“Stand clear,” he warns. If Adam were a real person, he’d be puffing out his chest and strutting forward with self-importance. Now he’s the center of attention, and he knows it. He’s the man.
The news of ventricular fibrillation seems to breathe new life into the team, too, no pun intended. Now they know what to do, and in fact this is probably something they’ve done—as practice or for real—dozens if not hundreds of times.
Things start to move quickly. The protocol for ventricular fibrillation begins with three “stacked” shocks, and Adam is delighted to administer the first. Mark doesn’t have a pulse, someone announces. And a look at the monitor makes it clear that he’s still in ventricular fibrillation—or, in medical-speak, “v-fib.” So Adam delivers the second shock, with much the same result, which is to say none at all.
Nevertheless, Adam is still the man. All eyes are on him as he winds up to administer a third shock. He does so with gusto, announcing his intent with a gleeful “Stand clear!”
Then the doctors and nurses descend like birds diving onto a pile of bread crumbs. Mark is still in ventricular fibrillation, and still, there’s no pulse. So they follow a carefully choreographed protocol of CPR, shocks, and drugs.
Mark has an endotracheal tube in place, and an anesthesiologist is crouched over him, squeezing a bag that forces 100 percent oxygen into his lungs. Now that the intensive phase of shocks is over, and now that Adam is no longer shouting “Stand clear” warnings, the team can restart CPR. A nurse and a medical student are taking turns doing chest compressions at a rate of about 120 per minute.
The team gives Mark a dose of amiodarone, a drug that stabilizes cell membranes and that is used to prevent or control abnormal rhythms like ventricular fibrillation. It doesn’t have any appreciable effect on Mark, so Adam jumps into the fray and administers yet another shock. Then the team follows up with a second dose of amiodarone.
It’s at this point that I notice one of the anesthesiologists looking at his watch. At first it strikes me as odd that a physician would be more concerned about an impending lunch date than he is about Mark’s future. But then I get it. He’s looking at his watch to see how long Mark has been without a pulse. And a brief frown tells me that he’s not liking what he’s seeing.
It’s been—I glance surreptitiously at my own watch—ten minutes. That’s ten minutes during which Mark’s fictional brain is getting by with no more fictional blood flow than what these intermittent chest compressions provide. CPR is better than nothing, but it’s not the same as a normal heartbeat. The anesthesiologist is thinking, probably, that someone had better pull a rabbit out of a hat very soon. And as I look around the room, I notice that others on the team are looking worried too.
Then Adam delivers another shock, which the team follows with a dose of intravenous lidocaine. Lidocaine is one of the most venerable drugs in the crash cart pharmacopeia and is also widely used as a local anesthetic. It works by blocking the channels in a cell membrane that let sodium in. Since the flow of sodium is a key part of the process that changes the electrical balance of a cell, blocking sodium effectively blocks neural impulses like a pain signal or, in this case, an abnormal heart rhythm.
Sometimes it works. This is not one of those times. But since Adam is eager to administer yet another shock, the team presses on.
Then, during what’s become an almost perfunctory post-shock check, one of the nurses notices that Mark’s heart has slipped into a sinus tachycardia. That means that a normal (albeit fast) rhythm is back. All around the room, there are expressions of triumph and relief. For a moment, the din is so loud that it’s hard to hear Adam’s forlorn announcement that “the rhythm is sinus.” He sounds almost plaintive, as if he realizes that pretty soon everyone will ignore him and shortly thereafter, he’ll be powered down and wheeled back into a closet.
Now Mark has a pulse and a blood pressure. The resistance against the ventilator is signaling to the team that he’s waking up. So they give him lorazepam, a benzodiazepine antianxiety drug (like Valium), to calm him down. Then they prepare him for a quick trip to the ICU.
Greg thanks the team and reassures them that Mark has survived. All is well. They’re done.
There are high-fives all around as the team heads off to debrief. But poor Adam, lacking arms or hands, is left out of the victory circle. Almost as an afterthought, one of the last nurses out the door reaches over and flicks Adam’s power switch as she passes. I swear I can hear a despondent sigh as his lights flicker and then go out.
Everyone’s gone except Mark and me, and I’m thinking that he’s a very lucky mannequin. He was only “out” for fifteen minutes, so this little interlude without a heartbeat probably didn’t hurt him too much. He’s still as smart as he was before we started, although, since he’s a mannequin, that’s not saying much.
For a real person, though, with real family members out in the waiting room, fifteen minutes is an uncomfortably long time. With each passing minute, the cells that depend on blood and oxygen begin to die. The brain is especially sensitive. As more time goes by without a heartbeat, there’s a smaller chance that you’d be able to play catch with your son or go horseback riding with your daughter if you come out of it, or that you’d be able to recognize your spouse.
So the science of reviving someone like Mark is only part of the resurrection process. It’s one thing to restart a heart. But protecting a brain and other organs until the heart starts beating again is a whole different problem. We’ve seen how to get a heart working again, but how do we help brains like Mark’s to get through incidents like these more or less intact? In other words, how was Anna Bågenholm able to go back to an almost normal life after what she experienced?
The answer, it turns out, is inside our cells. Every single one of them. Figure out what happens inside our cells when they’re deprived of blood flow as Mark’s were, and you’ll figure out how to protect them.
WHAT HAPPENS WHEN CELLS GO BAD
What happens when our vital organs are deprived of blood flow and oxygen? And how can we protect those organs when the heart takes a vacation the way Mark’s did? To find out, I’m listening to a man who arguably knows more than anyone else about how our organs respond when the body they’re part of is having a very bad day.
Dr. Lance Becker is an internationally recognized researcher in the science of resuscitation, and he looks the part. He’s short, balding, and wears square geeky glasses. In fact, if you saw him standing in a hospital hallway, in his plain trousers, open-collar shirt, and thick buttoned shawl sweater, you’d say to yourself: “That’s a guy who spends a lot of time thinking about how our innards work.” And you’d be right.
Becker studies what happens when cells are deprived of oxygen and when they begin to fall apart. For him, cell innards really only begin to be worthy of our attention when things go very, very wrong. In this respect, he’s a little like a forensic psychiatrist who couldn’t care less whether you love your spouse but who becomes very interested in you once the police find eighteen decapitated bodies in your basement.
I’ve heard that Becker is a fantastic teacher, and so in order to hear about his research, I’ve joined a classroom of medical students who are taking an elective course on resuscitation. Young and enthusiastic, they all want to save lives. And today Becker is teaching them how to do it.
As he tells us about how cells are damaged by a lack of oxygen, it turns out that a cell’s descent into pathology is both unbelievably complex and also brutally simple.
The problem, he explains, is energy depletion. Adenosine triphosphate, or ATP, is the main energy source of cells. It’s the form in which energy can be stored and used, but the problem is that there’s not very much of it in our cells at any given time. So without a constant flow of glucose and oxygen, it vanishes.
The result is cell death, also known as apoptosis. Shortly thereafter, you get person death. T
his is known simply as death.
But that’s just a description of what happens. The question is, how do we slow that process or avoid it altogether? The place to look for the answer is inside the cell. And we’re about to get the grand tour.
The first stop on our tour is the cell membrane, which is a thin double layer of lipids (fats) and proteins that keeps a cell’s innards inside and the rest of the world outside. One key function of this membrane is to ensure that cells contain the right concentrations of ions, which are charged atoms or molecules. In a healthy, non-dead person, there’s more sodium outside cells and more potassium inside. (Each has a positive charge, so their concentrations balance each other.) These gradients are maintained by pumps in our cell membranes, which require energy in the form of ATP. When there’s a shortage of ATP, these ions begin to flow freely (more or less). When that happens, they end up in places where they shouldn’t be.
Think of the cell membrane as an electric fence surrounding a Kenyan game reserve. The fence keeps people and livestock out, and lions and giraffes inside. And if one or two should slip through, there’s a team of park rangers who drive them back to where they belong. But now imagine that the park’s budget is tight, so they cut the power to the electric fence. They also fire the park rangers. Now you have giraffes sticking their heads into people’s kitchens and hapless cows wandering into the jungle, becoming an ambulatory buffet for the lion population.
As you can imagine, once that starts happening—in cells and in the jungle—everything goes to hell pretty quickly. In the brain, wild swings in ion concentrations prompt neurons to release all of their neurotransmitters in a final kamikaze burst, leading to dramatic increases in unfocused neural activity—essentially many tiny seizures. That’s bad.
In the brain and elsewhere, enzymes known as lipid peroxidases break free. These enzymes steal electrons from the lipids in the cell membrane, breaking them down. That’s really bad.
Finally, all of these events also lead to problems outside the cell, and particularly in the bloodstream. Out there, inflammation, a lack of oxygen, and general chaos cause platelets to aggregate and clot in small microvessels. This in turn results in further decreases in blood flow, so less oxygen and glucose get into cells. Then ATP becomes further depleted, and more cells die until the organism itself dies. That’s about as bad as it gets.
Becker is explaining this descent into anarchy, yet he doesn’t seem bothered in the least. In fact, he’s grinning. I’m thinking that’s because he’s got a happy ending hiding in there somewhere. And he does, but it’s not exactly what I’m expecting.
As these processes reach a critical point, cell apoptosis pathways are activated. In English, this means that our cells, sensing perhaps that things are looking grim, decide that now would be an excellent time to become dead. And so they check out, leaving someone else to fix things. Or not.
Why is Becker smiling as he’s explaining that cells die? It’s not exactly a happy ending. But it is. It’s what helps us survive a cardiac arrest. And the secret of how that happens can be found in our mitochondria.
Mitochondria are organelles—structures within a cell—that are less than one one-thousandth of a millimeter long. There are a couple of odd things about mitochondria. The first is that they have two membranes, folded over each other like the inner and outer lining of a sleeping bag. The second is that mitochondria come equipped with their own stash of genetic material. This makes them like cells within cells.
The most interesting thing about mitochondria, though, is that they’re responsible for creating ATP. To accomplish this trick, they’re equipped with an electron transport chain that uses the energy generated by moving electrons from one molecule to another (usually oxygen) to add a phosphate ion to adenosine diphosphate (ADP). ADP plus this third phosphate produces ATP.
You can think of this conversion of ADP to ATP as refining a fuel into a more potent source of energy. An oil refinery starts with crude oil, which isn’t useful for much of anything. But with the addition of energy in the refining process, you get gasoline, which is useful for all sorts of things, like powering a 1978 MG, for instance. So the process adds energy, which is stored in a more concentrated form until it’s released.
That analogy also helps to explain why mitochondria close up shop when things aren’t going well. In a cell, oxygen drives the conversion of ADP to ATP in the same way that electricity is used to power the processes in a refinery that extract gasoline from crude oil. But if the process is disrupted, then the electron transport chain in mitochondria leaks electrons.
The result is pretty much what you’d see in an oil refinery that’s on fire. This is why refineries need a safety switch that can shut down operations to prevent a massive explosion. Trip that switch and the refinery shuts down and volatile products like gasoline stop flowing out, hopefully avoiding a front-page disaster.
Mitochondria seem to have a similar safety switch. They produce ATP when things are good, but when the cell they inhabit loses its supply of oxygen, they shut down. If that causes cell death, that’s OK with them because the benefits of that strategy, these little organelles seem to think, outweigh the risks.
Becker is oddly placid about this predilection for self-destruction. More placid than I would be, if all of my mitochondria were thinking about hanging up a GONE FISHING sign. But this impulse to bail out is perfectly normal, he says. It’s not pathological. Our mitochondria are just doing what they’re programmed to do.
Remember all of the destruction that happens as cells are deprived of oxygen? Chaotic neural activity? Enzymes that dissolve cell membranes? Mitochondria are programmed to avoid all that by shutting down in a controlled way.
Becker isn’t happy about this outcome, of course. He knows better than anyone how devastating brain injury can be. No, he’s happy simply because these mitochondria are behaving predictably. Their behavior makes sense. And if you’re a scientist, that’s good news because if you know what a mitochondria is going to do, then at least you have a chance to “reason” with it.
But how?
“What do we do for patients who are in crisis?” he asks the class, changing the subject. “For instance, a patient in cardiac arrest, a patient whose heart isn’t beating—what sorts of things do we do?”
“You’d try to restart the heart,” offers one student.
“Why?”
“To increase blood flow?”
Becker nods. “What else?”
The group offers a long list of other suggestions. Oxygen? Mechanical ventilation? Drugs to increase blood pressure? Becker nods and smiles.
All of these interventions, Becker explains, give the mitochondria more energy. More oxygen, more blood flow, and a higher blood pressure all deliver more energy to the mitochondria, making them work harder. We’re shoveling more energy into cells that can’t deal with the energy they’ve got. We are behaving stupidly.
The problem with resuscitation techniques as we use them now is that they’re designed to flood mitochondria with more energy, at precisely the point when those mitochondria are trying their darnedest to shut down. Think back to the refinery analogy. Imagine the moments after a serious refinery accident, when all the safety mechanisms are activated and the plant shuts down. Now imagine wading into the middle of a raging petroleum fire and wrestling the safety valve open.
When Mark the mannequin experienced cardiac arrest, the resuscitation team gave him chest compressions, oxygen, and epinephrine. In other words, all sorts of things that mitochondria in trouble really don’t want. And that, Becker thinks, is a really, really bad idea.
And it gets worse. The damage that physicians can do, despite our best intentions, doesn’t stop after resuscitation is successful. In fact, much of what we do in the name of good medical care after we restart someone’s heart is just as dangerous and misguided. To illustrate that new danger, Becker hits us with
a new analogy.
“Imagine,” he says, “that you buy a car. And imagine that, due to carelessness, you let it run out of gas. You trek to the nearest gas station, buy a gallon of gas, and fill it up. Then you turn the ignition and . . . the car explodes.” He turns deadly serious, looking out under arched eyebrows for dramatic emphasis. “Would you have bought that car if you knew this was what was going to happen?”
The students around the table are shaking their heads and I follow suit. No. I most certainly would not buy that car.
Becker smiles. He explains that this is a pretty good description of what happens inside a cell after it’s been deprived of oxygen. Like a car, our cells run fine when the tank is full. Just as predictably, our mitochondria shut down like a car does when the tank is empty.
But if we try to force fuel into mitochondria that aren’t ready to handle it, they’re not happy. Like that exploding car, the refueling process is spectacularly disastrous. Not only do we have to be careful about what we put into people during cardiac arrest, we also have to be careful about what we put into cells after we get the heart beating again.
But what’s the alternative? We can’t just let cells die. We have do something, don’t we?
Actually, it turns out that we don’t. We don’t have to do anything. We can, quite literally, walk away.
THE DEEP-FREEZE MENAGERIE
How can we protect cells—and organs—by walking away? One answer is the one that the Russians thought of two hundred years ago. Cold.
We’ve known about the benefits of cold for a long time. Longer, even, than we’ve known what mitochondria are and what role they play in this drama. One of the first—or at least one of the most prolific—researchers to study the Russian Method was Dr. Wilfred Bigelow, a Canadian cardiologist. Initially at least, he wasn’t interested in resuscitation, but rather in preserving hearts and brains during surgery.
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