Investigating paradoxical hysteresis effects in the mouse neocortical slice model.

Clinically, anesthetic drugs show hysteresis in the plasma drug concentrations at induction versus emergence from anesthesia induced unconsciousness. This is assumed to be the result of pharmacokinetic lag between the plasma and brain effect-site and vice versa. However, recent mathematical and experimental studies demonstrate that anesthetic hysteresis might be due in part to lag in the brain physiology, independent of drug transport delay - so-called "neural inertia". The aim of this study was to investigate neural inertia in the reduced neocortical mouse slice model. Seizure-like event (SLE) activity was generated by exposing cortical slices to no-magnesium artificial cerebrospinal fluid (aCSF). Concentration-effect loops were generated by manipulating SLE frequency, using the general anesthetic drug etomidate and by altering the aCSF magnesium concentration. The etomidate (24 µM) concentration-effect relationship showed a clear hysteresis, consistent with the slow diffusion of etomidate into slice tissue. Manipulation of tissue excitability, using either carbachol (50 µM) or elevated potassium (5mM vs 2.5mM) did not significantly alter the size of etomidate hysteresis loops. Hysteresis in the magnesium concentration-effect relationship was evident, but only when the starting condition was magnesium-containing "normal" aCSF. The in vitro cortical slice manifests pathway-dependent "neural inertia" and may be a valuable model for future investigations into the mechanisms of neural inertia in the cerebral cortex.

[Neurological consequences after long-term sedation in the ICU]. / Conséquences neurologiques de la sédation en réanimation.

Experiments performed in mammals, including non-human primates, have demonstrated an increase in neuronal death rates normally seen in normal brain development. Such an increase is encountered in diseases but also after exposure of the brain to various class of anaesthetics. In living animals, it can (but not always) result in persistent cognitive impairment. Most of the experiments have been conducted in animals which were never exposed to any pain, which questions their relevancy. On the clinical side, all data comes from retrospective studies. Given the multiple bias, they cannot definitely state that a protocol, if toxic, is more or less when compared to another. Until now, prospective follow-up of children exposed to anaesthetics in utero or during the first months of life do not suggest a major deleterious effect. Yet, a minor one, if existing, would be hard to detect among polluting variables (e.g. pathology requiring anaesthesia, long hospitalization after birth, preterm birth, environmental stress...). For sure, when surgery is mandatory during pregnancy, it is generally for maternal indication and should not be a motif strong enough for foetal extraction, especially in terms where the baby has few chances to survive. Second, it is known for years than anaesthesia before 1 year of age is much riskier than after 1 year, whatever the theorical neurotoxicity is. Third, this enforces the need to develop tools enhancing the precision of anaesthesia as much as possible. Meanwhile, when an infant has undergone numerous general anaesthesias, we strongly recommend a long-time neurological follow-up.

Investigations into pharmacological antagonism of general anaesthesia.

The effects of convulsant drugs, and of thyrotropin releasing hormone (TRH), were examined on the general anaesthetic actions of ketamine, ethanol, pentobarbitone and propofol in mice. The aim was to investigate the possibility of selective antagonism, which, if seen, would provide information about the mechanism of the anaesthesia. The general anaesthetic effects of ketamine were unaffected by bicuculline; antagonism was seen with 4-aminopyridine and significant potentiation with 300 mg kg(-1) NMDLA (N-methyl-DL-aspartate). The calcium agonist, Bay K 8644, potentiated the anaesthesia produced by ketamine and antagonism of such anaesthesia was seen with TRH. A small, but significant, antagonism of the general anaesthesia produced by ethanol was seen with bicuculline, and a small, significant, potentiation with 4-aminopyridine. There was an antagonist effect of TRH, but no effect of NMDLA. Potentiation of the anaesthetic effects of pentobarbitone was seen with NMDLA and with 4-aminopyridine and the lower dose of bicuculline (2.7 mg kg(-1)) also caused potentiation. There was no significant change in the ED(50) value for pentobarbitone anaesthesia with TRH. Bicuculline did not alter the anaesthetic actions of propofol, while potentiation was seen with NMDLA and 4-aminopyridine. TRH had no significant effect on propofol anaesthetic, but Bay K 8644 at 1 mg kg(-1) significantly potentiated the anaesthesia. These results suggest that potentiation of GABA(A) transmission or inhibition of NMDA receptor-mediated transmission do not appear to play a major role in the production of general anaesthesia by the agents used.

[Mechanism of action of general anesthetics. Effect on ion channel proteins or on membrane phospholipids?]. / Mecanismo de acción de los anestésicos generales. Efecto sobre proteínas de canales iónicos o sobre fosfolípidos de membrana?

General anesthesia is defined by reversible unconsciousness, lack of response to noxious stimuli, and amnesia, induced by chemical agents. Mechanisms underlying the anesthetic effect are not known. The most prevalent belief was that anesthetic drugs acted on the lipid cell membranes, based on the correlation between oil solubility and anesthetic potency. Later, it has been proposed that anesthetic agents act on specific proteins of the cellular membrane of neurons. Voltage-gated ionic channels are inhibited by anesthetic agents, being some subtypes more sensitive. Clinical concentration of anesthetic agents inhibit or stimulate excitatory or inhibitory neurotransmitter receptors, respectively. Specific receptor agonists and antagonists modify this effect. Intercellular channels (gap junctions) are also affected by anesthetic agents through direct interaction with some of their protein subunits. Thus, anesthesia would result from combined effects on specific proteins acting on neural cell excitability as well as transmission and propagation of nerve impulses.