Suspended Animation  
   
         
   
RAPID INTERVENTION

Mitigating ischemic injury may substantially reduce a cryonics patient’s risk of brain injury before and after cryoprotection.


Understanding Ischemia

A primary function of the blood is to transport oxygen and glucose to all living cells in the body, including brain cells. These cells require glucose as a fuel, and they use oxygen to metabolize it. Although the human brain comprises only 2% of total body mass, it accounts for about 20% to 25% of total oxygen consumption, and depends on an uninterrupted supply to satisfy its demands. Reserves of oxygen in the brain are extremely limited.

When blood flow ceases or is inadequate to oxygenate the tissue, it is known as ischemia. Many people have experienced mild, transient cerebral ischemia in the form of a “dizzy spell” or faintness, for instance, when standing up suddenly after lying down for a while. As blood pressure falls in the brain, cells receive less oxygen than they need, and the visual field may darken while sounds seem to recede for a couple of seconds. Then the pulse rate increases, blood pressure is restored, brain cells are resupplied with oxygen, and senses return to normal.

Cardiac arrest inflicts sudden and total ischemia, terminating the brain’s supplies of oxygen and glucose completely. Unconsciousness occurs within less than 10 seconds, and a flat EEG is seen after about 20 seconds1.

For the next four to six minutes, brain cells continue to burn some remaining reserves of glucose in the absence of oxygen. This can be compared with a flame on a gas stove which burns blue when oxygen is mixed with the gas but turns yellow, creating waste byproducts, if oxygen is insufficient. In brain cells, the transition from aerobic (oxygen-based) metabolism to anaerobic (oxygen free) metabolism creates byproducts including lactic acid. Acidity also increases as carbon dioxide (which is no longer being removed by the blood stream) dissolves in water to form carbonic acid. The increase in acidity alone has harmful consequences, but other processes also begin to disrupt the extremely complex chemistry of brain cells, jeopardizing their survival.

Cells normally use a large part of their energy to maintain a higher concentration of potassium salts and a lower concentration of sodium salts inside their membranes than outside them. When a cell runs out of energy, it cannot sustain these chemical differentials. Potassium leaves the cell and sodium enters, together with water, which causes cells to swell.

The imbalance of sodium and potassium results in the release of glutamate (glutamic acid), which is a neurotransmitter. This in turn triggers receptors which allow calcium ions to enter the cell, provoking a further release of glutamate in a positive-feedback loop. High levels of calcium eventually activate proteolytic enzymes that destroy many cell proteins (especially in cell membranes) and initiate apoptosis, causing cells literally to self-destruct 2.

Inhibiting Ischemic Injury

Suspended Animation uses three approaches to limit the cascade of harmful events that normally begins after the blood stops flowing.

1. Cardiopulmonary support
Chest compressions squeeze the heart, restoring some blood flow. The lungs can be ventilated to oxygenate the blood, although this may be contraindicated if warm ischemia has persisted for too long.

2. Medications
A variety of medications can block damaging biochemical processes or may help to mitigate their negative effects.

3. Rapid cooling
Hypothermia (lowered body temperature) slows the chemical reactions that cause injury. At normal body temperature, successful resuscitation becomes unlikely after more than five minutes without blood flow. If the body temperature is reduced sufficiently (for example, during hypothermic surgery), resuscitation may be possible after as long as one hour without a heartbeat.

 

Glossary


Apoptosis:
Controlled cell death.

Aerobic Metabolism: An energy generating chemical process in cells requiring oxygen.

Anaerobic Metabolism: An energy generating chemical process in cells not requiring oxygen.

Cryogenics:
The study of low temperatures.

Cryonics:
The practice of cryopreserving patients after legal death for long-term care at cryogenic temperatures until future advances make it possible to restore them to life. Also called human cryopreservation.

Cryopreservation:
Preservation of tissue or organs at cryogenic temperatures.

EEG:
Electroencephalography: measurement of the electrical activity of the brain.

Enzyme:
A protein that acts as a catalyst for biochemical changes, while remaining unchanged in the process.

Glutamate:
An amino acid and neurotransmitter.

Hypothermia:
A core body temperature (significantly) lower than 37°C.

Ion:
An ion is an electrically neutral atom or atom group that loses or adds one or more electrons. (e.g. calcium and sodium.)

Ischemia:
No or inadequate blood flow to an area of the body.

Metabolism:
All biochemical processes in an organism or cell.

Neurotransmitter:
A family of chemicals involved in communicating between neurons and cells.

Vitrification (in cryobiology): Rapid cooling of biological tissue below the freezing point without ice formation.

   
Why Ischemic Injury Matters
 
To maximize the chances for successful cryopreservation without ice damage, we must minimize the harmful processes that normally begin soon after cardiac arrest.

It’s reasonable to expect that nanotechnology may enable cellular repair at some time in the future, nevertheless, there are three vital reasons for minimizing ischemic injury:
   
1.
Protect a patient from all forms of injury. Since there is no comprehensive understanding of the mechanisms of memory or encoding of identity, the extent to which biological damage may be destructive is poorly understood.
   
2.
Biological damage may be harder to reverse than structural damage. After cells are destroyed, their chemical residues may offer few clues about them.
   
3.
When patients suffer long periods of circulatory arrest at room temperature, blood vessels may become blocked by atherosclerotic plaque that becomes dislodged, leukocytes and platelets sticking to the inner walls of blood vessels as a result of chemical imbalance, and swollen tissue constricting blood vessels. This makes the vessels harder to perfuse with a cryoprotective vitrification solution.
The development of organ vitrification has been a huge step forward for cryonics patients. However, if the circulatory system has deteriorated beyond a certain point, vitrification may be impossible.

The lesson is clear:

To minimize freezing damage, vitrification solution must be perfused throughout the brain.
   
To achieve this perfusion, blood vessels must be protected from chemical disruption and pressure from swollen tissue.
   
To achieve this protection, warm ischemia must be limited or eliminated altogether.

The only way to achieve this is through prompt intervention by team members who are present when cardiac arrest occurs.

 
More information on the pathophysiology of cerebral ischemia

Ischemic Cell Death in Brain Neurons (by Peter Lipton):
http://physrev.physiology.org/cgi/content/full/79/4/1431

The Pathophysiology of Ischemic Injury (by Mike Darwin):
http://www.alcor.org/Library/html/ischemic.html

Ischemia and Reperfusion Injury in Cryonics (by Ben Best):
http://www.benbest.com/cryonics/ischemia.html

References

1. Antonio E. Muniz, Cardiopulmonary Resuscitation (Humana Press, 2004), “Postresuscitation Cerebral Dysfunction,” p. 529
   
2. Paul Morley, Joseph S. Tauskela, and Antoine M. Hakim, Cerebral Ischemia: Molecular and Cellular Pathophysiology (ed. Wolfgang Walz, 1999), “Calcium Overload,” pp. 69–105