Does the Brain Die After a Few Minutes Without Oxygen?

The brain is more resilient than commonly believed

“Cryonics can’t work. Dead is dead! Besides, everyone knows that the brain dies after three to five minutes without oxygen.” We hear that often. Sometimes “everyone knows” means genuine established facts as in “everyone knows the Earth orbits the sun.” But often this means something completely different: It can mean that the speaker has heard the assertion a few times, assumed it to be a fact, and has not investigated further.

Most people have strong psychological barriers diverting their attention from issues closely related to death. Clear and certain answers are preferred to more complex and uncertain answers. “Dead is dead” is one of those mind-numbing expressions of avoidance. The claim about oxygen and brain death is another, if a little less stark.

If the assertion were true without qualification – and taking “death” to mean actual, final, irreversible death and not mere clinical death – this would be fatal for cryonics and other forms of biostasis. Even a quick look at the actual evidence shows this assertion to be incorrect or – to be charitable – correct only in specific circumstances.

What truth is there in the assertion? We can say that it correctly identifies a problem in specific circumstances. The truth is that if we try to resuscitate someone after more than 4 to 6 minutes without blood flow at normal body temperature the result is likely to be irreversible brain injury, coma, and eventually death. Oxygen deprivation will kill cells but not after just a few minutes. Even a few hours after cardiac death, the brain retains its structural and chemical integrity surprisingly well.

In the first hour or so with no circulation most of the problem is not with lack of oxygen but the damage caused when circulation is restarted. If brain death results, the cause would be better understood as restarting circulation without preventing damaging side effects. Damage done by getting things flowing again is called reperfusion injury or, sometimes, ischemia-reperfusion injury (IRI) or reoxygenation injury. Reperfusion injury is referred to as “paradoxical injury” because the act of restoring normal blood flow, meant as a therapeutic measure, actually induces damage.

It means the tissue damage caused when blood supply returns to tissue (reperfuses) after a period of ischemia or lack of oxygen (anoxia or hypoxia). Starved of oxygen and nutrients, during ischemia a condition develops so that when circulation is restored, inflammation and oxidative damage result from oxidative stress rather than normal function being restored.

Restart the heart and get blood flowing again and the brain will be well oxygenated, right? Alas no. The lack of blood circulation kicks off an inflammatory cascade. Inflammation closes off blood vessels (contributing to cerebral ischemia or brain swelling). Four mechanisms of injury have been identified:

• Oxidative stress in which the sudden reintroduction of oxygen leads to the generation of reactive oxygen species (ROS), which can damage cell membranes, proteins, and DNA.

• Inflammation: The restored blood flow brings immune cells that release inflammatory cytokines, further damaging tissues.

• Calcium Overload: Reperfused cells often experience calcium overload, disrupting cellular function and leading to cell death.

• Endothelial Dysfunction: Damage to the endothelial cells lining blood vessels can increase vascular permeability, contributing to swelling and tissue injury.

Reperfusion injury can worsen the extent of damage initially caused by ischemia, leading to worsened neurological outcomes after a stroke. Deprived of oxygen, brain will “die” (cease to function in a currently irreversible way) but not in minutes; more like hours. If we want to give the brain a sporting chance to recover then we should address the reperfusion problem.

And we do that! Not in all cases. Not in enough cases, but we do it. The interventions currently available to us include post-resuscitation hypothermia and support from hydrogen sulfide treatment, cyclosporine, TRO40303, stem cell therapy, superoxide dismutase, metformin, riboflavin, and cannabinoids. With effective interventions, reperfusion injury is not inevitable.

As interventions have improved people have been rescued after increasingly long periods without heart function. Clinical research shows that we have already extended the window for successful recirculation to 15, 20, or 60 minutes. There is no reason to expect zero further progress although further progress is not essential for biostasis to work.

Cooling the brain is the single most effective way to minimize reperfusion injury. Cooling helps address all three main causes of death in the post-resuscitation phase: continuing brain injury, continuing heart injury, and massive inflammation throughout the body leading to breakdown of the organs. Cooling reduces cellular activity, taking away the activation energy involved in the process of cell death. This helps cut the chances that a patient will have a seizure because the brain cells will have less energy to produce one.

A related but distinct complication is the “no-reflow phenomenon.” This means the tissue does not fully recover due to inadequate microcirculation. Despite reopening the major artery adequate blood flow at the microvascular level is not restored. This occurs due to persistent microvascular obstruction or damage, even after the larger vessels have been cleared. The mechanisms are microvascular obstruction, capillary damage, edema (swelling), and increased vascular permeability.

To protect the brain while restarting it we need to increase its supply of oxygen while reducing its need for oxygen until they reach a healthy balance. Effective cooling and good postresuscitation care can enable a patient to continue on living without the horrible burden of brain damage. Today, this practice goes under the group name of “therapeutic hypothermia.”

Therapeutic hypothermia took off in the 1990s due in considerable part to the work of Peter Safar. Safar discovered that reducing body temperature by three degrees Celsius after restarting blood circulation could double the time window of recovery from clinical death without brain damage from 5 minutes to 10 minutes. Since then this recovery window has been further expanded.

Peter Safar

Dr. Peter Rhee has used even lower temperatures to multiply the time available to perform surgeries that would otherwise be impossible. He has proposed reducing body temperature down to 10° C, extending the time available for surgery fourfold. (I was delighted to discuss this in person with Dr. Rhee when he visited Alcor in June 2014.)

Careful cooling and medication has made possible recovery without loss of brain function up to 16 minutes after the heart stops. Even after 60 minutes without blood flow, scientists have recovered normal electrical function in isolated mammalian brains after high pressure reperfusion. Another milestone: Whole cats have been recovered after one hour of no blood flow to the brain, although this did result in some neurological deficit.

We also know that living neurons can still be cultured from brains after 8 hours without blood flow. The basic structure of cells persists even longer than 8 hours – perhaps for several days. Electron micrographs of rat brains with cold cerebral ischemia showed structural signatures of energy depletion such as vessel leaking and chromatin clumping only after an hour at 37°C and after 24 hours at 0°C, with synapse degradation after 6 hours at 37°C and 1 week at 0°C. Evidence of advanced necrosis appeared only after 36 hours at 37°C and 2 months at 0°C.

Even with today’s medical technology, five minutes without oxygen need not be fatal. And this time limit has been extended multiple times. There is no reason to think that a limit has been reached. The period of time between the start of clinical death and successful resuscitation keeps stretching. In the not too distant future, we may be able to recover loved ones hours or days after they seemed lost to us.

Two points stand out here. The first is that these observations reinforce the idea that death is a process, not an event. With the right interventions that process can be slowed, halted, or reversed. Patients who would have been considered dead a few decades ago are now considered potentially recoverable and in need of critical care.

The second point is that whatever current limit exists for undamaged brain resuscitation, it is not a limiting factor for the workability of cryonics. The biostasis process is not trying to revive the brain today. The evidence shows that a good protocol can extend the period in which a brain circulation can be restarted without damage. That shows that the crucial cellular machinery is in place. But revival of biostasis patients will not be attempted for decades. By then, far more advanced protocols and sophisticated technologies will be available.

Sufficient damage may have been done to prevent us from successfully reviving a brain today but the medical technology of the future may be able to overcome the problem given that critical structure remains and that function can resume with a little help. In other words, today’s limited abilities to reverse brain injury do not mean that future methods cannot do better. Whether today’s limit for successful revival is 16 minutes or 60 minutes, we know that death comes gradually. So long as we intervene in the process of dying and halt it, plenty remains for us to work on with more advanced tools.

The 3-to-5-minute claim is one instance of the tendency to dismiss cryonics hastily on the grounds that “you’re working on dead people.” A bit of thought and knowledge of the current state of the art reveals that “dead” is a moving target and not a stationary point. What we need to do is to support the viability of the cells until they can be treated in such a way as to remain unchanged for many years until medicine’s ability to revive people has developed much further.