杏吧原创

Try resuscitating someone and the chances are you will fail. But Lance Becker is spearheading efforts to better understand death and use this knowledge to figure out how to bring people back from the brink. Amanda Gefter spoke to the man who is overturning everything we thought we knew about resuscitation

You鈥檝e been in emergency medicine resuscitating patients for a long time. How has that affected you?

The public watch TV shows like ER or Grey鈥檚 Anatomy and think that when we resuscitate people we bring them back most of the time. This just isn鈥檛 true. Today, the survival rate is probably less than 5 per cent, and in many major cities it鈥檚 probably less than 2 per cent. I still work in the emergency department, I still have to do the best I can to fix patients and I still lose patients. It鈥檚 a strong motivator.

What are the criteria for declaring someone dead?

It鈥檚 complicated. It is typically about both heart and brain function. If someone has a flat line and you can鈥檛 restart their heart with reasonable advanced therapies, then as a clinician I would say: I don鈥檛 know what their brain function is but their heart has not beat for an hour and I鈥檝e been doing CPR (cardiopulmonary resuscitation), I鈥檝e been giving them epinephrine, I鈥檝e been shocking them, I鈥檝e been doing all the things our current techniques tell me to do and it hasn鈥檛 worked. This heart is not going to restart and I can pronounce them dead.

There are also people who we pronounce dead with their heart still beating. Those are people who we believe to have 鈥渋rreversible鈥� brain injury. We call that brain death, whatever that might be, but we know that our current techniques won鈥檛 get them back.

Those are the two major criteria we would use to pronounce someone dead and I would suggest that both of them will undergo modification and alteration as we develop new techniques and prove that something we thought was irreversible is actually reversible.

How likely is it that someone who has had a cardiac arrest will be successfully resuscitated?

Large studies of people with cardiac arrest show that if they are treated within a window of about 5 minutes, we can keep 50 per cent of those people alive. After 15 minutes, that drops to 1 per cent or less. My aim is to make it as likely that people will survive after 15 minutes as after 5. There are a number of things we could do to make this happen: for example, better CPR as well as earlier and faster defibrillation.

Is there anything more fundamental you can do?

Death is an active process. After 15 minutes, many of our cells give off complicated biochemical signals that trigger their self-destruction, so one thing we can figure out is how to undo this death message. I think that鈥檚 something we can do chemically. Cooling the body can protect the cells, although nobody knows how, so learning how to do this more quickly will be important. We鈥檙e also trying to develop other therapies that will allow us to communicate better with cells.

So the death message causes the cell to shut down?

It鈥檚 more than that 鈥� some cells blow up. The intense reintroduction of oxygen to oxygen-starved cells makes some cells actively explode. It is a program, like the Star Trek self-destruct sequence, and we鈥檝e only just begun to learn about it. Other cells respond by quietly committing suicide. When cells die, they don鈥檛 just run out of gas, they flip a series of switches that set off a self-destruct sequence and each cell kills itself in a very active and intentional way.

鈥淲hen some cells die, they explode. It鈥檚 like the Star Trek self-destruct sequence鈥�

What provokes the death message?

There are competing chemical pathways in cells. We normally live with a few death signals and a few life signals that usually stay in balance. When the blood flow stops 鈥� a process called ischaemia 鈥� the death signals start to increase. The life signals try to keep up, but we鈥檝e learned that the way we restore oxygen when we restart blood flow actually flips the balance so the death signals dominate.

So giving oxygen in resuscitation is actually a bad thing?

Giving oxygen can be a double-edged sword. You鈥檝e got to have oxygen, but it has some positive effects and some negative effects. It was a big surprise when we first learned this. We grew cardiac cells that actually started to beat, and then we took their oxygen away. They stopped beating and just sat there. They didn鈥檛 look too healthy but they didn鈥檛 look dead. Then we gave the cells back their normal oxygen and under the intense conditions of reperfusion, they suddenly exploded.

We wrote it up and sent it to a journal, but they rejected it immediately, saying it couldn鈥檛 be true. So we did more tests and were eventually able to publish our findings. It sparked our whole line of research into what we call reperfusion injury 鈥� the idea that giving the cells oxygen can kill them.

How can you improve that situation?

It may come down to new drugs and devices, as well as figuring out where exactly the death signals are coming from and somehow stopping them.

I think of the cell as being booby-trapped for death and there鈥檚 actually an important reason for this. There are cells all the time that we have to kill off 鈥� old cells that aren鈥檛 working too well, malignant cells that we don鈥檛 want to grow into a cancer, infected cells that we don鈥檛 want infecting the rest of the body. There鈥檚 no way to have multicellular life without having very active death pathways. So we think that after ischaemia there鈥檚 a response that tells more cells to die. If we can temporarily put that on hold, we can make significant headway.

How can you stop cells dying after ischaemia?

We can work on how we give oxygen and we can learn more about how mitochondria handle oxygen. A point of real surprise for me was when many indicators started to point to mitochondria as being not the organelles of energy, as I thought they were, but the organelles that control death. Many of us grew up thinking that mitochondria provide energy for the cell, but it turns out that one of their most important functions is cell death. That鈥檚 a very new understanding. There are actually scientists who say that of the two functions 鈥� death and energy production 鈥� the more important one is death.

One of the differences between our, eukaryotic, cells and bacteria, which are prokaryotic, is that bacteria lack mitochondria. If you鈥檙e a bacterium, what is your goal in life? To be two cells. What cells in our body are sort of like that? Cancer cells. So in many ways, cancer is a very natural thing, it鈥檚 a throwback to the way our cells behaved before they had mitochondria.

So could studying cancer help you improve resuscitation techniques?

I think cancer and resuscitation are two sides of the same coin. One of the things we鈥檝e done at Penn is brought in cancer biologists to think about resuscitation. Chemotherapy is something that promotes apoptosis, or cell death. What I want to do is to temporarily inhibit apoptosis. Some of the things that don鈥檛 work for cancer might be terrific after cardiac arrest. That鈥檚 why we need this interdisciplinary team.

If you could extend the resuscitation window to 15 minutes, is there a quality of life issue? It鈥檚 absolutely important that while we extend this window, we bring people back with good brain function. Nobody wants to be bringing people back who are seriously impaired. But we have to be realistic about this. Things happen slowly in medicine. As we creep forward we probably will bring back some people who have brain injuries before we figure out how to prevent this.

Are physicians going to have to rethink when they can declare someone dead?

I believe so. I believe it will be pushed back. But physicians are very cautious and fairly conservative, so we鈥檙e going to have to do some things to convince people that we鈥檙e right. We have a lot of work ahead of us. That鈥檚 why we need a big team that鈥檚 committed and focused on making that happen, and doing it the right way 鈥� doing solid scientific trials, publishing in the best of journals鈥� that鈥檚 what we鈥檙e committed to. It won鈥檛 happen overnight, we鈥檙e here for the long haul. The field of resuscitation science is in its infancy and we鈥檙e in the process of learning about it. That鈥檚 why I鈥檓 happy to be in it.

Death 鈥� Delve deeper into the riddle of human mortality in our special report.