Abstracts

Rationale: We have shown previously that epileptic seizure activity can spread through brainstem areas to cause sufficient laryngospasm for obstructive apnea and that the period of seizure-associated obstructive apnea can last long enough for respiratory arrest to occur.  As the seizure ends, on its own or because of hypoxia, it also ceases to be a stimulus for laryngospasm, and the airway can open.  If respiratory arrest occurs before the airway reopens, the individual will progress from respiratory arrest to cardiac arrest and death unless immediately mechanically resuscitated.  If the airway reopens before respiratory arrest occurs, the individual will spontaneously resume breathing and recover from the event. Audiogenic seizure-prone mice can be protected from seizure-associated death by exposure to an oxygen atmosphere or treatment with selective serotonergic reuptake inhibitors (SSRIs).  We hypothesized that both the oxygen-rich atmosphere and SSRIs function by prolonging the time to respiratory arrest, thus ensuring that seizure activity stops before the point of respiratory arrest to allow recovery of respiratory function.  To test this hypothesis, we evaluated each preventative treatment in a rat model of controlled airway occlusion where the times to respiratory arrest can be measured. Methods: We evaluated each preventative treatment in a rat model of controlled airway occlusion that permits (1) controlled complete airway closure, (2) control of the atmosphere available to the animal, and (3) continuous monitoring of physiological variables including airway pressures associated with normal spontaneous breathing and attempts to breathe during occlusion.  This last element enables the precise determination of the point of respiratory arrest.  This direct measure of the impact of SSRIs on the time to respiratory arrest would also be free from the confound of the drugs’ effects on the intensity of seizure activity Results: We found that both oxygen exposure and fluoxetine significantly increased the time to respiratory arrest by up to 65% and, given that neither treatment has been shown to significantly alter seizure duration, these increases can account for the protection of either manipulation against death in sudden death models.  Importantly, we found that 30 seconds of exposure to oxygen produced nearly the same protection as 5 minutes exposure suggesting that oxygen exposure could start after a seizure starts.  Experiments with 50% oxygen / 50% air mixtures indicate that the oxygen concentration needs to be above about 60% to ensure that times to respiratory arrest will always be longer than a period of seizure-induced airway occlusion.  Selective serotonin reuptake inhibitors, while instructive with regard to mechanism, require impractical dosing and may carry additional risk in the form of greater challenges for resuscitation. Conclusions:  We speculate that the remarkable protections from oxygen exposure against death that have now been demonstrated in both mice and rats can be translated into practical protections for epilepsy patients.  FIGURE LEGEND.   LEFT: Rats exposed to room air experienced respiratory arrest about 50 seconds after the onset of controlled airway occlusion.  Rats breathing an oxygen enriched atmosphere lasted nearly twice as long before respiratory arrest occurred.  Mean times were: 53.6 (air) and 88.4 (oxygen) seconds (other conditions not shown). RIGHT: Rats exposed to systemic fluoxetine (25 mg/kg IP) experienced respiratory arrest at an average time after occlusion onset of 63.8 seconds compared to 49.8 seconds for saline injected animals. Funding: Supported by philanthropic and institutional funds.