Four genes encode electroneutral, Na+-independent, K-Cl cotransporters. KCC2, is exclusively expressed in neurons where it is thought to drive intracellular Cl- to low concentrations and shift the reversal potential for Cl- conductances such as GABA(A) or glycine receptor channels, thus participating in the postnatal development of inhibitory mechanisms in the brain. Indeed, expression of the cotransporter is low at birth and increases postnatally, at a time when the intracellular Cl- concentration in neurons decreases and gamma-aminobutyric acid switches its effect from excitatory to inhibitory. To assert the significance of KCC2 in neuronal function, we disrupted the mouse gene encoding this neuronal-specific K-Cl cotransporter. We demonstrate that animals deficient in KCC2 exhibit frequent generalized seizures and die shortly after birth. We also show upregulation of Fos, the product of the immediate early gene c-fos, and the significant loss of parvalbumin-positive interneurons, both indicative of brain injury. The regions most affected are the hippocampus and temporal and entorhinal cortices. Extracellular field potential measurements in the CA1 hippocampus exhibited hyperexcitability. Application of picrotoxin, a blocker of the GABA(A) receptor, further increased hyperexcitability in homozygous hippocampal sections. Pharmacological treatment of pups showed that diazepam relieved the seizures while phenytoin prevented them between postnatal ages P4-P12. Finally, we demonstrate that adult heterozygote animals show increased susceptibility for epileptic seizure and increased resistance to the anticonvulsant effect of propofol. Taken together, these results indicate that KCC2 plays an important role in controlling CNS excitability during both postnatal development and adult life.

Objective: The study evaluated the clinical intraoperative effects of intrathecal administration of fentanyl on shoulder tip pain in patients undergoing laparoscopic total extraperitoneal inguinal hernia repair (TEP) under spinal anaesthesia. Methods: Patients undergoing TEP were allocated in a double-blinded, prospective, randomized manner to two groups. Spinal anaesthesia was induced by intrathecal administration of 2.8 ml of 0.5% hyperbaric bupivacaine (14 mg) in the control group and with 2.6 ml of 0.5% hyperbaric bupivacaine (13 mg) and 10 mg fentanyl (0.2 ml) in the experimental group.Results: The quality of muscle relaxation, adequacy of operative space and incidence of pneumoperitoneum were similar in the two groups (n ¼ 36 per group). Compared with the control group, the experimental group had significantly fewer cases of hypotension (12 [

Clinical doses of ketamine typically increase blood pressure, heart rate, and cardiac output. However, the precise mechanism by which ketamine produces these cardiovascular effects remains unclear. The voltage-gated K(+) (K(V)) channel is the major regulator of resting membrane potential (E (m)) and vascular tone in many arteries. Therefore, we sought to evaluate the effects of ketamine on K(V) currents using the standard whole-cell patch clamp recordings in single myocytes, enzymatically dispersed from rat mesenteric arteries. Ketamine [(+/-)-racemic mixture] inhibited K(V) currents reversibly and concentration dependently with a K ( d ) of 566.7 +/- 32.3 microM and Hill coefficient of 0.75 +/- 0.03. The inhibition of K(V) currents by ketamine was voltage independent, and the time courses of channel activation and inactivation were little affected. The effects of ketamine on steady-state activation and inactivation curves were also minimal. Use-dependent inhibition was not observed either. S(+)-ketamine inhibited K(V) currents with similar potency and efficacy as the racemic mixture. The average resting E (m) in rat mesenteric artery myocytes was -44.1 +/- 4.2 mV, and both racemic and S(+)-ketamine induced depolarization of E (m) (15.8 +/- 3.6 and 24.3 +/- 5.0 mV at 100 microM, respectively). We conclude that ketamine induces E (m) depolarization in vascular myocytes by blocking K(V) channels in a state-independent manner, which may contribute to the increased vascular tone and blood pressure produced by this drug under a clinical setting.

BackgroundFor patients in the intensive care unit (ICU) or under monitored anesthetic care (MAC), the precise monitoring of sedation depth facilitates the optimization of dosage and prevents adverse complications from underor over-sedation. For this purpose, conventional subjective sedation scales, such as the Observer's Assessment of Alertness/Sedation (OAA/S) or the Ramsay scale, have been widely utilized. Current procedures frequently disturb the patient's comfort and compromise the already well-established sedation. Therefore, reliable objective sedation scales that do not cause disturbances would be beneficial. We aimed to determine whether spectral entropy can be used as a sedation monitor as well as determine its ability to discriminate all levels of propofol-induced sedation during gradual increments of propofol dosage.MethodsIn 25 healthy volunteers undergoing general anesthesia, the values of response entropy (RE) and state entropy (SE) corresponding to each OAA/S (5 to 1) were determined. The scores were then analyzed during each 0.5 mcg/ml- incremental increase of a propofol dose.ResultsWe observed a reduction of both RE and SE values that correlated with the OAA/S (correlation coefficient of 0.819 in RE-OAA/S and 0.753 in SE-OAA/S). The RE and SE values corresponding to awake (OAA/S score 5), light sedation (OAA/S 3-4) and deep sedation (OAA/S 1-2) displayed differences (P < 0.05).ConclusionsThe results indicate that spectral entropy can be utilized as a reliable objective monitor to determine the depth of propofol-induced sedation.

Background. Lung recruitment maneuver (LRM) during thoracic surgery can reduce systemic venous return and resulting drop in systemic blood pressure depends on the patient's fluid status. We hypothesized that changes in systemic blood pressure during the transition in LRM from one-lung ventilation (OLV) to two-lung ventilation (TLV) may provide an index to predict fluid responsiveness. Methods. Hemodynamic parameters were measured before LRM (T0); after LRM at the time of the lowest mean arterial blood pressure (MAP) (T1) and at 3 minutes (T2); before fluid administration (T3); and 5 minutes after ending it (T4). If the stroke volume index increased by >25% following 10 mL/kg colloid administration for 30 minutes, then the patients were assigned to responder group. Results. Changes in MAP, central venous pressure (CVP), and stroke volume variation (SVV) between T0 and T1 were significantly larger in responders. Areas under the curve for change in MAP, CVP, and SVV were 0.852, 0.759, and 0.820, respectively; the optimal threshold values for distinguishment of responders were 9.5 mmHg, 0.5 mmHg, and 3.5%, respectively. Conclusions. The change in the MAP associated with LRM at the OLV to TLV conversion appears to be a useful indicator of fluid responsiveness after thoracic surgery. Trial Registration. This trial is registered at Clinical Research Information Service with KCT0000774.