What is the mechanism for CNS O2 Toxicity?

[t-mac]

I was in DM class last night and got into a discussion with my instructor on O2 CNS toxicity and like many of these discussions we often end up with more questions than answers. Two things I'm having difficulty reconciling. The first is the common statement that convulsions caused by high PO2 at depth are not in and of themselves harmful. They the tend to be fatal not due to the seizure per se, but rather to the environment in which they occur -- ie, you probably will lose your reg and drown. The other was a partial explanation as to why you get CNS toxicity: that it is due to an overload of reactive oxygen species in the CNS. O2 becomes singlet oxygen in tissue, which is highly reactive. Normally you have things like superoxide dymutases that keep this under control. You are able to maintain a balance of the positive metabolic properties of oxygen without having reactive oxygen species torching your organelles and essential macromolecules. At high PO2, you disrupt the balance by overloading the system and then I would have to presume that you have reactive oxygen species doing bad things that ultimately kill neurons through apoptosis and possibly other mechanisms. In other words, if this truly is the/a mechanism, it results in dead brain cells and I am having a hard time understanding how that cannot be harmful. Is it a matter of degree -- you don't kill enough brain cells to see clinical neurological deficit? Is the common wisdom about seizures wrong or an over-simplification? Or is this all a bunch of crap and we just don't really know what's going on?

Thanks for the insight!

 

[gsk3]

I haven't researched the specifics of CNS toxicity much, but speaking in general terms....

The first step in necrosis is generally disruption of the cell membrane permeability barrier. In neurons, disruption of permeability tends to cause ion flows across the membrane. Since ion flows cause signaling, and seizures are essentially just too much disorganized signal, I don't see any conflict in the theory. In other words, I don't think free radical-induced seizure necessarily means massive cell death--at least not in the initial minutes.

 

[t-mac]

Thanks. So your point is that there is cell death, but at least with each incident it is probably not clinically meaninful? This makes sense, but it also means that it is not exactly true that seizures alone are harmless. They probably aren't, but each incident doesn't kill enough brain cells to see neurological problems. I'm still interested in learning more. Any references you can point me to?

 

[Mr Carcharodon]

Try googleing: “Current Thoughts on Mechanisms of Hyperoxic Seizures” by Johnny E. Brian, Jr., M.D.

The author suggests that the breathing higher than normal levels of oxygen may ultimately lead to compromise of some of the enzymes associated with neurotransmitters which leads to seizure. He does suggest that this is a unvalidated hypothesis however. That said he provides a considerable amount of background that suggests it is reasonable. He also goes through some older theories on mechanisms of seizures which are no longer thought to be correct.

 

[TSandM]

As Mr. Carcharodon says, the current theory about oxygen toxicity is not that oxygen is cytotoxic per se, but that it is affecting neurotransmitters. Which makes sense -- there are many conditions that lead to death of brain cells that do not result in seizures (seizures, for example, are a very rare presentation of stroke). Seizures themselves do surprisingly little damage to the brain, so long as the patient's blood oxygen levels are kept in the normal range (which would not really be a problem , with most diving seizures, as the starting ppO2 is so high). What kills ox-tox victims is drowning, because of the lack of ability to control the airway as the patient comes out of the seizure.

 

[Duke Dive Medicine]

Repetitive convulsive doses of oxygen have been shown to cause brain damage in laboratory animals, but like TSandM said, from a practical standpoint, drowning is the biggest danger in CNS O2 toxicity under water.

 

[t-mac]

Thanks, the Brian article is interesting. It argues that elevated levels of catecholamines are involved, likely via production of hydrogen peroxide through the action of monoamine oxidase on them and then it gets very murky. One paper is cited for H2O2 production inducing release of excitatory amino acids, which makes sense in terms of inducing the seizure, but it still may somehow be through conversion of peroxide back to reactive oxygen species. So we may have come full circle. Anyway, very interesting subject that I intend to explore further. Thanks for all the comments.