A new way to monitor induced comas

After suffering a traumatic brain injury, patients are often placed in a coma to give the brain time to heal and allow dangerous swelling to dissipate. These comas, which are induced with anesthesia drugs, can last for days. During that time, nurses must closely monitor patients to make sure their brains are at the right level of sedation — a process that MIT’s Emery Brown describes as “totally inefficient.”

“Someone has to be constantly coming back and checking on the patient, so that you can hold the brain in a fixed state. Why not build a controller to do that?” says Brown, the Edward Hood Taplin Professor of Medical Engineering in MIT’s Institute for Medical Engineering and Science, who is also an anesthesiologist at Massachusetts General Hospital (MGH) and a professor of health sciences and technology at MIT.

Brown and colleagues at MGH have now developed a computerized system that can track patients’ brain activity and automatically adjust drug dosages to maintain the correct state. They have tested the system  — which could also help patients who suffer from severe epileptic seizures — in rats and are now planning to begin human trials.

Maryam Shanechi, a former MIT grad student who is now an assistant professor at Cornell University, is the lead author of the paper describing the computerized system in the Oct. 31 online edition of the journal PLoS Computational Biology.

Tracking the brain

Brown and his colleagues have previously analyzed the electrical waves produced by the brain in different states of activity. Each state — awake, asleep, sedated, anesthetized and so on — has a distinctive electroencephalogram (EEG) pattern.

When patients are in a medically induced coma, the brain is quiet for up to several seconds at a time, punctuated by short bursts of activity. This pattern, known as burst suppression, allows the brain to conserve vital energy during times of trauma.

As a patient enters an induced coma, the doctor or nurse controlling the infusion of anesthesia drugs tries to aim for a particular number of “bursts per screen” as the EEG pattern streams across the monitor. This pattern has to be maintained for hours or days at a time.

“If ever there were a time to try to build an autopilot, this is the perfect time,” says Brown, who is a professor in MIT’s Department of Brain and Cognitive Sciences. “Imagine that you’re going to fly for two days and I’m going to give you a very specific course to maintain over long periods of time, but I still want you to keep your hand on the stick to fly the plane. It just wouldn’t make sense.”

To achieve automated control, Brown and colleagues built a brain-machine interface — a direct communication pathway between the brain and an external device that typically assists human cognitive, sensory or motor functions. In this case, the device — an EEG system, a drug-infusion pump, a computer and a control algorithm — uses the anesthesia drug propofol to maintain the brain at a target level of burst suppression.

The system is a feedback loop that adjusts the drug dosage in real time based on EEG burst-suppression patterns. The control algorithm interprets the rat’s EEG, calculates how much drug is in the brain, and adjusts the amount of propofol infused into the animal second-by-second.

The controller can increase the depth of a coma almost instantaneously, which would be impossible for a human to do accurately by hand. The system could also be programmed to bring a patient out of an induced coma periodically so doctors could perform neurological tests, Brown says.

This type of system could take much of the guesswork out of patient care, says Sydney Cash, an associate professor of neurology at Harvard Medical School.

“Much of what we do in medicine is making educated guesses as to what’s best for the patient at any given time,” says Cash, who was not part of the research team. “This approach introduces a methodology where doctors and nurses don’t need to guess, but can rely on a computer to figure out — in much more detail and in a time-efficient fashion — how much drug to give.”

Monitoring anesthesia

Brown believes that this approach could easily be extended to control other brain states, including general anesthesia, because each level of brain activity has its own distinctive EEG signature.

“If you can quantitatively analyze each state’s signature in real time and you have some notion of how the drug moves through the brain to generate those states, then you can build a controller,” he says.

There are currently no devices approved by the U.S. Food and Drug Administration (FDA) to control general anesthesia or induced coma. However, the FDA has recently approved a device that controls sedation not using EEG readings.

The MIT and MGH researchers are now preparing applications to the FDA to test the controller in humans.

Coma: researchers observe never-before- detected brain activity

Researchers from the University of Montreal and their colleagues have found brain activity beyond a flat line EEG, which they have called Nu-complexes (from the Greek letter n). According to existing scientific data, researchers and doctors had established that beyond the so-called “flat line” (flat electroencephalogram or EEG), there is nothing at all, no brain activity, no possibility of life. This major discovery suggests that there is a whole new frontier in animal and human brain functioning.

The researchers observed a human patient in an extreme deep hypoxic coma under powerful anti-epileptic medication that he had been required to take due to his health issues. “Dr. Bogdan Florea from Romania contacted our research team because he had observed unexplainable phenomena on the EEG of a coma patient. We realized that there was cerebral activity, unknown until now, in the patient’s brain,” says Dr. Florin Amzica, director of the study and professor at the University of Montreal’s School of Dentistry.

Dr. Amzica’s team then decided to recreate the patient’s state in cats, the standard animal model for neurological studies. Using the anesthetic isoflurane, they placed the cats in an extremely deep—but completely reversible—coma. The cats passed the flat (isoelectric) EEG line, which is associated with silence in the cortex (the governing part of the brain). The team observed cerebral activity in 100% of the cats in deep coma, in the form of oscillations generated in the hippocampus, the part of the brain responsible for memory and learning processes. These oscillations, unknown until now, were transmitted to the master part of the brain, the cortex. The researchers concluded that the observed EEG waves, or Nu-complexes, were the same as those observed in the human patient.

Dr. Amzica stresses the importance of understanding the implications of these findings. “Those who have decided to or have to ‘unplug’ a near-brain-dead relative needn’t worry or doubt their doctor. The current criteria for diagnosing brain death are extremely stringent. Our finding may perhaps in the long term lead to a redefinition of the criteria, but we are far from that. Moreover, this is not the most important or useful aspect of our study,” Dr. Amzica said.

From Nu-complexesto therapeutic comas

The most useful aspect of this finding is the therapeutic potential, the neuroprotection, of the extreme deep coma. After a major injury, some patients are in such serious condition that doctors deliberately place them in an artificial coma to protect their body and brain so they can recover. But Dr. Amzica believes that the extreme deep coma experimented on the cats may be more protective.

“Indeed, an organ or muscle that remains inactive for a long time eventually atrophies. It is plausible that the same applies to a brain kept for an extended period in a state corresponding to a flat EEG,” says Professor Amzica. “An inactive brain coming out of a prolonged coma may be in worse shape than a brain that has had minimal activity. Research on the effects of extreme deep coma during which the hippocampus is active, through Nu-complexes. is absolutely vital for the benefit of patients.”

“Another implication of this finding is that we now have evidence that the brain is able to survive an extremely deep coma if the integrity of the nervous structures is preserved,” said lead author of the study, Daniel Kroeger. “We also found that the hippocampus can send ‘orders’ to the brain’s commander in chief, the cortex. Finally, the possibility of studying the learning and memory processes of the hippocampus during a state of coma will help further understanding of them. In short, all sorts of avenues for basic research are now open to us.”

Research shows brain hub activity different in coma patients

A team of French and British researchers has found that brain region activity for coma patients is markedly different than for healthy people. In their paper published in the Proceedings of the National Academy of Sciences, the group describes the differences found when comparing fMRI scans of people in a coma with healthy volunteers.

To gain a better understanding of what goes on in the brain when a person is in a coma, and perhaps the nature of consciousness, the researchers performed fMRI brain scans on 17 people who had recently become comatose due to medical conditions that led to blockage of oxygen to the brain. They then compared those scans to those taken of 20 healthy volunteers.

In analyzing the results the team found that global comparisons between the two groups revealed very few if any differences. Blood continued to flow to all of the parts of the brain. When focusing on the brain as a network however, they found very large differences.

To look at the brain as a network requires looking at its different parts as regions that communicate with one another, forming hubs. In healthy people, certain regions or hubs are busier than others as evidenced by more blood flow. But for the people in a coma, the team found, the normally busy hubs grew less busy, while other hubs grew busier, indicating a major change in the flow of information.

The researchers suggest that the brain scans reveal that the normally busy hubs in healthy people are centers of consciousness and their reduced role in communications in comatose patients suggests that they are most likely not conscious of their existence. They point to prior research that has suggested that being in a coma is more likely closer to the experience of being under anesthesia than being asleep. They add that the their research indicates that regions of the brain that are responsible for conscience thought likely require more oxygen rich blood, and are thus likely to be more sensitive to oxygen deprivation than other areas of the brain, which might explain why people go into a coma when those regions are harmed.

Auditory test predicts coma awakening

A coma patient’s chances of surviving and waking up could be predicted by changes in the brain’s ability to discriminate sounds, new research suggests.

Recovery from coma has been linked to auditory function before, but it wasn’t clear whether function depended on the time of assessment. Whereas previous studies tested patients several days or weeks after comas set in, a new study looks at the critical phase during the first 48 hours. At early stages, comatose brains can still distinguish between different sound patterns. How this ability progresses over time can predict whether a coma patient will survive and ultimately awaken, researchers report.

“It’s a very promising tool for prognosis,” says neurologist Mélanie Boly of the Belgian National Fund for Scientific Research, who was not involved with the study. “For the family, it’s very important to know if someone will recover or not.”

A team led by neuroscientist Marzia De Lucia of the University of Lausanne in Switzerland studied 30 coma patients who had experienced heart attacks that deprived their brains of oxygen. All the patients underwent therapeutic hypothermia, a standard treatment to minimize brain damage, in which their bodies were cooled to 33° Celsius for 24 hours.

De Lucia and colleagues played sounds for the patients and recorded their brain activity using scalp electrodes — once in hypothermic conditions during the first 24 hours of coma, and again a day later at normal body temperature. The sounds were a series of pure tones interspersed with sounds of different pitch, duration or location. The brain signals revealed how well patients could discriminate the sounds, compared with five healthy subjects.

After three months, the coma patients had either died or awoken. All the patients whose discrimination improved by the second day of testing survived and awoke from their comas. By contrast, many of those whose sound discrimination deteriorated by the second day did not survive. The results were reported online November 12 in Brain.

(Image credit: ANP)