC pumps in Standby Kits. However, even in situations where only an AC pump is available, the SCCD may still be very useful, particularly in situations where medications are to be administered before vehicular transport. (Administering medications typically requires 45 minutes to an hour to accomplish.) There will also be many situations where transportation (local mortician, ambulance, etc.) must be summoned after the start of CPS and external cooling and where there is likely to be a delay of 15 to 30 minutes before transportation arrives. Keep in mind that the SCCD, when used in conjunction with the PIB, can lower a thin patient’s temperature as much as 12ºC in 30 minutes. Thus, every minute that the SCCD can be used, it should be used. If use of the SCCD has to be interrupted, restart it as soon as possible.

Figure 37: The Attwood Waterbuster™ pump is a self contained pump that runs for 5 hours on 3 “D-cell” batteries. It is almost completely silent and produces exactly the right amount of flow to facilitate effective convective cooling. The Waterbuster™ also greatly decreases ice consumption since, unlike it AC counterparts, it generates very little waste heat.

Limitations of External Cooling

Despite the development of immersion cooling employing a well stirred ice bath, there are fundamental limits on the amount of heat that can be moved using only the surface of the patient. These limits are a function of the patient’s mass, degree of insulating fat-covering, adequacy of circulation to the skin and surface body tissues, and the patient’s volume and surface area. In practice, the maximum rate at which low-mass emaciated patients can be cooled externally is in the range of 0.25 to 0.35ºC/min., while the maximum rate for larger mass patients with a significant layer of subcutaneous fat is in the range of 0.12 to 0.15ºC/min. Figure 38 shows the rate of cooling for a number of patients with different masses, adequacy of perfusion, and degrees of cachexia.

As Figure 38 shows, the maximum rate of cooling achievable in the first 30 minutes of CPS in a patient of average mass and with minimal subcutaneous fat is in the range of 0.5ºC/min. If this cooling rate is compared with what could be achieved starting at the same patient core temperature (~37ºC) and using extracorporeal cooling with a high efficiency heat exchanger (0.6 coefficient of heat exchange) and a “wall water” (water to the heat exchanger) temperature of 0ºC, cooling rates of two or three times that achievable with external cooling are possible (i.e., 1.5 to 2.0ºC/min for the brain in a 65 kg adult with a surface area of 2.0 square meters). As previously noted, the difficulty with this approach is that it requires a considerable amount of skill and time. Even under the best circumstances it is unlikely that cardiopulmonary bypass (CPB) can be safely established in less than 60 minutes from the time of pronouncement, even by experienced operators.

The reality is that far longer periods of time may elapse between the start of transport and the beginning of extracorporeal support. Logistic constraints, such as the need to move the patient from the home, or an acute or chronic care facility to a mortuary, the availability of skilled personnel, and pre-existing medical or anatomical complications all may greatly delay or even prevent the application of in-field CPB.

Figure 38: Comparison of the cooling rates of four cryopatients. Immediately following pronouncement of medico-legal death patients were given closed chest mechanical cardiopulmonary support and placed in a stirred ice water bath for induction of hypothermia. Epinephrine was administered as per ACLS guidelines; thus peripheral vasoconstriction would be expected to be comparable to that seen in the typical SCA patient undergoing cardiac resuscitation. The number of asterisks after the case number indicates the overall score (from zero to ****) for response to cardiopulmonary support as evaluated by EtCO2, skin color, femoral pulse, and other parameters, when available.

Ensuring Adequate Refrigeration of the Patient’s Head

Recently, experiments have been conducted that show show something that may seem surprising, principally that cooling in an unstirred water bath at 0ºC is not even twice as effective as cooling in a still (unstirred) air bath at 0ºC, as shown in Figure  50, below.

The reason for this is the limitation imposed by the very low value for the heat conductivity of the human head. This has the following important practical implications:

1)         External conductive cooling of the human head/brain is extremely slow, even under ideal conditions of maximum surface contact with ice at 0^oC, where the melt water is filmed over the patient’s head.[7],[8]

2) Once the surface of the patient’s head reaches 0^oC, the brain cannot be cooled any faster regardless of the type or amount of conductive media used. In other words, using more conductive refrigerating media, or delivering them at higher flow rates than necessary to keep the skin at 0^oC, will not work, and may well be counterproductive (i.e., consume limited battery power and cause splashing and aerosolization of potentially biohazardous cooling bath water).[9],[10]

3)         If conditions are less than ideal because of poor contact with refrigerant (and retention of melted ice water in plastic bags) then cooling is slower still, and this is undesirable.

4)         The basic requirement of uniformly cooling the surface of the patient’s head to near 0^oC is, in practice, quite difficult to achieve, because holding refrigerant in contact with the patient’s head involves problems associated with melting ice, which is messy, damaging to bedding and furnishings, and can cause a slip hazard if dripped onto the floor. Containing ice in plastic bags results in considerable loss of contact with the skin, and reduces the efficiency of cooling, by causing melt water to be retained; creating a relative convective and conductive barrier. It is also virtually impossible to keep ice bags in position around the patient’s head during movement from one location to another (or for that matter, even when the patient is not being moved.

While there is no easy solution to problems 1 and 2 above, there is a solution to problems 3 and 4: an enclosure to hold ice or another acceptable refrigerant around the patient’s head in situations where there is no portable ice bath (PIB); the Head Ice Positioner (HIP). Why is having an “ice holder” to keep ice around the patient’s head so important? Again a look at Figure 19, above, is proof that a picture is worth a thousand words. The patient in this picture is being cooled with ice bags and Kwik Kold eutectic cooling packs. As just noted, this cuts the effectiveness of ice dramatically by confining it to bags, and it is also messy, which decreases compliance and creates a real danger of slipping and falling for personnel when tile or linoleum floors become wet and slick (something that is especially likely in institutions with well waxed and polished floors; and inside ambulances). The HIP should be used inside the PIB in order to ensure uniform contact of refrigerating water with the patient’s head.

RhinoChill

In 2009, the RhinoChill, a new noninvasive method for rapid induction of MTH under development by Benechill, Inc., began clinical trials.^[162] The RhinoChill uses a novel method to achieve intra-cardiac arrest cooling; transnasal evaporative cooling, wherein a liquid coolant–oxygen (or oxygen-air mixture) is sprayed into the nasal cavity and frontal sinuses where the liquid is rapidly evaporated with the high-flow compressed gas (typically O₂). The heat of vaporization of the perfluorocarbon azeotrope causes cooling of the nasal passages and brain. The device is highly portable, can be used on a patient within minutes of cardiac arrest, and has been demonstrated to be safe for use in humans in the hospital setting^.[162],[163]

Figure 39: The RhinoChill device (R) and the anatomical areas cooled by the evaporation of the PFC refrigerant from the nasal cavity and sinuses.^[163]

Figure 40: Photograph of RhinoChill nasal cannulae used for nasopharyngeal cooling. The perfluorochemical (PFC)-oxygen mixture is delivered from the oxygen tank and the PFC reservoir in a single tube (1) that then bifurcates into a left and right nasopharyngeal cannula (2). The perfluorochemical-oxygen spray (3) exits in dorsal and lateral direction from the distal end of the cannulae.^[164]

Figure 41: Change in brain temperatures from baseline (mean ± SD) during untreated cardiac arrest (ZF; n = 3), CPR (LF; n = 4) and anesthesia (NF; n = 3) over the course of 60 min of nasopharyngeal cooling. *indicates first significant decrease from baseline (<0.01).^[164]

Perfluorochemical (PFC) is delivered via a proprietary cannula, the two legs of which are passed through the nares and into the nasal cavity. PFC is delivered at a rate of 1 mL/kg/min while oxygen is co-administered at a rate of 1 L/kg/min. When circulation is present, heat is removed from the brain predominantly hematogenously, through the submucosal nasal venous plexuses by the rich subepithelial vascular plexus to the deep venous sinuses of the brain, and secondarily by direct convection. The device can reduce tympanic temperature (a surrogate for brain core temperature) at the rate of 2.4°C per hour. Systemic cooling proceeds more slowly at a rate of 1°C per hour.

The liquid evaporates instantaneously, thereby removing heat. The coolant is a proprietary perfluorochemical or perfluorochemical mixture (azeotrope) the composition of which is not disclosed. No patents appear to have been filed disclosing the PFC chemical structure, or mixture of PFCs being use as the refrigerant. The PFC used by Benechill must have a temperature well below the freezing point of water since inadvertent freezing of the nasal mucosa is a complication of operation.^[163] Perflourochemicals are a family of chemicals that are generally regarded as both chemically and biologically non-reactive. These chemicals are among the least acutely toxic compounds known, although they are known to be potent immunomodulators and inhibit white blood cell chemotaxis at fentogram concentrations.^{[165],[166],[167]} They cannot reach appreciable concentrations in tissues of air-exposed animals since they have limited ability to dissolve in biological media. Many are highly volatile and have a high air–blood partition coefficient, which facilitates their rapid elimination through pulmonary expiration (more information is available via 3M Specialty Materials. Robust summaries and test plan: perfluorocompounds, C5–C18; revised summaries. EPA Report 201-14684B, Aug 2003). The cooling and safety profile associated with the specific perfluorochemical used in the coolant was determined by Wolfson et al., in an ovine model, where no damage to the epithelial surface was noted.[168]

The nasal cavity with its proximity to the cerebral circulation, basal brain regions, hippocampus and the brain stem, offers an approach that allows for preferential cooling of some of the most selectively vulnerable areas of the brain.^[169] The device has been tested in a porcine model of prolonged ventricular fibrillation cardiac arrest both with and without cardiopulmonary resuscitation (CPR). In the CPR group, jugular venous temperature, which was used as surrogate for brain temperature, dropped from 38.1^oC to 34.2^oC within 5min of the onset of CPR and cooling. Importantly, the rate of brain cooling as measured by a temperature probe placed in the center of the right frontal lobe was almost the same at 60 min in the zero flow (no CPR) group as it was in the groups with spontaneous circulation and low flow (CPR) circulation (see Figure 38).[164]  When perfusion is absent, cooling of the brain is by conduction, via the cribiform plate and frontal sinuses.

The RhinoChill device (Figure 39) consists of the tubing set, the control unit, and the coolant bottle. The tubing set delivers oxygen and coolant to the patient. The cooling cannulae rest in the nasal cavity adjacent to the chonchae and have spray ports on their dorsal surface (Figure 40). The coolant is nebulized by turbulent mixing with oxygen at the spray ports. A battery operated control unit controls coolant flow rate and acts as an over-pressure shut-off valve. The patient pressure safety circuitry switches the system to a standby mode if the pressure in either nasal cavity exceeds 60 cm H₂O. Coolant delivery is maintained at a constant ratio to oxygen flow such that cooling level is controlled by setting the oxygen flow rate between 0 and 80 L/min. The patient’s mouth is kept open to provide venting of the coolant vapor. Duration of nasopharyngeal cooling in the clinical trial has been 60 minutes (50;90; range 25–195 min), and the amount of  refrigerant per-patient used was 3.5 liters (2.0; 4.0 L).^[163]

Figure 42: Time to target temperature (tympanic) of 34°C in minutes (median) from the cardiac arrest in the treatment and control groups among those patients admitted to the hospital.

In the latest human trials a tympanic temperature of 34°C was achieved by a median of 102 minutes (interquartile range 81 to 155 minutes) in the treatment group compared with 291 minutes (interquartile range 183 to 416 minutes, P0.03) in control patients (Figure 42). Median time to target temperature (core) of 34°C in the treatment group was 155 minutes (interquartile range 124 to 315 minutes) versus 284 minutes (interquartile range 172 to 471 minutes) in control patients (Figure 42). The time required to apply the device was ~2 min. The improvement in outcome in neurologically intact survival is shown in Figure 43.

These cooling rates may not seem impressive, and the relevance of this device to human cryopreservation may seem questionable. Undoubtedly the cost of the device and the PFC refrigerant will be prohibitive if the device is FDA approved for widespread clinical application. However, neither the likely high cost nor the modest cooling rate should obscure the fact that this technology demonstrates that a substantial increase in the rate of brain cooling can be achieved by using the heretofore unutilized surface area of the nasopharynx and frontal sinuses. Whether exploited by evaporative PFC cooling, or by the use of an aqueous heat exchange medium, this surface area should be used in inducing hypothermia in cryopatients, and in particular for cooling the brain. The advantages that the RhinoChill system has of not requiring bulky, heavy equipment and of leaving the nasooropharynx (NOP) devoid of liquid are also substantial. Introducing saline or other liquids into pharynx carries with the risk of aspiration in the mechanically ventilated patient.

Figure 43: Rates of neurologically intact survival (defined as having a cerebral performance category [CPC] of 1 or 2) in the treatment and control groups among those patients admitted to the hospital for the entire group, those who received rescuer CPR within 10 minutes, and those with a presenting rhythm of VF. RR indicates relative risk.

*Unadjusted 2 test.

**In one  admitted patient, outcome data were missing.[163]

While the RhinoChill uses compressed oxygen and a fairly sophisticated delivery device, it is easily possible to substitute compressed air for oxygen, fabricate a less expensive delivery system, and presumably find an acceptable azeotrope of PFCs to use as the refrigerant. Perfluropropane and one or more of the 3M Fluorinert liquids would seem to be a good starting place. Alternatively, chilled saline can certainly be used as it was in the RhinoChill swine pilot study. While liquid assisted pulmonary cooling (LAPC) may seem an attractive alternative to transnasal cooling, there are many problems with this approach including the risk of serious systemic embolization with PFC during closed chest CPS in patients with friable or seriously injured lungs.

Finally, it is important to keep in mind that, with due consideration to cost and logistics, the various approaches to cooling discussed here are complementary and synergistic rather than opposing or exclusive. As is the case with cold IV saline and external cooling, the RhinoChill, as a standalone method for rapid induction of hypothermia (-3^oC in ≤ 15 min) will not suffice. However, in combination with other easily applied and non- or minimally-invasive modalities, it may prove the long sought answer to the problem of cooling the brain by 3^oC in (ideally) 10 minutes.

Liquid Assisted Transpulmonary Cooling

As has been noted many times before, the most powerful moderator of ischemic injury at the disposal of the Transport Technician is induction of hypothermia.^{[170],[171],[172]} In the absence of the ability to provide adequate perfusion, reduction of the patient’s core temperature will be even more important. As the discussion of liquid ventilation in Chapters 4 and 7 makes clear, rates of cooling using this technique approach those achievable with CPB (Figure 44). However, due to current technological limitations it is not possible to continuously deliver and aspirate the PFC to/from the lungs through a heat exchanger. Thus, the initial load of PFC will only cool the patient approximately 2º to 4ºC during the first 10 minutes of cooling, and thereafter heat exchange will decrease as the PFC comes to thermal equilibrium with the patient.^[173] The theory and technique of liquid assisted transpulmonary cooling (LATC) will not be discussed in detail here since they are complex enough to merit treatment in a separate Chapter (Chapter 7).

Figure 44: LATC PFC delivery and withdrawal patient tubing configutation.

Intraperitoneal Cooling

The  lungs of the patient are not, of course, the only spaces into which cold fluid can  be introduced. In theory, any body cavity accessible via a natural orifice, or rapidly accessible surgically, could be used as a reservoir for cold heat exchange fluid. In particular, the peritoneum, the stomach and the colon all have a capacity for loading with a significant amount of refrigerant.

Figure 45: Self retaining and sealing peritoneal irrigation catheter. The catheter is inserted through a small mid-ventral incision in the abdomen into the peritoneal space at which time the silastic balloon is inflated with air to hold the catheter in position and make a reasonably water tight seal. This eliminates the need for a purse string suture. The body of the catheter and the Normosol-R supply line must be affixed to the abdomen with Backhaus forceps to prevent the catheter from becoming dislodged during use.

The optimal refrigerant for intraperitoneal cooling is a physiological saline-ice slurry,^[174],[175] but owing to logistic constraints in preparing and pumping such slush on-site, this is not a viable option for the immediate future.^[176] The next most effective heat exchange medium would be ice-chilled balanced electrolyte solution. An off-the-shelf, sterile product such as Normosol-R pH 7.4 would be suitable, since it is inexpensive, readily available, ruggedly packaged, and can be refrigerated by packing in ice. Consideration of the amount of heat that could be removed with gastric, peritoneal and colonic lavages of reasonable amounts of Normosol-R indicate that approximately 0.50º to 0.75ºC/min heat removal should be possible in a 65 kg man.^{[177],[178],[179]}

Peritoneal lavage has the added advantage of being repeatable: the peritoneal cavity can be repeatedly filled and drained of cold Normosol to exchange heat in the same fashion that peritoneal dialysis is used to exchange mass. Colonic lavage may be similarly repeated. Application of 0ºC colonic and peritoneal Normosol lavages in addition to standard PIB cooling has been undertaken in one human cryopreservation patient to date with a resultant threefold increase in the cooling rate over that anticipated with external cooling alone. On the basis of this data and data obtained from animal experimentation, colonic and peritoneal lavage has been added to the standard protocol for induction of hypothermia in cryopatients.

Even with an endotracheal tube in place, gastric lavage cooling is not recommended at this time due to concerns about possible compromise of the airway as a result of reflux and aspiration. Experimentation is currently underway to develop a device with a cuffed infusion tube, similar in design to the Esophageal Gastric Tube Airway, which can be passed blindly into the stomach via the esophagus. The cuff would then be inflated to achieve a seal between the tube and the esophagus, preventing the possibility of stomach contents being aspirated.

Peritoneal Lavage Cooling

Intraperitoneal cooling is far more efficient than colonic cooling but requires surgical opening of the abdomen. This is neither a complex procedure, nor one fraught with complications if the procedure outlined below is scrupulously followed.  Basic surgical experience on animals or humans is required, and it is preferable that the operator has previous experience entering the abdominal cavity, and is familiar with basic anatomy of the body wall from first-hand experience.

Figure 46: The peritoneal lavage assembly consists of two 4 liter peritoneal dialysis bags and a peritoneal dialysis (PD) infusion and drain line set. One bag is filled with Normosol-R™ using aseptic technique and attached to infusion leg of the PD set. A second bag is emptied of PD fluid (again using aseptic technique) and attached to the drainage leg of the PD set and the entire assembly is placed inside double ZipLoc bags and refrigerated on ice. Additional 4 liter bags of Normosol may be prepared in advance as needed and the entry port plugged with a sampling site connector. The bag containing the Normosol may be raised above the patient on an IV pole to facilitate gravity infusion of cold solution. Optimum dwell time is ~5 minutes. The Y-connector on the PD set connects the catheter to the waste fluid collection bag when the clamp on the drain line is opened.

Technique for Peritoneal Catheter Insertion

1)      Prepare the Peritoneal lavage set-up for use by aseptically unwrapping the infusion/drainage set, waste fluid collection bag and peritoneal catheter. Be sure clamps are present on both the infusion and drainage legs of the infusion/drain line. Spike a bag of chilled Normosol-R and prime the infusion leg of the infusion/drain line. Once the peritoneal catheter is in position and secured a fresh (cold) bag of Normosol R should be used to replace the bag employed to prime the lines.

2)      Select an entry site in the mid-line of the abdomen one third of the distance from the umbilicus to the pubis. Do not deviate from the midline unless scarring from prior surgery requires you to do so. Staying on the midline is important because, as shown in Figure 47, the epigastric arteries lie 3-4 cm to either side of the midline.

Figure 47: Site of incision for placement of peritoneal lavage catheter is in the midline of the abdomen well away from the epigastric arteries. The optimum site is marked with a ● on the drawing above.

3)      3) Use sterile technique, protective clothing and a face shield (See Chapter 16 for details on Universal Precautions and infection control).

4)      Disinfect the skin and apply a 3M adhesive drape to the incision site.

5)      Using a #10 scalpel blade make a 1 cm incision in the skin using the broad part of the blade.

6)      Deepen the incision using sharp dissection until the muscular body wall is encountered.  Mobilize the overlying tissues to expose a window of muscle approximately 2 cm square using blunt dissection with the index finger.

7)      Reflect the margins of the wound in the skin to expose the body wall with a self-retaining Weitlaner retractor.

8)  Using the broad cutting surface of the scalpel, divide the muscle taking care not to cut too deeply through the body wall and injure the underlying viscera. As the muscle is divided, pause and explore the incision with the finger tips to gauge the remaining thickness of the body wall to be cut.

Figure: 48: Once the ventral abdominal wall has been opened the peritoneum will be visible as a grayish membrane with a smooth consistency. The peritoneum is then grasped and tented with forceps and opened with a #11 scalpel blade or Metzenbaum scissors.

9)  Continue sharp dissection until the muscle is penetrated and the peritoneum can be seen. The peritoneum can then be incised by careful use of sharp dissection using the scalpel and Metzenbaum scissors. Be careful to keep the opening in the muscle and peritoneum to no wider than 0.5 cm.

10)  Upon opening the peritoneum, insert a finger into the abdominal cavity and expand the wound using blunt dissection. The size of the opening sought should be roughly one-half to three quarters the diameter of the peritoneal lavage catheter. Avoid making the incision too large as it will prevent a tight seal of the catheter and will allow leakage of lavage fluid out of the peritoneum and entry of non-sterile and hypotonic water from the PIB into the abdominal cavity.

11)  While grasping the catheter and supporting it with your hand, push it through the opening in the body wall and peritoneum until the balloon on the distal end of the catheter is fully past the peritoneal membrane. A twisting motion may be necessary to achieve this. It may also be necessary to expand the diameter of the muscular and peritoneal incisions to facilitate entry of the catheter. Entry into the peritoneum with the catheter through a tight incision is indicated by a “pop” and sharp decrease in resistance to insertion.

12)  Inflate the catheter balloon with 50 cc of air.

13)  Secure the infusion/drain line to the skin of the abdomen using a large Backhaus towel clamp.  The clamp should be used to pierce the full thickness of the skin and firmly anchor the line near the catheter to the patient. Adhesive tape or clear 3-M adhesive drape may be used to cover the wound site and the body of the catheter where it exits the abdomen.

Procedure for Peritoneal Cooling Fluid Exchanges

1)      Once the catheter is placed and secured, spike the 4 liter bag of ice-cold Normosol-R and hang it for infusion.

2)      Unclamp the clamp on the infusion leg of the infusion/drain line and insure that the drainage leg of the line leading to the waste reservoir bag is clamped. Fluid should start to flow from the reservoir into the abdomen under the force of gravity. Adjust the reservoir height to achieve rapid filling. Infuse l liter of ice-cold Normosol-R for every 20 kilos (44 lbs) of pre-morbid body weight to a maximum of 4 liters.

3)      When the bag is empty, clamp the infusion leg of the infusion/drain line. Optimum dwell time in humans of chilled Normosol-R in the peritoneum under transport and cool down conditions is unknown but is thought to be in the range of 3-5 minutes.

4)      As soon as the infusion is completed, unclamp the drainage leg of the infusion/drain line and allow the lavage solution to drain into the waste reservoir bag which should be positioned on the floor below the patient at least 1 meter above the level of the patient’s abdomen.

5)      As drainage slows, the next bag of hilled chilled Normosol-R should be spiked and hung. After drainage has stopped, the drainage leg of the infusion/drain line should be clamped and the infusion leg unclamped and another lavage carried out.

Colonic Lavage Cooling

In order to carry out internal lavage cooling with multiple exchanges of fluid it is necessary that the PIB be elevated on two or three sawhorses, a sturdy folding table, or some other stable work surface, so that gravity dependent drainage can be carried out after each infusion of chilled solution.

Once CPR and medication administration is underway and the patient is situated in the PIB, the Fecal Retention Device (FRD) should be placed if it has not been already. The balloon on the FRD is inflated, and an initial temperature reading taken.  Connection of the infusion/drainage set to the FRD is made and lavage of the colon with 1 liter of buffered, ice-cold Normosol-R is then carried out per the following procedure:

1)      Spike a pre-chilled bag of Normosol-R with the infusion leg of the infusion/drain line set.  Prime the infusion leg of the line till fluid exits the FRD.

2)      Lubricate the FRD with K-Y or other water soluble surgical lubricant. Do not use Vaseline, silicone oil based or any other oil based lubricants because they will cause failure of the retention balloon on the FRD.

3)      Insert the FRD well into the rectum through the anus. Be sure the balloon on the FRD is well beyond the anal sphincter.

4)      Inflate the balloon of the FRD with 50 cc of air.

5)      Elevate the bag of chilled Normosol-R 20-30 cm above the patient’s abdomen.

6)      Unclamp the infusion leg of the infusion/drain line and insure that the drainage leg of the line leading to the fluid waste bag is clamped. Fluid should start to flow from the Normosol bag into the colon under the force of gravity. Fill the colon with 20 cc of Normosol-R per kilogram of the patient’s pre-morbid (i.e., healthy) weight to a maximum of 1.5 liters. In the case of patients who are chachectic and weigh far under their pre-morbid weight at the time of cardiac arrest, their healthy body weight should be used as the index in determining the lavage volume. Thus, in the case of a man who in health weighed 79.5 kg (175 lbs) but due to end-stage adenocarcinoma of the lung weighs only 50 kg (110 lbs) a full 1.5 liter exchange of lavage should be used.

7)      After 10 minutes, remove the clamp from the drainage leg of the infusion/drain line and allow the lavage solution to drain into the waste reservoir bag which should be positioned on the floor below the patient. For optimum drainage the patient should be at least 1 meter above the bag. Be careful to place the waste bag so that it is not stepped on or punctured.

In the event that colonic lavage is going to be used prior to peritoneal lavage, lavage of the colon should be carried out prior to or during surgery to place the peritoneal lavage catheter. Colonic and peritoneal lavage may not be used at the same time. Once the peritoneal catheter is in place, the colon should be drained while the peritoneum is lavaged; this is best accomplished by leaving the drain line to the fluid waste bag open during peritoneal lavages in order to allow any retained fluid in the colon to escape. This increases the available space in the abdomen for the cold peritoneal lavage solution.

Optimum Number of Lavages

The optimum number of colonic and peritoneal exchanges is not known. While infusion of fluid is quite rapid, it is anticipated that drainage will take considerably longer.  In the only human case in which Intraperitoneal cooling has been used to date each exchange of 4 liters took approximately 10 minutes, with most of the time required for drainage before refilling the abdomen.  In the absence of extracorporeal cooling the limitation on the number of exchanges is likely to be the availability of Normosol-R.

Termination of Lavages

Whether the reason for discontinuing exchanges is the beginning of bypass or the exhaustion of the supply of chilled heat exchange fluid, the colon and peritoneum should be drained of fluid as completely as possible at the conclusion of the lavages. The reason for this is that the continued presence of “thermally spent” lavage solution during extracorporeal cooling or external iced cooling during subsequent transport or air shipment will act as thermal ballast, in effect increasing the patient’s total mass, and will thus impede further cooling.

Once drainage is complete the infusion leg of the infusion/drain lines of both the peritoneal catheter and the rectal tube are double-clamped within 2-3 cm of the peritoneal catheter or rectal tube with the clamps placed 3-4 cm apart. The lines are then cut with scissors, and a tubing plug inserted into the stub of the line attached to the peritoneal catheter and rectal tube. A sterile plug must be used in the case of the peritoneal line, and the peritoneal line should be divided using aseptic technique.

The infusion reservoirs are emptied of any fluid, the infusion/drain lines are clamped near the exit port from the infusion reservoirs, the infusion/drain lines are disconnected from the reservoirs and the tubing and drainage bag assembly are properly disposed of as biohazardous waste in accordance with local regulations.

Ice Bags and Alternative Methods

If a standard PIB is not available, use a makeshift PIB by using a mortuary air transfer case lined with plastic sheeting, an inexpensive casket similarly waterproofed a heavy-duty mortuary body pouch (“disaster bag”), or even a plastic tarpaulin or plastic sheeting under the patient on the bed.

If the patient is in the morgue and the morgue tray has drainage capability, mound ice up over the patient in direct contact with the skin. Whenever possible use ice in contact with the skin, as it is a far more efficient refrigerant than ice in plastic bags.

Figure 49: If ice is in limited supply, the head should be completely packed in ice first. If CPS is underway the next areas to pack in ice are the vascular areas of the body; those places where large caliber, high flow blood vessels lie close to the skin surface; the neck, axilla and groin.

If the PIB or a reasonable facsimile is unavailable, pack the patient in crushed ice contained in high quality Zip-Loc plastic bags per Figure 49. (Bags with the Zip-Loc brand name and manufactured by Johnson & Johnson, Co., are preferred.) Leaking bags present a serious safety hazard in the form of water on the floor, and an electrical hazard if the patient is in an electrically operated bed. Special attention should be paid to packing the head, neck, axilla (armpits), and groin in ice, since large vessels which carry a significant fraction of the cardiac output lie close to the skin in these areas, and are thus available for heat exchange.

Cooling Absent Cardiopulmonary Support

Unfortunately, in many cases Transport of the patient will occur under conditions where CPS is not possible or is contraindicated due to the presence of too much warm ischemic time. Under such circumstances the only option for inducing hypothermia will be external cooling. As has been previously noted, the first requirement for maximally effective external cooling is that all of the surface area of the patient be continuously in contact with refrigerant that is as near to 0ºC as possible. It is not possible to go lower than 0ºC because the patient would freeze in the absence of cryoprotection. This constraint on the temperature of the refrigerant has profound implications for the rate at which cooling is possible. To understand why this is so, and to understand the importance of uniform and continuous contact of the patient’s skin with the refrigerant, it is first necessary to understand how cooling occurs.

A good place to start is with the simplest situation, and the one most frequently encountered in sudden and unexpected cardiac arrest, where CPS is not possible. This situation is simple in the sense that the only kind of cooling that will be possible is external cooling with ice (or another appropriate refrigerant) and cooling of the head/brain will be by conduction alone. This is so because the human head is a solid consisting of gels (skin, muscle, brain) and bone. Convection does not occur in solids, and the kind of cooling experienced such a situation is called non-Newtonian cooling or non-convective cooling.^[180] Conduction cooling is comparatively straightforward mathematically because the parameters which determine its behavior are fewer than in convective cooling (where there is a complex interplay between conduction, convection and radiation)^†. However, while cooling within the patient’s head is purely conductive, cooling at the interface between the scalp and other skin of the head will typically be convective, since it will involve not only conduction, but also convection (air movement in a morgue cooler, or liquid movement from melting ice, or even convection of water in an “unstirred” ice water bath).

Fortunately, this problem is of concern to forensic pathologists who are interested in determining the time of death of persons who die under different conditions (including being immersed in cold water) and lying undisturbed either in room temperature or cold ambient air. This has historically been a virtually impossible problem to apply any precision to because most of the human body is usually covered in varying amounts of insulating clothing and fat. People also have widely varying surface to volume ratios depending upon their body type, height, weight and body composition (i.e., 50 kg of muscle conducts heat far better than 50 kg of fat). The exception to this is the human head which is typically not covered with such variable amounts of insulating clothing and fat, and which has a reasonably uniform shape, size and mass; it has an approximate radius of 10 cm, a typical mass of 4.5 kg, and is more or less spherical.

Very recently, the French forensic pathologists Baccino, Cattaneo, and Jouineau, et al.,^[181] conducted a series of experiments using pig heads to empirically determine the rate of cooling under a variety of conditions, all of which are importance to cryonicists. While pig heads are not human heads, the data from this study map the spotty and less rigorous data obtained in human cryopreservation cases. These data show something that may seem surprising, principally that cooling in an unstirred water bath at 0ºC is not even twice as effective as cooling in still (unstirred) air at 0ºC as shown in Figure 50, below.

Figure 50: Cooling rate observed in porcine heads subjected to unstirred air or water cooling at 0^oC from data by Baccino, et al. [181]

The reason for this is the limitation imposed by the very low value for k (heat conductivity) of the human head. This has the following important practical implications:

1)            External conductive cooling of the human head/brain is extremely slow even under ideal conditions of maximum surface contact with ice at 0^oC where the melt water is filmed over the patient’s head.

2)            Once the surface of the patient’s head reaches 0^oC, the brain cannot be cooled any faster regardless of the type or amount of conductive media used. In other words, using more conductive refrigerating media or delivering them at higher flow rates than necessary to keep the skin at 0^oC will not work and may well be counterproductive (i.e., consume limited battery power and cause splashing and aerosolization of potentially biohazardous cooling bath water).

3)             If conditions are less than ideal because of poor contact with refrigerant and retention of melted ice water in plastic bags then cooling is slower still and this is undesirable.

4)            The basic requirement of uniformly cooling the surface of the patient’s head to near 0^oC is, in practice, quite difficult to achieve because holding refrigerant in contact with the patient’s head involves problems associated with melting ice which is messy, damaging to bedding and furnishings, and can cause a slip hazard if dripped onto the floor. Containing ice in plastic bags results in considerable loss of contact with the skin and reduces the efficiency of cooling by causing melt water to be retained; creating a relative convective and conductive barrier. It is also virtually impossible to keep ice bags in position around the patient’s head during movement from one location to another (or for that matter, even when the patient is not being moved).

OroChill Oronasopharyngeal Cooling

Figure 51: The OroChill oronasopharyngeal (ONP) cold saline irrigation system consists of a fenestrated catheter that is introduced oropharynx at the level of the vallecula, or deeper to allow for irrigation of the oropharynx and sinuses with ice cold saline. This results in ~30% improvement in cooling time to ~5 ^oC in porcine heads placed in a stirred normal saline bath chilled to ~1-2 ^oC.

While there is no easy solution to problems 1 and 2 above, there is a solution to problems 3 and 4: an enclosure to hold ice or another acceptable refrigerant around the patient’s head allowing for maximal contact of the patient’s head with the refrigerant. This is why the HIP was invented. Figure 52 shows just how bad conductive cooling is, even in water at 0 ^oC both in absolute terms; 3.5 hours after the start of cold water cooling the brain core temperature is still ~20 ^oC! The situation is worse for ice bag cooling (see Figure 38) where brain temperature will still be ~20^oC 6.5 hours after the start of cooling. At a minimum the HIP must be used with ice in direct contact with the patient’s skin and with the ice being replenished before any part of the patient’s head becomes exposed. A stirred ice water bath will confer additional advantage, but the most effective way of cooling is to continuously irrigate the ONP with ice cold solution.

Figure 52: Cooling curve obtained using the OroChill ONPcooling device in a porcine head as compared to conductive cooling in air and water at 0 ^oC. The TC probe was placed in the cerebral cortex at a depth of ~70 mm from the skin on the dorsal surface of the head. Modified from Baccino, et al.

The OroChill kit contains 4 packets of mannitol and sodium chloride designed to be added to the PIB ice and water. This will yield a hypertonic solution that will decrease in osmolality as the ice in the PIB melts. The purpose of these added osmolytes is to prevent edema and ‘water logging’ of the nasopharyngeal mucosa which can significantly impede heat exchange. Isoosmolality is not important; the important thing is to avoid edema and, if possible, to induce dehydration in soft tissues overlying the brain. This has the effect of decreasing the thickness of the insulating gel layer surrounding the brain and thus improving heat exchange.

In the event rigor is present and sufficiently advanced, the pharyngeal irrigating tube may be replaced with the OroChill nasal cannula. The nasal cannula is ~20% less effective at cooling the brain than the pharyngeal irrigating tube.

Procedure for Using the OroChill

Figure 53: OroChill osmolyte concentrate is prepared by adding 3L of warm water to the osmolyte powder and blue food dye present in the flexible plastic mixing container. Once the osmolyte powder is fully dissolved it is added to the water of the PIB.

1) The OroChill osmolyte powder is packed in collapsible, heavy walled, screw cap containers. Unfold the container and add ~3 L of warm tap water. Agitate the contents by shaking the closed container until all of the powdered components have dissolved in solution.

2) Add the OroChill osmolyte concentrate to the water of the PIB and ensure that it is well distributed. It is not necessary for it to be evenly dispersed. The Osmolyte mix contains an innocuous blue food dye which serves both as indicator of the degree to which the concentrated has become well distributed in the water of the PIB, and to mask the presence of any blood or urine in the PIB water, the latter of which is disturbing to medical and mortuary personnel who may be unaware of the presence of antimicrobials in the PIB water. A color indicator strip is attached to the concentrate mixing bottle and it should be used to determine when distribution of the concentrate has reached a level sufficient to initiate ONP irrigation.

3) In order to prevent the OroChill heat exchange medium from entering into and accumulating in the lungs or the stomach, both the patient’s airway and esophagus must be sealed. These two objectives may be met in a variety of ways; an endotracheal tube may be used in combination with the obturator from a DEGTA (or EGDTA), or a DEGTA or D-Combitube airway may be used.

Figure 54: Oral wire reinforced OroChill catheter(A) for delivery of refrigerated cold solution to the oronasopharynx.The catheter rests within a sleeve that allows it to be advanced to retracted as necessary (B). The catheter is contained within a bite block assembly (D) with a positioning handle (C). The catheter has a fenestrated tip (E) for more even dispersion of coolant in the patient’s oropharynx. The entire assembly is held in place with a Velcro head strap (F).

4) Once the airway is secured, the patient’s head is positioned in the OroChill Head Cooling Positioner (OCHCP) and the oral irrigation cannula is placed. Advance the cannula until the tip is positioned in the vallecula.

5) Secure the OCHCP to the patient’s head using the integral Velcro strap. Exercise care not to excessively tighten the strap; it should be just tight enough to prevent the oral cannula from becoming dislodged. It should be possible to easily slip two fingers between the securing strap and the patient’s face.

Figure 55: The Orochill catheter line is attached to the quick disconnect fitting (C) on the OroChill pigtail line issuing from the SCCD cold water supply line (A) to the HIP (H). Coolant flow to the OroChill catheter is adjusted with green control valve (B).

6)  Using the quick disconnect fitting on the OroChill pharyngeal or nasal catheter (as appropriate) attach the male quick disconnect fitting on the end of the catheter supply line to the female end of the connector on the green flow control valve of the SCCD supply line in the HIP.

7) Open the flow control valve and adjust the flow until a steady stream of heat exchange liquid can be seen to be issuing from both nares (and alternatively, if a nasal cannula has been used, from the mouth).

8) As additional ice is added to the PIB, or as ice melt occurs, re-check to color of the PIB bath liquid (osmolyte solution) and add additional osmolyte concentrate as needed to maintain the concentration of the osmolyte in the PIB bath in a acceptable range.

Figure 55: The OroChill nasal cannula may be used if the patient’s jaw is in rigor, or it is otherwise impossible to place the oral catheter.  Flows are considerably lower through the nasal cannula and a significant amount of back flow may occur from the nares. For these reasons, the use of the pharyngeal catheter is preferred, when possible.

 

Monitoring Temperature Descent

As is hopefully clear from much ofthe foregoing discussion, it is critical that cooling data be obtained from every patient where it is possible to do so, as soon as it it possible to do so. Not only is documenting the patient’s temperature descent an important element of care, it also serves as a surrogate marker for the quality of that care, as well as providing valuable scientific data to allow for improvements to the care of future patients. Thus, it is essential that temperature probes be placed, and data acquisition be started as soon as possible after stabilization begins. Where possible, the patient’s agonal temperatures should be recorded at 15 minute intervals up until the time of pronouncement, using whatever method the attending medical staff are using, or are comfortable with being used.

Figure 56: Two examples of remote sensing thermometers that can be used to monitor patient cool down. The device on the left is a non-recording thermocouple thermometer from which temperature measurements must be recorded by hand. It is shown connected to a probe attached to a gastric medication and esophageal (intrathoracic) pressure monitoring balloon. The gastric tube TC probe may be used in cases where an endotracheal tube is in place or will be used.

The DEGTA and the Darwin Rectal Tube (DRT) are both outfitted with copper (CU++)/Constantan (C+) thermocouples (TCs) so that as soon as they are placed, temperature monitoring and data acquisition may be initiated.This is best accomplished by either pre-connecting the TC probes to an automatic datalogging thermocouple thermometer, such as the Digi-Sense DualLogger, or to the data acquisition laptop computer which is collecting other data from the patient’s stabilization and transport. Detailed instructions for the use of the DualLogger, including how to interface it with its waterproof perspex case, are present as Appendix 2 (NOTE: Not included in this article). If the DualLogger is used, it must be not be water proofed in an expedient way, such as by placing it in Ziploc bags, because this still leaves the data entry/setting keys susceptible to being accidentally depressed. This has proved a major source of data loss in the past; the device must be placed in a waterproof hard case to protect the keys from accidentally being depressed while the patient is being moved or air shipped.

Figure 57: Bilateral tympanic temperature monitoring device.

If the patient has an endotracheal tubbe (ET) or will be intubated, tympanic temperature probes may be placed using a device such as one shown in Figure 57. This earphone-like assembly contains two wells of a fast setting silicone sealant which is injected into the ear canal using syringes that are pre-attached to each probe holder (not shown). Once the TC probes have been advanced into the auditory canal to abut the eardrum, the sealant is injected to prevent the ingress of cold water from the HIP, and to secure the probes against accidental dis-lodgement. These, and all other probes, should be left in place at the conclusion of Transport. If such a device is not available, a soft, flexible vinyl TC probe may be advanced into the auditory canal until it abuts the eardrum, where it may be sealed in place using silione swimmer’s ear canal sealing putty, as shown in Figure 58, below.

Figure 58: Silicone swimmer’s ear sealing putting may be used to seal and secure TC probes into the auditory canal. If this method is to be used, it is important to clean the external auditory meatus with alcohol swabs to remove waxy secretions which may prevent the putty from adhering well and creatina good seal. The probe line should be looped over the top of top of the pinna (after it is secured in the ear canal ) and taped firmly in place to prevent it from accidentally become dislodged.

Where automatic logging equipment is available, temperatures should be collected at 5 second intervals, with consideration given to limitations that may present as a result of the available memory in the data collection device. The lowest acceptable rate of temperature data acquisition is intervals of 5 minutes.

Figure 58: Sample data collection sheet for manual collection of temperature data in the field. This sheet also includes columns for the entry of total body washout/perfusion data. Note that there is a space for recording the time post-pronouncement; this allows for immediate feedback as to how how effectively (rapidly) the patient is cooling. The exact anatomical or physical location in the extracorporeal circuit of thetemperature probes must be entered in the shaded boxes.

At the conclusion of stabilization, the temperatures probes should be left in place and the lead wires carefully separated, coiled up, and placed atop the patient’s thorax. Vinyl coated wire twist ties are ideal for both separating and holding the probes in the coiled position.

Only Cu++/C- TC probes since these may, if necessary, be left in position and used for data acquisition throughout cooling to liquid nitrogen temperature. This eliminates the requirement for replacing the probes with different probes for the subzero parts of the operation, and also helps to ensure continuity of data acquisition, since the same probe should be in the same position from the stat to the finish of the patient’s cryopreservation.

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140.        Husby P, et al.: Accidental hypothermia with cardiac arrest: complete recovery after prolonged resuscitation and rewarming by extracorporeal circulation. Intensive Care Med 1990, 16(1):69-72.

141.        Sekar T, et al.: Survival after prolonged submersion in cold water without neurologic sequelae.Report of two cases. Arch Intern Med 1980, 140(6)):775-779.

142.        Martin T: Near drowning and cold water immersion. Ann Emerg Med 1984, 13(4):263-273.

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144.        JB. R: Hypothermia: pathophysiology, clinical settings, and management. Ann Intern Med 1978 89(4):519-527.

145.        Conn A, Barker, GA, Edmonds, JF, et al. (ed.): Submersion hypothermia and near drowning. Minneapolis: University of Minnesota Press.; 1983.

146.        Bolte R, Black, PG, Bowers, RS, et al.: The use of extracorporeal rewarming in a child submerged for 66 minutes. JAMA 1988, 260(3):377-379.

147.        Alexander L: The Treatment of Shock from Prolonged Exposure to Cold, Especially in Water. Item No. 24, File No. XXVI. In. Edited by Subcommittee CIO. Washington, D. C.: United States Congress; 1945 (July): 1-228.

148.        Mitscherlich  A MF: Doctors of Infamy: The Story of Nazi Medical Crimes. New York: Henry Schuman; 1949.

149.        Vogelaere P: Cardiac output variations in supine resting subjects during head-out cold water immersion. . Int J Biometeorol 1995, 39(1):40-45.

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152.        Hayward J, et al.: Physiological responses and survival time prediction for humans in ice-water. Aviat Space Environ Med 1984, 55(3):206-211.

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158.        Borlaug G, Fox, BC, Davis, JP.: Community associated methcillin resistant staphylococcus aureus (CA MRSA). Guidelines for Clinical management and control of transmission. In. Edited by Wisconsin Division of Public Health bdswu, 608-267-7711. Madison; 2005.

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Appendix 1

Qualifications to the Q₁₀ Rule

‘Reaction rates double for every 10^oC rise in temperature’ – it is almost axiomatic in biology in medicine and it is in the pages of learned articles that the the Q₁₀, the ratio of reaction rate at temperature T to that at T + 10. The doubling is usually offered as a fact of chemical (or biochemical) life; unfortunately, it isn’t true.

As originally promulgated in university texts it was “Reaction rates roughly double or triple…”; but in the rapidly proliferating number of papers in biology and medicine a number of fairly important words were omitted such as ‘roughly’, “double or triple.” A number of other important caveats disappeared as well. In fact, the first hint of trouble comes when the diligent scholar tries to cite the Q10 rule. What is then discovered is that while there are many references to the Q10 rule, there is no proper citation. Even searches for the vant Hoff Q₁₀ rule yield disappointment. There is a reason for this, and that is that no such rigorous citation exists. Further consideration of the Arrhenius equation is now in order.

The Arrhenius Equation

The rate of a chemical reaction is described by an empirically-determined equation of the form

rate = k [A]^x [B]^y

where k is the rate constant, [A] and [B] are the molar concentrations of the species A and B, and x and y are the orders of reaction with respect to A and to B. There may, of course, be only A, or there may be more than two species involved.

The concentrations do not depend significantly upon temperature; the term that changes with a change in temperature  is k. That is why all experiments on reaction rates must be done at constant temperature. The temperature-dependence of k is described by the Arrhenius equation (S Arrhenius, 1889, building on earlier work of J H van’t Hoff (1884)):

ln (k₂/k₁) = (E_a/R) (1/T₁ – 1/T₂)

where k₁ and k₂ are the rate constants at (absolute, i.e. Kelvin) temperatures T₁ and T₂, E_a is the activation energy for the reaction in J mol^-1, and R is the gas constant, 8.314 J K^-1 mol^-1.

The term that is Q₁₀ is k₂/k₁, and this is how I shall refer to it from now on.

Two Important Points

What is not usually stated by biologists and physicians using the “Q₁₀ rule” kinetics:

• • k₂/k₁ depends on the value of E_a;
  • k₂/k₁ depends on temperature – Q₁₀ is not constant. Increasing the temperature decreases k₂/k₁ .

A Few Calculations

A value for E_a:

Firstly we shall find the value of E_a that would give a doubling of reaction rate between 0^oC and 10^oC, i.e. for k₂/k₁ = 2. Then with this value of E_a we shall see what the effect is on k₂/k₁ at two different 10^oC ranges. Remember that the temperatures in the Arrhenius equation must be in K.

For the calculation of E_a we take k₂/k₁ = 2, T₁ = 273 K, T₂ = 283 K, R = 8.314 J K^-1 mol^-1:

Arrhenius:	ln (k2/k1) = (Ea/R) (1/T1 – 1/T2)
Therefore:	ln (k2/k1) / (1/T1 – 1/T2)  = Ea/R
Substituting the values given:	(8.314 x ln 2) / (1/273 – 1/283)  = Ea
thus	(8.314 x 0.693) / (1/273 – 1/283) = Ea

and it is only arithmetic to show that E_a = 44,500 J mol^-1 = 44.5 kJ mol^-1.

 

The effect of increasing the temperature on k₂/k₁:
If we now use this value of E_a and find the value of k₂/k₁ at different temperatures for this hypothetical reaction, i.e. evaluate

ln (k₂/k₁) = (44,500/8.314) (1/T₁ – 1/T₂)

more arithmetic shows the following:

	T1/K	T2/K	k2/k1
	273	283	2.00
	373	383	1.45
	473	483	1.26

Indeed, the value of k₂/k₁, our old – but now unreliable – friend, Q₁₀, falls as the temperature increases.

Finally,  the rate of a reaction seems to be determined by E_a. This is true to a good approximation (unlike Q₁₀); but in fact it is the free energy of activation that is the important factor. However, that’s another mini-dissertation: E_a is pretty good until then.

 

By Mike Darwin

Understanding Hypothermia

The Q10 Rule and Protective Hypothermia

Hypothermia is widely understood to protect against ischemia by virtue of its ability to slow metabolic rate. In man, each 10^oC decrement of temperature reduction (below 37^oC) results in an approximate halving of metabolic rate, or to be more precise, a reduction of metabolic activity by a factor of ~ 2.2. This consistent reduction in metabolic rate as a function of temperature is known as the “Q₁₀ rule” where Q is oxygen consumption (O₂ used per unit of time) which decreases by 1/2.2 with each 10^oC drop in body temperature).^[2] The Q₁₀ is calculated as:

Where:

R is the rate

T is the temperature (^oC)

(Q₁₀ is a unit-less quantity, as it is the factor by which a rate changes, and is thus a useful way to express the temperature dependence of a process.)

In point of fact, the Q₁₀ rule (or more accurately, the Arrhenius equation from which it was derived) serves as one of the three pillars upon which human cryopreservation rests; [1] i.e., continued reduction in temperature eventually results in the slowing of metabolic and catabolic activity to the extent where, at approximately the boiling point of liquid nitrogen (-196 ^oC ), all biochemical change is arrested, more or less indefinitely.^[3]

The Q₁₀ rule shows surprising constancy across species, with the value being typically between 1 and 3 and, under conditions of hypothermia, has been verified as operational in the brains of rats, dogs and men to ~5^oC, at a value of ~2.2.^[2] It is important to understand that the decrease in metabolic rate predicted by the Q₁₀ rule is exponential; thus, a decrease in body temperature from 37^oC to 17^oC results in a decrease in metabolic rate by a factor (1/2.2)² = 1/4.8. If the Q₁₀ rule is applied to the human brain, using the tolerable limit of cooling before ice formation occurs inflicting freezing damage (~0^oC), the predicted slowing of catabolism during ischemia would be such that each hour spent at 0^oC would be the equivalent of approximately three and a quarter minutes spent under conditions of normothermic ischemia ([60 min]* 2.2^-3.7 =  3.24).

The Q₁₀ rule has important implications for surgery employing deep hypothermic circulatory arrest (DHCA) where there is the need to bound the safe period of cold ischemia with a high degree of confidence. In 1991 Greeley, et al.,^[2] derived an equation for approximating the safe circulatory arrest time at any temperature; the Hypothermic Metabolic Index (HMI) which is written as follows:

HMI (min) = (37^oC / CRMO₂ x X^oC)

Where:

CRMO2 = cerebral minute O₂ consumption

X = patient cold ischemic temperature

Two important caveats accompany the HMI and they are that the HCT and pH be taken into consideration when making the calculation. HCT determines the hemoglobin decay curve that will take place during the period of hypothermic circulatory arrest (in essence the stored oxygen available in the blood at the time that circulation is interrupted). The pH strategy management strategy management employed during cardiopulmonary bypass (CPB) will affect cerebral blood flow and thus may impact brain metabolic housekeeping. Use of pH stat management[2] results in higher cerebral blood flow (CBF) during CPB and thus, typically, better brain oxygenation and overall metabolic status at the time circulatory arrest begins.^[4] Applying the HMI equation to humans yields the spectrum of times vs. temperatures shown in Figure 1 below, and these are in close agreement with what would be predicted on the basis of the Q₁₀ rule. The advantage that the HMI enjoys over the Q₁₀ rule is that it has been empirically “proved” in humans via the Boston Circulatory Arrest Trial.^[5],[6]

Figure 1: Probable safe circulatory arrest time vs. temperature for humans, as calculated using the Hypothermic Metabolic Index (HMI).

Applying the Q₁₀ rule to cryopatients, or to dogs or rats for that matter, would suggest that 3 hours of cold ischemia is the limit beyond which recovery (absent reparative therapies) would be impossible, and this is indeed the case. Application of the Q₁₀ rule to cryopatients who experience prolonged periods of cold ischemia during Transport, on the order of 24 to 72 hours, would suggest a grim situation pertains; indeed one where decomposition has begun. However, there are problems in extending the Q₁₀ rule over long periods of time at temperatures close to 0^oC; with apparent contradictions surfacing in the form of successful preservation of meat and other foodstuffs by simple refrigeration (~4-10^oC) for prolonged periods of time,^[7] and of even more relevance, the successful storage of human organs (which are comparably sensitive to the brain in terms of cold ischemic injury), for periods of 48 to 72 hours at 1-4 ^oC[3].^{[8],[9],[10],[11]}

Preservation of ischemia-intolerant organs such as the liver and kidney is made possible not by any sophisticated interruption of metabolism, but by the use of intracellular organ preservation solutions which act primarily by inhibiting cellular edema and scavenging free radicals.[12]  So, while the Q₁₀ rule predicts the mammalian brain’s response to ischemia (at least to ~5^oC) reasonably well,^{[13],[14],[15],[16]} it does not predict the behavior of other ischemic mammalian organs under the conditions of cold storage for transplantation. Preservation of foodstuffs by refrigeration and prolonged storage of organs near 0^oC are possible because the Q₁₀ rule does not take into account several important facts; the first, and probably most important of which, is that much of  the metabolic and catabolic activity characteristic of biological systems is facilitated by the catalytic action of enzymes. In fact, biology as we know it is largely an artifact of the greatly accelerated speed of chemical reactions made possible by enzymes, as compared to the rate of reaction predicted on the basis of the Arrhenius equation.^[17]

Enzymes are proteins with complex shapes – shapes that are essential to their action as facilitators of chemical reactions – and these shapes are critically dependent upon the structure of the enzymes – in particular, their folding pattern. Profound and ultraprofound hypothermia can destabilize the folding of proteins resulting in a loss of stereospecificity in the case of many enzymes. This phenomenon was first described during cooling of enzymes to below 10^oC by Irias and Olmstead in 1969, who referred to it as “cold scission,” or “cold lability,” and noted its effectiveness in halting their biochemical activity.^[18] Additionally, phase changes in the non-aqueous lipid components of cells, brought on by deep cooling, can also relieve these molecules of their normal physical mobility and thus their availability for biochemical activity.[19] Additionally, enzymes embedded in lipds that undergo phase change upon cooling to below room temperature may be spatially inhibited by being confined in the solidified membrane.^[20]

Figure 2: The  Gibbs-Donnan Equilibrium; An unstable situation occurs in a solution if one side (I) of the semi–permeable membrane contains a solution consisting of a permeable cation such as K⁺ with an impermeable anion (Pr^–), whereas the other side (II) contains a solution of K⁺ and Cl^–, both of which are permeable to the membrane. The K⁺ concentrations are equimolar on both sides I and II.

Since side I does not contain Cl^–, the Cl^– from side II will diffuse along the Cl^– concentration gradient from side II to side I. This results in a negative charge on side I relative to side II due to the excess concentration of anions ( Pr^– _I + Cl^–_I > Cl^–_II ) on side I. The Cl^– concentrations will not become equal on sides I and II because the negative charge on side I will repel Cl^– movement from side II to side I so that side II will have the higher concentration of Cl^–. The presence of excess anion in the form of Cl^– on side I establishes a negative electrical gradient between side I and side II. The negative electrical gradient attracts K⁺ to migrate from side II to side I. However, the [K⁺] on side I now exceeds that of side II , hence K⁺ will move back from side I to side II along a K⁺ -concentration gradient.

The net result at equilibrium is that K⁺ and Cl^– move in equimolar amounts together from one side to the other. Each side is electrically neutral within itself due to equimolar concentrations of cations and anions, but there is an unequal concentration of the diffusible ions with [K+] highest on side I and [Cl-] highest on side II.

The effectiveness of intracellular organ preservation solutions provides a clue that, at least near 0^oC it may be the case that much of the cold ischemic injury predicted by the Q₁₀ rule (and which is in fact observed to occur) results from not from biochemical activity, per se, but rather from biophysical changes which proceed in the absence of metabolism or catabolism. Under normal metabolic conditions approximately 1/3^rd of resting cellular energy expenditures are on ion homeostasis. The protein rich intracellular milieu is positively charged, and the sodium chloride (NaCl^- ) rich extracellular milieu is negatively charged (Figure 2). Because NaCl^- is osmotically active, movement of NaCl^- from the extra- to the intracellular space across the cell membrane (to balance the charge difference represented by the positively charged intracellular protein; the Gibbs-Donan Equilibrium), the result is cellular edema. It is cellular edema, and the biophysics of the Gibbs-Donan Equilibrum, that appear to be a major driver of cold ischemic injury. This is antagonized by intracellular organ preservation solutions by removing most of the offending sodium from the extracellular spaces and replacing it on a roughly equimolar basis with cell membrane impermeable osmotically active species; typically sugars such as lactobionate and raffinose or the sugar-alcohol, mannitol.

Developing a Performance Score for Cryopatient Transport

The Hypothermic Metabolic Index

While thoracic surgeons and neurosurgeons are interested in knowing what the safe limits of DHCA, human cryopreservation professionals have an interest in the reverse problem; how much ischemic injury occurs at a given temperature over a given period of time. This is an important question to answer, even if just approximately, because it offers a quantifiable and reproducible surrogate measure for the quality of care a given patient receives. Absent feedback in the form of neurological deficit or other adverse effects, there is no way for those delivering care to cryopatients to know how well or how poorly they are performing. Such feedback is essential in any enterprise or human undertaking. Absent feedback, quality inevitably deteriorates and science vanishes from the picture.

Measure of Ischemic Exposure (MIX)

By inverting the HMI, or more simply using the Q₁₀ rule in a straightforward calculation of injury vs. ischemic time, it is possible to generate a number for ischemic injury, as opposed to for ischemic protection. In fact, this is exactly what has been proposed by Perry and Harris with their Measure of Ischemic Exposure (MIX)^[21] and Equivalent Homeothermic Ischemic Time (E-HIT).^[22] Harris’ E-HIT proposal was laid out in an unpublished paper in 2003and is a complex, but potentially very useful mathematical analysis of both cooling in cryopatients, as well as consideration of ischemic injury versus temperature. While neither Harris nor Perry consider the confounding problem of cold inactivation of enzymes in trying to bound ischemic injury, both proposals will serve adequately as a  first approximation for surrogate markers (as opposed to reliable objective indicators) of ischemic injury in cryopatients.

Because of its simplicity and ease of use, I have chosen the MIX as the surrogate marker for use here. The mix is a straightforward adaptation of the Q₁₀ rule which normalizes the measurement such that a MIX score of 1 corresponds to 1 hour of cold ischemia at 0^oC. Thus, the MIX for 1 hour of ischemia at 10^oC would be 2, for 1 hour at 20 ^oC, 4, at 10 ^oC, and so on. The MIX for fixed temperatures scales linearly with time so that twice as much ischemia at any given temperature would double the MIX score. This can be expressed by the equation:

MIX  =  ^2T/10t

Where:

t = hours at a constant temperature (^oC)

^T = patient temperature (^oC)

Since patient temperature during cooling is dynamic and continuously changing as a function of time T(t) it is necessary to integrate the expression 2 ^T/110 over the time period of the ischemic interval; t₀ to t₀ in which case the MIX iscalculated usingthe following equation:

Where:

t = hours at a constant temperature

^T = patient temperature (^oC)

dt = change in temperature (^oC)

 

The MIX has a simple form for cases involving a constant cooling rate, r degrees per minute starting at the patient’s measured body temperature at the timeof cardiac arrest. For a patient being cooled from 37^oC to 0 ^oC the MIX would be 2.88/r. Thus, for a patient cooled at a rate of 15 ^oC per hour (T = 2.5 hours to reach 0^oC) the MIX would be ~14. For patients who experience peri-arrest cerebral hypoxic or ischemic exposure, this time, beginning with loss of pupillary responsiveness, would be added to the MIX score using the same calculation and using the patient’s  body temperature(s) (T) at which the insult was experienced.

The lower the MIX score, the less ischemic injury the patient can be expected to have experienced. Abstracting a performance MIX score from the raw MIX score involves a subjective assessment of what segments of the ischemic insult were avoidable via actions of the human cryopreservation personnel caring for the patient. Unfortunately, this where the opportunity for self delusion, or the delusion of others (unintentional or otherwise), may enter the equation.  This is worth exploring, briefly, by using the following scenario.

A terminally ill cryopatient experiences cardiac arrest 45 minutes before Standby personnel arrive on the scene. During that interval he receives no CPS and no refrigeration. The human cryopreservation organization (HCO) may be either blameless, or fully responsible, depending upon a great many factors that were, or were not, under their control. For instance, did the HCO provide proper advice, counseling and support to deal with the possibility of cardiac arrest occurring in their absence (deployment of a field kit, instructions for caregivers on how to perform effective CPS, counseling about the need for ice or other refrigerant to be at hand, etc.)? If not, are they responsible for the extra MIX hit, or some fraction of it? Was their late arrival due to lack of proper medical assessment of the patient that, were it available, would have lead to deployment of the Standby team hours or even days earlier? Or, did the late arrival result from poor logistics by the HCO personnel responsible for booking the flight(s) for the Standby team? If the MIX is to be used as a feedback tool to hold the HCO and the Standby team personnel accountable, then many factors (aside from the fact of the ischemic insult) must be considered, and considered objectively. This is unlikely to happen, absent a set of objective standards for HCO performance, and an outside agency being responsible for evaluating HCO performance with respect to such standards.

Nevertheless, the raw MIX scores for all of a given HCO’s patients for any reasonable given period of time (say on a yearly basis) will necessarily provide a fairly strong indication of the quality of care a member or patient can expect from a given cryonics organization or service provider. For instance, HCOs that provide no Standby, Transport or CPS will have very high MIX scores compared to those that do.

Therapeutic Hypothermia

Figure 3: Cooling curve of a cryopatient given excellent cardiopulmonary support (CPS) (and who responded well to that support) who was cooled using external cooling via submersion in a stirred ice water bath, intraperitoneal cooling using ~1-2C ^o Normosol lavages and, at 145 minutes post arrest, extracorporeal cooling and blood washout.

Today, yet another factor is confounding the ability of the Q₁₀ rule to delineate the limits of ischemic tolerance (or at least warm ischemic tolerance). That factor is therapeutic, as opposed to preservative, hypothermia. Therapeutic hypothermia may seem to have little relevance to the cryopatient since the primary objective of cooling during Transport is to arrest metabolism and induce a state of preservative hypothermia. However, given current legal and logistic constraints rapid induction of protective hypothermia is not possible for cryopatients. Cooling times to below 20^oC are typically in the range of 2-4 hours under good circumstances, and in patients who do not receive intraperitoneal or extracorporeal support may exceed 6 hours, even with AC-DC HI mechanical CPS. The fastest rate at which a cryopatient has been cooled is shown in Figure 3 above, and serves to illustrate that, absent the therapeutic effects of mild and moderate hypothermia, ischemic injury would be far worse in cryopatients. Therefore, a review of the mechanics of therapeutic hypothermia is very much in order.

Over the past 25 years a vast number of therapeutic interventions have shown great promise in animal models of regional and global cerebral ischemia-reperfusion injury (RCIRI & GCIRI) in the laboratory.^{[23],[24],[25],[26]} In the last 6 years alone, over 1000 experimental papers and over 400 clinical articles on pharmacological neuroprotection have been published.^[27],[28] However, with one exception, none of these interventions has been successfully applied clinically despite many attempts. ^{[29],[30],[31],[32],[33],[34],[35],[36]} The sole exception to this frustrating debacle has been the introduction of mild therapeutic hypothermia (MTH) as the standard of care for a select (and very small) minority of  sudden cardiac arrest (SCA) patients.^{[37],[38],[39],[40],[41],[42],[43]}

Since the demonstration by Safar, et al., of the neuro-salvaging effects of mild systemic hypothermia after prolonged cardiac arrest in dogs ^[44],[45] there has been an explosion of translational research which has lead to a revolution in the understanding and application of mild hypothermia.^[46],[47] Once seen only as a protective tool which conferred benefit solely by reducing metabolism, it has become clear that mild hypothermia (33°C–35°C) [48] has therapeutic effects which appear to be primarily anti-inflammatory and anti-apoptotic in nature, and which operate independently of hypothermia’s effect on metabolic rate.^[49],[50] Table 1-1 reviews some of the known pro-inflammatory factors inhibited or moderated by mild therapeutic hypothermia (MTH) and documents the supporting literature.

Table 9-1: Inhibition of Injury Cascades by Mild Therapeutic Hypothermia (MTH)

 

Reproduced with modifications from Zhao, H., Steinberg, GK, Sapolsky, RM., General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. J Cerebr Blood Flow Metab, 2007. 27: p. 1879-1894.

Table 1-1: Intraischemic hypothermia delays or attenuates both ATP depletion (Ibayashi et al, 2000; Sutton et al,1991; Welsh et al, 1990) and anoxic depolarization (Bart et al, 1998; Nakashima and Todd, 1996; Takeda, et al, 2003), it also blocks glutamate release (Busto et al, 1989b; Patel et al, 1994; Winfree et al, 1996), suppresses inflammation (Kawai et al, 2000; Wang et al, 2002), maintains the integrity of the BBB (Dietrich et al, 1990; Huang et al, 1999; Kawanishi, 2003), reduces free radical production (Maier et al, 2002), inhibits protein kinase C translocation (Cardell et al, 1991; Shimohata et al, 2007a, b; Tohyama et al, 1998), inhibits matrix metalloproteinase expression (Hamann et al, 2004), and blocks both necrosis and apoptosis. Intraischemic hypothermia also preserves the base-excision repair pathway, which repairs oxidative damage (Luo et al, 2007). In addition to those cascades directly associated with neuronal injury, hypothermia further blocks astrocyte activity, and inhibits white matter injury. (Colbourne et al, 1997; Dempsey et al, 1987; Kimura et al, 2002). Similarly, postischemic hypothermia blocks free radical generation (Horiguchi et al, 2003), attenuates inflammation (Horstmann et al, 2003; Ohta et al, 2007), prevents BBB permeability (Preston and Webster, 2004), and suppresses caspase activities (Van Hemelrijck et al, 2005). Indeed, a browse through the literature gives an overwhelming impression that hypothermia seems to block every damaging event associated with necrosis or apoptosis. One reason for this impression of pan-inhibition may lie in the causality of ischemic damage.  For example, is the inflammatory response the cause of tissue damage or is it induced by brain injury? If it is the latter, then since hypothermia prevents tissue damage, it certainly also prevents the inflammatory response.

The journey from the laboratory to the clinic for MTH has been long and difficult. Seven years after the publication of the prospective randomized trials clearly showing that MTH improves survival and neurological outcome in out-of-hospital cardiac arrest patients, and 6 years after the ILCOR and AHA Guidelines  ^[51] recommended that: “Unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32°C to 34°C for 12 to 24 hours when the initial rhythm was ventricular fibrillation (VF),” ^[41] only a minority of SCA patients are being treated with MTH. In surveys of emergency and critical care physicians conducted in 2005 and 2006, 74% of those responding in the US ^[52] and 64% of the international respondents indicated they had never used MTH.[53],[54] The use of pre-hospital, in-field MTH, is virtually nonexistent.^[55]

No doubt, the commonly cited ‘obstacles’ of lack of institutional protocols, lack of physician education about the benefits and guideline changes, as well as the inevitable inertia that accompanies any paradigm shift in treatment are playing a significant role in the failure of MTH to become the practiced standard of care for the post resuscitation syndrome.^[56],[52] However, what is not being said, or considered, is that while MTH as currently practiced represents a large relative improvement in outcome, the benefits are still modest in absolute terms. Only a miniscule subgroup of SCA patients currently can benefit from MTH; and even in its best clinical implementation MTH still fails to rescue ~60% of that sub-group of SCA patients to whom it is applied.^{[57],[58],[59],[60],[61]} This is in stark contrast to what can be achieved with MTH in ameliorating post-ischemic encephalopathy in the laboratory, where post-resuscitation MTH consistently provides rescue with stunning efficacy.^[62],[63]

Figure 4: 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 34^oC 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 hypothermia 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). [64],[65] Histological damage scores were obtained by neuropathological examination of 19 discrete 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 damage.[66] 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 primary obstacle to realizing this bonanza in translation research has been the practical impossibility of achieving systemic cooling within the narrow therapeutic window demonstrated in animal models of SCA and resuscitation.^{[67],[59],[57],[58],[59],[60],[61]} If the clinical outcome of MTH was even half that achievable in the laboratory, widespread application would likely have been rapid and uniform; there is rarely resistance to the ‘miraculous’ if it is simple, easy to understand, biophysically well characterized and highly cost-effective. MTH applied immediately post ROSC would be all of these things.^[4]

Figure 5: The results of the Nozari, et al., [63] study on the effects of delayed MTH are presented graphically at above, with the addition of historical controls from the literature treated similarly, but with no hypothermia (no survivors). This graphic illustrates the potency of truly rapid post arrest hypothermia increasing survival.

The data in Figures 4 and 5 exemplify what is possible when MHT is induced within its optimum therapeutic window of 0-15 min post ROSC versus a delay of even 10 minutes. In this study by Nozari, et al., of Peter Safar’s group, [63] VF was electrically induced in 17 dogs all of whom were subjected to a period of 3 minutes of no flow beginning when the MAP dropped below 30 mm Hg, followed by 7 minutes of mechanical CPR and 50 minutes of advanced life support during which time VF was maintained and mechanical CPR was continued. Nine animals were treated with rapid (early) induction of MTH to 34^oC starting at 10 min post arrest (EH group) (concurrent with the start of ALS to simulate the time course of arrival of EMS paramedics) using a combination of cold IV saline and veno-venous heat exchange. Induction of hypothermia was not begun until 20 min post arrest in the delayed hypothermia group (DH group) which consisted of 8 dogs. Target core temperature was achieved at 6.0±2.7 minutes after the initiation of cooling (3.5 minutes after the start of veno-venous cooling) in both groups. The delay from arrest to reaching ~34^oC was 16.6 min in the EH group and 25.4 minutes in the DH group.

Figure 6: Results of a study of 48 cardiac arrest patients treated with MTH via endovascular cooling. A strong correlation was found between rapidity of cooling and both neurological outcome and serum neuron specific enolase levels. Left: Time course of MTH among patients with good and poor neurological outcome. The curves indicate the course of mean body core temperature during MTH among patients with good (¢) and those with poor (p) outcome as well as in the entire (▬) patient group. Right: Correlation between time to coldest temperature (minutes) and the maximum NSE values (μg/L). Normal serum NSE is 9.6±0.7 μg/L. Redrawn from Wolff B, et al., Early achievement of mild therapeutic hypothermia and the neurologic outcome after cardiac arrest, Int J Cardiol. (2008).

After 60 minutes of VF, ROSC was achieved with cardiopulmonary bypass for 4 hours, and intensive care was given for 96 hours. In the early hypothermia group,

7 of 9 dogs survived to 96 hours, 5 with good neurological outcome. By contrast, in the delayed hypothermia group 7 of 8 dogs died of multiple organ failure within 37 hours (P=0.012); 3 animals in secondary VF that was resistant to CPR with antiarrhythmic treatment and repeated defibrillations. Only one dog in the EH group died, and that animal succumbed to single organ failure; pulmonary edema with hemoptysis. This study extends the previous work by this group documenting an optimum therapeutic window for MHT (in dogs) of ~10-15 min.^{[68],[68],[69]} The therapeutic window of MTH after cardiac arrest has been demonstrated to be similarly short in other species.^{[70],[71],[72],[73]}

The dramatic efficacy of MTH in the laboratory made quick converts of the pioneering researcher-clinicians who forged ahead with the application of MTH to SCA in the clinic precisely because it was dramatic; indeed it was as close to the miraculous as interventions in medicine come. The real barrier to translating that ‘miracle’ to everyday practice has been the seemingly intractable problem of achieving cooling over the same time course that has proven so effective in the research setting.

The problem is that the optimum therapeutic window for the treatment of cerebral ischemia-reperfusion injury appears to be in the range of 0 to 15 minutes post ROSC. One of the first follow-up studies on MTH carried out by Safar, et al., demonstrated that in a standardized model of cardiac arrest in dogs a delay in the application MTH of as little as15 min after ROSC abolished most of the benefit.^[69],[74] While the work of Bernard, et al., ^[38] and that of the Hypothermia after Cardiac Arrest Study Group ^[40] demonstrated that delays in cooling of up to 2-3 hours post ROSC in humans still have sufficient clinical utility to justify the routine application of MTH in a selected group of SCA patients, this benefit is marginal when contrasted to that achievable in the laboratory when MTH is rapidly induced during the first 15 minutes after ROSC.^[69] Thus, the optimum clinical benefit of MTH in ischemic and very likely traumatic, CNS injury requires the ability to achieve very rapid core cooling.^[75]

Figure 7: Survival after cardiac arrest declines rapidly as a function of time to ROSC, exhibiting the sigmoidal curve shown at left, above (¢>¢), with essentially all patients failing to survive with normal mentation after arrest intervals of @ 10 min. Application of MTH (¢) within the window of @ 15 min offers the promise of squaring the survival curve in SCA of @ 10 min duration yielding a survival rate of ~65-70% with little or no neurological deficit. Application of deep (10-22^oC) or profound hypothermia (5-9^oC) (¢) may allow survival after intervals of as long as 1-2 hours of CPR.

In the clinical arena the time to reach the target core temperature under ‘good’ circumstances is in the range of 3-4 hrs; not 10 to 30 min, as is the case in the laboratory. Even with such long delays in cooling the adverse effect of delay is still present. Wolf, et al., recently published a study of 49 out of hospital cardiac arrest patients who were treated with MTH (32.0-34.0°C; with a target temperature of 33.0°C) of 24 h duration using endovascular cooling.^[61] The study endpoints were neurological outcome on discharge from hospital and serum neuron specific enolase (NSE) levels (a sensitive and specific marker of neuroinjury) at 24 h intervals to 3 days (Figure 6).

Figure 8: The graph above shows the hypothesized relative effect on survival of effectively administered CPR started at 5 min post-arrest followed by defibrillation at 6 min and ACLS at 8 min post arrest (~30% survival). The light blue shaded area of this graph shows the expected improvement in survival if MTH is induced at the start of ACLS (8 min post-arrest) and target temperature is reached by 15 min post ROSC. The dark blue shaded area shows the potential of Emergency Preservation resuscitation (EPR) using moderate (10-22^oC ) or profound (5-9^oC) hypothermia to not only square the curve of survival with CPR, but to facilitate survival in patients who would otherwise not benefit from either BCLS or ACLS (i.e., refractory to defibrillation, hypovolemic, etc.). Graphic by M.G. Darwin

As is the case in laboratory studies of MTH in cardiac arrest in dogs, Wolff, et al., found that neurological outcomes were binary, with no patients who survived experiencing moderate degrees of disability; patients either recovered well with no or /mild neurological impairment, or experienced severe disability (n = 1) coma or PVS (n = 6). Twenty-eight patients were discharged with a good outcome and a strong correlation was found between good outcome and the time interval from the start of cooling to the lowest temperature (p =.035) and a less robust correlation with the time to reach target temperature (p=.071).

Similarly, NSE levels were found to correlate well with the time required to reach the lowest temperature achieved in each patient (Figure 6).

Even with delays in the start of cooling that averaged 2.5 hrs; and a mean time to reach target core temperature of 6.8 hrs, additional injury accruing from slowness in cooling was still clinically and biologically apparent. Despite the homogeneity of the patients, their arrest times, and their course of treatment, ~60% of the patients in this study either did not survive, or were comatose or PVS.

The Benefits and Limits of ‘Delayed’ MTH: Real World Experience

To understand the benefits and limits of MTH when it is aggressively and competently implemented with currently available technology, it would be hard to find a better example than that of Wake County, SC. Wake County, is located in the northeast central region of North Carolina and is part of the Research Triangle metropolitan area, which consists of Raleigh, Durham, Chapel Hill, and surrounding urban and suburban areas. The area serviced by the Wake County Emergency Medical System (Wake EMS) has a population of 832,970 (as of 2007). The Wake County EMS operates 35 ambulances from 23 locations with 825 ALS personnel; ambulances are staffed with two paramedics 95% of the time and there is always one paramedic responding.^[76] In 2002 the Wake EMS answered more than 50,000 medical requests for service. Based on the latest national data Wake County ranks third in the US for recovery from “survivable” cardiac arrests (primarily ventricular fibrillation-ventricular tachycardia). Nationally, the average survival rate is 17% for patients presenting with these arrhythmias.

Figure 9: (right): Improvement in overall survival of patients in cardiac arrest in response to the phased introduction of CPR per AHA 2005 Guidelines, use of an impedance threshold device (ITD) and in-field induction of MTH.[77]

Beginning in January 2004 Wake EMS initiated a study to evaluate the efficacy of CPR as they then practiced it, and to evaluate the effectiveness of the impending change in the American Heart association (AHA) guidelines for CPR, the introduction of an impedance threshold valve (the ResQPod™) and Wake EMS’ planned implementation of the ILCOR Guidelines for post-arrest MTH.^[77],[78] From January 2004 until April of 2005, Wake EMS personnel employed the then extant AHA guidelines, which mandated an emphasis on intubation and a 15:2 compression-to-ventilation ratio; with interruption of chest compressions for ventilation. This period constituted the baseline of the study, and data were collected per protocol; not gathered retrospectively.

During the baseline period survival to discharge from hospital was 2.4% for all patients given CPR and 12.1% for patients with ventricular fibrillation-ventricular tachycardia (VF-VT) arrhythmias. In April 2005 Wake EMS implemented continuous cardiac compression CPR with a 30:2 compression-to-ventilation ratio with emphasis on no, or very minimal, interruption of chest compressions.  After 12 months, the overall survival rate had risen to 4%; and had more than doubled to 21.8% for patients who presented in VF-VT.

In April 2006, Wake EMS added the use of an impedance threshold device (ITD) to improve cerebral and coronary perfusion during CPR. Introduction of the ITD resulted in an increase in overall survival to 4.5% and an increase in the survival of patients with VF-VT to 28.5%.

Figure 10: (right): Dramatic improvement in neurologically intact survival as a result of the phased introduction of CPR per AHA 2005 Guidelines, use of an impedance threshold device (ITD) and in-field induction of MTH.^[77]

The final phase of the investigative protocol began in October of 2006 when Wake EMS added in-field induction of MTH to the two previous interventions. MTH was induced using a combination of external cooling employing ammonium nitrate-water eutectic ‘instant cold packs’ applied to the axilla and groin, and  cold IV saline (1-2^oC, 30mL/kg to a maximum of 2 liters) given rapidly via two large bore catheters and/or intraosseous infusion. Criteria for induction of hypothermia were that the patient have ROSC and show no return of consciousness (Glasgow Coma Score (GCS) <8).

Induction of hypothermia was initiated two to three minutes after ROSC. There was heavy emphasis on avoiding over-ventilation and on attempting to maintain end-tidal CO₂ (EtCO₂) at a minimum of 40 mm Hg.  Patients undergoing MHT were sedated with etomidate, paralyzed with vercuronium and given a titrated dopamine drip to maintain mean arterial pressure (MAP) between 90-100 mm Hg. The mean time to target temperature (34^oC) in this study was extraordinarily short: 68 minutes (95% CI 47 to 88); compared to the 2-3 hours typically required to induce MTH.

With the combination of continuous compression CPR, use of the ITD and prompt application of MTH, survival rates for the 12 months from October of 2006 to October 2007 had increase to 6.7% overall and 37.4% for patients with VF-VT. The odds of overall survival increased three-fold (95% CI 1.7 to 5.0) and the odds of survival for patients in VF-VT increased 4.3-fold (95% CI 2.2 to 8.6) from the beginning of the study (Figures 9 and 10).The probability of a good neurological outcome increased from 20% at baseline to 80% at the conclusion of the study (Figure 11). In a multivariate analysis, the odds ratios for survival for each phase of implementation were as follows:

Figure 11: (right): Multivariate odds for all factors in outcome evaluated during the Wake EMS study. MTH was by far the most powerful intervention. As in most previous studies of survival factors associated with CPR age and residence (home versus extended care or assisted living facility) had only modest impact on survival.^[77]

• New CPR protocol: 2.13 (95% CI 1.12 to 4.04)
• Addition of impedance threshold device: 2.33 (95% CI 1.09 to 5.00)
• Addition of early hypothermia: 3.99 (95% CI 2.19 to 7.27)
• Patients who received bystander CPR 1.79-fold (95% CI 1.18 to 2.72) more likely to survive.

Figure 12: (right): The Engel-15 portable, (compressor-type) refrigerator/freezer has a 14 L capacity, weighs 11.5 kg and can maintain 12-13 liters of saline at 1-2^oC at ambient temperatures as high as 40^oC. It retails for ~$380 US. [Photo courtesy of Engel, Ltd., Australia]

 

Interestingly, all three elements of the Wake EMS protocol were implemented at a cost of less than $200 per patient. Due to budget constraints, Wake EMS chose simple, inexpensive commercial products for refrigeration of IV fluid and implementation of external cooling, as opposed to more costly products developed specifically for medical application, such as the EMCOOLS surface cooling system (Emergency Medical Cooling Systems, AG, Austria). Saline was kept at the requisite temperature of 1-2^oC with a compact, 12V operated, consumer travel refrigerator/freezer (Figure 9-12, Engel-15: http://www.i-m-d.com/) and surface cooling was with generic ammonium nitrate cooling packs.

The Wake County EMS program is extraordinary in every way. It represents the best application of the best available technology by arguably some of the best medical and paramedical personnel in the US. The mean time to target temperature of 68 minutes is unprecedented in any clinical study employing MTH. Of the 359 patients who participated in the study (all comers) after MTH was in place; 25 survived. In the subgroup of 93 patients who presented with VF-VT; 34 survived, with 78% or 27 patients being discharged with a good neurological outcome. Put another way 92% of patients who presented under the most favourable circumstances (VF-VT), treated with the best currently available interventions, at the fastest rate of cooling so far reported, failed to survive or did so with profound neurological debility.

The primary difference between the survivors and the profoundly disabled or dead was the development of the post-resuscitation syndrome and the primary reason for this complication was not comorbidity, or delay in paramedical assistance, but rather delay in the rapidity of cooling which, if achieved within the first 15 min post ROSC, would have offered the prospect of neurologically intact survival in the range of 70-80% in patients presenting with VF-VT, and 30-40% in all comers.

These interventions, remarkable achievements that they are, do not escape from the harsh reality that the 400% increase in survival from cardiac arrest in Wake County, when expressed in absolute terms, means that the number of lives saved increased from ~5 to 25 – out of 395 SCA patients; a huge relative gain, but a comparatively small increase in the absolute number and percentage of lives saved, and minds salvaged. The true life saving potential of MTH remains elusive by virtue of its exceedingly small therapeutic window.

The Problem of Heat Exchange

Because of this minute therapeutic window, there is a pressing need to achieve rapid and durable core cooling of patients during CPR by simple, easily accessible means.  External cooling is only effective at reducing core temperatures by 0.15 to 0.25ºC/min in the average patient undergoing CPR (Figure 38) and this is achieved only by complete immersion of patients in a stirred ice water bath.

The most effective external cooling achieved by a commercial, FDA approved system using direct, whole body surface cooling employing circulation of ice water (ThermoSuit,™ Life Recovery Systems, Kinnelon, NJ)  is probably the work of Janata, et al., using human human-sized swine.^[79]

They were able to achieve core cooling at a rate of 0.3^oC/min; however it is important to note that the animals in this study were not in cardiac arrest while undergoing CPR in the presence of profoundly peripherally vasoconstricting agents, such as epinephrine or vasopressin; as would usually be the case during ACLS in humans ^[51] and which is known to further slow surface cooling.^[80]

Figure 13: The Life Recovery Systems ThermoSuit™ employs direct ice water contact with the patient’s skin to achieve the maximum possible rate of cooling by external means. The system consists of an inflatable insulating and water containment patient enclosure inside of which the patient rests on a mat of Dacron bonded polyester ‘wool’ which acts to diffuse and film water pumped over the dorsal surface of the patient’s body. Water at 2-4^oC is thin-filmed over the ventral surface of the body by a thin, transparent blanket with many hundreds of small perforations through which water under pressure pours out and over the patient. Cold water is recirculated over crushed or cubed ice in an insulated reservoir containing a disposable liner and pumps. Cooling is computer controlled via a thermistor which can be placed in any desired anatomical location. All patient contact items are single-use and disposable (including, as previously mentioned, the pumps) http://www.life-recovery.com/.

The obvious problems with this system are its bulk (Figure 13), its high cost ($1,800 per patient for disposables), lack of ease in field deployment (again related to its bulk and weight) and the intrinsic physiological problems associated with the induction of hypothermia via external cooling. As extensively discussed in Section Two, the mammalian body consists of multiple thermal compartments transiently ‘isolated’ from each other by differences in blood flow and heat conductivity.^[81] Broadly, these compartments can be classified as strongly and weakly circulated (perfused); corresponding to the body core and periphery. The core tissues receive ~63% of the resting cardiac output (CO) but constitute only ~19% of the total body mass. By contrast, the peripheral tissues receive ~37% of the basal CO and constitute ~81% of the body’s mass (Figure 14).

Figure 14: The parenchymatous organs that comprise the visceral core of the body receive an aggregate of ~63% of resting the cardiac output while comprising only ~19% of the body mass. By contrast, the peripheral tissue mass which accounts for ~81% of body mass receive only ~19% of the cardiac output. External cooling profoundly chills peripheral tissues before significantly reducing core temperature. Values for organ and tissue masses were obtained from: IAEA. Compilation of anatomical, physiological and metabolic characteristics for a Reference Asian Man. Volumes 1 and 2. Report IAEA-TECDOC-1005, (Vienna, Austria: International Atomic Energy Agency) (1998), Boecker, BB. References values for Basic Human Anatomical and physiological characteristics for use in radiation protection. Radiation Protection Dosimetry.105(1–4): 571–574;2003, de la Grandmaison GL, Clairand I, Durigon M. Organ weight in 684 adult autopsies: new tables for a Caucasoid population. Forensic Sci Int. 2001 Jun 15;119(2):149-54 and Heymsfield SB, Gallagher D, Mayer L, Beetsch J, Pietrobelli A. Scaling of human body composition to stature: new insights into body mass index. Am J Clin Nutr 2007;86:82–91.Values for organ and tissue blood flows were obtained from: Williams, LR, Leggett, RW. Reference values for resting blood flow to organs of man. Clin Physiol Meas. 10:187-212;1989. Graphic by M.G. Darwin

Pathophysiology and Biophysical Limitations of External Cooling

The objective of MTH is to provide protection against ischemia-reperfusion injury to the brain, heart, kidneys and liver; the visceral organs that constitute the strongly circulated core of the body. The peripheral tissues (skin, skeletal muscle, connective tissues and bone) are at once much more resistant to ischemia and less well perfused.  External cooling rapidly chills the ischemia-resistant peripheral tissues cooling them profoundly, while failing to provide protection to the vulnerable parenchymatous organs in the body core. This is not only undesirable in terms of its inefficiency; it also poses a number of hazards and risks.^[82] Hypothermia is therapeutic in ischemia-reperfusion because it down-regulates the immune-inflammatory response; a response that is vital for host defense, wound healing and hemostasis. Hypothermia, like any major medical intervention that perturbs fundamental physiological processes, carries with it serious risks, as well as benefits. In both animals and humans, hypothermia is markedly immunosuppressive.^[83],[84] and interferes with the both the biochemistry of the clotting cascade and the production of platelets and clotting proteins.^[85],[86]

In humans perioperative minimal hypothermia (MinH) (36^oC) increases the rate of wound infections ^[87] and prolongs hospitalization. [88] These effects occur in part due to the regional thermoregulatory vasoconstriction MinH induces; which in turn leads to reduced oxygen delivery to injured  tissues, ^[89] inhibition of oxidative killing by neutrophils,^[90] and reduced collagen deposition.^[88] MinH induces significant suppression of mitogenic responses to Concanavalin A (con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM) and these changes are known to persist for at least 48 h. The mitogens PHA and ConA activate T cells, whereas PWM stimulates both T and B cells, thus indicating that the suppressive effects of MinH involve a variety of lymphocyte subpopulations. Hypothermia of as little as 1^oC significantly inhibits production of  interlukins (IL-1б, IL-2, IL-6) and TNF-α in post-surgical patients, ^[91] and this suppression of cytokine production persists for least 24 hours after even a brief post-operative hypothermic interval.^[88] The inhibition of pro-inflammatory cytokine production by IL-1б and TNF-α induce tissue factor which is critical to angiogenesis, collagen elaboration and fibroblast activation; all essential processes in wound repair and hemostasis.^{[92],[93],[94]} Significantly, many of these of adverse effects of post-operative MinH can be prevented by maintaining normothermia in the perioperative period.^[88]

In the Hypothermia After Cardiac Arrest Study Group, patients treated with MTH experienced twice the incidence of sepsis. This finding is consistent with other studies where MinH and MTH were found to double the rate of post operative wound infection.^[88] A recent meta-analysis of MTH for traumatic brain injury (TBI) found that the incidence of pneumonia was also doubled for patients undergoing MTH.^[95]

External cooling causes greater perturbation in hemodynamics than does central cooling, ^[96] resulting in increased systemic vascular resistance and decreased cardiac index; a phenomenon observed in all of the patients in the Bernard, et al., study that employed MTH for post-arrest cerebral resuscitation.^[38] This is particularly undesirable in the setting of MI, CHF and cardiogenic shock. For these reasons, as is the case with any potent therapy, careful attention must be paid to the dose-response curve, and overshoot or excessive regional cooling must be minimized or avoided.^[97]

When the tissues of non-hibernating (or unprepared hibernating mammals) are cooled to £20ºC a wide range of deleterious changes occur. The saturated fats which comprise cell membrane lipids undergo phase change, resulting in red and white blood cell rigidity; with accompanying inability to deform and pass through capillaries. Red cell aggregation also occurs and this, in association with reduced flow as a result of vasoconstriction, results in blood sludging and failure of the microcirculation.^[98],[99] Profound hypothermia, either local or systemic, results in hemoconcentration as a consequence of translocation of vascular water and electrolyte to the interstitial space.^{[100],[96],[101],[102],[103]} This hemoconcentration further exacerbates regional ischemia in deeply chilled tissues.

Independent of injury from the freezing of water, moderate, profound or ultraprofound hypothermia is known to cause cellular damage which is referred to as ‘chilling injury.’ Chilling injury appears to be a multifactorial process in which alterations of membrane structure (reorganization of lamellar lipid sheets with lateral phase separation between regions of gel phase and regions of liquid crystal phase result in loss of membrane integrity), ^[104],[105] failure of ion pumping (with consequent disruption of cellular ionic homeostasis), ^[106],[107] depolymerisation of some elements of the cytoskeleton, ^[108],[109] generation of free radicals, ^[110],[111] and metabolic disruption due to selective inactivation of critical enzymes ^[112] all appear to play a role.

Cooling of tissues to 5ºC for as little as 1 hour has been shown to cause microvascular endothelial damage similar to that observed in ischemia-reperfusion injury; loss of endothelial cell tight junctions, infiltration of capillary and venule walls with leukocytes, and frank extravasation of red cells from injured vessels.[^113] A possible reason for the similarity in the histological appearance of chilling injury with ischemia-reperfusion injury may be due to the fact that both types of injury appear to be caused, at least in part, by reactive oxygen species and by disruption of the cytoskeleton.

The molecular changes induced by moderate, profound and ultraprofound hypothermia may also directly compromise endothelial cell integrity. For example, chilling of several types of epithelial cells has been shown to result in disassembly (depolymerisation) of the intracellular microtubules resulting in compromise of the polarized membrane expression and function of some transport proteins in these cells.^[114] These functions are slow to return to normal (@20 hr) and are associated with prolonged dysfunction of allografts that have undergone cold preservation storage.^[115],[116]

Deep cooling of the peripheral tissues may also result in immunosuppresion in chilled limbs and skin, and possibly impaired hematopoiesis due to localized moderate hypothermia in bone marrow in the cranium, sternum, vertebrae, and to a lesser extent, in the pelvis. [In children, the long bones are the principal repository of hematocytoblasts, and this marrow would also be disproportionately chilled during external cooling.] In contrast to the anti-inflammatory effect of MTH, systemic hypothermia to £28ºC, either accidental or induced has been shown to increase levels of pro-inflammatory cytokines.

Figure 15: (right): Typical (idealized) cooling and re-warming curve achievable with maximum extracorporeal (cardiopulmonary bypass) cooling.

Core cooling is thus the gold standard for the induction of systemic hypothermia (mild, moderate, profound or ultraprofound) and external (peripheral) cooling should be used only where there is no other alternative for achieving truly rapid cooling, or maintaining it for the required 24-48 hours following induction.

Consideration of Invasive Core Cooling Methods

Figure 16: An example of a mobile extracorporeal membrane oxygenation (ECMO) cryopatient support cart. This unit was fabricated by the Alcor Life Extension Foundation and was designed for extended (12-24) hour extracorporeal support of patients in profound or ultraprofound hypothermia.

Extracorporeal cooling via cardiopulmonary bypass (CPB) ^[117] or high flow veno-venous heat exchange ^[118],[119] allows for cooling rates of 0.8ºC/min to 1.0ºC/min (Figure 15) However, it cannot be applied rapidly enough given existing logistic and regulatory constraints. CPB requires complex hardware and highly skilled personnel who must maintain their clinical reflexes by practicing perfusion on a regular (preferably daily or at least weekly) basis. Even in centers of excellence, with a highly skilled, rapid-response CPB team at the ready (including a well-practiced surgeon or cardiologist), the soonest CPB can be initiated after cardiac arrest is typically 15-20 minutes.^[120],[121]

The use of emergency CPB applied in this time frame is largely confined to patients undergoing cardiac catheterization and/or revascularization (i.e., angioplasty or stent placement) who arrest in the cardiac catheterization lab. When such patients experience cardiac arrest that is refractory to treatment with drugs and defibrillation – they are usually otherwise healthy – they have normally functioning lungs, normal fluid balance and fluid distribution (are neither dehydrated nor edematous from fluid overload), and have failure of a only a single organ –  the heart. Even under such ‘ideal’ conditions, CPR is often inadequate to maintain brain viability during the brief interval between cardiac arrest and the start of CPB.

Figure 17: Cryopatient undergoing ECMO and blood washout in the home. Even under ideal circumstances cardiopulmonary bypass takes in excess of 30 minutes to initiate

While veno-venous extracorporeal cooling is less technically demanding, it still requires skill-intensive vascular access under field conditions, and reported rates of cooling are modest; ~0.012ºC/min. ^[122],[79] Both of these techniques may require anticoagulation and certainly require coagulation monitoring; which again is a barrier to in-field application.

Administration of large volumes (40mL/kg) of chilled intravenous fluid has also been used to reduce core temperature in the field in patients undergoing CPR. However this method is extremely slow (~0.058ºC/min),^{[123],[124],[125]} and is sharply constrained by the maximum volume of fluid that can be administered.

The effectiveness of intravascular fluid administration in achieving durable core cooling is also a function of body composition. Obesity, which has become epidemic in the developed world, is now rapidly becoming a global problem with 1.1 billion adults worldwide classified as overweight, and 312 million of them as obese by the World Health Organization (WHO).^[126] Vascular volume does not increase proportionally to increase in body weight; in fact, the vascular volume to body weight ratio falls toward an asymptotic value of approximately 45 ml/kg in the obese human.^[127] Thus, the use of cold intravenous infusions will necessarily be even less effective in the obese than might be expected since the maximum volume of fluid that may be safely given does not increase linearly with body weight. Fat is also an extraordinarily good insulator, and obesity often unfavorably alters body surface to volume area. Both of these factors combine to dramatically reduce the speed and overall effectiveness of external cooling.

The limits of efficiency of core cooling that can be achieved by irrigating the peritoneal or pleural spaces with cold liquid are in the range of 0.05 to 0.3ºC/min ^[128],[129] and both of these techniques are invasive, require considerable technical skill, and carry with them risks of serious iatrogenic consequences.

As noted earlier, the ideal way to address these needs would be extracorporeal membrane oxygenation (ECMO) and cooling. However, the practicality of rapidly bringing this demanding technology to bear in the EMS setting is negligible. Surgery (or time-consuming percutaneous vascular access; at or beyond the optimum therapeutic window of 15 min post ROSC) is required to access the circulation and this cannot be accomplished under field conditions. Experience with emergent initiation of ECMO in patients presenting for experimental cryopreservation (Figure 38) are probably representative of the time required to achieve extracorporeal support under field conditions for patients with SCA. Such patients typically experience a delay of 60 to 80 minutes (and not infrequently longer) after the initiation of closed chest CPR before the application of CPB, even under optimum circumstances.^{[130],[131],[132]}

Thus, what is needed for cryopatients, patients who have suffered prolonged (³5 min) cardiac arrest, or in whom ROSC cannot be effectively established, is the ability to rapidly induce hypothermia via core cooling simply and noninvasively.  In addition to moderating the injury cascade initiated by ischemia-reperfusion, mild (33-35^oC) or moderate (28-32^oC) hypothermia can indirectly act to improve gas exchange and hemodynamics by bringing the patient’s cerebral and systemic metabolic demands closer to those that can be delivered by CPR.

The clinical experience of the Wake EMS and in-house research into accelerated non-invasive cooling methods will be combined in the next section to allow far greater rates of cooling of cryopatients than have been possible in the past.

Induction of Hypothermia in the Cryopatient

Figure 18: Idealized optimal core brain cooling curve. The solid black line (^___) indicates the brain core (69.2 mm depth) cooling curve achieved using external cooling with ice water immersion during CPS. The broken blue line (—-) shows the theoretical cooling curve that might be possible by combining surface cooling with either cardiopulmonary bypass (CPB) cooling, or with liquid assisted pulmonary cooling (LAPC) and intraperitoneal cooling using ~1-2^oC physiologic salt solution, such as Normosol-R.™

Figure 19: Maintaining contact between the patient and the refrigerating ice bags was virtually impossible in the early days of human cryopreservation since the bags continually slide off the patient during Transport.

In the early days of cryonics, post-cardiac arrest cooling was exclusively “external” cooling which was achieved by covering the patient with plastic bags containing crushed or small cubed ice (Figure 19).^{[133], [134],[135]} This approach had the obvious advantage of being simple, straightforward to implement, and very inexpensive. Unfortunately, years of actual field experience with this approach have disclosed a number of serious limitations and problems:

1)      Heat exchange is greatly attenuated by both the insulating properties of the plastic and the reduction of convective transfer due to containment of the ice water generated from the melting ice.

2)      It is difficult to properly and completely pack the patient in ice because the bags are constantly falling off or not staying properly positioned, i.e. in good contact with the patient’s skin. Maintaining ice bags around the head and neck is a particular problem.

3)      It is virtually impossible to get ice packs under the patient, which means that 35% to 45% of the patient’s surface area is unavailable for heat exchange.

4) Ice bags leak and sweat which cause water to wet the patient and drip off the cot or gurney during transport. This presents both an immediate safety hazard (creating slippery floors and a potential electrical hazard) and also serves to contaminate staff and the working environment with potentially infectious fluids.

The PIB was developed after in-field core temperature measurements during the transport of a human cryopreservation patient employing ice bags to facilitate external cooling disclosed that this method was grossly unsatisfactory resulting in a core cooling rate of approximately 0.05°C/min during the first 4 hours of cooling.^{[134], [136], [137], [138]} Subsequent cases confirmed very slow rates of cooling using externally applied plastic bags filled with water ice ranging between a high of 0.12°C/min to a more typical 0.064°C/min.^[134] For these reasons, a lightweight, Portable Ice Bath (PIB) was developed by the author to allow for direct contact of ice water with essentially the entire surface area of the patient to simulate rates of heat exchange presumably encountered in cold water drowning where recovery of adults without neurological deficit after 20-40 minutes or more of submersion in ice water has been repeatedly clinically documented.^{[139],[140], [141],[142]} The rate of heat-loss for an adult human in water is 32 times that of in air5. Indeed, in such cases of cold water drowning, it is sometimes possible to successfully resuscitate adults who have been chilled in the absence of any cardiopulmonary support for up to 30 minutes.^{[143],[144],[145]} Children have been known to recover following up to 66 minutes of cold water drowning.^[146]

Determining the rate of cooling likely to be achieved with the PIB, particularly with the addition of convection cooling by stirring or circulating the PIB water around the patient was important prior to expending the considerable resources required and logistic difficulties to be overcome if these techniques were to be implemented routinely during Transports. A careful examination of the literature was undertaken by the author circa 1987 to determine if there were any published data on the rate(s) of core cooling likely to be feasible with these modalities.

Unfortunately, the only published data were those of the SS (Schutzstaffel) Nazi physicians Holzloehner, Finke, and Rascher, et al., conducted in 1942 on prisoners in the German concentration camp Dachau as part of an effort to understand the mechanisms and time course of hypothermia (as well as methods of  safe re-warming) in Luftwaffe pilots downed in cold North Sea water (Figure 20). Most of the actual work was conducted by Sigmund Rascher, M.D. and was summarized after its post-war recovery by Major Leo Alexander of the U.S Army Medical Corps in 1946.^[147] This document, now referred to as the “Alexander Report,” contains detailed information in both graphic and tabular form on the effects of convective cold water external cooling on human prisoners.

Figure 20: Sturmbannfuerher Dr. Sigmund Rascher (R) and Dr. Ernst Holzhoen (L) experimenting on a prisoner from Dachau using cold-water immersion to induce hypothermia followed by attempted re-warming after loss of consciousness. (Art from photo via Vad Yashem, Jerusalem, Israel.)

At this time, the citation and use of this data are extremely controversial and their relevance, integrity, and scientific usefulness have been called into question.^[148] There is no question in the author’s mind that the work of Holzloehner, et al., constitutes an atrocity and a crime against humanity of the worst kind. One of the principal criticisms of the scientific validity of this work has been the observation that many of the more than 300 victims of this research were chachectic and weakened from malnutrition and frank starvation making their physiological responses non-representative of that of the healthy German aviator. Ironically, it is just this criticism that makes the data obtained in this study uniquely valuable to human cryopreservation.

Data from the Alexander Report must be interpreted with caution and within the context of both the typical conditions under which human cryopreservation takes place and more recent data on the effects of cold water immersion on human subjects which is unquestionably both ethically and scientifically sound.^{[149],[150],[151]}

Several important caveats apply: Cooling curve data obtained by Holzloehner, et al., must be evaluated with the understanding that non-paralyzed, conscious individuals subjected to immersion in water cooled to between 2°C and 12°C will shiver either until exhaustion or until the temperature of the skeletal muscle drops below 30°C at which point shivering is impossible.^[151] Until either or both of these events happen core temperature will either transiently increase or will not decrease appreciably. Thus, use of these data to evaluate the efficacy of convective cold water immersion must subtract the first 10 to 20 minutes of core temperature data when shivering and elevated oxygen consumption are effectively maintaining homeostasis in the face of profound external cooling.^[152]

From the graphic data it is very apparent when this point is reached, typically at about 15 minutes post-immersion, for the unclothed emaciated subject. At this point the cooling curve begins to decline markedly and within 5 minutes achieves a steady rate of descent of approximately 0.26°C/min to 28°C after which it slows appreciably to 0.13°C/min until cardiac arrest typically occurs at ~27°C. This slowing is probably due to deteriorating hemodynamic status (BP was typically 40 mmHg to 50 mmHg near the terminal portion of the cooling curve) and a decrease in the ∆T between subject core temperature and bath temperature. In one series of 7 subjects the mean time from immersion to ventricular fibrillation (VF) was 66 minutes with a mean rectal temperature at the point of VF of 26.94°C. The fastest rate of cooling observed was 0.36°C/min in malnourished females.

One potentially very important observation made by of Holzloehner, et al., was the lack of any difference in the rate of early core temperature drop between subjects immersed in stirred water baths at 2°C or 12°C. This would seem to imply that the rate limiting factor in cooling, at least to ~27°C, is not the volume of water flowing over the subject, nor the ∆T, but rather peripheral vasoconstriction resulting in decreased blood flow to tissues in contact with cold water. Stirring of the PIB water in excess of that required to achieve optimum heat exchange is also undesirable for the following reasons:

• Given the modest amount of stirring employed in the experiments of Holzloehner, et al., it is unlikely that movement of large volumes of water over the patient will increase the rapidity or efficiency of heat exchange.

• Excessive stirring may result in unnecessary heat exchange with surrounding air, and unnecessarily waste heat generated by stirring pumps.

• Smaller more efficient pumps will allow for the use of household alkaline or lithium batteries facilitating initiation of SCCD cooling in the field and during vehicular transport where 110VAC wall current is unavailable.

• Increasing the efficacy of external cooling further will require improvements to either or both cardiac output and peripheral perfusion by either pharmacologic and/or mechanical means.

It is important to consider that temperature was measured rectally in the subjects of these experiments as opposed to esophageally or tympanically and thus cardiac and brain core temperatures were probably 2- 4°C lower than those reported since rectal temperature is known to lag significantly behind esophageal temperature during induction of hypothermia during both external cooling and extracorporeal cooling.^{[153],[154],[155]}

Third, comparison between subjects is difficult due to the lack of body mass or surface area measurements, or any determination of fat cover; this is a problem which must also be resolved in human cryopreservation cases to facilitate comparisons of the efficacy of cooling methods among cases.

Finally, quantification of hemodynamic status during cooling was not done. Blood pressure was measured only after the subject was removed from the cooling bath; not during active cooling. Similarly, measurement of cardiac output and peripheral and systemic vascular resistance were not techniques available at that time. However, it seems reasonable to presume that as the investigators reported, most subjects were maximally peripherally vasoconstricted. This can be inferred from the gruesome clinical descriptions contained in the data which report facial skin becoming immediately pale and then cyanotic after the first 45 to 50 minutes of cold water immersion (i.e., near the point of cardiac arrest).

The data also disclose the importance of cooling both the neck and the occiput of the head if the maximum rate of temperature descent was to be achieved, presumably reflecting both the rich perfusion of the scalp and the cooling of the high flow and relatively superficial jugular and carotid blood flows. Failure to cool the neck and occiput were sufficient to reduce core temperature drop by approximately 0.16°C/min.

The data contained in the Alexander Report were sufficiently convincing for the author to initiate a change in Alcor protocol from ice bag cooling to one employing cold water immersion using the PIB. This decision was financially costly and introduced serious new logistical hurdles. PIBs must be constructed, air transported and add hundreds of additional pounds of weight in water and ice which must be picked up and moved during Transport necessitating additional personnel.

Late in 1989 Fred Chamberlain, co-founder of Alcor, developed a prototype SCCD using an AC powered sump-type submersible pump to facilitate convective cooling. The SCCD was first used in 1990 on a profoundly chachectic patient with a mass of only 32.8 kg and virtually no fat cover^.[156] This patient exhibited an extraordinarily good and sustained response to CPS maintaining excellent peripheral tissue perfusion and oxygenation throughout the entire 2.5 hours of Thumper supported CPS. The patient’s core cooling rate 0.41°C/min during the first 12 minutes of closed chest CPS and external cooling and of 0.33°C/min during the first 43 minutes of closed chest CPS and external cooling still appears extraordinary for cryopreservation patients; although it is consistent with the data for chachectic human concentration camp victims generated by Holzloehner, et al. In the future comparisons between patients can be better facilitated by using the patient’s Body Mass Index (BMI) as an objectifying comparison tool. BMI is calculated as follows:

BMI=KG/m²

The patient’s weight and height are required to calculate BMI. Thus, it will be critical to measure the patient’s weight in kg (either prior to cardiac arrest or upon arrival at the cryoprotective perfusion facility) and measure their height in cm prior to the start of cryoprotective perfusion.

Figure 21: Skinfold caliper; both analog and digital versions are available.

It may also be very useful to estimate body fat and more reliably determine subcutaneous fat cover by using a Skinfold Caliper. A Skinfold Caliper is a device which measures the thickness of a fold of skin with its underlying layer of fat. By measuring skin fold thickness at precise places on the thorax, abdomen and thigh a reasonably accurate measurement of total body fat can be obtained in a healthy individual. In the case of the cryopreservation patient the interest is not primarily in the accuracy of the tool in determining total body fat per se, but rather in the creation of a database of measurements which can serve as an objectifying guide to determining a patient’s degree of fat cover at the time of cardiopulmonary arrest.

Illustrated in the charts and tables below is the procedure for taking Skinfold Caliper measurements in both adult males and females:

Measuring Sites for Males

Site	Direction of fold	Measurement
Thorax	Diagonal	Fold is taken ½ the distance between the anterior auxiliary line and nipple.
Abdomen	Vertical	Fold is taken vertical 2 cm lateral to the umbilicus.
Thigh	Vertical	Fold is lifted on anterior aspect of thigh midway between inguinal crease and proximal border of patella. Body weight is shifted to left foot.

Table 2: Measuring Sites for Skincaliper Body Fat Determination:

 

Measuring Sites for Female

 

Site	Direction of fold	Measurement
Triceps	Vertical	Fold is taken midway between the shoulder and elbow joint, on the center of the back of the arm.
Waist	Diagonal	Fold is taken diagonally above the iliac crest along the anterior auxiliary line.
Thigh	Vertical	Fold is lifted on anterior aspect of thigh midway between inguinal crease and proximal border of patella. Body weight is shifted to the left foot.

 

 

 

 

 

 

 

 

 

Multiple regression equations exist for calculating the percentage of body fat from the Skinfold Caliper measurements depending upon age and sex (50-52). However, at this time the author believes that the selection of a particular algorithm is not very important. Because there is no typical cryopreservation patient, the consistent collection of reliable data and their reduction to arbitrary numbers which can be compared from case to case is the most important consideration.

Collection of BMI and Skinfold Caliper measurements from multiple patients combined with some objectification of the efficacy of CPS during transport will likely be the most useful tools for comparing various methods of cooling; both external and internal.

Below are the Jackson, et al., equations for calculation of percentage body fat in females and males:

FEMALES:

D = 1.0994921 – (0.0009929 x sum of triceps, suprailiac, thigh) + (0.0000023 x square of the sum of triceps, suprailiac, thigh) – (0.0001392 x age), based on a sample aged 18-55.
Jackson, et al. (1980) Generalized equations for predicting body density of women. Medicine and Science in Sports and Exercise, 12:p175-182.

MALES:

D = 1.10938 – (0.0008267 x sum of chest, abdominal, thigh) + (0.0000016 x square of the sum of chest, abdominal, thigh) – (0.0002574 x age), based on a sample aged 18-61.
Jackson, A.S. & Pollock, M.L. (1978) Generalized equations for predicting body density of men. British J of Nutrition, 40: p497-504.

Figure 22: Actual cooling curves for three adult patients on HLR support, using ice bags, portable ice bath (PIB), and PIB plus SCCD cooling. Patient A-1133 weighed 56.8 kg, patient A-1169 weighed 57.3 kg, and patient A-1049 weighed 36.4 kg. As this data indicates, PIB cooling is approximately twice as effective as ice bag cooling. The spray cooling device (SCCD) increases the rate of cooling by yet another 50% over the PIB (roughly adjusting for differences in patient weights).

As can be seen in Figure 38, cooling rates with the PIB, even when using stirred water to maximize convective cooling; still result in unacceptably slow rates of cooling. To solve this problem four other methods of cooling, which are amenable to immediate, in-field application have been developed:

1)      Use of chilled parenteral medications; bulk IV fluids given to provide cerebroprotection, such as buffers and hyperosmotic agents are administered (where possible) chilled to 1-2 ^oC.

2)      Peritoneal lavage with 4 liters of Normosol-R™ chilled to 1-2 ^oC is used 2x as soon as feasible after pronouncement.

3)      Colonic lavage with1 liter of Normosol-R™ chilled to 1-2 ^oC is used 4x, as an alternative or prior to peritoneal lavage, as soon as possible during CPS (total of 8 liters).

4)      Liquid assisted pulmonary cooling (LAPC) with 4 liters of 3M FC-75™ perfluorocarbon is used 2x during CPS; the first as soon as possible after placement of an endotracheal tube, and the second 15 minutes following the first.

Detailed instruction on how to perform these adjunct procedures to external cooling are provided later in this Chapter.

References

References are given at the end of Part II of this article.

Footnotes

 

“Are you interested in the whole body or the neuro? And would you like fries and a Coke with that?”

By Mike Darwin

Introduction

A short while ago, I hosted 3 visitors from the Russian cryonics organization KrioRus. During my visit with them in Moscow two and a half years previously, I had exhorted them to visit the US and see first-hand any hub of cryonics activity there, so that that they could see and learn for themselves what cryonics was really like, and how it was actually being pursued in the US. When I wrote to Alcor President and CEO Max More to try and schedule a visit on short notice, I jokingly included the aside that if I was not permitted to be on premises, I would go elsewhere… It was intended to be a humorous reference to a time in the not so distant past when I was not allowed into Alcor because my homosexuality was “unacceptable” to a former Alcor President (apparently being incompatible with his religious beliefs).

To my considerable surprise, Max took this remark seriously, and polled the Alcor Board on the matter. Surprise was replaced with shock when I subsequently learned that Alcor Director Saul Kent had expressed concerns that my visit to Alcor accompanying the Russians would be used as tool to “attack Alcor.” I still find this shocking, but depending upon how you define attack, maybe Saul was closer to the truth than I imagined possible. I’ve since been told that apparently there were speculations that “touring Russians” might be just an excuse of some kind to gain entry to Alcor.[1] Why this should be necessary is still a mystery to me, since as far as I knew I could visit by making by an appointment, presumably like anyone else.

Figure 1: The Alcor Mobile Advanced Rescue Cart (MARC), a portable extracorporeal support platform.

I saw quite a few unexpected things at Alcor, such as that the MARC is no longer in use and lies covered in dust (not even tarped) and laden with ‘junk’ in the ambulance bay; it has been replaced by waist high PIB fabricated from stainless steel. All of which begs the point of why a hugely complex and costly technological platform, in the form of a mobile operating room was developed, if it isn’t going to be used for extracorporeal support?

Figure 2: Left to right, Danila Medvedev, President of the Russian Transhumanist Association, Max More, Ph.D., President and CEO of Alcor and Valerija Pride, President of KrioRus. Photo by Stanislaw Lipin; courtesy of KrioRus.

A Long History of Serious Deficiencies in Patient Care

Shortly after he took office, I sent Max the 100+ plus page “Report of the Committee to Evaluate Alcor Procedures” which was presented to the Alcor Board of Directors on 04 April, 2002. This report came about because Saul Kent invited me over to his home in Woodcrest, California to view videotapes of two Alcor cases which troubled him – but he couldn’t quite put his finger on why this was so. What I saw shocked and disgusted me. Patients were being stabilized at a nearby hospice, transported to Alcor (~20 min away) and then CPS was discontinued, the patients were placed on the OR table and, without any ice on their heads, they were allowed to sit there at temperatures a little below normal body temperature for 1 to 1.5 hours, while burr holes were drilled, and the neck vessels were cannulated. Distilled water was being used to irrigate the brain and burr holes were done with a wood burr and electric drill with no cooling of the bone under the burr – smoke could be seen coming from the burr wound! Since the patient had no circulation to provide blood to carry away the enormous heat generated by the action of the burr on the bone, the temperature of the underlying bone (and brain) must have been high enough to literally cook an egg.

In one case, a patient’s head was removed in the field and, because they had failed to use a rectal plug, the patient had defecated in the PIB. The result was that feces had contaminated the neck wound, and Alcor personnel were seen pouring saline over the stump of the neck whilst holding the patient’s severed head over a bucket trying to wash the fecal matter off the stump. These are just a few of the grotesque problems I observed.

As a consequence, a “blue ribbon” Committee was put together to comprehensively review Alcor patient videos and records, and to make a field inspection of the Alcor facility. This Committee produced a comprehensive report and presented it to the Alcor Board. [Darwin, M., et al., Report of the Committee to Evaluate Alcor Procedures, Presented to the Alcor Board of Directors on April 4th, 2002.] Max More knew nothing of this until I sent him a copy after he was President for about one and a half months.

A Profound and Fundamental Error Unendingly Repeated

A short while later, Alcor published the first detailed case report since the A-1097 case report was published in 2006. A careful reading of this case report which is available at http://www.alcor.org/Library/pdfs/casereportA2435.pdf discloses that there is something terribly wrong that happens during this case, but unless you really understand cryonics as medicine, you are not likely to see it. The patient was pronounced at 6:58 PM and was transported to Alcor packed in ice while receiving CPS with the LUCAS. At ~ 8:42 PM, 1 hour and 42 minutes later, a median sternotomy is begun (excerpt from the case report, emphasis mine):

Continuation of CPS

Move to surgical table

7. Surgical Procedures

Manual CPS was continued on the patient while fresh ice was brought in from Alcor’s ice machine. The existing ice was removed from on top of the patient and she was pulled out of the ice bath and placed on the OR surgical table at 8:11 pm.

Testing of the sternal saw prior to the surgery revealed that the flexible shaft had frozen up. The problem was handed to Richard to deal with, and he had it unfrozen in a few minutes. The shaft was subsequently disassembled and lubricated.

The patient’s head was shaved to prep for the burr holes to be drilled. These are used to monitor the temperature of the patient’s brain as well as a way to visually watch for swelling. While the burr holes were being drilled using a craniotome perforator, Aaron prepped the patient’s sternum with Betadine, an antiseptic agent used topically to destroy microbes. Dr. McEachern cleaned each of the burr holes as they were completed. At 8:42 PM, she stood on a step stool to gain a higher position above the patient in order to perform a median sternotomy. This is a procedure in which a vertical inline incision is made along the sternum, after which the sternum itself is divided to provide access to the heart for cannulation. Dr. McEachern cut through the skin of the chest with a scalpel. The guide of the saw blade was placed below the sternum. Richard operated the foot pedal on the floor as she guided the saw up the sternum. She talked through the procedure, step by step, to Aaron so he could gain additional training in its operation and application. After the sternum separation was completed, the chest was opened with Finochietto spreaders and the pericardial sac was exposed. Access to the heart was accomplished by cutting through the pericardium.

Dr. McEachern performed an arterial cannulation of the heart by sewing a purse-string suture into the wall of the aortic arch, puncturing the vessel within the purse-string, and advancing and securing the catheter. She then repeated this process for venous cannulation of the heart, going into the right atrium and advancing the cannula into the inferior vena cava. This process took approximately one hour and was completed at 9:48 PM. A thermocouple was placed under the dura through the burr hole at 3.0 hours post-arrest. Brain temperatures were taken under the dura and beneath the brain (nasopharyngeal).

Now the washout could begin. This process is used to replace the patient’s blood with cryoprotectant. The extracorporeal perfusion circuit had been primed with B1 base perfusate solution prior to the surgery and was being circulated through the bypass loop. When cannulation was complete, the circulation was transferred from the bypass loop into the cannulas. The circuit was switched from closed to open circulation and the blood was washed out of the patient’s vascular system, the visual blood concentration going from opaque to light pink.

The graph of below shows a typical patient’s cooling rate in the PIB.

Figure 3: The red-boxed areas of the two cooling curves above show the likely temperature range a patient would have cooled to during 1 hour and 44 minutes of closed chest cardiopulmonary supported external cooling using ■ ice bags or □ Portable Ice Bath (PIB) cooling.

Assuming the patient cooled at the rate that A-1169 did above, then the best that could be expected is that the patient was at ~ 22-24 deg C at 1 hour and 44 min post arrest. Examination of the graph below (Figure 4) shows that the “safe” circulatory arrest times for a “healthy” patient who has had no prior ischemic insult and who is fully oxygenated at various temperatures during cardiac or neurosurgery:

Figure 4: Probable safe circulatory arrest time vs. temperature for humans, as calculated using the Hypothermic Metabolic Index (HMI). [Ungerleider R, Gaynor,  JW.: The Boston Circulatory Arrest Study: An analysis. J Thorac Cardiovasc Surg 2004, 127:1256-1261.]

The reason these graphs are of relevance is that in order to do a median sternotomy you must, necessarily, stop CPR. So, yet again, Alcor took a patient with essentially uninterrupted CPS, brought them into the OR and then exposed her 1 hour and 42 minutes of ischemia! A few days before we went to Alcor, I had sent Max a letter pointing out that this had happened yet again, and that Aaron Drake’s report was badly flawed and that it was clear he was wholly inadequately trained to be doing cases unsupervised. I received no reply.

Our visit to Alcor was surreal – absolutely surreal. The first thing Max did when we entered was to show Danila Medvedev and Valerija Pride swatches of wall paper and explain that the office was he was occupying was “not his” and that it was to be redecorated. He then proceeded to do the same with me. Danila and I looked at each other as if to say, “Are you kidding us? Can this even be real?”

An Unkempt Kitchen in a 2-Star Hotel?

When we arrived at Alcor we were informed that a member was in need of Standby and very likely cryopreservation, and shortly after we entered the facility, the Remote Standby Team left with their equipment. I have been at Alcor only at brief intervals over the past 20 years, with the exception a stint for a month or so as subcontractor working for Suspended Animation, Inc. (SA) in 2002. I thus have mental “snapshots” of the state of the facilities separated by considerable intervals of time. This was the most disturbing snapshot I’ve seen so far. The operating room was unkempt. The floors were scuffed, stained, dirty, and had obviously not been waxed in a long time (Figure 5).

Figure 5: Scuffed and dirty floors, dusty shelves and a disorganized appearance are fair descriptors of the Alcor operating room. I wouldn’t consider medical treatment in a facility with this appearance – nor for that matter would I like to dine in a restaurant with a kitchen in such a state. Photo by Stanislaw Lipin; courtesy of KrioRus.

I inquired when preparation of the operating room would start for the patient who was to be perfused, presumably the next day, and I was told that they were “done.” When we entered the OR I observed tubing strung on the pumps of the heart lung machine console, and had assumed it was training tubing, since some of it was hanging down to the floor in front of the console inside a large, open ZipLoc bag (Figure 5).

Figure 5: Cryoprotective tubing dangling from pump console in a Ziploc bag; proper gas permeable sterilization wrapping (such as Kimlon™) was nowhere in evidence. Photo by Stanislaw Lipin; courtesy of KrioRus.

There were discarded tubing (ethylene oxide) sterilization caps lying around, and refuse, some of it apparently in place for some time, such as twist ties and paper backing from discarded sterilization pouches, lying covered in dust on the computer/instrumentation cart adjacent to the pump console (Figures 7 & 8).

Figure 6: Alcor operating room perfusion and data acquisition equipment. The refractometer heads used to continuously acquire cryoprotectant agent concentration to the left of the computer. Photo by Stanislaw Lipin; courtesy of KrioRus.

Figure 7: Dust covered lower shelf of the stainless steel data acquisition cart. The piece of sterilization packaging and the twist tie appeared to be covered in a film of dust, as well. Photo by Stanislaw Lipin; courtesy of KrioRus.

Figure 8: The recirculating reservoir perched precariously atop the magnetic stirring table used to mix cryoprotectant concentrate into the recirculating perfusate. Photo by Stanislaw Lipin; courtesy of KrioRus.

On the monitor shelf atop the pump console there was a spray bottle that had apparently been labeled “alcohol” (what kind? one wonders) with a Sharpie marker, and a laboratory wash bottle sitting next to it containing a liquid – but with no label (Figure 8).

Figure 9: At top, long view of the neuroperfusion enclosure and at bottom close up showing area of apparent blood contamination. Photo by Stanislaw Lipin; courtesy of KrioRus.

Disturbingly, the neuroperfusion enclosure had what appeared to be a residue of dried blood/perfusate in what appeared to be a defect in the adhesive seal where the waste diversion plate is cemented to the side wall of the enclosure (Figure 9). The drain line from the neuroperfusion enclosure (where biohazardous fluid will collect to be disposed of) was sitting unsecured in a ~20 L Costco Kirkland laundry detergent pail (Figure 10).

Figure 10: Costco laundry soap pail containing the unsecured biohazardous waste line from the neuroperfusion enclosure. Photo by Stanislaw Lipin; courtesy of KrioRus.

Figure 11: Alcor Operating room tableaux “fully readied” for a human neuropatient cryoprotective perfusion. Photo by Stanislaw Lipin; courtesy of KrioRus.

The recirculating reservoir was dangerously small making microbubble embolization of the patient during cryoprotective perfusion all but inevitable, since the cold, polymer-rich, viscous perfusate develops stable foam as a consequence of vortex formation and air entrapment from the action of the mixing magnetic stir-bar.

Figure 12: One possible scheme for achieving uniform mixing of cryoprotectant concentrate with the perfusate recirculating through the patient using a static mixer. A concentrate mixing pump continuously removes a large fraction of the recirculating perfusate from a cardiotomy or venous reservoir. This perfusate is then passed through a combination static mixer-heat exchanger where turbulent flow from inertia reversal and radial mixing uniformly blend the added cryoprotectant concentrate with the recirculating perfusate. The static mixer also serves as a heat exchanger. The blended and chilled perfusate then return to the venous reservoir.

Figure 13: At (A), a typical static mixer array. Static mixers allow thorough mixing of almost any kind of liquid or slurry without the introduction of air or the use of moving parts with the attendant seals. Because static mixers are of necessity a mixing element housed within a tube or cylinder, they make ideal heat exchangers since the fluid flowing inside the mixing tube elements is repeatedly thin-filmed and passed over the tube surface. It is thus possible to very efficiently combine mixing with heat exchange, as can be seen in the combination mixer-heat exchanger seen in B, above.

This has been a repeated problem in previous cases, and has been the subject of numerous advisory communications between Alcor Director Brian Wowk and me, among others. In fact, despite these repeated warnings (increase depth and volume of the recirculating reservoir, use a floating lid or replace the stir bar assembly with an in-line mixer: Figures 12 & 13), this same phenomenon was noted on during the cryoprotective perfusion of patient A-1097 in January of 2006. A detailed paper documenting this effect and demonstrating a simple way to eliminate it was first published in 1994. ( see: http://www.cryocare.org/index.cgi?subdir=bpi&url=tech5.txt)

I quote from this 1994 paper:

“A consequence of the stirring of the recirculating reservoir by the rapidly spinning magnetic stir bar is the generation of an air vortex in the recirculating perfusate. While this vortex is very effective at both rapidly and completely mixing the concentrate with the perfusate in the recirculating reservoir, it is also very effective at introducing air into the recirculating perfusate as well. At rates of rotation fast enough to achieve good mixing; the bottom of the vortex of air reaches the rapidly rotating stir bar. Air is thus turbulently mixed into the perfusate where it forms bubbles of widely varying size; the smallest of which are very stable. As the concentration of cryoprotectant rises, and the viscosity of the solution correspondingly increases, air bubbles generated by stirring in the recirculating reservoir become more and more stable and begin to saturate the recirculating perfusate creating large amounts of foam.”

And from A-1097’s case report:

“A differential vascular resistance check was done by clamping off and then unclamping the left and right carotid artery respectively. After clamping off the left carotid artery the pressure rose to 72 mm. After clamping off the right carotid artery the pressure rose to 140 mm. At 11:55 foaming was identified in the mixing reservoir, with worse foaming observed at 12:17.”

Figure 14: The recirculating reservoir sitting unsecured atop the mixing stir table. Note that the PVC tubing has not been adanced the requisite 3 barbs over the connector at the bottom (right) of the reservoir and that there is no cable tie in place to prevent accidental disconnection of the tubing. Photo by Stanislaw Lipin; courtesy of KrioRus.

It was also sitting akimbo on the magnetic stir table and the connections to and from it, including the critical withdrawal connection at the bottom was neither cable tied, nor pushed over the third barb of the tubing connector at the bottom of the reservoir (these are standard minimum practices for securing tubing against disconnection in extracorporeal medicine).

When I inquired as to how the recirculating reservoir would be secured during perfusion, I was told, “It’ll sit still when it has liquid in it.” If you can look at the picture above and concur with that answer, especially considering that Alcor has a history of pumping this small reservoir dry during perfusion and introducing air in the extracorporeal circuit, then you are a more courageous soul than me. Consider the recommendation made to Alcor by the formal Committee commissioned to evaluate and suggest corrective actions when Alcor’s cryopreservation procedures were found to be severely deficient in 2002:

4.13: Enlarge and alarm the recirculating reservoir.

The recirculating perfusate reservoir ran dry more than once during a recent case. The reservoir should be larger and should have an alarm system that is triggered by a low level of perfusate. At the least one specific person should be assigned the task of monitoring the reservoir.

Cargo Cult Security for Patients?

Then there was the lunacy of the “armored” patient care bay, which Max proudly showed us (Figure 15).

Figure 15: Blast resistant bullet proof window looking into the Alcor patient care bay. The hardened transparent window is backed up with a retractable steel curtain window cover. Photo by Stanislaw Lipin; courtesy of KrioRus.

I can’t even begin to imagine what all this cost (including reinforcing the perimeter walls). It looks very impressive, and no doubt has considerable “sales” value to the naive, or the foolish.

However, if anyone actually looks past the looking glass (which happens to be blast resistant, in this case) what they will see is the following reality.

Figure 16: View through the window into the patient care bay (PCB). A loose piece of the foil faced cardboard sheeting which covers the plywood roof decking and structural supports that comprise the roof of the PCB are highlighted by the red arrows. Photo by Stanislaw Lipin; courtesy of KrioRus.

The red arrows point to the foil-faced cardboard reflective “insulation” that covers the space between the perlins in the patient care bay. One piece has been left (un-anesthetically) loose adjacent to what appears to be a run of sprinkler pipe. What this told me was that roof of the PCB bay is a paper bag. It almost certainly consists of sheets of plywood or particle board decking covered with a layer of roofing felt, and finally the roofing material itself. Typically, this kind of construction can barely withstand the weight of a 250 lb man. Go up on the roof and walk around yourself, and you’ll immediately get a feel for what I’m talking about – the roof will give and spring back as you walk on it. It is minimally engineered for load bearing, and this fine, and a damn good thing in earthquake country, where tilt-up concrete industrial building construction was first developed.

I can then go to Google Earth and quickly verify that, as of 11-2009, there were no structural or other evident reinforcements to the outside of the roof over the PCB. Maybe there are now (doubtful), but this is very easy to determine, either directly, for the cost of an aerial photograph ($300), or by checking with building and code enforcement to see if any structural permits were issued, and inspections subsequently done. Of course, the easiest way is just to climb up on the building and take a look. The single most important and most elementary security precaution any institution can take to increase the safety of its physical plant is to protect its perimeter. This is why sensitive and vulnerable government and corporate installations are surrounded by fences, patrolled by guards (and often dogs) and where feasible, protected by bollards against bomb bearing vehicular attack. Alcor’s perimeter is unsecured.

Figure 17: Google Earth view of the Alcor facility in 2009 shows no evidence of external (surface) reinforcing and no evidence of razor wire or other perimeter defenses on the roof of Alcor building in general, or the patient care bay in particular.

Figure 18: Metal lid covering bigfoot dewar at Alcor. Photo by Stanislaw Lipin; courtesy of KrioRus.

It is also evident that the dewars have no cladding, and that the softest spot is the top of the units where, in order to save both weight and money (again perfectly reasonable), the tops of the foam neck-plugs, as is the industry standard for cryogenic dewars, are fabricated from aluminum, or perhaps a tough plastic, such as ABS. However, in this case, no guessing is required; it is evident that the cover is metal and it is, judging from its thickness, aluminum.

Figure 19: Unsecured facility perimeter and roof of the patient care bay at the Alcor facility in Scottsdale, AZ. The blast and fire resistant neurovaults sit abandoned in the parking lot (red hash mark).

Google even shows me the long abandoned blast resistant neuro-vaults sitting in the parking lot (red hash mark), and confirms that the PCB roof is a standard wooden deck and asphalt configuration which will look structurally just about like this:

Figure 20: Type of roof construction used in the Alcor facility. The large composite wooden beams running from left to right are gluelams – machined pieces of wood glued together under high pressure. The gluelams are the primary load bearing elements of the roof. The single beam structural elements that connect the gluelams are the perlins. The perlins provide most of the structural support for the plywood or chipboard decking of the roof.

What is more, very few, if any people who want to do the patients harm will walk into Alcor on a tour. That’s almost ludicrous, especially when there are much more attractive alternatives. And the most attractive alternative is simply walk up to or drive by the building, and hurl a fragmentation-type explosive device, such as a pipe bomb, on the roof. A more serious and targeted approach would be to climb up on the roof and position heavy explosive charges exactly where they are deemed to do the most damage.

Figure 21: Historically, bollards made of wood, metal or concrete have been used to prevent accidental or deliberate vehicular intrusion into areas where unacceptable damage would result (above, top right).  More recently, concrete barriers such as the ones seen at top left have been used for this purpose. (Photos by Mike Darwin.) The use of concrete barriers, or K rails is, however, not only unaesthetic, it does not provide  protection against the intrusion of armed pedestrians, or 2-wheel vehicles such as bicycles and motorcycles. An effective alternative is the use of high impact and climb-over resistant fencing such as Ameristar Fence Products, Inc., (Tulsa, OK), Impasse™ high-security fencing system. With the company’s integrated cabling system, this product provides anti-ram defense against forced entry and ballistic attack, and is able to stop one 15,000 lb vehicle traveling 40 mph. This product meets Department of State’s K8/L1 and K8/L2 ratings.

So, in effect, the Alcor PCB is the equivalent of a Bugatti Verynon Sports car, which has excellent door locks and a great alarm system – all of which are of little utility in the event you leave the roof off!

Figure 22: The Bugatti Verynon features an excellent alarm system and a sporty, removable roof. The value of the alarm system is considerably diminished if the car is left parked with the roof off.

It is, of course, possible to really protect the patients against these kinds of threats, as well as radiation damage by placing the patient dewars in below ground silos as seen in Figure 23. But it isn’t pretty, although I guarantee you that this, or some variation of it, will be a whole lot more effective and less costly.

Figure 23: Truly effective blast, earthquake and radiation protection were achieved by CryoSpan in the late 1990s by the expedient of constructing in-ground steel reinforced concrete silos. At top, engineer Mark Connaughton works on the wooden support framing used to maintain the shape of the mold prior to pouring the concrete. While not offering “sexy” photo opportunities, such silos provide robust and affordable protection to cryonics patients. Photos by Charles Platt.

Subsequently, Max and I corresponded about these issues until it became clear that he was becoming angry with me. He denied that there was any current wastefulness at Alcor (including their 10 paid employees), challenging me to come up with line item examples; except, of course, I couldn’t do this because Alcor has published no financial reports in four years. In fact, such reports don’t exist (not yet, anyway). He did not respond to my query about why the MARC is no longer in use and lies covered in dust (not even tarped) and laden with ‘junk’ in the ambulance bay; it has been replaced by a waist high PIB fabricated from stainless steel. All of which begs the question of why a complex and costly technological platform, in the form of a mobile operating room was developed, if it isn’t going to be used for extracorporeal support?

Our correspondence pretty much ended with me telling him, “You may not agree with what my vision for Alcor was (in 1987) at this point in time, but the really unfortunate thing, for all involved, is that you probably have no idea what it was, nor why I am unhappy at the waste of millions of dollars of contributed member money[1] in the intervening decades. And Max, those millions were wasted.”

Every “criticism” I made he took as a personal challenge to his competence. Danila described it aptly as, “Horrible.” It now seems clear to me that nothing I can do from behind the scenes will change Alcor. I’ve been working quietly for over a decade now, and things just keep getting worse. I had planned for this contingency, and now I think it is time to proceed in creating an alternative organization and to providing some of the nocioception that Alcor has been spared these past 20 years. I like Max a great deal – we have been good friends for over 20 years.But this is business, serious life or death business.

I have been through at least 4 iterations of what amounted to effectively rebooting, or trying to be reboot cryonics organizations. It takes a long time to do that: ~5 years just to get some equilibrium and the core resources in place. Surprisingly, even throwing vast amounts of money into such efforts does nothing to accelerate the pace, and may even slow it. I’m old, and I am sickened at the thought of having to go through this exercise, even as a participant, let alone as a leader, yet again. Having said that, it is becoming clear with each passing year that this kind of effort was probably inevitable given our nearly complete lack of understanding of what was (and arguably still is) really required to do cryonics in a sustainable fashion. Certainly, there is no escape from this in most other endeavors – and especially not in fundamentally new ones. I rarely meet innovators or entrepreneurs on the “cutting edge” (an expression I loathe) who don’t have sad tales to tell about how many corporate entities they created and cycled through before they found a stable and durable platform (if they ever succeeded in doing so at all).

As to Alcor’s status and prospects, I don’t think Alcor is likely to fail in any kind of immediate or catastrophic way. It’s current and past deficiencies are primarily of a kind that, given cryonics’ fundamental lack of normal market feedback, will not be evident to cryonicists, let alone to the public, even if pointed out to them. The legacy of the Cryonics Society of California (CSC) is proof of that reality. So, that’s not what I’m saying.

The Stench of Impending Failure?

What I am saying is that there are certain infallible signs that an enterprise is in deep trouble, and while perhaps not in immediate danger of going under, is only going to continue to exist under highly favorable conditions. I’ll be quite specific in a moment, but I want to a spend few moments more on what is the really the more important point I have to make.

I’ve traveled the world and visited just about every kind of enterprise imaginable. Whether it is a restaurant Florence, a medical clinic in Hyderabad, or an ICU in Mumbai or Moscow, there is often this unmistakable gestalt (stench) of a profoundly dysfunctional business which is evident within minutes of being on the premises. Please note that I am not saying that all failing enterprises exhibit this aura, because I’m sure they don’t. Enron probably seemed in fine fettle until just before the end. But I am saying that when that ambience is present, the enterprise is in extremis. Under normal market conditions that would mean that you could reasonably (soon) expect the doors to be shuttered (or the floor to be removed, in the Middle East). The exceptions are small town businesses that constitute micro-monopolies, government operated facilities in the undeveloped world, and occasionally, religious orders or other institutions in terminal decline, but who have a trust fund or other stipend to sustain them.

Cryonics: A Product or an Unproven Experimental Procedure?

While in many important ways Alcor is the descendant of Cryonics Society of New York (CSNY) and the no-nonsense, tell like it is approach to cryonics of Curtis Henderson, this is not by any means the full picture. CSNY had perhaps half the paradigm right. The other half that came to constitute the “mature” Alcor approach of the 1980s was pioneered by Fred and Linda Chamberlain, and was one of the Alcor assets already in place, if dormant, when IABS and I arrived on the scene in 1981. That approach was a clear acknowledgement and understanding that cryonics was an experimental procedure, that Alcor was a mutual aid organization, and that recruiting members who were also experimental subjects, was not the same as selling cryonics to customers.

There was, in fact, a strong aversion to marketing cryonics as an ordinary product, or even as a “regular” medical treatment. A consequence of this attitude was that everyone who interfaced with the public, until shortly before I left, had an almost fanatical attitude about how signing up should be communicated to the member. The interesting, and indeed remarkable thing about this is that I do not ever recall doing any training or any scripting of how to handle callers who were prospective members, or who were gathering information for same. It was just something that was “organic” and a part of Alcor’s small, but very well defined corporate culture at that time.

A corollary or a logical extension of this “first contact” strategy was that we spent a lot of time and expended a lot of effort not only continuously educating already signed up members, but actively ensuring that their informed consent was maintained over time. The Cryonics Institute (CI) never had that paradigm and Alcor lost it, and as result, members got translated into customers. I believe this is a critical failure mode for a cryonics organization – any cryonics organization – because whatever else cryonics patients are, they are not customers, and neither are members customers before they become patients. The definition of customer is innocuous enough: A party that receives or consumes products (goods or services) and has the ability to choose between different products and suppliers. Superficially it would seem to fit the bill for cryonics. Unfortunately, it is not what is present in that definition that is problematic, it is what is missing.

By contrast, consider the definition of the word patient:

1. Bearing or enduring pain, difficulty, provocation, or annoyance with calmness.

2. Marked by or exhibiting calm endurance of pain, difficulty, provocation, or annoyance.

3. Tolerant; understanding: an unfailingly patient leader and guide.

4. Persevering; constant: With patient industry, she revived the failing business and made it thrive.

5. Capable of calmly awaiting an outcome or result; not hasty or impulsive.

6. Capable of bearing or enduring pain, difficulty, provocation, or annoyance: “My uncle Toby was a man patient of injuries” (Laurence Sterne).

noun:

1. One who receives medical attention, care, or treatment.

2. Linguistics A noun or noun phrase identifying one that is acted upon or undergoes an action. Also called goal.

3. Archaic One who suffers.

The core of the definition of patient, which was the basis of the adoption of the word in medicine, is “one who demonstrates calm endurance of pain, difficulty, provocation, or annoyance.” Anyone involved in cryonics for very long will quickly come to know, viscerally, which of these terms best applies.

No law yet prohibits marketing cryonics as a consumer product, though some do exist prohibiting its marketing at all. One of the few advantages to age (especially if accompanied by global travel) is that you get to see how diverse societies handle certain classes of problematic services or undertakings – ones that are destabilizing to the social matrix, or which carry a high potential for fraud or exploitation of the individual, especially vulnerable individuals. While there is considerable variation in the details, the general approaches used are remarkably similar within societies that share the same basic values. So, while there is the sale of vital organs in places like India (something that is fast being regionally legislated against), you see either a complete absence of this practice, or the same limited workarounds, in virtually all of the West and Near East. As a relevant aside, it was fascinating to watch the arc of gambling in the Russian Republic, which went from ubiquitous, to exactly where it was in the US 20 years ago; mostly prohibited, except in special zones that are problematic to gain access to and which focus the predation on the wealthy (there is essentially no middle class in Russia). This change occurred in ~2 years!

The point here is that any enterprise operating as a low temperature mausoleum with the added benefit of prospective resurrection, and doing so on a razor thin margin of costs, is very likely headed for trouble. And precisely because they are primarily a customer service organization engaged in selling only the first half of the “product” (i.e., cryopreservation and storage) they will simply not “get it” when the second half of the product is neglected or threatened (i.e., stewardship and resuscitation). Reanimation is a matter for our friends in the future, and an inevitable consequence of this is that day-to-day things that impact its likelihood today are likely to be viewed as of little or no consequence. Indeed, they are not even likely to be perceived at all. I gained enormous respect for Melody Maxim’s ability to inflict harm[2] when she correctly perceived that CI (and thus ACS) had surrendered all practical control over their patients to the Michigan Cemetery Board by the “simple” act of submitting to state regulation.

That and (many) other insights aside, the one of most relevance to this discussion happened when I was dozing on the couch in the reception area (the Russians proved equally exhausting and rewarding to travel with). As I went in and out of consciousness, I could hear the phone being answered at Alcor, and the first thing that caught my attention and increased my level of alertness for the next call was that most of the incoming calls were from people who were apparently inquiring about cryonics services. Maybe I was just there on an unusually busy day, but I heard several calls – more than two and less than five, in the hour plus interval I intermittently slumbered. The side of the calls I could hear went very much like this: “Alcor Foundation,” silence “yes we offer that.” Silence “Are you interested in the whole body or the neuro. The whole body is $200,000 and the neuro is $80,000. Silence. “The whole body is your entire body, and the neuro is just your head.” Silence. “We’re located in the Scottsdale Airpark, which is just outside of Phoenix, and if you would like to arrange a tour we would be glad to show you through our facilities.” Silence. “Most people pay for it with life insurance, and if you like, I can refer to our life insurance representative.” Silence. “Well, if you are ever in the Phoenix metro area, please consider making arrangements to see our facilities.” Silence. “Thank you.”

As I sat there, semiconscious, I had two recurring thoughts that played tag with each other in my fogged brain:

1) Are you interested in the whole body or the neuro? And would like fries and a coke with that?

2) Please, please, let me be dreaming.

I told Max about this and he expressed some concern, informed me that the person handling the inquiries was not a signed up cryonicist, but was nevertheless “a very good employee and very loyal to cryonics.” He told me he would look into the matter (after all, I was dozing) and that he would see about scripting such encounters should it prove necessary. As I sit here in Dulwhich, London, and watch the heavy gray North Sea clouds parade across the fast darkening sky whilst spitting rain, I shudder at the thought of the theatre d’absurb that scipt will be written and performed in.

There is a large and very material difference between continuing to advertise for and accept guests if you are a hotel with fire code deficiencies (that is aware of this and working to fix them), versus being a hotel that is actually on fire. It is a peculiarity of certain kinds of institutions that they will, in fact, continue to solicit and escort new guests to their rooms, even as fire from an already engulfed kitchen, barrels up stairwells with no fire doors. Such behavior happens not infrequently in enterprises where there is any material separation of “operations” from “feedback” (as any number of the recent real estate and financial debacles demonstrate).

What Next?

In my opinion, Alcor is a hotel on fire, already seriously engulfed, and with no plan of any kind, let alone a detailed one, for extinguishing the blaze and rebuilding the infrastructure. A better analogy might be a sinking ship – because the passengers can’t just stroll over to the venue across the street – they are stuck where they are. I expect that most reading this will tell me that this is not so, that I am mistaken, or that I am excessively pessimistic, or even malicious…and that’s fine. I’m not about insisting that everyone share my opinions. I may in fact be wrong. However, what I am not wrong about is that Alcor is profoundly dysfunctional, and that many discrete and general problems can be objectively identified that will likely lead to its eventual failure or replacement. I can also say with a high degree of confidence that those members who are not customers, are either aware of this situation, or are very dissatisfied with Alcor’s performance (particularly its wastefulness and low quality of service).

Opinions aside, what I believe is necessary, which in this case is both an opinion and a fact, is some sort of detailed, credible acknowledgement and understanding of the problems, coupled with a realistic plan for fixing them. Preferably a plan that does not involve asking members for yet more money to hire yet more staff.

Footnotes