Cardiovascular disease is the number one cause of death in the United States, with stroke contributing as a major player in death caused by cardiovascular disease. Basically, a stroke is when blood and oxygen supply to any part of the brain is cut off, and an ischemic stroke in particular is where the cause of deprived blood flow is a blood clot that clogs up a blood vessel that feeds the brain. It is common knowledge that a stroke is a medical emergency that needs to be dealt with as soon as possible. Currently the best treatment for is thrombolytic therapy (clot busting drugs) which is only effective within about three hours of the clot formation. This ischemic stroke can cause permanent brain damage and even death. However, even if the person survives the ischemic stroke, there are still more fatal dangers lurking in the near future.
Although the lack of blood and oxygen to the brain causes severe damage, the negative impact of an overactive inflammatory response is responsible for much of the damage. This is because “Cerebral ischemia evokes an inflammatory response characterized by activation and release of cytokines, chemokines, endothelial-leukocyte adhesion molecules, and proteolytic enzymes that exacerbate tissue damage” and “increased levels of proinflammatory cytokines are related to a greater extent of vertebral infarct and poor clinical outcome in patients with ischemic stroke.” In experimental models, it has been shown that anti-inflammatory molecules IL-10 and IL-4 (released by lymphocytes, monocytes, and macrophages) greatly block the negative inflammatory response. In human studies it was shown that IL-10 production was increased during a stroke (most likely a countermeasure to the increase of inflammatory molecules) but more importantly, the data showed that people that naturally had a higher amount of IL-10 in their bloodstream suffered less damage from stroke. Now this is perfect, right? All that needs to be done is to undergo gene therapy to produce the IL-10 or inject exogenous IL-10….. right? Unfortunately no, the cascade of events that is initiated by IL-10 is more complex than that, and more importantly, too much anti-inflammatory can cause problems as well. [Source of information for this paragraph comes from http://stroke.ahajournals.org/cgi/content/short/34/3/671 ]
In addition to inflammation causing problems post ischemic stroke, infection also commonly causes more damage or death. Regardless of how optimal the ischemic stroke treatment is, many patients will develop a central nervous system infection shortly after. The two major theories behind this is one, that “the central nervous system and the immune system are 2 supersystems closely linked and the is functional interaction could pave the way to the appearance of immunological manifestations as the result of central nervous system injury, and vice versa” and two that “two that the emergence of systemic infection after acute brain damage could be a symptom of central nervous system-mediated decrease of immune competence”. Either way, it is saying the immune system is somewhat compromised after a stroke. Maybe this could be the IL-10 taking effect. This down regulation of the immune system can then cause an infection that can lead to death. [Source of information for this paragraph comes from http://stroke.ahajournals.org/cgi/content/abstract/38/3/1097 ]
So how do these two problems relate? Right after an acute Ischemic stroke, excess inflammation can cause greater permanent damage but too little inflammation and immune response leads to potential fatal central nervous system infections (which is likely to happen if a patient had too much IL-10 in their system). These contrasting potential actions and effects of the immune system and inflammation make post stroke therapy difficult. Treatment thus causes you to “pick your poison”, and I am assuming that physicians must closely monitor this balance of the immune system right after an acute ischemic stroke. Any thoughts?
I know this is far to simple, but what would happen if you treated stroke victims with both anti-inflammatories and antibiotics?
ReplyDeleteI tried to find if there was some sort of linked treatment for tissue and inflammation and immune response. I came across this new line of drugs called immune selective anti-inflammatory derivatives. Apparently "the ImSAIDs are a new generation of anti-inflammatory and appear to block inflammation regardless of the cause, making them useful for all types of inflammation." (http://www.prweb.com/releases/2008/05/prweb945804.htm)
ReplyDeleteFrom wikipedia, "early work in this area demonstrated that the submandibular gland released a host of factors which regulate systemic inflammatory responses and modulate systemic immune and inflammatory reactions. It is now well accepted that the immune, nervous and endocrine systems communicate and interact to control and modulate inflammation and tissue repair." Perhaps a drug like this can target whatever immune response is compromised and administer it in conjunction with the other anti-inflammatory drugs. This should decrease the inflammation and still keep immune responses strong enough to fight opportunistic infections. This is probably a similar method to Sierra's line of thought.
Immune parameters are not something we routinely monitor post-ischemic stroke in the ICU, but we do worry about the post-ischemic “inflammatory cascade.”
ReplyDeleteFor decades, investigators have sought treatments that would improve neurologic outcome after a stroke or cardiac arrest. As you mention, thrombolytics are an important step. Another important step is “therapeutic hypothermia.”
Within the past ten years, two trials demonstrated that among patients who have had a cardiac arrest are likely to have neurologic injury (ie are not waking up immediately after being resuscitated from arrest), therapeutic hypothermia substantially improves outcomes.
One paper “Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest” (http://www.nejm.org/doi/full/10.1056/NEJMoa012689) showed that post-arrest patients cooled to 32-34 degrees Celsius (approx. 89-93 Fahrenheit) were significantly less likely to die (41 versus 56% among non-cooled patients). The cooled patients were also significantly more likely to have a “favorable neurologic outcome” (meaning good recovery or only moderate disability). The second paper, “Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia” (http://www.nejm.org/doi/full/10.1056/NEJMoa003289) had similar findings.
The benefit of cooling far exceeds any drug treatment we have available for improving the neurologic sequelae of cardiac arrest. A number of commentators have noted that, if this were a drug rather than a strategy nurses could implement, it would be considered a “wonder drug” and would likely cost tens of thousands of dollars!!
The exact mechanism of how cooling protects the brain is unknown. It is proposed that decreased temperatures prevent the injured brain from generating free radicals at the time that circulation returns to the injured brain. Cooling reduces metabolic and enzymatic activity. Sounds like the details remain to be worked out, but surely it slows the inflammatory process you described.
Interestingly, therapeutic hypothermia is a recommended part of American Heart Association guidelines for post-arrest patients, but it is not recommended for patients after ischemic stroke. Apparently there are trials of cooling underway… so stay tuned!