Abstracts

Rationale: Propofol, a GABA A receptor agonist, is frequently used as a first line intravenous therapy for refractory status epilepticus (RSE) because it allows rapid control of the depth anesthesia and has a short duration of action. While patient's clinical status and electroencephalography (EEG) are most commonly used to govern the propofol infusion rate in RSE, there are no reliable noninvasive methods to quantify the extent to which propofol is augmenting GABAergic intracortical inhibition. In the current study, using a rat model, we tested whether changes in cortical inhibition can be detected by ppTMS over a range of intravenous (IV) propofol infusion rates and boluses. Methods: Rats (n=50) were anesthetized with IV propofol 1 mg/kg/min. Pairs of stimuli were delivered with 20-sec interval for all experiments. Both conditioning (CS) and test stimuli (TS) were set to 120% motor threshold. Long interval (100 msec) ppTMS was used to approximate human protocols as previously described by our lab (Vahabzadeh et al., J. Neurophysiol, 2011) Motor-evoked potentials (MEPs) were obtained from the contralateral brachioradialis muscle for a 5-min baseline. Rats were then randomized to one of two experiments: In the first experiment, animals received IV propofol bolus of 10 mg/kg (n=18), 20mg/kg (n=8) or no bolus (n=9) after the baseline and was followed with 15 min of ppTMS monitoring. In the second experiment, the IV propofol infusion rate was increased to 2 mg/kg/minfor 15 min, before returning to 1 mg/kg/min for another 15 min, also while monitoring cortical excitability by ppTMS (n=8). A control group (n=9) had a continue infusion rate of 1mg/kg/min during 30 min. Results: In the first experiment, we found a dose-dependent reduction (p<0.01) in both the first (post-CS) and second (post-TS) MEP after either propofol bolus. However, the depression of the post-TS MEP persisted longer (p<0.004) and thus appeared as a more sensitive measure of propofol-mediated cortical inhibition. The change in ppTMS measures of cortical inhibition was evident within 20 sec of the propofol bolus, and lasted for approximately 10 min. In the second experiment, we found a significant (p<0.03) and progressive post-CS and post-TS MEP reduction correlated with increased propofol infusion rate, and, as after a propofol bolus, the post-TS MEP recovered slower to baseline. Conclusions: We showed that ppTMS can detect changes in cortical inhibition associated with either bolused or continuously-infused propofol, and that the ppTMS metric varies with sub-minute temporal resolution. In realistic embodiments, this ppTMS measure of cortical inhibition may also provide a measure of seizure susceptibility.