What is Stroke Reperfusion Injury?
Stroke is a serious health issue affecting about 2.5% of people worldwide and is a major cause of death and disability. Drug treatments for strokes target the “penumbra”, the area between the dead brain tissue and the healthy brain tissue, which experiences mild-to-moderate lack of oxygen. This zone can get severely damaged if not swiftly treated. When a stroke happens, the brain can lose a huge amount of tissue, approximately 1.9 million neurons, 14 billion connections, and 12 kilometers of nerve fibers every minute without any interventions.
Every hour of stroke damage is equivalent to about 3.6 years of normal brain aging. One drug, alteplase, which breaks up blood clots, is approved in the United States for treating strokes. It’s been proven effective in many studies. However, some treatments can actually harm stroke-affected tissue. For example, some new procedures for restablishing blood flow to the brain in combination with alteplase can paradoxically increase damage due to complicated biochemical and pathological events. Other procedures could also lead to additional injury.
This kind of damage, known as ischemia-reperfusion injury, is a clinical challenge. It happens when blood flow is restored to tissues that were not getting enough blood supply and leads to more cellular dysfunction and death. This sort of damage, which can occur in numerous organs, including the heart, lungs, kidneys, and brain, can have far-reaching effects, potentially leading to multiple organ failure. The process of reperfusion injury involves complex molecular and cellular mechanisms and can result in major tissue damage.
What Causes Stroke Reperfusion Injury?
When the brain doesn’t get enough blood for an extended period, it can’t get the energy it needs. This can cause brain cells to stop working properly and eventually die out. This doesn’t happen right away, though. First, there are a lot of changes in and around the cell, like the lack of energy, increased lactic acid levels, changes in how oxygen and glucose are used, blocked protein production, cell structure damage, and cell shrinkage.
The reduced blood flow to the brain starts a series of events that cause damage on multiple levels, all the way from the molecules in the cells to changes that can be seen with the naked eye. Some of the main effects include stress from damaging molecules called oxidants, the triggering of white blood cells, and damage to the blood-brain barrier, which normally protects the brain.
Risk Factors and Frequency for Stroke Reperfusion Injury
Getting a global perspective on AIS reperfusion injury following thrombolysis and mechanical thrombectomy is quite difficult due to a shortage of assessment data. Nevertheless, using the term “hemorrhagic transformation” helps to give us a picture of what happens during reperfusion injury. Statistically, during a significant trial by the National Institute of Neurological Disorders and Stroke (NINDS), it was found that 6.4% of patients treated with a certain type of therapy experienced a hemorrhagic transformation. This is compared to just 0.3% who were given a placebo. This condition is also known as symptomatic hemorrhagic transformation (sHT).
- In the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), 7.3% of ischemic stroke patients who underwent thrombolysis had sHT.
- The epidemiology of thrombectomy-based reperfusion injury was well presented in the Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES), where a 4.4% incidence of sHT was reported by Goyal et al.
- In recent extensive window endovascular trials, DEFUSE 3 and DAWN, the rates of sHT were 7% and 6% respectively.
In simple terms, these studies help provide insight into the frequency and effects of reperfusion injury after certain stroke treatments. The figures mentioned above highlight the incidence rate of symptomatic hemorrhagic transformation (a condition that can occur as a result of these treatments).
Signs and Symptoms of Stroke Reperfusion Injury
When someone has a stroke, every second counts. That’s what the phrase “time is brain” signifies. It means that the longer a stroke goes untreated, the more healthy brain tissue is lost. Therefore, patients need quick treatment either through a procedure that dissolves blood clots (thrombolysis) or a process that helps remove the blockage (endovascular therapy). This is especially important for patients suffering from an acute ischemic stroke (AIS).
A swift and thorough examination is crucial for patients who come in with sudden symptoms that could mean they are having an AIS. During these checks, doctors need to find out:
- When the patient was last well
- The start time of symptoms
- Any potential risk factors and current medications
- Any relevant information that could point towards an underlying condition
Doctors also check vital signs and examine the state of the patient’s consciousness, any irregularities in head or eye movement, and any issues with voluntary movement. A heart check-up is crucial before conducting imaging tests. In addition, doctors also use the National Institutes of Health Stroke Scale (NIHSS) to conduct a focused neurological evaluation. The results from this exam can then be classified using the Hunt-Hess scale or the World Federation of Neurological Surgeons scale. More information on acute stroke and acute ischemic stroke can be found in StatPearls’ resources.
Testing for Stroke Reperfusion Injury
After using treatment with recombinant tPA to clear a blocked blood vessel, it typically takes about 12.9 hours for the blood-brain barrier (BBB) to be affected. This timeframe can vary depending on the patient’s age.
Ordinarily, images of the penumbra (the part of the brain that’s deprived of blood but not yet dead) are not taken if the patient qualifies for regular recombinant tPA treatment. However, if the lack of blood supply (ischemia) has been going on for more than 6 hours, images become vital.
Knowing the age of the lesion can guide further treatment options and prevent unintended harm, such as a tear in the BBB or a blood vessel bursting inside the brain due to the treatment itself. Medical imaging techniques like CT and MRI are used to identify the ischemic core and penumbra. These images help doctors weigh the pros and cons of treatments that re-establish blood flow, aiming to avoid any potential side effects of unblocking a clotted brain blood vessel.
The HARM is a radiological phenomenon observed in the fluid within the brain and spinal cord after contrast injection. An increased signal, or brighter image, in this fluid can indicate changes to the BBB during an acute stroke. SPECT imaging with a specific tracer called 99mTc-duramycin proved helpful in a rat study for detecting the death of nerve cells due to ischemia-reperfusion injury, where the restoration of blood supply after a stroke can sometimes lead to further damage.
Treatment Options for Stroke Reperfusion Injury
Current research is exploring various potential treatments for ischemia-reperfusion injury (IRI), a type of injury that occurs when blood supply returns to tissue after a period of lack of oxygen. The treatments target several key areas, such as reducing excessive harmful molecules called Reactive Oxygen Species (ROS), decreasing inflammation, and preventing over-activation of certain cells involved in the immune response.
One approach involves treating inflammation with a class of medicines called glucocorticoids. While this treatment showed some positive results in experiments on rats, clinical trials in humans have not been successful.
Experiments also suggest that a treatment involving the inhalation of hydrogen gas could limit cell damage and death caused by ROS. The gas is thought to neutralize harmful ROS, converting it to water and thereby reducing the damage they can cause. But while this has worked in animal studies, it has not yet been tried in humans.
Other promising treatments for IRI, according to animal studies, include the use of superoxide dismutase, a substance that could prevent IRI in patients with severe loss of blood pressure, and inhibitors that stop the production of ROS. Treatments including hyperbaric oxygen, cooling the body, inhaling a type of anesthetic called isoflurane, and stimulating the vagus nerve non-invasively have also shown effectiveness in reducing damage.
However, there’s a key challenge: many of the treatments that have worked in animal studies have not been successful in clinical trials on humans. This has led to questions about whether the use of animals in research accurately reflects human responses. Nevertheless, ongoing research and the use of advanced imaging techniques may help in finding effective treatments.
In managing IRI, it’s also crucial to maintain a balance of fluid and blood pressure in the patient’s body, prevent low blood sugar, manage seizures if they occur, keep the blood pressure within the brain above 70 mmHg, and use therapies like mannitol or saline to manage significant brain swelling. In severe cases, surgery may be needed to relieve pressure on the brain. Importantly, steroids are not recommended for these cases and have been linked to poorer outcomes.
What else can Stroke Reperfusion Injury be?
When a person has been recently admitted to the hospital and is showing worsening signs typically linked with improved blood flow (reperfusion), there are usually fewer conditions that could be the cause. But, doctors still need to consider other potential issues. These could be bleeding from a tumor, irregular blood vessel connections (known as arteriovenous malformations), infections, bleeding in the space around the brain (subarachnoid hemorrhage), blood collections under the protective coverings of the brain (subdural hematomas), and brain inflammation caused by infections (meningitis). While these conditions are less likely to occur in a state of reperfusion, they must be thoroughly checked for, based on the patient’s history, physical check-up results, and additional assessments.
What to expect with Stroke Reperfusion Injury
The outcome for patients experiencing stroke reperfusion injury can greatly differ depending on several factors, like the patient’s age, the size of the affected area in the brain, the strategies used to restore blood flow, the severity of the reperfusion injury itself, and other health indicators.
Treatments such as thrombolysis and endovascular clot retrieval, which are used to quickly restore blood flow to the brain, have dramatically improved stroke care. However, they also carry a risk, as they can potentially worsen tissue damage through reperfusion injury.
Those with severe reperfusion injury may face a higher risk of nerve damage, memory and thinking problems, as well as difficulties in performing daily tasks. Still, early and targeted treatment strategies, like specific damage control measures and restorative therapies, can greatly help in significant recovery and improve long-term outcomes for some patients.
In order to give the best odds and to enhance the life quality of those affected by stroke reperfusion injury, it’s crucial to keep a close track of the patient’s condition, deliver personalized care, and promote teamwork between the various health fields.
Possible Complications When Diagnosed with Stroke Reperfusion Injury
Ischemia-Reperfusion Injury (IRI) in stroke patients can lead to complications that can greatly affect their lives in the long run. When blood flow returns to the area of the brain that was deprived of oxygen – a process known as reperfusion – it can paradoxically increase the damage to the brain tissue. Such damage can result from oxidative stress, inflammation, and excitotoxicity. These complications may show up as damage surrounding the area of decreased blood supply (Ischemia), expansion of ischemia, bleeding changes, severe brain swelling and displacement, seizures and disruption of the blood-brain barrier. These can lead to additional brain damage and neurological decline.
Moreover, reperfusion injury can lead to further complications after a stroke such as repeated ischemic events, blood vessel spasms, and a generalized inflammatory response in the body. Managing these complications requires a careful approach that includes close monitoring to spot signs early, specific interventions to prevent further damage, and a comprehensive plan for rehabilitation to maximize recovery and minimize long-term disability.
Multidisciplinary healthcare professionals can significantly improve patient outcomes and enhance the level of care by tackling the intricacies of IRI and its related complications.
Here are some common complications of IRI:
- Damage surrounding the area of decreased blood supply (penumbra)
- Bleeding changes (hemorrhagic transformation)
- Expansion of ischemia
- Severe brain swelling and displacement (malignant cerebral edema and herniation)
- Seizures
- Disruption of the blood-brain barrier (BBB)
- Repeated ischemic events
- Blood vessel spasms (vasospasm)
- Generalized inflammatory response in the body (systemic inflammatory response syndrome)
Preventing Stroke Reperfusion Injury
It’s crucial to prevent and educate patients about stroke reperfusion injuries for the best possible health outcomes. By teaching patients about risks they can control like high blood pressure, diabetes, and smoking, we give them the chance to make healthy lifestyle changes. These changes can lower their chances of experiencing a stroke and the following reperfusion injury. It’s also important to inform everyone about how vital it is to seek immediate medical help if they have stroke symptoms. Doing this can minimize the harm caused by a stroke and lessen the need for extensive reperfusion therapy.
Patient education should also include details about the risks tied to reperfusion therapies. These can include reperfusion injury, hemorrhagic transformation, and other complications. By understanding these risks, patients can make informed decisions about their treatment and are more likely to stick to their treatment plan. By working together with patients, prevention strategies and patient education efforts can lead to the best possible outcomes and help prevent stroke reperfusion injury.