Researcher discovers improved stroke therapy
through ultrasound

By Darla Brown

The serendipitous match of a neurologist skilled in diagnostic ultrasound and an observant research nurse coordinator has resulted in a method that improves ischemic stroke patients’ outcomes.

Andrei Alexandrov, M.D., associate professor of neurology, came to The University of Texas Medical School at Houston in 1996 on a Canadian grant to learn about t-PA (tissue plasminogen activator) therapy and its safety.

“That was the year t-PA was approved, and I was using diagnostic ultrasound on the stroke patients treated with t-PA to determine if it was working – to see where a blockage was and if there were any openings,” Dr. Alexandrov explains.
After about six months of this work, Patti Bratina, who was the nurse coordinator for the pivotal t-PA stroke trial, noticed a difference in the patients whom Dr. Alexandrov monitored with the noninvasive ultrasound.

“She said, ‘Ever since you showed up with ultrasound, our patients have been doing better,’” Dr. Alexandrov recalls. “She had never seen anything like the results after ultrasound.”

Dr. Alexandrov then started looking into scientific literature and found that over the last 30 years, basic scientists had been reporting that a thrombus would dissolve faster in a test tube or animal when exposed to both t-PA and ultrasound.

“But no one had tried it in humans in a properly designed study,” he says.

One-hundred and twenty-six patients later, the findings of a clinical trial showing the efficacy of using ultrasound with t-PA appeared in the Nov. 18, 2004, issue of the New England Journal of Medicine.

For those patients who received ultrasound and t-PA, 49 percent showed dramatic clinical improvement and no blockage left compared to 30 percent of those who received t-PA alone. With the combined therapy, 73 percent showed complete or partial clearance of the clot versus 50 percent who received just the drug therapy.

“We now have robust clinical evidence that diagnostic ultrasound – the same ultrasound used to scan babies – has a positive biological effect in the delivery of the clot-busting medicine t-PA,” Dr. Alexandrov says.

The ultrasound was given continuously up to two hours on each patient – during the one-hour infusion of t-PA and then an additional hour monitoring the patient.
“Diagnostic ultrasound is harmless, gentle, and safe, and the patients usually cannot tell when it is being administered,” Dr. Alexandrov adds.

Stroke victim Erma Marshall received diagnostic ultrasound as a participant in the clinical trial in 2002 and made a full recovery. “That machine is amazing, and every hospital should have it,” she says. “It can tell where the blood clot is in the brain immediately.”

Despite the tremendous improvement in stroke patients as a result of this safe and harmless procedure, hospitals have not been quick to embrace diagnostic ultrasound for stroke therapy.

“Ultrasound is so operator dependent – it takes one to six months of daily exercise to learn this technique,” Dr. Alexandrov says, adding that many health professionals have been interested in the Stroke Team’s course that teaches diagnostic ultrasound.

As a result of the complexity of operating this tool, Dr. Alexandrov and his colleagues have created a start-up company, Vitason, to develop an operator-independent device that would allow physicians and nurses without ultrasound experience to perform diagnostic ultrasound on stroke patients in the emergency room.

“We expect a prototype of this machine in a year and in three to five years we’ll have clinical trials with it,” he says. “The ultrasound machines that are out there have been optimized for imaging, whereas therapeutic applications are totally different.”

Dr. Alexandrov and his colleagues plan to further their diagnostic ultrasound research by adding a microbubble to the equation of t-PA plus ultrasound. An FDA-approved perfluorocarbon gas that is 1 nanometer in diameter covered in a stable lipid shell would be added intravenously with the t-PA. This experimental approach will be carried out at Memorial Hermann Hospital, and it is only for patients who arrive at the hospital within three hours of the onset of stroke symptoms.

“The microbubble circulates in the body – it’s stable and harmless – and as it meets the ultrasound beam, it expands and moves. The benefit of the bubble is that it sends back strong ultrasound echoes and improves the resolution of ultrasound imaging, and it creates a motion of fluid to deliver more of the drug to the clot,” Dr. Alexandrov says. “In Barcelona, scientists were able to show a 50 percent complete clot break up with a less stable air microbubble in two hours, and that was using a less optimal bubble.”

Having received FDA approval to carry out this study, Dr. Alexandrov is optimistic about the future uses of ultrasound in combination with other therapies.

“We’re not standing still when it comes to this research. We’re going to pursue diagnostic ultrasound because right now t-PA therapy is only available to less than 4 percent of stroke patients nationwide,” Dr. Alexandrov says.