Added Oxygen During Stroke Reduces Brain Tissue Damage

Posted by: admin in Pharmacy Drugs on July 25th, 2010

Written by Emily Caldwell

Source:
Savita Khanna

Ohio State University

Scientists have countered findings of previous clinical trials by showing that giving supplemental oxygen to animals during a stroke can reduce damage to brain tissue surrounding the clot.

The timing of the delivery of 100 percent oxygen – either by mask or in a hyperbaric chamber – is critical to achieving the benefit, however.

“The use of supplemental oxygen after blood flow is restored in the brain appears to actually cause harm by unleashing free radicals,” said Savita Khanna, assistant professor of surgery at Ohio State University and principal investigator of the research. “The resulting tissue damage was worse than stroke-affected tissue that received no treatment at all.”

Previous clinical trials in humans have suggested that administering oxygen under pressure could harm stroke patients. But the studies did not take into account the status of blood flow in the brain at the time the oxygen was delivered, Khanna noted.

The types of stroke under study are ischemic, meaning a clot is blocking blood flow in the brain, rather than hemorrhagic, strokes that occur when blood vessels rupture in the brain.

The new Ohio State study showed that the use of pure oxygen that was delivered by mask during stroke was also effective, making for easier clinical application of such a therapy when the time for that is right.

However, technology doesn’t yet allow for quick and continuous real-time measurement of blood flow in the brain in a hospital. This means clinicians treating stroke patients cannot risk administering hyperbaric oxygen that could do more harm than good if it is not timed properly.

“Hyperbaric oxygen during stroke shows the promise of being an effective tool, but there are things that need to occur before this can be applied in a clinical setting,” said Cameron Rink, assistant professor of surgery at Ohio State and a co-investigator on the research. “We need to find better ways to monitor blood flow in humans in real time.”

Rink presented the research during a poster session at the Society for Neuroscience annual meeting in Chicago.

Stroke is the third-leading cause of death in the United States, and an effective treatment remains elusive. So-called “clot-busting” drugs dissolve the clots, but typically must be administered within three hours of the stroke’s onset. The average time between the start of a stroke and a patient’s arrival at a hospital is about four hours – which adds to the treatment challenge, according to the researchers.

Khanna, Rink and colleagues tested the effects of supplemental oxygen therapy on five groups of rats in which the scientists induced a 90-minute ischemic stroke and then restored blood flow in the animals’ brains.

Two groups of animals received either normal oxygen or pressurized oxygen while blood flow was blocked in the brain. Two other sets of rats received normal or pressurized oxygen after blood flow was restored. A control group received no supplemental oxygen, breathing room air instead.

Two days later, the researchers examined the rats’ brains using powerful 4.7-Tesla magnetic resonance imaging to calculate the volume of damaged tissue. The images showed the size of the infarct, or the area of tissue susceptible to stroke damage as a result of poor oxygenation.

The images showed that the animals that received supplemental oxygen treatment while blood flow was blocked had a significantly smaller amount of tissue damage compared to the rats that received oxygen after blood flow was restored, Khanna said.

By further examining images of the rats’ brains, the scientists determined that the supplemental oxygen during the active period of a stroke specifically reduced the death of neurons and prevented the damage that free radicals can cause to lipids that help protect those brain cells. By comparison, more dead neurons and oxidative stress were found in the brains of rats receiving oxygen only after blood flow was restored.

“Ultimately, the supplemental oxygen after blood flow is restored is more than the tissue can handle, and is more than it needs. Why add oxygen on top of tissue that’s already oxygenated?” Rink said. “Supplemental oxygen during the blockage, on the other hand, is highly protective.”

The researchers are using other technologies to determine how the loss of oxygen affects the functions of genes in the brain. Of the approximately 30,000 genes investigated to date, at least 6,000 are either inactivated or highly activated when a stroke reduces the oxygen in the brain. Their future work will explore the ramifications of those changed gene functions.

Khanna and Rink conducted this research with Sashwati Roy, Pavan Ananth and Chandan Sen of Ohio State’s Department of Surgery, and Mahmood Khan and Periannan Kuppusamy of the Department of Internal Medicine.

Stroke Recovery with Hyperbaric Oxygen Therapy (HBOT) in San Francisco

June 2, 2010 (MMD Newswire) — When Kuhldeep Grewall woke one morning in November of 2007, she knew immediately that something was wrong. Her Husband Harbhajan, 72, was lying on the living room floor, seemingly paralyzed, unable to speak.
The massive stroke would lead to a three year uphill battle to regain Mr. Grewall’s quality of life. “We went to many therapy sessions,” said Kuhldeep,”but not a lot of progress was made. And it was very difficult to get Harbhajan to go.”

Once a proud leader of the bay area Sikh community, Mr. Grewall was now less than willing to commit to rehab routines that exposed his frailties. It wasn’t long before Kuhldeep began to feel that they needed something more to drive Harbhajan’s recovery.

Enter Hyperbaric Oxygen Therapy and the San Francisco Institute for Hyperbaric Medicine. Hyperbaric Oxygen Therapy, in which patients breathe 100% oxygen in a pressurized environment, was first introduced to the Grewalls via a friend, who told them that local doctors were employing the treatment to facilitate post-stroke recovery. Kuhldeep made an appointment with the San Francisco Institute for Hyperbaric Medicine the next day.

For the next two months, Mr. Grewall underwent daily treatments at the institute. It wasn’t long before they had reason to hope. At 30 treatments Harbhajan, previously unable to walk, had regained enough function in his right leg to make two full laps of the clinic floor. By 60 treatments, he was making four laps, moving his right arm and speaking a few simple words.

“The change in him was really amazing”, said Mrs. Grewall.”His headaches lessened, and the right side of his face stopped being slack. He began smiling and laughing… he’s a totally new person.”

Dr. Stoller, Medical Director at the SF Hyperbaric Institute, says that administering oxygen at hyperbaric pressures reduces brain swelling and aids in new blood vessel formation, restoring circulation of oxygen to damaged parts of the brain such that “idling” brain cells “wake back up again”, restoring functionality.
However, according to Gayle Link, Nursing Director at the San Francisco Hyperbaric Institute, it is for more than these benefits alone that the Institute is quickly becoming a go-to destination for brain damage patients like Mr. Grewall. “We’re the only hyperbaric clinic in the area that assists with our patient’s physi- cal therapy in-clinic. We began pursuing this integrative approach a few months ago, and we’re seeing great results”.

Effect of large dose hyperbaric oxygenation therapy on prognosis and oxidative stress of acute permanent cerebral ischemic stroke in rats.

Neurol Res. 2008 May

Xue L, Yu Q, Zhang H, Liu Y, Wang C, Wang Y.

Department of Hyperbaric Oxygenation, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

OBJECTIVE: To evaluate the therapeutic effect and the oxidative stress effect of 9 and 18 hour hyperbaric oxygenation therapy (HBOT) protocols on the earliest stage of acute permanent middle cerebral artery occlusion (MCAO) in rats. METHODS: The permanent MCAO model of rats was used. The animals were randomly divided into 9 and 18 hour HBOT groups, as well as a control group. MAIN OUTCOME MEASURES: (1) The Garcia neurological grading system was used to assess the therapeutic effect of hyperbaric oxygenation therapy; (2) the infarct volume was calculated with the 2,3,5-triphenyltetrazolium chloride (TTC) pathologic staining and NIH Image J software 24 and 120 hours after MCAO; (3) the level of reactive oxygen species determined by superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) in ischemic brain tissue were separately examined at the 18, 48 and 120 hour post-ischemia time points using spectrophotometry. RESULTS: (1) There were significant improvements in the neurobehavioral outcome of the rats in the 9 and the 18 hour groups, as compared with rats from the control group (p<0.01); (2) cerebral infarct volume decreased 63-64% in the rats of 9 hour group and 51-66% in the 18 hour group at the 24 and 120 hour time points, as compared with that of the control group; (3) the SOD levels of the 9 and 18 hour groups were remarkably lower than those of control group after both 18 and 48 hours (p<0.01 and p<0.05); (4) the MDA level of the 9 and 18 hour groups were both remarkably lower than the control groups, especially at 18 hours (p<0.05). Meanwhile, the MDA level in the 9 hour group was remarkably lower than both the 18 hour group and the control group (p<0.01 and p<0.05); (5) the level of NO in both hyperbaric oxygenation therapy groups were remarkably higher than that of the control at 18 and 48 hour time points (p<0.01). While the level in 18 hour group was remarkably lower than that of 9 hour group at 18 hour time point (p<0.05). At the 120 hour mark, the NO levels were basically the same in all the three groups. CONCLUSIONS: (1) The two protocols of large dose hyperbaric oxygenation therapy are highly efficient in reducing infarct volume and improving neurobehavioral outcome in permanent MCAO rats within the earliest stages of stroke; (2) increased duration of hyperbaric oxygenation therapy does not appear to equate to improved outcomes; in fact, the longer duration may aggravate the oxidative stress in ischemic tissue.

Neuroprotection by oxygen in acute transient focal cerebral ischemia is

dose dependent and shows superiority of hyperbaric oxygenation.

Cerebrovasc Dis. 2008

Eschenfelder CC, Krug R, Yusofi AF, Meyne JK, Herdegen T, Koch A, Zhao Y, Carl UM, Deuschl G.

Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany. c.eschenfelder@neurologie.uni-kiel.de

The neuroprotective effect of oxygen after acute stroke in rats has been shown previously. However, the question of optimal dosing still remains unanswered. Thus, we investigated the use of oxygen at different concentrations by either normobaric oxygenation (NBO) or hyperbaric oxygenation (HBO) at different pressures in a model of transient ischemia/reperfusion in rats. Animals underwent 90 min of middle cerebral artery occlusion (MCAO) followed by 90 min of reperfusion before oxygen treatment. Oxygen was applied either by NBO (100% O(2); 1.0 absolute atmosphere, ATA) or HBO (100% O(2); 1.5, 2.0, 2.5 or 3.0 ATA) for 1 h. Primary endpoints were infarct volume and clinical outcome measured 24 h and 7 days following the MCAO. A statistically significant and long-lasting reduction in infarct volume was seen in the HBO 2.5 ATA and 3.0 ATA groups over a period of 7 days. The reduced infarct volume was accompanied with a statistically significant improvement in clinical outcome in the high-dose oxygen-treated groups. The presented data indicate that oxygen is a highly neuroprotective molecule in transient focal cerebral ischemia in rats, when applied early and at high doses. The effect is dose dependent and shows a superiority of HBO over NBO, when the primary endpoints infarct volume reduction and clinical outcome are analyzed. These data are important for the development of new acute stroke treatment studies in humans.