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LE Magazine April 2002
Life-Saving Work at Critical Care Research
Cardiovascular disease is the leading cause of death in the United States.[1] According to various estimates, between 225,000 and 350,000 people die suddenly from cardiac arrest each year.[2] We can minimize our risk of a heart attack by exercising, watching our weight and blood pressure, and using appropriate dietary supplements-yet still some danger remains, and even very healthy people may go into arrest if they suffer unexpected accidents.
Unfortunately, paramedics often can't reach a cardiac patient quickly enough, if the emergency occurs outside of a hospital. Brain death begins after just 5 minutes, and becomes irreversible soon after that. This is why the survival rate after sudden cardiac arrest is a mere 5%.[3]
Still, in urban areas, paramedics can often reach a patient within ten minutes. If there were some way to double the time that a patient can last without a heartbeat, probably about 100,000 lives could be saved annually.
Twenty years ago, a resuscitation researcher named Peter Safar discovered a way to achieve this. Safar had introduced the technique of CPR to the United States during the 1950s. In 1980 he found that mild hypothermia-lowering the body temperature by about seven degrees Fahrenheit-enabled dogs to recover after ten minutes of arrest.[4]
To achieve fast cooling, Safar used extracorporeal bypass, which entails piping the blood out through a cooling unit and then back into the body. Safar suggested that paramedics might be able to do this in the field, but virtually no one agreed with him, because bypass is such a major operation.
Unfortunately, there was no obvious alternative. Packing a patient in ice, for instance, cools the skin but doesn't extract heat quickly enough from inside the body. Thus, for more than a decade, no one could see a way to apply Safar's remarkable discovery that the onset of brain death could be delayed simply by reducing body temperature.
In 1997 a researcher named Michael Darwin had an idea: Why not use the lungs to cool a patient? Darwin at that time was director of research at 21st Century Medicine, a company largely financed by Life Extension Foundation. He saw that since the lungs are subdivided into tiny compartments (alveoli) and densely wrapped in blood vessels, they provide an excellent opportunity to cool the blood, which can then cool the brain after the heart has been restarted with a defibrillator. Using cold air to cool the lungs isn't practical, because gases don't transport heat rapidly enough. But a cold breathable liquid could do the job, and Darwin knew that a whole chemical family, called perfluorocarbons, has the unique ability to transport oxygen and carbon dioxide.
Darwin and his colleague, Steven B. Harris MD, tested their ideas and found they could reduce the brain temperature of dogs by 13.3 degrees within 18 minutes. Of a dozen anesthetized animals that underwent the procedure, all were revived successfully. Harris developed a theory to explain why hypothermia prevents brain damage: He compares it with the first-aid procedure of putting a cold compress on a sprained ankle. Even if you wait ten minutes before applying the compress, it still helps to alleviate long-term trauma and swelling. Almost certainly, a similar process occurs in the brain.
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| Dr. Harris checking data on a Critical Care Research experiment. | |
Currently this exciting work is being pursued by Critical Care Research, a company that grew out of 21st Century Medicine and is being wholly funded by Life Extension Foundation. The work has been published in the Journal of Resuscitation, in the longest paper ever to appear there. The team from Critical Care Research made a presentation at the annual conference of the Society for Critical Care Medicine in January of this year.
Harris is now President of Critical Care Research. We asked him for an update on his company's work.
Life Extension Foundation (LEF): Why has resuscitation research developed so slowly?
Steven Harris (SH): Historically there have been three main approaches. One is raising blood pressure after restarting the heart. The second is using drugs that block toxic chemicals and neurotransmitters which are released after brain cells use up all their oxygen and glucose. The third method is to cool the brain after resuscitation.
Raising blood pressure works because, when the brain runs out of energy, water leaks out of capillaries while leaving the red cells behind. You get red-cell sludge, and higher blood pressure is thought to blow the sludge out. However, I don't think this technique will be used anytime soon, because if someone has had a heart attack, increasing the blood pressure may be very difficult. Also, you have to have a healthy heart in a young person.
In 1992, we began our work using the second approach-drugs to block the toxic cascade that occurs after cardiac arrest. Then we read about Safar's achievements using hypothermia, and decided to add it, using extracorporeal bypass, as he had done. Two of our dogs survived after more than 14 minutes of arrest, and one after more than 15 minutes. Having proved that we could get good results, we decided to look at better ways of inducing hypothermia, and Mike Darwin came up with the idea of breathable liquids.
LEF: Do you still plan to augment hypothermia with the drug cocktail that you developed?
SH: Unfortunately, with a drug cocktail, the FDA requires us to test each drug separately and prove that it is effective. But these drugs aren't effective if they are applied individually to a human patient. They only work if they are used together, probably because there are so many different kinds of free radicals that we have to block, and neurons can be killed by many different things. Since each drug inhibits a separate process, you have to stop them all to avert brain damage.
LEF: None of the drugs in your cocktail has any effect on its own?
SH: Some resuscitation drugs have been proved individually in animal trials, where the animals are all identical, and circumstances can be controlled perfectly. In human trials you don't know exactly how long the heart has stopped, and people's ages are different, and their genetic backgrounds are different. To overcome these variables, a drug would need to have a huge effect, and it doesn't.
So, this is mostly an FDA problem. The FDA doesn't like a combination treatment when the individual drugs have not been approved. This doesn't make any sense to me. Also, the FDA requires us to explain the mechanism by which the drugs work, and we lack the knowledge to do this in detail. We just have results proving that they do work. We resorted to hypothermia partly because using drugs is so problematic.
LEF: How exactly does hypothermia work?
SH: It has an effect on a whole variety of problems, from neurotransmitters to free radicals. It is many treatments in one. But it has to be applied fast. Peter Safar found that after 15 minutes, hypothermia was no longer effective on the brain.
To do it quickly, you either have to get into a major artery within fifteen minutes and connect to a machine, or thread a catheter into the brain to inject cold saline-or you have to cool the blood some other way. The way we chose was to put cool fluid into the lungs. Water cannot be used, because it causes damage. The only safe fluids to use are perfluorocarbons, which are medium sized molecules, usually about eight carbon atoms and perhaps 16 or 17 fluorine atoms.
LEF: How do you hope to apply this in practice?
SH: A device to deliver cold fluids has to be portable. We have built one weighing less than 50 lbs. It uses ice to cool the perfluorocarbon liquid, because ice extracts more heat, per gram, than almost anything else. We need less than five pounds of ice to lower a subject's temperature by seven or eight degrees Fahrenheit. Currently we have some prototypes, but the pump needs to be redesigned. That's easy, we know what to do. After that we will reduce the weight of the unit, and look at different perfluorocarbons, to find the one that is least damaging to the lungs.
LEF: What kind of damage do you see?
SH: It's minor. It's caused by the pressure of the liquid, although we don't know the complete nature of it. We'd rather it didn't happen. But there's every evidence that the lungs heal themselves with no scarring.
LEF: When will we see this technique tested on human patients?
SH: I think the first human trials will be done in Latin America or India, because they don't have the FDA to cope with. I imagine that small trials in South America would be published in journals, and this would create political pressure-and sooner or later the news will get into the New England Journal of Medicine. Eventually there will be sufficient demand for this technique to force the issue, because of the number of lives it can save. It also has uses outside of cardiac arrest. It could provide a natural treatment for drowning. Fresh water and sea water damage the lungs, because the proportion of saline is wrong. The faster you get them out of the lungs, the better, and if you flow in some perfluorocarbon, it's denser than water, so the water floats out.
LEF: There's been a lot of publicity suggesting that defibrillators should be more widely deployed, to restart the heart after cardiac arrest. Would this reduce the need for hypothermia?
SH: If you have a heart attack in an emergency room, with a defibrillator just seconds away, you still have only a 65% chance of surviving. Deploying defibrillators is certainly valuable-but we can make all the people who go into arrest for 10 minutes look as if they have only been down for five minutes. That's a unique capability.
LEF: Are you faced with institutional inertia, as well as obstructive regulations?
SH: Of course. The irony is that I can explain this technique more easily to lay people than to physicians or the government. Physicians will be concerned that there's a little lung damage-but people will survive it, whereas after 10 minutes of cardiac arrest, without hypothermia, their chance of survival is virtually zero. So, this is definitely worth doing. It's difficult to communicate the idea right now, but in 20 years I think it will all seem obvious.
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| Sandra Russell (left), Staff Scientist, and Joan O'Farrell, Chief Operating Officer, Critical Care Research, in one of the company's laboratories. | |
References
1. American Heart Association at www.americanheart.org
2. The American College of Emergency Physicians at www.acep.org, and the Cardiac Arrhythmia Center at www.cardiacarrhythmia.org
3. The Red Cross at www.redcross.org
4. Discover magazine, October 2001.
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