For those of you unfamiliar with cerebral vascular accidents (a.k.a. stroke), stroke is a major cause of death and disability in the United States, acting as the number three cause of medical mortality and the number one cause of permanent disability. The National Institutes of Health predicts more than 750,000 Americans will suffer a symptomatic stroke this year (that’s about 1 every 42 seconds). As a medical resident specializing in emergency medicine, strokes are something we come in contact with every day and the treatment is often challenging.
A stroke occurs when blood flow to the brain is either blocked or interrupted; and there are 2 separate types, hemorrhagic and ischemic. A hemorrhagic stroke occurs when a major blood vessel in the brain is injured and causes bleeding into the surrounding tissue. This causes not only direct damage but also increased pressure, and thus, decreased blood flow to the brain. This is accountable for around 1 out of every 5 strokes we encounter and they are often quite devastating. The other type of stroke is an ischemic stroke and this kind is much more common by far. This occurs when one of the major arteries supplying the brain is partially or completely occluded, either from the formation of a clot (thrombotic) or from a clot formed elsewhere in the body that traveled to the brain (embolic). As you may know, the brain is an incredibly fragile organ requiring constant oxygenated blood flow for ATP production and has minimal ability to undergo any anaerobic respiration. When the production of ATP is halted, various ion channels are blocked and so there is a time sensitive build up of intracellular calcium and nitric oxide, generation of dangerous oxygen free radicals, and eventual attack by invading white blood cells. When an acute occlusion takes place, these changes occur first in the infracted core, which is the area of brain tissue denied the most blood flow, but eventually occur in the surrounding ischemic brain tissue, where blood flow is variably reduced but not always completely occluded. The brain tissue suffers slow damage over a period of hours and so, as we say in the emergency room, once a stroke occurs, time is literally brain.
So what do we do when a stroke comes into the emergency room? Well, first we stabilize the important things like breathing and blood pressure, and then we whisk them off to CAT-scan where a radiologist quickly determines whether we are dealing with a hemorrhagic stroke or an ischemic stroke. If it is hemorrhagic, the patient has an upcoming date with neurosurgeon and my job is pretty much done. If it is ischemic, treatment is also limited as we have only a single, time sensitive medication available called tissue plasminogen activator (TPA). This is a medication designed to dissolve the blood clot and restore blood to the brain, but unfortunately has a very strict administration criteria. It must be given within 4.5 hours of onset, may do nothing to improve symptoms, and even has a 1 in 20 chance of killing the patient by turning an ischemic stroke into a hemorrhagic one. It is no surprise that only an estimated 1-3% of acute ischemic stroke patients in the US receive TPA. You can probably see why we desperately need a new medication that we can deliver quickly and safely from the ER while there is still brain worth saving. This is where the FAST-MAG clinical trials come in.
Magnesium sulfate is a commonly used medication on the ER and we use it for a wide variety of reasons; it is an anti-arrhythmic agent used in certain fatal heart arrhythmias, a potent bronchodilator used in serious asthmatics, and it is even a treatment for severe eclampsia and pre-term delivery in pregnant females. Recent animal studies, however, have shown that magnesium sulfate may also have a significant role in, you guessed it, the treatment of acute ischemic strokes. Once administered, magnesium quickly crosses the A barrier between the brain itself and the blood supply of ... and disperses evenly throughout the brain, where it acts as a neuroprotective agent in multiple ways. First, it inhibits excessive neuronal activation by preventing the release of neurotransmitters, blocks NMDA receptors, and inhibits voltage-gated calcium channels. All of these effects lead to less build up of those nasty anoxic by-products we mentioned earlier. Second, magnesium serves as a neuroprotective agent by causing profound vasodilatation within the cerebral arteries. As the arteries expand, more blood is able to reach the fragile surrounding brain tissue, which is the area at greatest risk as time goes on, and thus prevents small strokes from becoming large ones. To date, eight out of nine laboratory research studies have demonstrated that magnesium sulfate substantially reduces the brain damage caused by acute ischemic strokes.
The FAST-MAG trial is a National Institutes of Health funded clinical trial currently in phase 3. This trial is a multicenter, randomized, placebo-controlled, double-blind, parallel group trial (meaning it is about the best level of evidence we can get from a prospective study) and it is currently being performed in hospitals and stroke centers throughout California. In a nutshell, the protocol directs paramedics to assess possible stroke victims in the field and, prior to even arriving to the ER, give 4 grams of magnesium sulfate IV as a single bolus injection. The patient must be in the acute phase of their stroke as their symptoms must have started within 2 hours of paramedic arrival. The primary outcome is the functional outcome of hyper acute stoke patients with secondary outcomes being the measure of neurological deficits, quality of life, and overall mortality at 3 months (FastMag.info).
As an ER doctor, FAST-MAG is an incredibly exciting study. We have a lot of experience in using magnesium in the ER for various medical conditions and are quite comfortable giving it on the fly. For example, when a severely asthmatic adult comes through the door, we can reflexively give 2 grams of magnesium sulfate IV before even checking baseline body magnesium blood levels because it is such a safe medication and toxicity is very rare and very hard to achieve. FAST-MAG also gives stroke patients an opportunity to receive early intervention before they get to the ER, avoiding potential delays by transportation and diagnostics. The only down side I can foresee is if magnesium was given to a hemorrhagic stroke (that other, bad kind of stroke), the potential vasodilatation may cause increased bleeding into the surrounding tissues, however the neuroprotective effects it has may outweigh this. Of course further studies are on the way, but in the world of acute ischemic strokes where the outcomes can be life changing and even life threatening, an intervention that is dirt cheap, widely available, safe for almost everyone, and can easily be administered by out of hospital paramedics is drastically needed. So far the research is promising, and magnesium sulfate is almost ready for prime time.
Written by Steven J. Mahon, D.O.
Illustrations by Jooyeun Lee.