Melatonin has a very short half life and is secreted as needed by the pineal gland. It’s apparent primary biological function is as a signal transduction/regulatory molecule. It’s unclear if this function is what is responsible for its protective effect in ischemia-reperfusion injury (IRI), because melatonin is also a powerful radical scavenger—and in fact, a particularly effective scavenger of the radical species associated with neuronal injury in IRI, such as peroxynitrite. Other factors to consider are the timing, route of administration and dose used in our studies. The drug was given intravenously in a micellized form to speed delivery across the blood brain barrier. This was done at the start of reperfusion. Finally, the effective dose given was very large (and was based on the stoichiometry of the radical species we wanted to scavenge). The drug was also given in conjunction with many others and, perhaps critically, in combination with the rapid induction of mild therapeutic hypothermia ( 3 deg C below normothermia). Next up on my agenda to test was whether the drug combination was effective without hypothermia since it is very problematic to achieve a 3 deg C reduction in body temperature in ~15 min or less! Unfortunately, that study was canned.
The point here is that the application of any such treatment in the setting of a critical illness would require that it be both an integrated and ACCEPTED part of the medical infrastructure. For instance, it was over 30 years ago that Peter Safar, et al., demonstrated that mild hypothermia AFTER cardiac arrest was profoundly effective in reducing ischemic brain injury, and it has been 9 years since ILCOR made post-cardiac arrest hypothermia the standard of care: http://circ.ahajournals.org/content/108/1/118.full. And yet, post-arrest hypothermia is used almost nowhere. So, even if a treatment is approved and demonstrated to be scientifically valid, it still may not see widespread clinical application for a host of reasons.
I recently watched a BBC documentary called “Back From The Dead”, mainly about using extreme hypothermia to prevent IRI in some rather extreme cases, though drug development was also mentioned (that portion mostly focused on the study of cell death).
One case was a Norwegian woman who fell in a crevasse while hiking on a glacier—the extreme cold plus 3+ hours of constant CPR was enough to keep her brain alive long enough to be revived. She made a full recovery and now works at the hospital that revived her.
Another was a man who’s blood was intentionally cooled to extreme hypothermic temperatures in order to repair an aortic aneurism. Doctors were able to operate for 45 minutes with the patient in full cardiac arrest with no ill effects.
It’s amazing to me that the basis for these techniques have been around for so long, and yet still they seem like science fiction when anyone discusses them. Since the benefits of mild hypothermia had been at least hinted at 30+ years ago, you would think researchers would have been playing with extreme hypothermia soon after and we’d be a lot further along with this stuff in general.
I don’t have any idea how often hypothermia is actually used to save lives, but the documentary made it seem rare, with extreme hypothermia being only used in one or two hospitals in the world. Your experience seems to back that up as well.
Melatonin has a very short half life and is secreted as needed by the pineal gland. It’s apparent primary biological function is as a signal transduction/regulatory molecule. It’s unclear if this function is what is responsible for its protective effect in ischemia-reperfusion injury (IRI), because melatonin is also a powerful radical scavenger—and in fact, a particularly effective scavenger of the radical species associated with neuronal injury in IRI, such as peroxynitrite. Other factors to consider are the timing, route of administration and dose used in our studies. The drug was given intravenously in a micellized form to speed delivery across the blood brain barrier. This was done at the start of reperfusion. Finally, the effective dose given was very large (and was based on the stoichiometry of the radical species we wanted to scavenge). The drug was also given in conjunction with many others and, perhaps critically, in combination with the rapid induction of mild therapeutic hypothermia ( 3 deg C below normothermia). Next up on my agenda to test was whether the drug combination was effective without hypothermia since it is very problematic to achieve a 3 deg C reduction in body temperature in ~15 min or less! Unfortunately, that study was canned.
The point here is that the application of any such treatment in the setting of a critical illness would require that it be both an integrated and ACCEPTED part of the medical infrastructure. For instance, it was over 30 years ago that Peter Safar, et al., demonstrated that mild hypothermia AFTER cardiac arrest was profoundly effective in reducing ischemic brain injury, and it has been 9 years since ILCOR made post-cardiac arrest hypothermia the standard of care: http://circ.ahajournals.org/content/108/1/118.full. And yet, post-arrest hypothermia is used almost nowhere. So, even if a treatment is approved and demonstrated to be scientifically valid, it still may not see widespread clinical application for a host of reasons.
I recently watched a BBC documentary called “Back From The Dead”, mainly about using extreme hypothermia to prevent IRI in some rather extreme cases, though drug development was also mentioned (that portion mostly focused on the study of cell death).
One case was a Norwegian woman who fell in a crevasse while hiking on a glacier—the extreme cold plus 3+ hours of constant CPR was enough to keep her brain alive long enough to be revived. She made a full recovery and now works at the hospital that revived her.
Another was a man who’s blood was intentionally cooled to extreme hypothermic temperatures in order to repair an aortic aneurism. Doctors were able to operate for 45 minutes with the patient in full cardiac arrest with no ill effects.
It’s amazing to me that the basis for these techniques have been around for so long, and yet still they seem like science fiction when anyone discusses them. Since the benefits of mild hypothermia had been at least hinted at 30+ years ago, you would think researchers would have been playing with extreme hypothermia soon after and we’d be a lot further along with this stuff in general.
I don’t have any idea how often hypothermia is actually used to save lives, but the documentary made it seem rare, with extreme hypothermia being only used in one or two hospitals in the world. Your experience seems to back that up as well.