Getting the human
is not an
impossible task. Cardiopulmonary resuscitation—a simple but critical manual procedure perfected at Johns Hopkins—can kick-start a heart back into rhythm, and the proliferation of portable, easy-to-use heart defibrillators (another device refined at Johns Hopkins) give an even better chance for survival.
Still, more than 460,000 Americans die from sudden cardiac
arrest every year—a toll that swells to some 17 million worldwide. The survival rate for people who suffer cardiac arrest outside a hospital is very, very low; it’s currently less than 10 percent. Mere minutes mean the difference between recovery from coma and death. “From studies, we know that if a person loses his pulse for more than six minutes and requires more than 15 minutes of CPR to regain an adequate pulse, there’s very little chance of meaningful recovery,” says Romergryko Geocadin, director of the Neurosciences Critical Care Unit at Johns Hopkins Bayview, and associate professor of neurology, neurosurgery, and anesthesiology, critical care medicine.
That’s because the real crisis faced by those who suffer cardiac arrest lies not in the heart—but in the head. A brain completely deprived of oxygen- and nutrient-rich blood begins to suffer damage almost immediately. “Within three to five minutes, that blood delivery stops,” Geocadin says. “Everything is shut down. There is a sudden and total cessation of blood flow that strikes the entire brain—boom! Cardiac arrest leads to brain arrest.”
By the time an ambulance arrives and paramedics use a defibrillator, most of those who are initially resuscitated will die in the hospital or remain in a vegetative state. Of the less than 20 percent of people who are successfully resuscitated, less than 10 percent recover their full cognitive abilities.
“If the heart is restarted within three to four minutes and blood flow is restored to the brain, there’s a very good chance of recovery,” says Nitish Thakor, principal investigator for the Neuroengineering and Biomedical Instrumentation Lab at Hopkins. “If it takes seven to nine minutes, or prolonged CPR, the outcome in terms of survival and intact neurological function is very poor.”
About six years ago, Thakor and Geocadin began to focus on a potential change in the focus of treatment for cardiac arrest victims. Traditionally, the focus has been, “Let us save the heart,” Thakor explains. “But it seems like maybe we should now focus on saving the brain. It was exactly this recognition that led to our work. You know that saying, ‘It’s the economy, stupid’? Well, for us, ‘It’s the brain, stupid.’”
That simple recognition has led to an intriguing, challenging, and little-explored path for research. “This is something of an ideal project for me,” says Thakor. “I worked on the heart for 10 years. I’ve spent the past 15 years working on the brain.”
Thakor describes his co-investigator as one of the few neurologists who has been focusing on the link between cardiac arrest and neurological damage. “In a crowd of cardiologists, here’s this one neurologist saying ‘Brain! Brain! Brain!’”
“There has been a lot of work on brain protection in the field of resuscitation medicine, and also in the field of neurology,” Geocadin explains. “Both fields have progressed almost independently, and it was rare to put those groups together. This is where my new drive is coming from.”
Creating a protocol to treat the brain during and after cardiac arrest has proven to have no simple steps. First Thakor and Geocadin needed to ask more questions about cardiac arrest and resuscitation in a laboratory model—work that showed the need for a simple device to accurately detect brain injury and monitor brain function. But before they could even invent that device, they had to create a new, more informative standard by which brain activity can be measured at the patient’s bedside, because none existed.
Unlike the heart, the brain has no easy central electrical signal to detect; the electroencephalogram (EEG) is really the only portable bedside device that exists to see what’s going on inside the brain. But interpretation of EEG brain waves is difficult for emergency responders who haven’t had special neurological training. “Wouldn’t it be great to have a brain monitor?” Thakor recalls thinking.
But the two researchers realized that they needed to start by creating a simple standard of brain measurement that’s easily understood by doctors and nurses.
“When you go to the cardiac ICU, what is one of the key tools that leads to successful cardiac treatment? The EKG [electrocardiogram],” says Geocadin. “In real time, you can see what effect key treatments are having. When you’re in the Neurological Critical Care Unit, outside of the pressure sensor in the brain, there’s no objective monitor that ICU personnel can easily and readily use.”
The need for a new bedside device to measure the health and performance of the brain was critical. “All the existing tools in neurology are either invasive or too complex or too large for the bedside—things that produce great neural imagery are all somewhere else, such as the basement of the hospital,” says Geocadin. “Is there anything we can learn from an EEG? We went back to the laboratory. Nitish is one of the best signal processors in the world. He looked at [the data from the EEG] and said, ‘Oh, I can put this in an algorithm.’ And we found something. We designed an algorithm that captured the essential aspects of brain injury.”
Thakor and his postdoctoral fellows, Hyunchool Shin and Youngseok Choi, developed a new measurement of brain waves and activity called Information Quantity, or IQ. It’s a measure of the brain’s entropy, the natural disorder of an immensely complicated organ filled with some 100 billion neurons. IQ looks at the complexity of the activity going on in the brain, rather than trying to decipher what all of the various brain waves (alpha, beta, theta, delta) are specifically doing. The researchers realized they could measure the entropy of the system and use that to create a scale and baseline of cognitive function.
“When we put IQ in, everything fell into place,” says Geocadin.
The resulting measurement data, called quantitative EEG and paired with IQ (qEEG-IQ), provide the kind of real-time information that physicians need to monitor the brain during and after cardiac arrest. Some of Thakor’s former students have even formed a start-up company to develop the new qEEG monitor.
While that qEEG monitor underwent an NIH-sponsored clinical trial in collaboration with emergency physicians and neurologists, what Thakor and Geocadin needed next was a treatment for an oxygen- and nutrient-starved brain. In February 2002, an article called “Hypothermia to Protect the Brain” was published in the New England Journal of Medicine. “The hypothermia study came out,” Geocadin says. “And things got very exciting for us.”
The study showed that the application of hypothermia to the brain—simply cooling the organ down—protected it from suffering damage during prolonged lack of oxygen and nutrients. Researchers in Europe and Australia cooled down the brains and bodies of cardiac arrest victims. “In Europe, they used a very complex contraption, sort of a self-chilling cocoon,” Geocadin says. “In Australia, they simply used packed ice. Both worked.”
The problem is that while physicians and researchers now know that hypothermia is effective, they have no way of telling if the brain is responding to their treatment at the time of cooling. “So they used a standard temperature range and hoped for the best,” Geocadin says. Currently, cooling leads to a good outcome for one of every six patients.
“The best method of treatment doesn’t yet exist,” Thakor notes. “What temperature should we freeze you to? Twenty-eight degrees? 32? 36? How soon after cardiac arrest should we apply coolant? Currently, we’re cooling people within 24 hours of cardiac arrest. It would seem that earlier is better, but we don’t know yet. How deep do we apply the cooling? And for how long?”
That’s only half of the problem. Warming up a chilled brain presents a completely new set of questions. Just like running a very cold hand under hot water produces pain, the same—or even worse—could happen to a brain. “What happens when we start warming the brain,” Thakor asks, “and the blood flow returns to the slumbering neurons?”
These are some of the questions that Thakor and his research associate Xiaofeng Jia; Geocadin and his colleague and former fellow Matthew Koenig; and graduate students Xiaoxu Kang and Jai Madhok are working on through experimentation with rats. By inducing cardiac arrest in the rats, then monitoring the success rates for the application and removal of hypothermia, the team hopes to build a body of knowledge about how to preserve and then re-awaken a brain that’s undergone the shock of ischemia.
Thakor uses an apt analogy to the problem. “Imagine a classroom full of young kids, all taking naps after recess. Now: How do these kids wake up? Do they all wake up together? Do they wake up one at a time? Do they wake up in groups?”
It’s probably the latter, according to Thakor. “That’s what we’re observing, that a brain awakens in sporadic bursts. And we can look at those bursts now and predict who will recover, based on the qEEG data.” Even more intriguing is a new theory that Thakor and his fellow researchers are beginning to examine from data they’ve gathered on how rats’ brains reawaken: It appears that the thalamus wakes up first, and serves as the brain’s “alarm clock.” Though preliminary, this finding could prove pivotal in developing a brain resuscitation protocol.
The ability for Thakor, a professor of biomedical engineering, and Geocadin, a neurologist, to interact so easily has been a huge advantage in keeping the research moving. “I can’t do this anywhere else,” says Thakor. “I’m doing bench work here in the Traylor Research Building. I can cross the footbridge and be in the Neurological Critical Care Unit, where Dr. Geocadin is working with the clinical challenges we’re addressing. That potential for translational research is so great and unique to Johns Hopkins.”
For Geocadin, there’s another, very personal guiding principle to the research that he always keeps in mind. “I’m from the Philippines,” he explains. “My friends and colleagues there said, ‘Make sure whatever you do can be used here.’ An EEG and a few dollars worth of packed ice are available in almost every hospital. A gold-covered catheter attached to a fancy cooling machine that costs more than a Lexus isn’t.
“If what we do isn’t available to hospitals like the one I was born in, in the central Philippines, I have betrayed my friends and my home country.”
Geocadin is excited about the progress and prospects for their work. “We’re in the process of developing a simple tool that will not only let us predict how a patient will recover from cardiac arrest, but we’ll also potentially have the ability to tweak how the hypothermia is given”—boosting the chances for regaining increased cognitive function. “We can alter the slope of recovery for the better.”