Looking Beyond t-PA for Effective Stroke Treatment

CHICAGO—Neurologists are employing novel therapies that go beyond the use of recombinant tissue plasminogen activator (t-PA) alone in critical care settings to enhance neuroprotection in patients with acute ischemic stroke, reported James C. Grotta, MD, Professor and Chairman, Department of Neurology, at the University of Texas Medical School at Houston. Dr. Grotta discussed two of these techniques—Doppler ultrasound and IV administration of caffeinol—at the 73rd Annual International Scientific Assembly of the American College of Chest Physicians.

According to Dr. Grotta, the key to the successful treatment of a patient with ischemic stroke is timely care. “Although [t-PA] is approved after three hours [of the onset of stroke symptoms], in our minds we have a two-hour time goal for treating patients with ischemic stroke,” he said. “By the end of three hours, the benefit has pretty much worn off.”

DOPPLER ULTRASOUND IMPROVES CLOTBUSTING POWER

Dr. Grotta noted that transcranial Doppler ultrasound has been used in thrombolytic research conducted at Memorial Hermann Hospital in Houston, where he is Director of the Stroke Program, to monitor the progress of therapies in real-time. However, the use of the ultrasound may actually amplify clot lysis as well, aiding clinicians in meeting the two-hour deadline. “[The Doppler ultrasound] produces morphologic changes in the clot, thins the fibrin strands, … and this results in more plasma streaming through the thrombus and allows more t-PA to be delivered to binding sites,” explained Dr. Grotta.

In the 2004 CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic t-PA) clinical trial, Andrei V. Alexandrov, MD, Dr. Grotta, and colleagues demonstrated success with the technique. They observed a 49% complete recanalization rate or dramatic clinical improvement in patients who received t-PA plus two hours of continuous ultrasound at 2 megahertz, compared with a rate of 30% in control patients who received t-PA only. There was also a nonsignificant trend toward an increased rate of recovery from stroke, but Dr. Grotta noted that “virtually every study has shown that if you can get the artery open in the first two hours, the better the clinical results.”

Microbubbles—which are injected intravenously as the ultrasound is being directed at the clot and then enlarge and explode, imparting even more energy on the clot—may be used to even further amplify the ultrasound’s effect, said Dr. Grotta. “[Based on] a trial carried out in Barcelona … with t-PA, ultrasound, and this microbubble technology, we can get the artery open over half the time,” he said. “It may be that we only have to carry out this study in a few centers to be able to see clinical benefit.”

However, an ultrasonographer must sit by the side of the patient and guide the Doppler probe through the whole course of treatment, and according to Dr. Grotta, there are not many who can do this. To remedy that problem, he and his team have developed a hands-free unit, a helmet, to deliver the ultrasonic energy. Although the device is still being tested in healthy volunteers, he asserted that it could be used “in any center, without any ultrasound expertise.” And while brain bleeding is a concern with higher frequency ultrasound, Dr. Grotta reported, “[with] the 2-megahertz diagnostic ultrasound, there have been no side effects of increased bleeding.”

CAFFEINE, ETHANOL, AND HYPOTHERMIA

The neuroprotective effects of “caffeinol”—the combination of caffeine and ethanol—were elucidated in Dr. Grotta’s laboratory at the University of Texas and may provide a larger window in which the primary occlusion can be removed without allowing infarct damage. “In combination, [caffeine and ethanol] are robustly neuroprotective at fairly low doses, the equivalent to maybe four to five cups of coffee, or a blood level of about 400 to 500 mg of caffeine, and ethanol at less than intoxicating doses, the equivalent of one strong cocktail,” he said.

Although a rat study showed almost complete suppression of infarct volume with the combination of hypothermia at 35?C and caffeinol, similar neuroprotective capabilities in human patients have yet to be proved. He referred to one patient with moderate stroke who received two hours of caffeinol with t-PA, 1 L of iced saline, external cooling, and meperidine hydrochloride to suppress shivering.
“Despite the middle cerebral artery occlusion that persisted in this patient, there was no cortical infarction that occurred that you would have expected,” he said.

However, Dr. Grotta noted that he and his colleagues are now using catheter-based cooling, as patients can be cooled more quickly and temperatures can be maintained more easily. “If it takes four or five hours to get the temperature down to 33?C, that’s probably going to be too long. We need to get the temperature down fast,” he asserted.

The mechanisms behind the successes of caffeinol are not clear, although Dr. Grotta noted that low doses of caffeine can block the release of excitatory neurotransmitters from the presynaptic membrane, and that ethanol suppresses excitatory neurotransmission through the N-methyl-d-aspartate receptor and enhances inhibitory neurotransmission through g-aminobutyric acid (GABA). “So we think that some sort of beneficial balance of neurotransmitter function is achieved by relatively low doses of this combination,” he said.

NR