“My Brain – it’s my second favorite organ” - Woody Allen in Sleeper
(Readers please note: this post is inspired by the preceding posts of Mitch and Andy. It's much more hard-science oriented than my other posts, but consistent with Mitch's vision for this blog.)
The central objective of all of anesthesia and critical care medicine is to save the brain, and to spare it as much injury as possible. Sadly, brain injury is epidemic and largely unavoidable in much of modern medicine. For those few who survive a CPR event in any setting, it is the presence of brain injury that distinguishes meaningful survival from all of its ugly alternatives. I have no doubt that most patients and their families would give up their kidneys (if they had them to give) in preference to losing even 5 IQ points. Anything that we might do to decrease the rate at which we discharge people NQR (Not Quite Right) would be worth princely sums to our patients, their families, and us as caregivers. Brain injury is the difference between mere survival and meaningful survival.
The annals of anesthesiology, neurology, neurosurgery, critical care, and now emergency medicine are filled with the scrapheap of failed ideas for neuroprotection. Moderate hypothermia at the time of an event is not nearly as helpful as moderate hypothermia for 24 hours subsequently. Most of the explanations of this entail far more hand-waving than solid science (see Yenari below). What little solid science there is seems to be a better held secret than most of the US government’s activities in the GWOT. Deep hypothermia provides protection, but at temperatures that can only be achieved with a cardiopulmonary bypass machine. There is some evidence that suggests that erythropoietin provides a benefit, but not sufficient evidence to drive widespread use for this purpose – yet.
When I was young, and dinosaurs roamed the earth, cells died, and that was all there was to say about that. Long after I finished medical school, a phenomenon called apoptosis was described, which is the process of programmed cell death. Apoptosis is the destiny of many cells in our body, and is a process whose regulation is important to the wellbeing of the organism. Importantly, cellular apoptosis can be triggered by a variety of abrupt events, including both hypoxia and loss of contact with your usual neighbors. Failure of a cell lines to undergo apoptosis according to plan is likely a central feature of many malignancies (e.g. colon cancer, lung cancer). Such cancers are more characterized by relative cellular immortality than rapid growth (this is likely why therapeutics directed at rapidly growing cells have been relatively ineffective against them). As you can imagine, such cells do not hear the usual hints that it is time to die, and thus are very hard to treat. Future biological treatments for such cancers are likely to be centered on triggering malignant cells to undergo apoptosis (by restoring the normal regulation of apoptosis to them).
Everything I know about apoptosis, I learned from journals. Think about that for a second. I’ve never heard a lecture about it, but teach students who have dozed through hours of them. This puts me at a huge disadvantage. Ironically, I’ve given talks about this both locally and at national meetings. I do understand a few simple truths, one of which is that apoptosis involves the orderly transcription and action of a cascade of proteins, and typically takes place over hours. Another truth is that most of the cells that die from hypoxia die from hypoxia- triggered apoptosis, and not from immediate, hypoxia-driven cellular necrosis. This suggests that you might prevent a large proportion of the cell death associated with hypoxia in the brain, at least you could if you could somehow interrupt apoptosis (stop it dead in its tracks so to speak). There also seems to be a growing consensus that apoptosis may be the underlying mechanism behind ‘ischemia-reperfusion’ injury, and that attenuating apoptosis may diminish or prevent ischemia-reperfusion injury entirely.
My belief is that modulating apoptosis is the future of both anesthesia and critical care medicine (as well as ER medicine and oncology). In fact, I believe it is likely to become the centerpiece of our activities. The ability to do this has the potential to not only dramatically improve outcomes, but will even change what we think of as surgically/medically possible. If we could suppress apoptosis, patients with aortic arch aneurysms would almost certainly tolerate longer circ arrest times. This would mean both that more patients would be considered candidates for surgery, and that more technically satisfying procedures could be performed. There is similar potential to revolutionize neurosurgery and cardiology. Neurologic recovery following CPR events could be dramatically improved. NQR would not go away, but would require more substantial insults than it does presently. Such a therapeutic approach has two obvious downsides, one of which is that there may a downstream increased risk of cancer, the other of which is that technical (immune response to the delivery virus) and biologic reasons may allow you to do this only once in a person’s lifetime. There will undoubtedly be others. The ability to modulate apoptosis will produce a revolution in therapeutics comparable to the discovery of anesthesia itself.
Science fiction you say? Nonsense. It’s already been done. The reference is here:
Borsello T, et al: A Peptide inhibitor of C-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nature Medicine 9:1180-6, 2003
I’d reproduce the figures, except that this journal is very, very picky about such stuff. Skeptics take note: this study describes an inhibitor you can administer systemically 6 hours AFTER a devastating injury that reduces its severity by about 70-80%. This is an animal study, but represents the potential for this approach in humans.
There’s more tantalizing science out there:
Yenari MA, et al: Gene Therapy and Hypothermia for Stroke Treatment. Ann. N.Y. Acad. Sci. 993: 54–68, 2003
Milano G, et al: A Peptide Inhibitor of c-Jun NH2-Terminal Kinase (JNK) Reduces Myocardial Ischemia/Reperfusion Injury and Infarct Size in Vivo. Am J Physiol Heart Circ Physiol 292: H1828–H1835, 2007
Ishii M, et al: Inhibition of c-Jun NH2-Terminal Kinase Activity Improves Ischemia/Reperfusion Injury in Rat Lungs. The Journal of Immunology 172: 2569-2577, 2004
Granziera C, et al: Thrombin-induced ischemic tolerance is prevented by inhibiting c-jun N-terminal kinase. Brain Research. 1148:217-25, 2007
And one nice review (if you’re a cripple about this stuff like myself):
Sedlak TW & Snyder SH: Messenger Molecules and Cell Death JAMA 295:81-89, 2006
I have seen the future, and this is it. It’s going to make being mostly dead all day much less fatal than heretofore.